Thalamo-Basal Ganglia Connectivity in Postmenopausal Women Receiving Estrogen Therapy

Cumulative data on the effects of estrogen therapy (ET) on brain function in postmenopausal women suggests that ET influences cerebral metabolism and may protect against age-related declines in various domains of cognitive function. The beneficial cognitive effects of ET may relate to its modulation of the thalamic-striatum cholinergic and dopaminergic systems, as the activity of both neurotransmitter systems in the thalamus appears to be positively influenced by estrogen. In the current study, we attempted to evaluated regional cerebral brain metabolism utilizing [18F]-fluorodeoxyglucose positron emission tomography in 11 healthy recently-postmenopausal women on ET (ET+) in comparison to 11 recently-postmenopausal and ET-naïve women (ET?) in order to assess the effects of ET on cholinergic and dopaminergic system regulation. Results showed thalamo-basal ganglia connectivity among ET+ women but not among ET? women. The presence of connectivity in the thalamo-striatal pathway in recently postmenopausal women suggests estrogen effects in preserving integrity of the cholinergic and dopaminergic systems. The results also suggest that ET initiated at or near the menopausal transition may modulate brain aging by mediating complex sensory-motor functions.     

Estrogen and hippocampal synaptic plasticity

During the past several years, there has been increasing interest in the effects of estrogen on neural function. This enthusiasm is driven, in part, by the results of early clinical studies suggesting that estrogen therapy given after menopause may prevent, or at least delay, the onset of Alzheimer's disease in older women. However, later clinical trials of women with probable Alzheimer's disease had contrary results. Much of the current research related to estrogen and brain function is focused in two directions. One involves clinical studies that examine the potential of estrogen in protecting against cognitive decline during normal aging and against Alzheimer's disease (neuroprotection). The other direction, which is the primary focus of this review, involves laboratory studies that examine the mechanisms by which estrogen can modify the structure of nerve cells and alter the way neurons communicate with other cells in the brain (neuroplasticity). In this review, we examine recent evidence from experimental and clinical research on the rapid effects of estrogen on several mechanisms that involve synaptic plasticity in the nervous system,including hippocampal excitability, long-term potentiation and depression related to sex and aging differences, cellular neuroprotection and probable molecular mechanisms of the action of estrogen in brain tissue.     

Estrogen therapy and brain muscarinic receptor density in healthy females: a SPET study

Estrogen Therapy (ET) may protect against age-related cognitive decline and neuropsychiatric disorders (e.g. Alzheimer's disease). The biological basis for this putative neuroprotective effect is not fully understood, but may include modulation of cholinergic systems. Cholinergic dysfunction has been implicated in age-related memory impairment and Alzheimer's disease. However, to date no one has investigated the effect of long-term ET on brain cholinergic muscarinic receptor aging, and related this to cognitive function. We used Single Photon Emission Tomography (SPET) and (R,R)[(123)I]-I-QNB, a novel ligand with high affinity for m(1)/m(4) muscarinic receptors, to examine the effect of long-term ET and age on brain m(1)/m(4) receptors in healthy females. We included 10 younger premenopausal subjects and 22 postmenopausal women; 11 long-term ET users (all treated following surgical menopause) and 11 ET never-users (surgical menopause, n=2). Also, verbal memory and executive function was assessed in all postmenopausal subjects. Compared to young women, postmenopausal women (ET users and never-users combined) had significantly lower muscarinic receptor density in all brain regions examined. ET users also had higher muscarinic receptor density than ET never-users in all the brain regions, and this reached statistical significance in left striatum and hippocampus, lateral frontal cortex and thalamus. Moreover, in ET users, (R,R)[(123)I]-I-QNB binding in left hippocampus and temporal cortex was significantly positively correlated with plasma estradiol levels. We also found evidence for improved executive function in ET users as compared to ET never-users. However, there was no significant relationship between receptor binding and cognitive function within any of the groups. In healthy postmenopausal women use of long-term ET is associated with reduced age-related differences in muscarinic receptor binding, and this may be related to serum estradiol levels.     

Estrogen and mitochondria: a new paradigm for vascular protection?

Mitochondrial dysfunction has been implicated as a cause of age-related disorders, and the mitochondrial theory of aging links aging, exercise, and diet. Endothelial dysfunction is a key paradigm for vascular disease and aging, and there is considerable evidence that exercise and dietary restriction protect against cardiovascular disease. Recent studies demonstrate that estrogen receptors are present in mitochondria and that estrogen promotes mitochondrial efficiency and decreases oxidative stress in the cerebral vasculature. Chronic estrogen treatment increases mitochondrial capacity for oxidative phosphorylation while decreasing production of reactive oxygen species. The effectiveness of estrogen against age-related cardiovascular disorders, including stroke, may thus arise in part from hormonal effects on mitochondrial function. Estrogen-mediated mitochondrial efficiency may also be a contributing factor to the longer lifespan of women.     

The critical period hypothesis of estrogen effects on cognition: Insights from basic research

Background

In addition to its primary role in reproduction estrogen impacts brain areas important for cognition, including the hippocampus and prefrontal cortex. It has been hypothesized that decline in estrogen levels in women following menopause is associated with, or can exacerbate, age-related cognitive decline. However, clinical evidence to support a role for estrogen in preventing cognitive decline in women as they age is equivocal. The critical period hypothesis of estrogen effects on cognition, which proposes that estrogen administration has to be initiated within a critical time period following the loss of ovarian function in order for it to exert positive effects on the central nervous system, is offered as one explanation for inconsistencies across studies.

Scope of review

This review details results from basic research using rodent models investigating the effects of estrogen on cognition in the aging female. Emphasis is placed on work investigating effects of timing of initiation of estrogen administration on its subsequent efficacy.

Major conclusions

Results of basic research provide support for the critical period hypothesis. Furthermore, results of work in rodent models suggest mechanisms by which the response to estrogen is altered if treatment is initiated following long-term ovarian hormone deprivation.

General significance

Understanding if and under what conditions hormone administration following the loss of ovarian function positively affects the brain and behavior could have important implications with regard to female cognitive aging. Results of basic research can contribute to this understanding and provide insight into the complex mechanisms by which estrogen affects cognition.     

Estrogen and memory in women: how can we reconcile the findings?

Although several randomized controlled trials (RCTS) of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the RCT, the Women's Health Initiative Memory Study (WHIMS), have reported inconsistent information with regard to the relationship between estrogen and aspects of cognitive function. Although numerous reasons could be offered to explain these discrepancies in research findings, recent evidence from rodent, nonhuman primate, and human studies consistently suggests that one possibility may be critical to our understanding of the estrogenic effect on memory. Results of these animal and human studies indicate that the initiation of estrogen treatment at the time of menopause, or soon after ovariectomy (OVX), provides a window of opportunity for the preservation of memory in females whereas the administration of the hormone following a considerable delay in time after OVX has little or no beneficial effect on cognition. Considering the evidence that, in several organ systems, heightened disease risks accrue to a longer duration of estrogen deprivation in women, it would seem important to determine whether this is also true for brain structure and function in order to protect the quality of life for the considerable number of women who undergo a surgical menopause before their natural menopause had occurred.     

Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory

Cognitive changes that occur during mid-life and beyond are linked to both aging and the menopause transition. Studies in women suggest that the age at menopause onset can impact cognitive status later in life; yet, little is known about memory changes that occur during the transitional period to the postmenopausal state. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of perimenopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the trajectory of cognitive change across time with normal aging and aging with transitional menopause via VCD-induced follicular depletion, as well as to evaluate whether age at the onset of follicular depletion plays a role in cognitive outcomes. Animals experiencing the onset of menopause at a younger age exhibited impaired spatial memory early in the transition to a follicle-deplete state. Additionally, at the mid- and post- follicular depletion time points, VCD-induced follicular depletion amplified an age effect on memory. Overall, these findings suggest that age at the onset of menopause is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study illustrates how age at menopause onset might impact cognition in menopausal women, and provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition period. Hormone therapy during this critical juncture might be especially efficacious at attenuating age- and menopause- related cognitive decline, producing healthy brain aging profiles in women who retain their ovaries throughout their lifespan.     

Action of estrogens in the aging brain: Dementia and cognitive aging

Background

Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging.

Scope of review

Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk.

Major conclusions

Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings.

General significance

Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause.     

Estrogen and Neurodegeneration

Although estrogen is best known for its effects on the maturation and differentiation of the primary and secondary sex organs, increasing evidence suggests that its influence extends beyond this system, and its activity in the CNS may initiate, or influence our susceptibility to neurodegenerative decline. Estrogen has been proposed to act as a general neuroprotectant at several levels and it is probable that deprivation of estrogen as a result of menopause exposes the aging, or diseased brain to several insults. In addition, estrogen deprivation is likely to initiate, or enhance degenerative changes caused by oxidative stress, and to reduce the brain's ability to maintain synaptic connectivity and cholinergic integrity leading to the cognitive decline seen in aged, and disease-afflicted individuals.     

Impact of Estrogen Therapy on Lymphocyte Homeostasis and the Response to Seasonal Influenza Vaccine in Post-Menopausal Women

It is widely recognized that changes in levels of ovarian steroids modulate severity of autoimmune disease and immune function in young adult women. These observations suggest that the loss of ovarian steroids associated with menopause could affect the age-related decline in immune function, known as immune senescence. Therefore, in this study, we determined the impact of menopause and estrogen therapy (ET) on lymphocyte subset frequency as well as the immune response to seasonal influenza vaccine in three different groups: 1) young adult women (regular menstrual cycles, not on hormonal contraception); 2) post-menopausal (at least 2 years) women who are not receiving any form of hormone therapy (HT) and 3) post-menopausal hysterectomized women receiving ET. Although the numbers of circulating CD4 and CD20 B cells were reduced in the post-menopausal group receiving ET, we also detected a better preservation of naïve B cells, decreased CD4 T cell inflammatory cytokine production, and slightly lower circulating levels of the pro-inflammatory cytokine IL-6. Following vaccination, young adult women generated more robust antibody and T cell responses than both post-menopausal groups. Despite similar vaccine responses between the two post-menopausal groups, we observed a direct correlation between plasma 17β estradiol (E2) levels and fold increase in IgG titers within the ET group. These findings suggest that ET affects immune homeostasis and that higher plasma E2 levels may enhance humoral responses in post-menopausal women.     

Selenium and cognitive impairment: a brief-review based on results from the EVA study

Preventing cognitive impairment and dementia in the elderly is a major public health challenge for our century and all hypotheses should be explored. Selenium (Se) is one of the factors that may affect the risk of cognitive decline. Its importance in the health and aging process has been documented. Because of the potential of selenoproteins to protect against oxidative stress, Se raises significant expectations for the prevention of chronic diseases including cancer, cardiovascular disease, and type 2 diabetes conditions commonly associated with oxidative stress. Thus, the relationships between Se and cognitive impairment or dementia can be examined through vascular risk factors for dementia, with particular interest in diabetes and dyslipidemia. In addition, in cases of Se deficiency, the brain is the organ that remains Se replete the longest suggesting that Se plays an important role in brain functions. This article presents results obtained in the frame of a longitudinal study on Se and cognitive impairment. They are consistent with the hypothesis that low Se status is a risk factor for cognitive decline even after taking into account vascular risk factors. The concomitant evolution between plasma Se decrease over a 9-year period and cognitive decline suggested that optimal Se status is potentially important to maintain neuropsychological functions in aging people. However, as our understanding of Se biology is incomplete, epidemiological studies are needed to define the groups of population that could benefit from Se supplementation.     

Protective role of n-3 lipids and soy protein in osteoporosis

It is well established that bone loss due to estrogen deficiency after menopause is greater in women consuming higher quantities of animal protein than in women consuming vegetable protein, particularly soy protein. Besides the dietary protein source altering bone loss, it has also been postulated recently that the source of a higher n-6/n-3 ratio in dietary oils is implicated in causing osteoporosis. Both animal and human studies have indicated that an increased intake of n-6 fatty acids from vegetable oils elevates prostaglandin E(2) levels as well as pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha. Interestingly, it has been found that lack of estrogen also increases the production of these cytokines by immune cells and thereby activates osteoclasts during the peri-menopausal period. We speculated that the use of n-3 fatty acids and soy protein, which are known to act as anti-inflammatory and down regulate pro-inflammatory cytokines, may also protect against bone loss by decreasing osteoclast activation and bone resorption. Similar to the results of others, our ongoing studies indeed show that the bone loss in ovariectomized mice is significantly attenuated by feeding diets enriched with either fish oil or soy protein when compared to corn oil and casein-fed mice. One of the mechanisms appears to be decreasing the activation of receptor activator of NF-kappaB ligand (RANKL) on T cells, which has been found to increase osteoclast activation along with increasing pro-inflammatory cytokines in OVX mice. Since hormone replacement therapy has been found to cause adverse effects, further both animal and human studies are required with moderate soy protein and fish oil supplements in understanding the mechanisms involved in altering immune function and bone loss during menopause in women and aging in men.     

Effects of botanical dietary supplements on cardiovascular,cognitive, and metabolic function in males and females

Background: The onset of menopause marks a pivotal time in which the incidence of hypertension and of cardiovascular disease (CVD) begins to increase dramatically in women. Before menopause, the incidences of these diseases are significantly lower in women than in age-matched men. After menopause, the rates of these diseases in women eventually approximate those in men. The loss of endogenous estrogen at menopause has been traditionally believed to be the primary factor involved in these changes.Objective: This review summarizes recent findings regarding the effectiveness of botanicals in the treatment of some menopausal symptoms and other symptoms of aging (eg, rise in arterial pressure, cognitive decline, insulin resistance, and hyperlipidemia).Methods: Articles were selected for inclusion in this review based on the significance of the research and contribution to the current understanding of how each botanical elicits cardioprotective effects. To this end, PubMed and MEDLINE databases were searched, using terms that included the name of the specific botanical along with the relevant aspects of its action(s), such as blood pressure, glycemic control, and lipids. Most of the articles used were published within the past 5 years, although some older articles that were seminal in advancing the current understanding of botanicals were also included.Results: Soy has been found to lower plasma lipid concentrations and arterial pressure in postmenopausal women and age-matched men, and to have protective effects in heart disease and atherosclerosis of the carotid and coronary circulation. Soy was also found to lower fasting insulin concentrations and glycosylated hemoglobin concentrations. Grape seed extract, another frequently used botanical, contains polyphenols that have been found to reduce arterial pressure and salt-sensitive hypertension in estrogendepleted animal models.Conclusion: Several botanical compounds have been found to have beneficial effects in the treatment of the symptoms of menopause and other symptoms of aging, including CVD, cognitive decline, and metabolic diseases.     

Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here?

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.     

Selenium-dependent Glutathione Peroxidase Activity is Increased in Healthy Post-menopausal Women

Selenium helps protect against peroxidation during aging as part of the glutathione peroxidase (GPx) antioxidant system. Selenium status, however, is often low in elderly persons who have low selenium intake, live in institutions, and have certain chronic diseases. In addition, a relationship has been observed between the female reproductive hormone, estrogen, and selenium status, with blood selenium and GPx activity coinciding with fluctuations in estrogen during the menstrual cycle. These findings suggest that the decrease in estrogen following menopause may cause a decrease in selenium status, and thus accelerate the process of aging and increase the risk of certain diseases. The current study compared selenium status in healthy premenopausal (n = 13, 21 to 43 years) and postmenopausal (n = 10, 57 to 86 years) women. Selenium intakes of both groups were similar and greater than the recommended dietary allowance (RDA) of 55 μg/day for adult women. Although neither plasma nor RBC selenium concentrations were significantly different between groups, postmenopausal women had significantly greater plasma (p < 0.02), and RBC (p < 0.05) GPx activities compared to premenopausal women possibly in response to oxidative processes associated with aging. These results indicate that the selenium status of healthy postmenopausal women did not decline with menopause and that their antioxidant capability, as measured by GPx activity, was preserved with dietary intake of selenium greater than the RDA. Presented in part at the Experimental Biology 2000, April 2000, San Diego, CA [Smith AM, Ha EJ, Medeiros LC. Selenium-dependent glutathione peroxidase activity is increased in healthy post-menopausal women. FASEB J 2000;14:A513.].     

Postmenopausal hormone therapy and cognition

This article is part of a Special Issue "Estradiol and cognition".Prior to the publication of findings from the Women's Health Initiative (WHI) in 2002, estrogen-containing hormone therapy (HT) was used to prevent age-related disease, especially cardiovascular disease, and to treat menopausal symptoms such as hot flushes and sleep disruptions. Some observational studies of HT in midlife and aging women suggested that HT might also benefit cognitive function, but randomized clinical trials have produced mixed findings in terms of health and cognitive outcomes. This review focuses on hormone effects on cognition and risk for dementia in naturally menopausal women as well as surgically induced menopause, and highlights findings from the large-scale WHI Memory Study (WHIMS) which, contrary to expectation, showed increased dementia risk and poorer cognitive outcomes in older postmenopausal women randomized to HT versus placebo. We consider the ‘critical window hypothesis’, which suggests that a window of opportunity may exist shortly after menopause during which estrogen treatments are most effective. In addition, we highlight emerging evidence that potential adverse effects of HT on cognition are most pronounced in women who have other health risks, such as lower global cognition or diabetes. Lastly, we point towards implications for future research and clinical treatments.     

Ovarian hormone replacement to aged ovariectomized female rats benefits acquisition of the morris water maze

Ovarian steroids have been suggested to aid in preserving cognitive functioning during aging in both humans and other animals. Spatial memory relies heavily on the hippocampus, a structure that is sensitive to the influence of both ovarian hormones and aging. The present study investigated the outcome of ovarian hormone replacement during aging on performance in a spatial version of the Morris water maze. Female rats were ovariectomized at 14 months of age and received one of three types of replacement prior to testing at 16 months: acute estrogen replacement (2 days), chronic estrogen replacement (28 days), or chronic replacement of both estrogen and progesterone (28 days). Control animals, which did not receive replacement hormones, displayed significant overnight forgetting during acquisition of the task. Ovarian hormone replacement, both acute and chronic, prevented forgetting. Previous studies have demonstrated that high levels of ovarian hormones are detrimental to performance of young adult female rats on this task (Warren and Juraska, 1997; Chesler and Juraska, 2000). The current study found an opposite effect during aging: ovarian hormone replacement was beneficial. This suggests that animal models of menopause, aimed at exploring the protective effects of hormone replacement therapy on cognition during human female aging, require the use of aged female animals.     

HRT in 2006

According to present terminology, the name: hormonal replacement therapy (as the use of ovarian hormones in postmenopausal women) is replaced by the systemic estrogen therapy (ET) and combined combined estrogen-progestogen therapy (EPT). Treatment with estrogen and progestagens in this period of women's life is accepted intervention only when the strict defined conditions of this therapy are maintained. This paper introduces present rules of the use of systemic ET and EPT according to statements of experts who are interested of menopausal women' treatment.     

Age-related changes in the regulation of luteinizing hormone secretion by estrogen in women

Despite the many studies that have been conducted using both primate and human models to understand the control of the menstrual cycle, there are many aspects of the hormonal dynamics of the menstrual cycle that are not understood. This Minireview summarizes the changes in estrogen regulation of luteinizing hormone (LH) secretion that occur throughout life in women from the time of maturation of the hypothalamic-pituitary axis resulting in the occurrence of the LH surge during puberty, through the reproductive years, to the changes in the regulation of the LH surge during premenopause and, subsequently, menopause.     

Nonhuman primate models of menopause workshop

The Nonhuman Primate Models of Menopause Workshop was held on the National Institutes of Health campus in January 2001. The purpose of this workshop, sponsored by the National Institute on Aging, was to review what is known about the female reproductive aging process in various species of monkeys (particularly rhesus, baboons, cynomolgus, and chimpanzees), including hormone profiles during the menopausal transition, occurrence of hot flashes, extent of age-related and menopause-associated changes in hormone levels on metabolism, bone loss, and impaired cardiovascular and cognitive function. Many aspects of the female reproductive aging process appear to be concordant between humans and these monkey species, but several important features may be species-specific. Those features that appear to parallel human menopause and aging include general similarity of hormone profiles across the menopausal transition, progression to cycle termination through irregular cycles, declining fertility with age, age-related gains in weight and percentage body fat content (with tendencies toward insulin resistance and glucose intolerance), increased low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol, declines in serum dehydroepiandrosterone, similarities in temperature-regulation systems, protective responses to estrogen replacement following ovariectomy in terms of bone metabolism, lipid profiles, and cognitive changes. Important differences include relatively short postmenopausal life span, timing in menopause-related changes in hormone secretion, and seasonal menstrual cycles. In addition, the question of whether ovariectomy in young adults is an appropriate model for the consequences of natural or surgical menopause in middle-aged and older adults is unresolved, and the numbers of older female animals available for research on menopause are very limited. The use of animal models is seen by workshop participants to be crucial for a mechanistic understanding of the human menopausal process and its connections to postmenopausal health problems; however, extensive in-depth and broad-based research is required to determine if nonhuman primates are appropriate models of human menopause.