Women's Health Initiative Memory Study Research Articles

Interaction Between Body Mass Index and Central Adiposity and Risk of Incident Cognitive Impairment and Dementia: Results from the Women's Health Initiative Memory Study

To assess the relationship between body mass index (BMI) and waist-hip ratio (WHR) and the clinical end points of cognitive impairment and probable dementia in a cohort of older women enrolled in the Women's Health Initiative Memory Study (WHIMS). Prospective, randomized clinical trial of hormone therapies with annual cognitive assessments and anthropometrics. Fourteen U.S. clinical sites of the WHIMS. Seven thousand one hundred sixty-three postmenopausal women aged 65 to 80 without dementia. Annual cognitive assessments, average follow-up of 4.4 years, including classification of incident cognitive impairment and probable dementia. Height, weight, waist, and hip measurements were assessed at baseline, and a waist-hip ratio (WHR) of 0.8 or greater was used as a marker of central adiposity. There were statistically significant interactions between BMI and WHR and incident cognitive impairment and probable dementia with and without adjustment for a panel of cognitive risk factors. Women with a WHR of 0.80 or greater with a BMI of 20.0 to 24.9 kg/m² had a greater risk of cognitive impairment and probable dementia than more-obese women or women with a WHR less than 0.80, although women with a WHR less than 0.80 and a BMI of 20.0 to 24.9 kg/m² had poorer scores on cognitive assessments. WHR affects the relationship between BMI and risk of cognitive impairment and probable dementia in older women. Underweight women (BMI < 20.0 kg/m²) with a WHR less than 0.80 had a greater risk than those with higher BMIs. In normal-weight to obese women (20.0-29.9 kg/m², central adiposity (WHR ≥ 0.80) is associated with greater risk of cognitive impairment and probable dementia than in women with higher BMI. These data suggest that central adiposity as a risk factor for cognitive impairment and probable dementia in normal-weight women.

Effects of Conjugated Equine Estrogens on Cognition and Affect in Postmenopausal Women With Prior Hysterectomy

The Women's Health Initiative (WHI) Study of Cognitive Aging studies have investigated the effects of specific treatment regimens containing a combination of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) or CEE only on longitudinal changes in domain-specific cognitive function in older postmenopausal women. In the previous reports, CEE + MPA had a deleterious impact on verbal memory but appeared to have a positive effect on figural memory over time in older postmenopausal women. The present study tests the possibility that CEE alone (unopposed by MPA) could protect against age-related declines in both verbal and figural memory. This randomized, double-blind, placebo-controlled clinical trial investigated the effects of CEE alone on changes in domain-specific cognitive function and affect in older postmenopausal women. The study was conducted between 1999 and 2004 at 14 WHI clinical centers. The study subjects were 886 postmenopausal women (mean age, 74 years) with prior hysterectomy who were free of probable dementia and were enrolled in the WHI and WHI Memory Study CEE-Alone trial for a mean of 3 years and followed for an additional 2.7 years. Participants were randomized to receive one daily tablet containing CEE, 0.625 mg or a matching placebo. The primary outcome measures were mean differences in annual rates of change of specific cognitive functions and affect, adjusted for time since randomization using analyses of covariance. The data showed that CEE alone had no significant effects on cognitive functions and affect. Compared with the placebo, women in the CEE only group had significantly lower scores on a measure of spatial rotational ability (P < 0.01) after an average of 3 years of treatment, but over the additional 2.7 years of treatment there was a greater rate of improvement in spatial rotational performance indicating some recovery of their initially poorer performance. These findings show that CEE does not improve cognitive domains, including figural memory or affect in postmenopausal women with prior hysterectomy. Accordingly, it does not slow the decline of age-related changes in memory in this population. Spatial rotational ability was lower after 3 years of CE treatment but appears to recover with continued treatment.

Relative Effects of Tamoxifen, Raloxifene, and Conjugated Equine Estrogens on Cognition

To compare the relative effects of conjugated equine estrogens (CEE), raloxifene, and tamoxifen therapies on cognition among women aged > or =65 years. Annual Modified Mini-Mental State (3MS) examinations were used to assess global cognitive function in the two randomized placebo-controlled clinical trials of CEE therapies of the Women's Health Initiative Memory Study (WHIMS) and the Cognition in the Study of Tamoxifen and Raloxifene (CoSTAR). Analyses were limited to women who had 3MS testing at baseline and the first 3 years of follow-up and, because of potential ethnic-related differences between studies, to Caucasian women (WHIMS n = 6211, CoSTAR n = 250). Covariate adjustment was used to compare the postrandomization mean 3MS scores among the three active therapies with placebo therapy while controlling for differences between groups with respect to dementia risk factors. At baseline, the average (SD) 3MS scores by group were 95.24 (4.28) for placebo, 95.19 (4.33) for CEE, 94.60 (4.76) for raloxifene, and 95.02 (4.03) for tamoxifen. Compared with placebo, each active therapy was associated with a small mean relative deficit in 3MS scores of < or =0.5 units, which was fairly consistent between women with and without prior hysterectomy. Relative deficits were slightly greater for tamoxifen (p = 0.001) and less marked for raloxifene (p = 0.06) and CEE (p = 0.02) therapies. Relative deficits appeared to be greater among women with lower baseline 3MS scores: p = 0.009 (tamoxifen), p = 0.08 (raloxifene), and p = 0.03 (CEE). Although unmeasured differences between trials may have confounded analyses, these findings raise the possibility that both tamoxifen and raloxifene adversely affect cognitive function in older women; however, the magnitude of the effect is small, and the long-term consequences are unknown.

Relationship of Hypertension, Blood Pressure, and Blood Pressure Control With White Matter Abnormalities in the Women’s Health Initiative Memory Study (WHIMS)—MRI Trial

This paper evaluates the relationship of blood pressure (BP) levels at Women's Health Initiative (WHI) baseline, treatment of hypertension, and white matter abnormalities among women in conjugated equine estrogen (CEE) and medroxyprogesterone acetate and CEE-alone arms. The WHI Memory Study-Magnetic Resonance Imaging (WHIMS-MRI) trial scanned 1424 participants. BP levels at baseline were significantly positively related to abnormal white matter lesion (WML) volumes. Participants treated for hypertension but who had BP > or = 140/90 mm Hg had the greatest amount of WML volumes. Women with untreated BP > or = 140/90 mm Hg had intermediate WML volumes. Abnormal WML volumes were related to hypertension in most areas of the brain and were greater in the frontal lobe than in the occipital, parietal, or temporal lobes. Level of BP at baseline was strongly related to amount of WML volumes. The results of the study reinforce the relationship of hypertension and BP control and white matter abnormalities in the brain. The evidence to date supports tight control of BP levels, especially beginning at younger and middle age as a possible and perhaps only way to prevent dementia.

Psychiatric Disorders and Cognitive Dysfunction Among Older, Postmenopausal Women: Results From the Women's Health Initiative Memory Study

To estimate the frequency of depressive symptoms and selected psychiatric disorders in the Women's Health Initiative Memory Study (WHIMS) cohort and related them to cognitive syndromes. WHIMS was a randomized, double-blinded, placebo-controlled prevention clinical trial examining whether opposed and unopposed hormone therapy reduced the risk of dementia in healthy postmenopausal women. Participants scoring below a designated cutpoint on a cognitive screener received a comprehensive neuropsychiatric workup and adjudicated outcome of no cognitive impairment, mild cognitive impairment, or probable dementia. Seven thousand four hundred seventy-nine WHIMS participants between age 65 and 79 years and free of dementia at the time of enrollment in WHIMS. Five hundred twenty-one unique participants contributed complete data required for these analyses. Depressive symptoms were measured with the 15-item Geriatric Depression Scale and the presence of selected psychiatric disorders (major depression, generalized anxiety, and panic and alcohol abuse) was made using the PRIME-MD. The 18% of women had at least one psychiatric disorder with depression being the most common (16%) followed by general anxiety or panic (6%) and alcohol abuse (1%). Depression and the presence of a psychiatric disorder were associated with impaired cognitive status. Participants having a psychiatric disorder were more than twice as likely to be diagnosed with cognitive impairment as those with no psychiatric disorder (odds ratio = 2.06, 95% confidence interval = 1.17-3.60). Older age, white race, and diabetes were also associated with cognitive impairment. The frequency of a psychiatric disorder is associated with poorer cognitive functioning among older women enrolled in WHIMS. That approximately one in five women had a probable psychiatric disorder, most typically depression, highlights the need for greater detection and treatment efforts in this population.

Effects of Conjugated Equine Estrogens on Cognition and Affect in Postmenopausal Women with Prior Hysterectomy

Different menopausal hormone therapies may have varied effects on specific cognitive functions. We previously reported that conjugated equine estrogens (CEE) with medroxyprogesterone acetate had a negative impact on verbal memory but tended to impact figural memory positively over time in older postmenopausal women. The objective of the study was to determine the effects of unopposed CEE on changes in domain-specific cognitive function and affect in older postmenopausal women with prior hysterectomy. This was a randomized, double blind, placebo-controlled clinical trial. The study was conducted at 14 of 40 Women's Health Initiative (WHI) clinical centers. Participants were 886 postmenopausal women with prior hysterectomy, aged 65 yr and older (mean 74 yr), free of probable dementia, and enrolled in the WHI and WHI Memory Study (WHIMS) CEE-Alone trial for a mean of 3 yr and followed up for a mean of 2.70 yr. Intervention was 0.625 mg of CEE daily or placebo. Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured. Compared with placebo, unopposed CEE was associated with lower spatial rotational ability (P < 0.01) at initial assessment (after 3 yr of treatment), a difference that diminished over 2.7 yr of continued treatment. CEE did not significantly influence change in other cognitive functions and affect. CEE did not improve cognitive functioning in postmenopausal women with prior hysterectomy. CEE was associated with lower spatial rotational performance after an average of 3 yr of treatment. Overall, CEE does not appear to have enduring effects on rates of domain-specific cognitive change in older postmenopausal women.

The Relationship Between Cognitive Function and Physical Performance in Older Women: Results From the Women's Health Initiative Memory Study

Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear. In the Women's Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change. Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS-gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p </= .01 both). Changes in 3MS and PPM were associated, particularly with chair stands and grip strength (p < .003 both). Baseline PPMs were not associated with subsequent 3MS change. Baseline global cognitive function and change in global cognitive function were associated with physical performance change, but baseline physical performance was not associated with cognitive change in this cohort. These analyses support the hypothesis that cognitive decline on average precedes or co-occurs with physical performance decline.

Women’s cognitive health special edition

Women’s cognitive health special edition

Postmenopausal hormone therapy and subclinical cerebrovascular disease

The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS. We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of alpha = 0.05 was used. In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo. Conjugated equine estrogen-based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.

Postmenopausal hormone therapy and regional brain volumes

To determine whether menopausal hormone therapy (HT) affects regional brain volumes, including hippocampal and frontal regions. Brain MRI scans were obtained in a subset of 1,403 women aged 71-89 years who participated in the Women's Health Initiative Memory Study (WHIMS). WHIMS was an ancillary study to the Women's Health Initiative, which consisted of two randomized, placebo-controlled trials: 0.625 mg conjugated equine estrogens (CEE) with or without 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet. Scans were performed, on average, 3.0 years post-trial for the CEE + MPA trial and 1.4 years post-trial for the CEE-Alone trial; average on-trial follow-up intervals were 4.0 years for CEE + MPA and 5.6 years for CEE-Alone. Total brain, ventricular, hippocampal, and frontal lobe volumes, adjusted for age, clinic site, estimated intracranial volume, and dementia risk factors, were the main outcome variables. Compared with placebo, covariate-adjusted mean frontal lobe volume was 2.37 cm(3) lower among women assigned to HT (p = 0.004), mean hippocampal volume was slightly (0.10 cm(3)) lower (p = 0.05), and differences in total brain volume approached significance (p = 0.07). Results were similar for CEE + MPA and CEE-Alone. HT-associated reductions in hippocampal volumes were greatest in women with the lowest baseline Modified Mini-Mental State Examination scores (scores <90). Conjugated equine estrogens with or without MPA are associated with greater brain atrophy among women aged 65 years and older; however, the adverse effects are most evident in women experiencing cognitive deficits before initiating hormone therapy.

A multi-center, randomized, double blind placebo-controlled trial of estrogens to prevent Alzheimer's disease and loss of memory in women: design and baseline characteristics.

Observational studies and small clinical trials suggested that hormone replacement therapy (HRT) decreases risk of cognitive loss and Alzheimer's disease (AD) in postmenopausal women and may have value in primary prevention. A clinical trial was designed to determine if HRT delays AD or memory loss. This report describes the rationale and original design of the trial and details extensive modifications that were required to respond to unanticipated findings that emerged from other studies during the course of the trial. The trial was designed as a multi-center, placebo-controlled primary prevention trial for women 65 years of age or older with a family history of dementia. Recruitment from local sites was supplemented by centralized efforts to use names of Medicare beneficiaries. Inclusion criteria included good general health and intact memory functioning. Participants were randomized to HRT or placebo in a 1:1 ratio. Assignment was stratified by hysterectomy status and site. The primary outcomes were incident AD and memory decline on neuropsychological testing. Enrollment began in March 1998. In response to the Women's Health Initiative (WHI) May 2002 report of increased incidence of heart disease, stroke, pulmonary embolism, and breast cancer among women randomized to HRT, participants were re-consented with a revised consent form. Procedural modifications, including discontinuation of study medication and a modification of the planned primary outcome based on a final enrollment below the target enrollment (N = 477), were enacted in response to the subsequent WHI Memory Study report of increased risk of dementia and poorer cognitive function with HRT. The mean length of treatment exposure prior to discontinuation was 2.14 years. Participants' mean age at baseline was 72.8; mean education was 14.2 years. Minority participation was 19% and 34% had a hysterectomy. The study continues to follow these participants for a total of 5 years blind to the original medication assignment. Results reported from the WHI during the course of this study mandated extensive procedural modifications, including discontinuing recruitment before completion and halting study medication. Alternative strategies for study redesign that were considered are discussed.

A Prospective Study of the Effect of Hypertension and Baseline Blood Pressure on Cognitive Decline and Dementia in Postmenopausal Women: The Women's Health Initiative Memory Study

To examine the relationship between baseline hypertension, blood pressure, and the development of cognitive decline in participants in the Women's Health Initiative Memory Study (WHIMS). Prospective analyses. Thirty-nine centers. Seven thousand one hundred forty-nine women aged 65 and older. The Modified Mini-Mental State Examination (3MS) was used to assess global cognitive functioning. Participants who scored below pre-established cutpoints were scheduled for more-extensive neurocognitive assessments. Results from these assessments were centrally adjudicated. The mean age of this group of 7,149 participants at baseline was 71.0 +/- 3.8, and the mean 3MS score was 95.2 +/- 4.3. During a mean follow-up period of 4.5 years, women without hypertension tended to have slightly higher 3MS scores than women with hypertension (P=.001), but the difference was not seen after adjustment for covariates (P=.17). Women with hypertension also appeared to be at greater risk for probable dementia or mild cognitive impairment (MCI) (hazard ratio=1.35, 95% confidence interval=1.07-1.70, P=.01), although when potential cofounders were accounted for, this association was no longer significant (P=.06). Hypertension and high blood pressure at baseline were not independently associated with MCI or probable dementia over time in older, cognitively intact, postmenopausal women enrolled in WHIMS after other potential confounders were taken into account. These analyses should not be viewed as discouraging appropriate medical treatment for hypertension.

Nonestrogen-Based Hormonal Therapies for Alzheimer‘s Disease

Alzheimer’s disease (AD) is becoming increasingly more prevalent worldwide and is a costly, devastating disease. The fact that females are more likely to be diagnosed with AD than men has contributed to the large amount of research and literature on estrogen’s ability to rescue cognitive decline in aging females. However, recent results from the Women’s Health Initiative Memory Study (WHIMS) and the Research into Memory, Brain Function and Estrogen Replacement (REMEMBER) study, in which estrogen-replacement therapy is shown not to be beneficial to cognition in postmenopausal women, especially in women of more advanced ages, have opened the study of hormones and hormone-based therapies beyond that of sex steroids. As such, recent findings, and the focus of this review, indicate that gonadotropins such as luteinizing hormone have a role on cognitive function and AD. It is likely that the interplay of age, and the timing of estrogen and these other less studied hormones will allow us to gain a better understanding of hypothalamic–pituitary–gonadal axis regulation after menopause and how it relates to AD, and will hopefully lead to new avenues of treatment for AD.

S1-01-03: The Women’s Health Initiative Memory Study (WHIMS): Methodology and update

S1-01-03: The Women’s Health Initiative Memory Study (WHIMS): Methodology and update

The clinical relevance of the relationship between estrogen and cognition in women

Randomized controlled trials (RCTs) and observational and longitudinal studies provide positive, albeit, inconsistent evidence that estrogen might protect against cognitive decline in postmenopausal women. The fact that the Women's Health Initiative Memory Study (WHIMS), the largest RCT to date, failed to find that estrogen therapy (ET) had a protective effect against cognitive aging led to the formulation of the critical period hypothesis which holds that ET will effectively protect against memory decline when it is initiated around the time of menopause but not when considerable time has elapsed since the menopause. Evidence from basic neuroscience, and from rodent, nonhuman primate, and human studies that supports this theory is presented. Although much work remains to be done on the timing of initiation of treatment, on the most effective hormonal compounds and on their routes of administration, the hope is that, eventually, hormonal treatments may be able to attenuate or prevent the decline in aspects of cognition that occur with normal aging.

Association between Alcohol Intake and Domain-Specific Cognitive Function in Older Women

Moderate levels of alcohol intake may be associated with better cognitive function; however, this relationship may vary between cognitive domains. Women, aged 65–80 years, enrolled in the Women’s Health Initiative (WHI) randomized clinical trials of hormone therapy, underwent annual standardized testing for global cognitive function through the ancillary WHI Memory Study (average follow-up of 4.5 years) and domain-specific cognitive function through the WHI Study of Cognitive Aging (average follow-up of 1.7 years). Compared to nondrinkers, women reporting moderate levels of alcohol intake (≤3 drinks per day) performed better on a measure of global cognitive function. Women reporting any alcohol intake also performed better on tests of verbal knowledge, verbal fluency, figural memory, verbal memory, attention and working memory, and motor speed (all p < 0.05), but not spatial ability (p = 0.36). After covariate adjustment, mean scores were higher among women reporting ≧1 drink/day by 5.7% for verbal knowledge (p < 0.001) and by 5.7% for phonemic fluency (p = 0.004), compared to never-drinkers. Moderate levels of alcohol intake are associated with somewhat better cognition, which may be expressed most strongly in functions related to verbal knowledge and phonemic fluency. However, our observational study cannot rule out confounding associations with unmeasured factors.

Select estrogens within the complex formulation of conjugated equine estrogens (Premarin®) are protective against neurodegenerative insults: implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer's disease

BackgroundResults of the Women's Health Initiative Memory Study (WHIMS) raised concerns regarding the timing and formulation of hormone interventions. Conjugated equine estrogens (CEE), used as the estrogen therapy in the WHIMS trial, is a complex formulation containing multiple estrogens, including several not secreted by human ovaries, as well as other biologically active steroids. Although the full spectrum of estrogenic components present in CEE has not yet been resolved, 10 estrogens have been identified. In the present study, we sought to determine which estrogenic components, at concentrations commensurate with their plasma levels achieved following a single oral dose of 0.625 mg CEE (the dose used in the WHIMS trial) in women, are neuroprotective and whether combinations of those neuroprotective estrogens provide added benefit. Further, we sought, through computer-aided modeling analyses, to investigate the potential correlation of the molecular mechanisms that conferred estrogen neuroprotection with estrogen interactions with the estrogen receptor (ER).ResultsCultured basal forebrain neurons were exposed to either β-amyloid25–35 or excitotoxic glutamate with or without pretreatment with estrogens followed by neuroprotection analyses. Three indicators of neuroprotection that rely on different aspects of neuronal damage and viability, LDH release, intracellular ATP level and MTT formazan formation, were used to assess neuroprotective efficacy. Results of these analyses indicate that the estrogens, 17α-estradiol, 17β-estradiol, equilin, 17α-dihydroequilin, equilinen, 17α-dihydroequilenin, 17β-dihydroequilenin, and Δ8,9-dehydroestrone were each significantly neuroprotective in reducing neuronal plasma membrane damage induced by glutamate excitotoxicity. Of these estrogens, 17β-estradiol and Δ8,9-dehydroestrone were effective in protecting neurons against β-amyloid25–35-induced intracellular ATP decline. Coadministration of two out of three neuroprotective estrogens, 17β-estradiol, equilin and Δ8,9-dehydroestrone, exerted greater neuroprotective efficacy than individual estrogens. Computer-aided analyses to determine structure/function relationships between the estrogenic structures and their neuroprotective activity revealed that the predicted intermolecular interactions of estrogen analogues with ER correlate to their overall neuroprotective efficacy.ConclusionThe present study provides the first documentation of the neuroprotective profile of individual estrogens contained within the complex formulation of CEE at concentrations commensurate with their plasma levels achieved after an oral administration of 0.625 mg CEE in women. Our analyses demonstrate that select estrogens within the complex formulation of CEE contribute to its neuroprotective efficacy. Moreover, our data predict that the magnitude of neuroprotection induced by individual estrogens at relatively low concentrations may be clinically undetectable and ineffective, whereas, a combination of select neuroprotective estrogens could provide an increased and clinically meaningful efficacy. More importantly, these data suggest a strategy for determining neurological efficacy and rational design and development of a composition of estrogen therapy to alleviate climacteric symptoms, promote neurological health, and prevent age-related neurodegeneration, such as AD, in postmenopausal women.

Effects of Combination Estrogen Plus Progestin Hormone Treatment on Cognition and Affect

Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions, particularly memory. The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women. This study was a randomized, double-blind, placebo-controlled clinical trial. Participants were women from 14 of 40 clinical centers of the Women's Health Initiative (WHI). Postmenopausal women (1416) aged 65 yr and older, free of probable dementia, and enrolled in WHI and the WHI Memory Study (WHIMS) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr, were studied. Intervention was conjugated equine estrogen (CEE; 0.625 mg) with 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet (CEE + MPA) or placebo. Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured. CEE + MPA had a negative impact on verbal memory (P <or= 0.01) and a trend to a positive impact on figural memory (P = 0.012) over time compared with placebo, but other cognitive domains were not affected. Both effects on memory were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms. The effect of CEE + MPA on cognitive function varies across cognitive domains in older women, reflecting both possible beneficial and detrimental actions of ovarian steroids on the aging brain. Our results extend prior findings about dementia and global cognitive function to age-related changes in specific cognitive functions and suggest directions for future research.

Hormone replacement therapy is associated with improved verbal declarative memory in healthy relatively recent postmenopausal women

The efficacy of Hormone Replacement Therapy (HRT) for cognitive health in postmenopausal women has been systematically questioned during the last decade. Although epidemiological and clinical research have suggested that HRT may exert protective effects on the prophylaxis of neurodegenerative diseases and beneficial effects on cognitive function, the Women's Health Initiative Memory Study (WHIMS) contradicted these claims. The purpose of this study was to reassess the effects of HRT on cognitive function in an attempt to account for two potential confounding factors that might have generated the negative clinical findings reported by the WHIMS i.e. subjects' age and educational level.

Age-Related Changes in Neuroprotection: Is Estrogen Pro-inflammatory for the Reproductive Senescent Brain?

Estrogen replacement therapy (ERT) is widely prescribed to postmenopausal women for relief from the adverse vasomotor effects of menopause, to reduce bone loss, to improve cardiovascular health, and to protect against metabolic disorders. However, there is now greater awareness of the increased risk to benefit ratio from the recently concluded Women's Health Initiative Memory Study (WHIMS), which reported that ERT increased the risk of cognitive impairment and dementia in elderly women. Studies from the experimental literature indicate that while estrogen is neuroprotective in many instances, estrogen replacement can be deleterious in some cases. These differences may be partly due to the age and species of the experimental model. The majority of the experimental data comes from studies where the age or endocrine status of the animal model is not comparable to that of menopausal or postmenopausal women, such as those in the WHIMS study. In this review, we will focus on age-related changes in estrogen's neuroprotective effects and evidence that reproductive senescence-related changes in the blood-brain barrier and the immune system may result in deleterious consequences for ERT.