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 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.     

A dominant negative ERβ splice variant determines the effectiveness of early or late estrogen therapy after ovariectomy in rats

The molecular mechanisms for the discrepancy in outcome of initiating estrogen therapy (ET) around peri-menopause or several years after menopause in women are unknown. We hypothesize that the level of expression of a dominant negative estrogen receptor (ER) β variant, ERβ2, may be a key factor determining the effectiveness of ET in post-menopausal women. We tested this hypothesis in ovariectomized nine month-old (an age when irregular estrous cycles occur) female Sprague Dawley rats. Estradiol treatment was initiated either 6 days (Early ET, analogous to 4 months post-menopause in humans), or 180 days (Late ET, analogous to 11 years post-menopause in humans) after ovariectomy. Although ERβ2 expression increased in all OVX rats, neurogenic and neuroprotective responses to estradiol differed in Early and Late ET. Early ET reduced ERβ2 expression in both hippocampus and white blood cells, increased the hippocampal cell proliferation as assessed by Ki-67 expression, and improved mobility in the forced swim test. Late ET resulted in either no or modest effects on these parameters. There was a close correlation between the degree of ERβ2 expression and the preservation of neural effects by ET after OVX in rats, supporting the hypothesis that persistent elevated levels of ERβ2 are a molecular basis for the diminished effectiveness of ET in late post-menopausal women. The correlation between the expression of ERβ2 in circulating white blood cells and brain cells suggests that ERβ2 expression in peripheral blood cells may be an easily accessible marker to predict the effective window for ET in the brain.     

Bridging advanced glycation end product, receptor for advanced glycation end product and nitric oxide with hormonal replacement/estrogen therapy in healthy versus diabetic postmenopausal women: a perspective

Cardiovascular diseases (CVD) are the most significant cause of death in postmenopausal women. The loss of estrogen biosynthesis with advanced age is suggested as one of the major causes of higher CVD in postmenopausal women. While some studies show beneficial effects of estrogen therapy (ET)/hormonal replacement therapy (HRT) in the cardiovascular system of healthy postmenopausal women, similar studies in diabetic counterparts contradict these findings. In particular, ET/HRT in diabetic postmenopausal women results in a seemingly detrimental effect on the cardiovascular system. In this review, the comparative role of estrogens is discussed in the context of CVD in both healthy and diabetic postmenopausal women in regard to the synthesis or expression of proinflammatory molecules like advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGEs), inducible nitric oxide synthases (iNOS) and the anti-inflammatory endothelial nitric oxide synthases (eNOS). The interaction of AGE-RAGE signaling with molecular nitric oxide (NO) may determine the level of reactive oxygen species (ROS) and influence the overall redox status of the vascular microenvironment that may further determine the ultimate outcome of the effects of estrogens on the CVD in healthy versus diabetic women.     

Postmenopausal estrogen synthesis and metabolism: alterations caused by aromatase inhibitors used for the treatment of breast cancer

Inhibition of postmenopausal estrogen production by aromatase inhibitors is an established drug treatment modality for postmenopausal breast cancer. In this article postmenopausal estrogen disposition and the alterations caused by treatment with aromatase inhibitors are reviewed. Recent investigations have challenged the hypothesis that aromatization of androstenedione into estrone is the sole production pathway for estrogens in postmenopausal women. The finding that estrogens persist in the plasma of patients receiving aminoglutethimide treatment despite a near total inhibition of the aromatase enzyme suggests that alternative pathways for estrogen synthesis exist. While nonspecific actions of aromatase inhibitors may be disadvantageous, certain effects may also be beneficial. Recent findings that aminoglutethimide may induce estrone sulfate metabolism questions whether this "prototype" aromatase inhibitor might have a dual mechanism of action. The importance of investigating the possible influence of different aromatase inhibitors on all components of estrogen disposition is considered.     

Cellular and molecular basis of estrogen’s neuroprotection

Alzheimer’s disease (AD) is one of the most common types of dementia among the aged population, with a higher prevalence in women. The reason for this latter observation remained unsolved for years, but recent studies have provided evidence that a lack of circulating estrogen in postmenopausal women could be a relevant factor. Moreover, follow-up studies among postmenopausal women who had received estrogenreplacement therapy (ERT), suggested that they had a markedly reduced risk of developing AD. In addition, studies among older women who already had AD indeed confirmed that a decrease in estrogen levels was likely to be an important factor in triggering the pathogenesis of the disease. In this review article, we will discuss the evidence suggesting that estrogen may have a protective role against AD, mainly through its action as: a trophic factor for cholinergic neurons, a modulator for the expression of apolipoprotein E (ApoE) in the brain, an antioxidant compound decreasing the neuronal damage caused by oxidative stress, and a promoter of the physiological nonamyloidogenic processing of the amyloid precursor protein (APP), decreasing the production of the amyloid-Β-peptide (AΒ), a key factor in the pathogenesis of AD.     

Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD) = 59.13 (5.5)) were randomly assigned to three months of 1 mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.     

Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons

Effects of estrogen therapy on cognitive performance appear to diminish with age and time following the loss of ovarian function. We hypothesize that this is due to a reduction in basal forebrain cholinergic function and that treatment with a cholinergic enhancer can reverse the effect. This study tested whether combining the cholinesterase inhibitor donepezil with estradiol treatment can enhance/restore estradiol effects on cognitive performance in young ovariectomized rats with selective lesions of septal cholinergic neurons. 192IgG-saporin was injected directly into the medial septum to produce selective cholinergic lesions. Rats were then treated with donepezil (Don, daily injections of 3 mg/kg/day, i.p.) or vehicle, and then with 17β-estradiol (E2, administered by silastic capsule implanted s.c.) or an empty capsule. Rats were trained on a delayed matching-to-position (DMP) T-maze task which previous studies have shown is sensitive to ovariectomy and estrogen replacement. Results show that neither estradiol nor donepezil alone significantly enhanced acquisition of the DMP task in rats with cholinergic lesions. Combination therapy was effective, however, depending on the severity of the lesion. Don + E2 significantly enhanced acquisition of the task in rats with partial lesions (< 50% loss of cholinergic neurons), but not in rats with severe lesions. This effect was due largely to a reduction in perseverative behavior. Don + E2 also improved working memory in rats with partial lesions, as evidenced by significantly better performance than controls during increased intertrial delays. These findings suggest that even partial loss of septal cholinergic neurons can reduce effects of estrogen therapy on cognitive performance, and demonstrate that combining a cholinesterase inhibitor with estrogen therapy can help to restore beneficial effects on performance. We propose that combination therapy may have similar beneficial effects in women, particularly in older women who have not used estrogen therapy for many years and are beginning to show signs of cognitive impairment or early Alzheimer's disease.     

Cognition, mood disorders, and sex hormones

Macaques (Macaca spp.) are useful models to evaluate effects of ovarian sex steroids and selective estrogen receptor modulators (SERMs) on mood and cognitive function due to similarities to women in their reproductive and central nervous systems. The results of nonhuman primate studies support the hypothesis that estrogen mediates specific aspects of attention and memory, yet much work is needed to understand which cognitive processes are affected, whether natural versus surgical menopause effects are different, and the interaction of age and ovarian senescence on cognitive function. This knowledge is necessary to determine whether to support the cognitive function of women in the menopausal phase of life and, if so, to determine efficacious therapeutic interventions. Mood disorders are prevalent in women and are associated with reproductive function in women and macaques. Exogenous steroid therapies, including oral contraceptives and postmenopausal hormone replacement therapies, have behavioral effects in women and appear to affect the behavior and underlying neural substrates of monkeys. Additional research is necessary to confirm and extend these observations. Ovarian steroids have multiple effects on serotonin synthesis, reuptake, and degradation, on neural activity that drives serotonin release, and on receptor activation in primates. This system modulates cognitive function and mood and is the target of a broad class of antidepressant therapies. Understanding the effects of ovarian steroids on the neural serotonergic system is necessary to understand depression in women. These studies are best carried out in primate models, which are more similar to humans in neural serotonergic function than other animal models.     

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.     

Hormone therapy in postmenopausal women affects hemispheric asymmetries in fine motor coordination

Evidence exists that the functional differences between the left and right cerebral hemispheres are affected by age. One prominent hypothesis proposes that frontal activity during cognitive task performance tends to be less lateralized in older than in younger adults, a pattern that has also been reported for motor functioning. Moreover, functional cerebral asymmetries (FCAs) have been shown to be affected by sex hormonal manipulations via hormone therapy (HT) in older women. Here, we investigate whether FCAs in fine motor coordination, as reflected by manual asymmetries (MAs), are susceptible to HT in older women. Therefore, sixty-two postmenopausal women who received hormone therapy either with estrogen (E) alone (n = 15), an E-gestagen combination (n = 21) or without HT (control group, n = 26) were tested. Saliva levels of free estradiol and progesterone (P) were analyzed using chemiluminescence assays. MAs were measured with a finger tapping paradigm consisting of two different tapping conditions. As expected, postmenopausal controls without HT showed reduced MAs in simple (repetitive) finger tapping. In a more demanding sequential condition involving four fingers, however, they revealed enhanced MAs in favour of the dominant hand. This finding suggests an insufficient recruitment of critical motor brain areas (especially when the nondominant hand is used), probably as a result of age-related changes in corticocortical connectivity between motor areas. In contrast, both HT groups revealed reduced MAs in sequential finger tapping but an asymmetrical tapping performance related to estradiol levels in simple finger tapping. A similar pattern has previously been found in younger participants. The results suggest that, HT, and E exposure in particular, exerts positive effects on the motor system thereby counteracting an age-related reorganization.     

Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD) = 59.13 (5.5)) were randomly assigned to three months of 1 mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.     

Modeling the Impact of Lesions in the Human Brain

Lesions of anatomical brain networks result in functional disturbances of brain systems and behavior which depend sensitively, often unpredictably, on the lesion site. The availability of whole-brain maps of structural connections within the human cerebrum and our increased understanding of the physiology and large-scale dynamics of cortical networks allow us to investigate the functional consequences of focal brain lesions in a computational model. We simulate the dynamic effects of lesions placed in different regions of the cerebral cortex by recording changes in the pattern of endogenous (“resting-state”) neural activity. We find that lesions produce specific patterns of altered functional connectivity among distant regions of cortex, often affecting both cortical hemispheres. The magnitude of these dynamic effects depends on the lesion location and is partly predicted by structural network properties of the lesion site. In the model, lesions along the cortical midline and in the vicinity of the temporo-parietal junction result in large and widely distributed changes in functional connectivity, while lesions of primary sensory or motor regions remain more localized. The model suggests that dynamic lesion effects can be predicted on the basis of specific network measures of structural brain networks and that these effects may be related to known behavioral and cognitive consequences of brain lesions.     

Estradiol treatment and its interaction with the cholinergic system: effects on cognitive function in healthy young women

The steroid hormone estradiol has been shown to modulate cognitive function in both animals and humans, and although the exact mechanisms associated with these effects are unknown, interactions with the cholinergic system have been proposed. We examined the neurocognitive effects of short-term estradiol treatment and its interaction with the cholinergic system using the muscarinic receptor antagonist scopolamine in healthy young women. Thirty-four participants (Mean age ± SD = 22.4 ± 4.4) completed baseline cognitive assessment and then received either 100 μg/day transdermal estradiol or transdermal placebo for 31 days. On days 28 and 31 of treatment, further cognitive assessment was performed pre- and 90 min post-scopolamine (0.4 mg) or placebo (saline) injection, under a randomized double-blind placebo-controlled design. Short-term estradiol treatment significantly enhanced spatial working memory with a trend for improvement in long-term verbal learning and memory. Overall, estradiol treatment did not protect against or attenuate the scopolamine-induced impairments in the cognitive domains assessed. Findings suggest that estrogen has minimal effects on cholinergic-mediated cognitive processes following short-term treatment. Effects of estradiol treatment may be dependent on age, dose of estradiol, integrity of cholinergic innervation and baseline endogenous estrogen levels, which may in part explain the inconsistent findings in the literature.     

Cholinesterases: New Roles in Brain Function and in Alzheimer's Disease

The most important therapeutic effect of cholinesterase inhibitors (ChEI) on approximately 50% of Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission–experimental or pathological, such as in AD–leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on -amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to cholinesterase inhibition. A second important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain acetylcholine.     

Estrogen, alcohol and breast cancer risk

Estrogen replacement has been used for many years to reverse the hypoestrogenic symptoms of menopause and prevent osteoporosis. Studies have found that estrogen replacement also decreases cardiovascular risk. In addition, social use of alcohol has been found to decrease cardiovascular risk. Therefore, both estrogen replacement therapy and alcohol use have been proposed to have cardiovascular benefits, and are often used in combination. Epidemiologic evidence indicates that estrogen replacement therapy after menopause increases breast cancer risk. Regular alcohol consumption is also associated with increase in risk. However, interactions between the two are poorly understood. In addition, if alcohol alters circulating estrogen levels in estrogen users, this may have implications in terms of altering the risks:benefit ratio of estrogen replacement in an undesirable direction. For example, there are data suggesting that the use of both alcohol and estrogen may increase breast cancer risk more than the use of either one alone. Data support both acute and chronic effects of alcohol in raising circulating estrogen levels in premenopausal women on no hormonal medications. In postmenopausal women studies focusing on acute effects of alcohol on estrogen metabolism indicate that alcohol has a much more pronounced effect in women using estrogen replacement than in those who do not. Studies evaluating chronic effects of alcohol ingestion on circulating estrogens in postmenopausal women are needed.     

Neuroendocrine effect of sex hormones

The paper provides a generalization of data and the results of own experiments on influence ovarian steroids on the hypothalamus and other brain areas related to reproduction. Ovarian hormones have widespread effects throughout the brain: on catecholaminergic neurons and serotonergic pathways and the basal forebrain cholinergic system, as well as the hipocampus, spinal cord, nigrostriatal and mesolimbic system, in addition to glial cells and blood-brain barrier. The widespread influences of these various neuronal systems ovarian steroids have measurable effects on mood and affect as well as on cognition, with implications for dementia. There are developmentally programmed sex differenced in hippocampal structure that may help to explain differences in the strategies which male and female rats use to solve spatial navigation problems. The multiple sites and mechanisms of estrogen action in brain underlie a variety of importants effects on cognitive and other brain functions--coordination of movement, pain, affective state, as well as possible protection in Alzheimer's disease. Estrogen withdrawal after natural or surgical menopause can lead to a host of changes in brain function and behavior.     

Effects of estrogens on cholinergic neurons in the rat basal nucleus

Estrogen replacement in postmenopausal women may help prevent or delay development of Alzheimer's disease. Because loss of basal forebrain cholinergic neurons with reductions in choline acetyltransferase (ChAT) concentration are associated with Alzheimer's disease, we investigated the effect of estradiol (E(2)) and J 861, a non-feminizing estrogen, on cholinergic neurons in the basal forebrain. Ovariectomized rats received E(2), J 861 or vehicle, and basal forebrain sections through the substantia innominata, medial septum, and nucleus of the diagonal band were immunostained for ChAT. ChAT-immunoreactive cells in the basal forebrain were significantly reduced in the ovariectomized rats compared to intact rats, but those ovariectomized rats receiving estrogen replacement with E(2) and J 861 had near normal levels of ChAT-positive neurons. While retrograde tracing experiments with fluorogold injected into the prefrontal cortex showed no significant differences in the number of fluorogold-labeled cells among the groups, ChAT-immunoreactive cells and double-labeled cells were significantly lower in OVX rats than in intact and E(2) rats. Some substantia innominata cells in the J 861 rats were ChAT/estrogen receptor alpha-positive. These results suggest that E(2) and J 861 have positive effects on cholinergic neurons that project from the basal nucleus to the forebrain cortex.     

Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats

Memory impairment induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in rats is associated with impaired brain glucose and energy metabolism, oxidative stress and impaired cholinergic neurotransmission. Treatment with antioxidants and cholinergic agonists has been reported to produce beneficial effect in this model. However, no reports are available on drugs that improve glucose utilization and metabolism. In the present study, we evaluated the effects of pioglitazone on cognitive performance, oxidative stress and glucose utilization in ICV STZ injected rats (3 mg/kg, on day 1 and 3). Pioglitazone (10 and 30 mg/kg) was administered per oral (p.o.) for 14 days, starting 5 days prior to STZ injection. Cognitive performance was assessed using step-through passive avoidance and Morris water maze task. Malondialdehyde (MDA) and glutathione levels in brain were estimated as parameters of oxidative stress. Glucose utilization by brain was assessed as the amount of glucose consumed from the media by the brain. ICV STZ injected rats showed a severe deficit in learning and memory associated with increased MDA levels (+67.5%), decreased glutathione levels (-29.2%) and impaired cerebral glucose utilization (-44.4%). In contrast pioglitazone treatment improved cognitive performance, lowered oxidative stress and improved cerebral glucose utilization in ICV STZ rats. The present study demonstrates the beneficial effects of pioglitazone in the ICV STZ induced cognitive deficits, which can be exploited for the dementia associated with diabetes and age-related neurodegenerative disorder, where oxidative stress and impaired glucose and energy metabolism are involved.     

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.