Decline In Postmenopausal Women Research Articles

Synergistic effects of age at menopause and vascular risk on cognitive decline in postmenopausal women

AbstractBackgroundMenopause‐related estrogen depletion is linked to greater vascular risk, Alzheimer’s disease (AD) pathology, and dementia risk in women. Age‐at‐menopause and vascular risk may together influence the likelihood of developing AD in women. We investigated whether earlier menopause and elevated vascular risk independently or synergistically contribute to cognitive decline in postmenopausal women compared to men.MethodWe used data from the Canadian Longitudinal Study on Aging. We included 7,678 postmenopausal women (mean age = 64.6±8.49 years, mean age‐at‐menopause = 50.1±5.02 years) and 7,678 age‐matched men (mean age = 64.6±8.49 years). Sex was operationalized using self‐reported sex at birth. Vascular risk was calculated using a summary score tallying the presence/absence of hypertension, diabetes, smoking, obesity, cardiovascular disease, and stroke. Participants completed cognitive assessments at baseline and 3‐year follow‐up. Self‐reported age‐at‐menopause was categorized into tertiles: early (<49), average (49‐52), and late (>52). Linear models tested independent and interactive effects of age‐at‐menopause and vascular risk on 3‐year cognition, adjusting for baseline cognition, baseline age, education, APOE4, and test language (English/French).ResultIn women, vascular risk and age‐at‐menopause were independently associated with cognitive decline (vascular risk: β = ‐0.107, p<.001). Relative to average age‐at‐menopause, early menopause was associated with greater cognitive decline (β = ‐0.026, p = .03), whereas late menopause was associated with less decline (β = 0.025, p = .04). In men, vascular risk was also associated with greater cognitive decline (β = ‐0.112, p<.001). Next, we examined synergistic effects of age‐at‐menopause and vascular risk in postmenopausal women. Early (vs. average) menopause and elevated vascular risk interacted to accelerate cognitive decline (β = ‐0.224, p = .002). There was no interaction between late (vs. average) menopause and vascular risk (β = ‐0.073, p = .3). In a model comparing sexes (Figure 1), vascular risk was more strongly associated with cognitive decline in women with early menopause compared to men (β = ‐0.127, p = .03). In women with average or late menopause, associations of vascular risk with cognitive decline did not significantly differ from men (average: β = ‐0.010, p = .07; late: β = ‐0.024, p = .7). Sensitivity analyses additionally adjusting for physical activity, race/ethnicity, depression, alcohol, and hormone therapy yielded similar results.ConclusionEarly menopause and vascular processes may synergistically contribute to increased AD risk in women. These findings have implications for sex‐specific dementia prevention strategies.

Higher circulating levels of non-esterified fatty acids are associated with faster kidney function decline in post-menopausal women with type 2 diabetes: a pilot prospective study.

Currently, there is little and inconsistent evidence regarding the possible adverse effects of circulating levels of non-esterified fatty acids (NEFA) on kidney function decline in patients with type 2 diabetes mellitus (T2DM). We followed for a median of 4.6 years 85 post-menopausal women with non-insulin-treated T2DM and preserved kidney function at baseline. Serum NEFA concentrations were measured using an enzymatic colorimetric method. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Enrolled patients had a baseline mean eGFRCKD-EPI of 83 ± 12mL/min/1.73m2 and a median serum NEFA concentration of 662uEq/L (interquartile range 524-842uEq/L). During the follow-up period, 13 patients developed kidney function decline at follow-up (defined as an eGFRCKD-EPI decline ≥ 30% from baseline). In Cox proportional hazards regression analyses, higher serum NEFA levels were significantly associated with an increased risk of developing kidney function decline (adjusted-hazard ratio 3.67, 95% CI 1.64-8.22, p < 0.001; for each 1-SD increment, i.e., 262uEq/L), even after adjustment for waist circumference, hemoglobin A1c, C-reactive protein, HOMA-estimated insulin resistance, hypertension, dyslipidemia, microalbuminuria, baseline eGFRCKD-EPI, as well as temporal changes in HbA1c levels or the use of renin-angiotensin system inhibitors over the follow-up. The findings of this exploratory prospective study show that in post-menopausal women with T2DM and preserved kidney function at baseline, higher circulating levels of NEFA were strongly associated with a faster kidney function decline, even after adjustment for established renal risk factors and potential confounders.

Combined Exercise Training Promotes More Benefits on Cardiovascular Autonomic Modulation in Ovariectomized Rats Than Isolated Aerobic or Resistance Training.

Cardiovascular risk increase after ovarian deprivation has been extensively demonstrated by our research group through cardiovascular autonomic analysis. Interventions involving different types of exercises, such as resistance exercises or combined exercises (aerobic and resistance) have been widely recommended to prevent or minimize neuromuscular decline in postmenopausal women, which is aggravated by a sedentary lifestyle. Experimentally, the cardiovascular effects of resistance or combined training, as well as comparison between aerobic, resistance, and combined training, in ovariectomized animals are scarce. In this study, we hypothesized that the combination of aerobic and resistance training may be more effective in preventing muscle mass loss, as well as improving cardiovascular autonomic modulation and baroreflex sensitivity, than aerobic or resistance training individually in ovariectomized rats. Female rats were divided into 5 groups: sedentary (C); ovariectomized (Ovx); trained ovariectomized submitted to aerobic training (OvxAT); resistance training (OvxRT); combined training (OvxCT). Exercise training lasted 8 weeks, with the combined group alternating between aerobic training and resistance training every other day. At the end of the study, glycemia and insulin tolerance were evaluated. Arterial pressure (AP) was directly recorded. Baroreflex sensitivity was assessed by heart rate response to changes in arterial pressure. Cardiovascular autonomic modulation was evaluated by spectral analysis. Combined training was the only training regime that increased baroreflex sensitivity for tachycardic response and reduced all systolic blood pressure variability parameters. Furthermore, all animals submitted to exercise training on a treadmill (OvxAT and OvxCT) presented lower systolic, diastolic, and mean pressure, as well as improvements in the autonomic modulation for the heart. Combined training showed to be more effective than isolated aerobic and resistance training, mixing the isolated benefits of each modality. It was the only modality able to increase baroreflex sensitivity to tachycardic responses, reduce arterial pressure and all parameters of vascular sympathetic modulation.

Does hormone replacement therapy prevent cognitive decline in postmenopausal women?

NO. Hormone replacement therapy (HRT) does not prevent cognitive decline in postmenopausal women-and in fact, it may slightly increase risk (strength of recommendation, A; systematic review, meta-analysis of randomized controlled trials [RCTs], and individual RCT).

Association between PNPLA3 rs738409 variant and 5-year estimated glomerular filtration rate decline in post-menopausal women with type 2 diabetes: A panel-data analysis

Background and aimsLittle is known about the relationship between patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 variant and decline in estimated glomerular filtration rate (eGFR) over time in individuals with type 2 diabetes (T2DM). Methods and resultsWe enrolled an outpatient sample of 46 post-menopausal women with T2DM and preserved kidney function at baseline (in 2017), who were followed through 2022. eGFR and albuminuria were measured annually. Genotyping of PNPLA3 rs738409 was performed by TaqMan-based RT-PCR system. Overall, 25 (54.3%) patients had PNPLA3 rs738409 CC (homozygous wild-type) genotype and 21 had CG or GG genotypes. During the 5-year follow-up, the presence of rs738409 CG/GG genotypes was associated with faster eGFR decline (coefficient: −6.55; 95% CI −11.0 to −2.08; p = 0.004 by random-effects panel data analysis). This association remained significant even after adjustment for 5-year changes in age, hemoglobin A1c, hypertension status, albuminuria and use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists. ConclusionsThis pilot study suggests that in post-menopausal T2DM women with preserved kidney function at baseline, the risk allele (G) of PNPLA3 rs738409 is associated with a faster eGFR decline during a 5-year follow-up, independent of annual changes in common renal risk factors and use of certain glucose-lowering medications.

Association of Diet-dependent Systemic Acid Load, Renal Function, and Serum Albumin Concentration

Inflammation may be present with CKD and diet composition high in protein intake and fats may affect inflammation thereby impacting kidney health. We investigated whether acid load estimated from urine measures is associated with kidney function decline and whether the effect of acid load on an inflammatory marker, serum albumin, is a pathway to this association. We studied 188 post-menopausal women in a randomized clinical trial of potassium bicarbonate treatment for up to 36 months. 24-hr urine and arterialized blood collections were done at baseline and at subsequent follow-up visits at 3 months interval. Acid load was estimated from potential renal acid load calculated using urinary measures of chloride, phosphate, sodium, potassium, calcium, and magnesium (UPRAL). Mixed effects model with random-intercept and slope was used to estimate subjects' annual decline rate in creatinine clearance (CrCl), and the association between (i) UPRAL and serum albumin and (ii) serum albumin and CrCl, adjusting for age, body mass index, systolic BP, and glucose. A Cox proportional regression model was used to study the relative hazard (RH) for rapid progression of kidney function decline (defined as loss of ≥5 ml/min CrCl/yr based on the last CrCl in the rolling window) with UPRAL, adjusting for the potential covariates and baseline CrCl. A 25 mEq/day increase in UPRAL was inversely associated with serum albumin (Adjusted β[95% CI]: -0.02[-0.09;-0.001). During a mean follow-up of 28 months, 19 women (10%) had a rapid decline in kidney function. For each 25 mEq/day increase in UPRAL, the risk of a rapid decline in CrCl increased by 17% (95% CI: 1.06-1.28). On adjustment for potential confounders, the risk attenuated to 5% (1.02-1.14). Mediation analysis indicated that of the total effect of the association between UPRAL and CrCl, the proportion mediated by serum albumin increased to 0.346 (i.e. 34.6%). Higher UPRAL was associated with lower serum albumin as well as greater kidney function decline in post-menopausal women. Our findings suggest inflammatory response may exert a modulatory effect on the association of UPRAL and kidney function and might be a potential pathway explaining the effects of systemic acid load on progression of kidney failure.

ODP406 Effects of hormone replacement therapy on memory cognitive function in postmenopausal women: a systematic review and meta-analysis

Abstract Objective To investigate the effect of hormone replacement therapy (HRT) on memory cognitive function in postmenopausal women. Methods PubMed, Cochrane, Embase, Chinese Biomedical Literature Database (CBM)and web of ClinicalTrials.gov were systematically searched for randomized controlled trials comparing the effect of HRT on memory function in postmenopausal women to Placebo. The primary outcome of interest is memory cognitive function (measured by tests used in the study). We assessed pooled data by using random-effects model. Results Ten studies with 2818 participants were finally eligible for inclusion in the analysis. Compared with placebo, HRT showed no significant differences on logical memory including both immediate (weighted mean difference [WMD] 0.34, 95% CI: -0.73, 1.40) and delayed(0.99, 95% CI: -0.51, 2.48) recall in postmenopausal women, also no differences on short-delay (-0. 00, 95% CI: -0.37, 0.37) or long-delay (-0.19, 95% CI: -0.69, 0.31) recall of California Verbal Learning Test, but yielded an a mean reduction in digit span forward of -0.20 (95%CI: -0.36,-0. 03), with no significant difference in digit span total scores (-0.67, 95% CI: -1.58, 0.24) or backward (-0.10, 95%CI: -0.26, 0. 05). In women within 5 years of menopause, HRT still shows no harmful or beneficial effects on immediate (WMD 0.45, 95% CI: -0.75, 1.65) or delayed recall (WMD 1. 03, 95% CI: -0.93, 3. 00) of logical memory, but no detrimental effects on digit span forward (WMD -0.11, 95% CI: -0.72, 0.50). Conclusion This review suggests that HRT do not improve verbal memory in postmenopausal women, may even impair some domains of short-term memory. HRT may thus not be a potential therapeutic strategy to prevent memory decline in postmenopausal women. Presentation: No date and time listed

Pilates and Cognitive Stimulation in Dual Task an Intervention Protocol to Improve Functional Abilities and Minimize the Rate of Age-Related Cognitive Decline in Postmenopausal Women.

It is already known the effectiveness of Pilates training on cognitive and functional abilities. It is also known that dual-task exercise and cognitive stimuli improve cognition and functional capacity. However, no previous report combined cognitive stimuli and Pilates in dual task and measured its effects on the cognitive and physical performances of postmenopausal women. Objective: To apply an interventional dual-task (PILATES-COG) protocol and to evaluate its influence on memory, language, and functional physical performances on healthy, community-dwelling postmenopausal older women. Methods: 47 women with amenorrhea for at least 12 months participated in this study. Those allocated on the PILATES-COG group underwent a 12-week, twice a week regimen of 50 min sessions of simultaneous mat Pilates exercise program and cognitive tasks. Cognitive and physical functional performance were assessed. Two-way mixed ANOVA was used for data analysis, and Bonferroni post hoc tests were used for within- and between-group comparisons. Results: The PILATES-COG group showed significant improvement after the intervention in semantic verbal fluency (p < 0.001; ηρ² = 0.268), phonological verbal fluency (p < 0.019; ηρ² = 0.143), immediate memory (p < 0.001; ηρ² = 0.258), evocation memory (p < 0.001 ηρ² = 0.282), lower-limb muscle strength (p < 0.001; ηρ² = 0.447), balance (p < 0.001; ηρ² = 0.398), and dual-ask cost (p < 0.05; ηρ² = 0.111) assessments on healthy, community-dwelling postmenopausal older women. Conclusion: This is the first report of a feasible and effective approach using Pilates and cognitive stimulation in dual task for the reduction of age-related cognitive decline and the improvement of physical functional performance in healthy postmenopausal women.

Association between physical and cognitive function in post menopause: a cross-sectional study

Functional tests have been performed to predict cognitive decline in postmenopausal women and may be an important tool to identify early reductions in cognitive performance in this population. However, it is still unclear which functional test is more sensitive for detecting cognitive decline in the investigated sample. The aim of this study was to verify the association between functional performance and cognitive function in postmenopausal women and to analyze whether the gait speed of 400 meters (400wt) and Timed Up and Go (TUG) tests are predictors of cognitive function in this sample. One hundred and twenty eight postmenopausal women (60.8 ± 7.9 years) participated in this cross-sectional study. Body composition was assessed using Dual Energy X-ray Absorptiometry (DXA), functional performance by the TUG and 400wt tests, cognitive performance by the Montreal Cognitive Assessment (MoCA) test and muscle strength by maximum voluntary isometric contraction (MVIC) in lower limbs. An association between functional performance and cognitive function was observed in middle-aged postmenopausal women. The TUG test was associated with the MoCA test (B = -0.79; SE = 0.29; p = 0.008). However, no association was observed between 400wt with the MoCA test (B = 3.03; SE = 1.92; p = 0.117). These results show that the TUG test is a good predictor of cognitive decline in postmenopausal middle-aged women.

25-hydroxyvitamin D status and its impact on cognitive functions in postmenopausal woman

Aim: The purpose of the study was to analyze the cognitive functions in postmenopausal women carriers of Apolipoprotein E gene polymorphisms (APOE) with different status of vitamin D levels. Material/Methods: 170 ambulatory individuals aged 50 years or older were evaluated. A computerized battery of Central Nervous System Vital Signs (CNS VS) was used for diagnostic cognitive functions. APOE genotype was performed by multiplex PCR. Serum 25(OH)D and estradiol levels were measured using the 25OHD EIA assay and Estradiol ELISA Kits. Results: Considerably worse scores in global cognitive performance index (NCI) were obtained by women with severe deficiency of 25(OH)D (p &lt;0.001). The cognitive effects of very low 25(OH)D levels were apparent in memory, executive functioning, complex attention, and cognitive flexibility. The genotype APOE ε3/ε4 or ε4/ε4 were most common (19.6%; 15.2%, respectively) in women with 25(OH)D severe deficiency which had the weakest average results in terms of NCI value. Conclusions: The severe deficiency of 25(OH)D vitamin was related with a greater likelihood of cognitive impairment and risk of cognitive decline in postmenopausal women with no dementia.

Lack of association of ovariectomy-induced obesity with overeating and the reduction of physical activities

Obesity commonly occurs in postmenopausal women, increasing the risk of various diseases. Estrogen can prevent obesity by activating lipid metabolism and suppressing depressive behavior. However, the reasons for obesity in postmenopausal women are not clearly elucidated.To mimic the effect of estrogen decline in postmenopausal women, we analyzed the behavior and the lipid metabolism-related genes, PPARγ and CD36 in ovariectomized (OVX) mice. The OVX mice showed increased visceral fat mass and PPARγ and CD36 expression in the visceral fat. In contrast, they were not significantly affected in terms of physical activity and food intake. Further, subcutaneous supplementation of estrogen effectively suppressed the increase in subcutaneous and visceral fat mass in OVX mice.We conclude that obesity in postmenopausal women is unlikely to be caused by overeating and reduction in physical activity, and subcutaneous supplementation of estrogen is an effective strategy to prevent obesity in postmenopausal women.

Menopausal hormone therapy and mild cognitive impairment: a randomized, placebo-controlled trial.

The aim of the study was to explore the therapeutic potential of menopausal hormone therapy (MHT) in women with mild cognitive impairment (MCI). Thirty-seven postmenopausal women (age range: 57-82 y) with multiple-domain, amnestic subtype MCI were randomly assigned to either placebo (n = 18) or MHT (n = 19) for 24 months (percutaneous estradiol [E2] gel [0.1%, 2 mg/d] and oral micronized progesterone [MP4] [100 mg/d]). All participants received donepezil, and apolipoprotein E genotype was determined. The primary endpoint was general cognitive function: Alzheimer's disease Assessment Scale, cognitive subscale, the Korean version of Mini-Mental State Examination (K-MMSE), and the Korean version of the Montreal Cognitive Assessment (MoCA_K) were performed in-person every 6 months. Twenty-one participants (placebo 13, MHT 8) completed the trial (56.8%). Progression rates to dementia were 52.9% (9/17) in the placebo group and 44.4% (8/18) in the MHT group. Within-group analysis showed that all three tests significantly worsened during the trial in the placebo, but not the MHT groups. Analysis adjusted for ε4 allele demonstrated that MHT significantly reduced deterioration of MoCA_K score, a sensitive tool for assessing global cognition in MCI (P = 0.0261). Compared with the control group, both MoCA_K (P = 0.043; mean difference, 3.85; 95% CI, -0.46 to 8.16) and K-MMSE (P = 0.0319; mean difference, 3.26; 95% CI, 0.04-6.48) scores were significantly better at 24 months in the MHT group. Long-term MHT using percutaneous E2 gel and oral MP4 might attenuate cognitive decline in postmenopausal women with MCI.

Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study

BackgroundData on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.Methods and ResultsProspective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.ConclusionsCVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.

Connecting Cardiovascular Disease and Dementia: Further Evidence

Cognitive impairment is highly prevalent in the elderly, and it accounts for a large part of the burden of disability and of the use of healthcare resources. The major types of dementia are Alzheimer disease and vascular dementia.[1][1] For many years, atherosclerosis was not considered to play a

Biomarker‐Calibrated Protein Intake and Physical Function in the Women's Health Initiative

To determine whether preservation of physical function with aging may be partially met through modification in dietary protein intake. Prospective cohort study. Women's Health Initiative (WHI) Clinical Trials (CT) and Observational Study (OS) conducted at 40 clinical centers. Women aged 50 to 79 (N = 134,961) with dietary data and one or more physical function measures. Physical function was assessed using the short-form RAND-36 at baseline and annually beginning in 2005 for all WHI participants and at closeout for CT participants (average ~7 years after baseline). In a subset of 5,346 participants, physical performance measures (grip strength, number of chair stands in 15 seconds, and timed 6-m walk) were assessed at baseline and Years 1, 3, and 6. Calibrated energy and protein intake were derived from regression equations using baseline food frequency questionnaire data collected on the entire cohort and doubly labeled water and 24-hour urinary nitrogen collected from a representative sample as reference measures. Associations between calibrated protein intake and each of the physical function measures were assessed using generalized estimating equations. Calibrated protein intake ranged from 6.6% to 22.3% energy. Higher calibrated protein intake at baseline was associated with higher self-reported physical function (quintile (Q)5, 85.6, 95% confidence interval (CI) = 81.9-87.5; Q1, 75.4, 95% CI = 73.2-78.5, P trend = .002) and a slower rate of functional decline (annualized change: Q5, -0.47, 95% CI = -0.63 to -0.39; Q1, -0.98, 95% CI = -1.18 to -0.75, P trend = .02). Women with higher calibrated protein intake also had greater grip strength at baseline (Q5, 24.7 kg, 95% CI = 24.3-25.2 kg; Q1, 24.1 kg, 95% CI = 23.6-24.5 kg, P trend = .04) and slower declines in grip strength (annualized change: Q5, -0.45 kg, 95% CI = -0.39 to -0.63 kg; Q1, -0.59 kg, 95% CI = -0.50 to -0.66 kg, P trend = .03). Women with higher calibrated protein intake also completed more chair stands at baseline (Q5, 7.11, 95% CI = 6.91-7.26; Q1, 6.61, 95% CI = 6.46-6.76, P trend = .002). Higher calibrated protein intake is associated with better physical function and performance and slower rates of decline in postmenopausal women.

Diphenyl diselenide ameliorates cognitive deficits induced by a model of menopause in rats

Ovarian hormone loss contributes to cognitive decline in postmenopausal women. Studies have demonstrated a positive role of the level of the element selenium in cognitive performance. The present study investigated the effects of the synthetic organoselenium compound diphenyl diselenide (PhSe)₂ on cognitive functions in ovariectomized rats. Ninety-day-old female Wistar rats were subjected to ovariectomy (OVX) or Sham operation. One week after surgery, rats were orally treated with (PhSe)₂ (5 mg/kg, per oral route) or vehicle once a day for 30 days. Next, the rats were evaluated in behavioral tests [Morris water maze (MWM) and open-field tests] and biochemical [cerebral acetylcholinesterase (AChE)] analyses were carried out. In MWM probe trial, (PhSe)₂ decreased the latency to reach the platform location and increased the number of crossings over the platform location, protecting against cognitive impairment induced by OVX. Furthermore, (PhSe)₂ prevented the stimulation of AChE activity caused by OVX. In conclusion, the present study showed a cognition-enhancing effect of (PhSe)₂ treatment for 30 days in ovariectomized rats in the MWM test, which could be related to its ability to prevent the stimulation of AChE activity caused by OVX in rats. These findings suggest that (PhSe)₂ might have a promising role in preventing the cognitive decline related to menopause.

Motherhood alters the cellular response to estrogens in the hippocampus later in life

Although controversial, estrogen replacement therapy has been implicated as a possible therapeutic agent for ameliorating age-related cognitive decline in postmenopausal women. We have shown previously that different types of estrogen promote hippocampal neurogenesis in a dose-dependent manner in young adult female rats. However, previous studies have not found a beneficial effect of 17β-estradiol in middle-aged female rats. The aim of the present study was to determine the acute effects of 17β-estradiol, 17α-estradiol, and estrone on hippocampal cell proliferation in middle-aged ovariectomized female rats and to determine whether effects are dependent on previous reproductive experience. Middle-aged multiparous female rats or age-matched virgin female rats were injected subcutaneously with vehicle or 10 μg dose of 17β-estradiol, 17α-estradiol, or estrone, and then given BrdU 30 min later and perfused 24h later to assess cell proliferation. All estrogens significantly upregulated cell proliferation in the hippocampus in middle-aged multiparous females but none of the estrogens upregulated cell proliferation in the middle-aged virgins. Therefore, previous reproductive experience may make the older brain more responsive to estrogens later in life. We also found that 17α-estradiol upregulated cell proliferation to a greater degree than the other estrogens in the multiparous females. Together these findings may lead to the development of new therapeutic advances in the treatment of symptoms associated with menopause in women.

Design, Synthesis, and Estrogenic Activity of a Novel Estrogen Receptor ModulatorA Hybrid Structure of 17β-Estradiol and Vitamin E in Hippocampal Neurons

We recently discovered that ICI 182,780 (1), an antagonist of estrogen receptor (ER)-dependent proliferation in reproductive tissues, functions as an estrogenic agonist in primary neurons. The present study investigated whether the agonist properties of 1 in neurons could be translated into structural analogs. 7alpha-[(4R,8R)-4,8,12-trimethyltridecyl]estra-1,3,5-trien-3,17beta-diol (2), a hybrid structure of 17beta-estradiol and vitamin E, was synthesized and found to bind to both ERalpha and ERbeta. In vitro analyses demonstrated that 2 was neuroprotective and effective in activating molecular mechanisms associated with estrogenic agonist activity in rat primary hippocampal neurons. Collectively, the data support an estrogenic agonist profile of 2 action comparable to 1 in primary neurons, confirming that estrogenic activity of 1 in neurons is not a unique phenomenon. These results provide support for the development of a brain-selective ER modulator, with potential as an efficacious and safe estrogen alternative to prevent Alzheimer's disease and cognitive decline in postmenopausal women.

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.

Estrogen use and brain metabolic change in postmenopausal women

Objective: We used positron emission tomography to evaluate cerebral glucose metabolic change in postmenopausal women in a naturalistic observational study. Method: Women estrogen users ( n=11) and non-users ( n=9) were studied at baseline and 2 years later. Analyses focused on glucose metabolism in regions previously reported to decline in older persons at risk for Alzheimer’s disease (AD) (posterior cingulate and lateral temporal cortex). Results: Region of interest (ROI) analysis at baseline showed no regional differences between women estrogen users and non users. ROI follow-up analysis revealed that women non-users declined significantly in the posterior cingulate cortex ( P=0.04). Statistical parametric mapping (SPM) analysis confirmed a significant decrease in metabolism of the posterior cingulate cortex among non-users at 2-year follow-up ( P=0.004). In contrast, women estrogen users did not exhibit significant metabolic change in the posterior cingulate. Conclusions: Estrogen use may preserve regional cerebral metabolism and protect against metabolic decline in postmenopausal women, especially in posterior cingulate cortex, the region of the brain found to decline in the earliest stages of AD.