Estrogen & Hormone therapy

Estrogen's effect on the brain is a complex story, one which we are only beginning to understand. We know it's important for women, but we're not sure about the details. One of the problems is that it appears to interact with stress. There are two aspects to estrogen's effects on women: normal monthly fluctuations in estrogen levels, and menopause.

It's also important to distinguish post-menopause (once you have completely stopped menstruating) from perimenopause (the years of menstrual irregularity leading up to this).

In general, the last few years of research seem to be coming to the conclusion that any cognitive problems women experience as they approach menopause is limited, both in time and in task, and depends in part on other factors. For example, those who experience many hot flashes may have poorer verbal memory, but the main cause for this may be the poorer sleep quality; those who are distressed or experience mood changes may find their memory and concentration affected for that reason.  These findings suggest the best approach to dealing with cognitive problems in perimenopause is to tackle the physical and/or emotional causes.

Post-menopause is different. Post-menopause is all about low estrogen levels, and the importance of estrogen for brain function. Nevertheless, estrogen therapy for postmenopausal women has had inconsistent results; there has even been some research suggesting it may increase the risk of later dementia. There is also some suggestion that it may not help those women who have cognitively stimulating environments, or are highly educated. And other indications that timing might be critical -- the age at which you begin hormone therapy. At the moment, we simply have too little clear evidence to warrant recommending hormone therapy for cognitive reasons (particularly in light of the possible cancer risk), or to know when it might be effective.

Excitingly, however (because there is no downside!), there is some evidence that physical exercise can counter the cognitive decline postmenopausal women may experience. There's also a study suggesting that the effect of low estrogen after menopause is not to impair cognition but simply to change it -- however, because women aren't prepared for, or understand, these changes, they perceive it as impairment. That would suggest that what is needed is an education program in how the brain changes (but first we have to understand exactly how it does change!).

The issue of the effect of menopause on women’s cognition, and whether hormone therapy helps older women fight cognitive decline and dementia, has been a murky one. Increasing evidence suggests that the timing and type of therapy is critical. A new study makes clear that we also need to distinguish between women who experience early surgical menopause and those who experience natural menopause.

The study involved 1,837 women (aged 53-100), of whom 33% had undergone surgical menopause (removal of both ovaries before natural menopause). For these women, earlier age of the procedure was associated with a faster decline in semantic and episodic memory, as well as overall cognition. The results stayed the same after factors such as age, education and smoking were taken into consideration.

There was also a significant association between age at surgical menopause and the plaques characteristic of Alzheimer's disease. However, there was no significant association with Alzheimer’s itself.

On the positive side, hormone replacement therapy was found to help protect those who had surgical menopause, with duration of therapy linked to a significantly slower decline in overall cognition.

Also positively, age at natural menopause was not found to be associated with rate of cognitive decline.

Bove, R. et al. 2013. Early Surgical Menopause Is Associated with a Spectrum of Cognitive Decline. To be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego, March 21, 2013.

Being a woman of a certain age, I generally take notice of research into the effects of menopause on cognition. A new study adds weight, perhaps, to the idea that cognitive complaints in perimenopause and menopause are not directly a consequence of hormonal changes, but more particularly, shows that early post menopause may be the most problematic time.

The study followed 117 women from four stages of life: late reproductive, early and late menopausal transition, and early postmenopause. The late reproductive period is defined as when women first begin to notice subtle changes in their menstrual periods, but still have regular menstrual cycles. Women in the transitional stage (which can last for several years) experience fluctuation in menstrual cycles, and hormone levels begin to fluctuate significantly.

Women in the early stage of post menopause (first year after menopause), as a group, were found to perform more poorly on measures of verbal learning, verbal memory, and fine motor skill than women in the late reproductive and late transition stages. They also performed significantly worse than women in the late menopausal transition stage on attention/working memory tasks.

Surprisingly, self-reported symptoms such as sleep difficulties, depression, and anxiety did not predict memory problems. Neither were the problems correlated with hormone levels (although fluctuations could be a factor).

This seemingly contradicts earlier findings from the same researchers, who in a slightly smaller study found that those experiencing poorer working memory and attention were more likely to have poorer sleep, depression, and anxiety. That study, however, only involved women approaching and in menopause. Moreover, these aspects were not included in the abstract of the paper but only in the press release, and because I don’t have access to this particular journal, I cannot say whether there is something in the data that explains this. Because of this, I am not inclined to put too much weight on this point.

But we may perhaps take the findings as support for the view that cognitive problems experienced earlier in the menopause cycle are, when they occur, not a direct result of hormonal changes.

The important result of this study is the finding that the cognitive problems often experienced by women in their 40s and 50s are most acute during the early period of post menopause, and the indication that the causes and manifestations are different at different stages of menopause.

It should be noted, however, that there were only 14 women in the early postmenopause stage. So, we shouldn’t put too much weight on any of this. Nevertheless, it does add to the picture research is building up about the effects of menopause on women’s cognition.

While the researchers said that this effect is probably temporary — which was picked up as the headline in most media — this was not in fact investigated in this study. It would be nice to have some comparison with those, say, two or three and five years post menopause (but quite possibly this will be reported in a later paper).

[3237] Weber, M. T., Rubin L. H., & Maki P. M.
(2013).  Cognition in perimenopause.
Menopause: The Journal of The North American Menopause Society.

It’s been unclear whether hormone therapy helps older women reduce their risk of Alzheimer’s or in fact increases the risk. To date, the research has been inconsistent, with observational studies showing a reduced risk, and a large randomized controlled trial showed an increased risk. As mentioned before, the answer to the inconsistency may lie in the timing of the therapy. A new study supports this view.

The 11-year study (part of the Cache County Study) involved 1,768 older women (65+), of whom 1,105 women had used hormone therapy (either estrogen alone or in combination with a progestin). During the study, 176 women developed Alzheimer's disease. This included 87 (7.9%) of the 1,105 women who had taken hormone therapy, and 89 (13.4%) of the 663 others.

Women who began hormone therapy, of any kind, within five years of menopause had a 30% lower risk of developing Alzheimer's within the study period (especially if they continued the therapy for 10 or more years). Those who began treatment more than five years after menopause, had a ‘normal’ risk (i.e., not reduced or increased). However, those who had started a combined therapy of estrogen and progestin when they were at least 65 years old had a significantly higher risk of developing Alzheimer’s.

The findings support the idea that the timing of hormone therapy, and the type, are critical factors, although the researchers cautiously note that more research is needed before they can make new clinical recommendations.

A study involving 75 perimenopausal women aged 40 to 60 has found that those with memory complaints tended to show impairments in working memory and attention. Complaints were not, however, associated with verbal learning or memory.

Complaints were also associated with depression, anxiety, somatic complaints, and sleep disturbance. But they weren’t linked to hormone levels (although estrogen is an important hormone for learning and memory).

What this suggests to me is that a primary cause of these cognitive impairments may be poor sleep, and anxiety/depression. A few years ago, I reported on a study that found that, although women’s reports of how many hot flashes they had didn’t correlate with memory impairment, an objective measure of the number of flashes they experienced during sleep did. Sleep, as I know from personal experience, is of sufficient importance that my rule-of-thumb is: don’t bother looking for any other causes of attention and memory deficits until you have sorted out your sleep!

Having said that, depressive symptoms showed greater relationship to memory complaints than sleep disturbance.

It’s no big surprise to hear that it is working memory in particular that is affected, because what many women at this time of life complain of is ‘brain fog’ — the feeling that your brain is full of cotton-wool. This doesn’t mean that you can’t learn new information, or remember old information. But it does mean that these tasks will be impeded to the extent that you need to hold on to too many bits of information. So mental arithmetic might be more difficult, or understanding complex sentences, or coping with unexpected disruptions to your routine, or concentrating on a task for a long time.

These sorts of problems are typical of those produced by on-going sleep deprivation, stress, and depression.

One caveat to the findings is that the study participants tended to be of above-average intelligence and education. This would protect them to a certain extent from cognitive decline — those with less cognitive reserve might display wider impairment. Other studies have found verbal memory, and processing speed, impaired during menopause.

Note, too, that a long-running, large population study has found no evidence for a decline in working memory, or processing speed, in women as they pass through perimenopause and menopause.

Obesity has been linked to cognitive decline, but a new study involving 300 post-menopausal women has found that higher BMI was associated with higher cognitive scores.

Of the 300 women (average age 60), 158 were classified as obese (waist circumference of at least 88cm, or BMI of over 30). Cognitive performance was assessed in three tests: The Mini-Mental Statement Examination (MMSE), a clock-drawing test, and the Boston Abbreviated Test.

Both BMI and waist circumference were positively correlated with higher scores on both the MMSE and a composite cognitive score from all three tests. It’s suggested that the estrogen produced in a woman’s fat cells help protect cognitive function.

Interestingly, a previous report from the same researchers challenged the link found between metabolic syndrome and poorer cognitive function. This study, using data from a large Argentinean Cardiovascular Prevention Program, found no association between metabolic syndrome and cognitive decline — but the prevalence of metabolic syndrome and cognitive decline was higher in males than females. However, high inflammatory levels were associated with impairment of executive functions, and higher systolic blood pressure was associated with cognitive decline.

It seems clear that any connection between BMI and cognitive decline is a complex one. For example, two years ago I reported that, among older adults, higher BMI was associated with more brain atrophy (replicated below; for more recent articles relating obesity to cognitive impairment, click on the obesity link at the end of this report). Hypertension, inflammation, and diabetes have all been associated with greater risk of impairment and dementia. It seems likely that the connection between BMI and impairment is mediated through these and other factors. If your fat stores are not associated with such health risk factors, then the fat in itself is not likely to be harmful to your brain function — and may (if you’re a women) even help.


Overweight and obese elderly have smaller brains

Analysis of brain scans from 94 people in their 70s who were still "cognitively normal" five years after the scan has revealed that people with higher body mass indexes had smaller brains on average, with the frontal and temporal lobes particularly affected (specifically, in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus, in obese people, and in the basal ganglia and corona radiate of the overweight). The brains of the 51 overweight people were, on average, 6% smaller than those of the normal-weight participants, and those of the 14 obese people were 8% smaller. To put it in more comprehensible, and dramatic terms: "The brains of overweight people looked eight years older than the brains of those who were lean, and 16 years older in obese people." However, overall brain volume did not differ between overweight and obese persons. As yet unpublished research by the same researchers indicates that exercise protects these same brain regions: "The most strenuous kind of exercise can save about the same amount of brain tissue that is lost in the obese."

Zilberman, J.M., Del Sueldo, M., Cerezo, G., Castellino, S., Theiler, E. & Vicario, A. 2011. Association Between Menopause, Obesity, and Cognitive Impairment. Presented at the Physiology of Cardiovascular Disease: Gender Disparities conference, October 12, at the University of Mississippi in Jackson.

Vicario, A., Del Sueldo, M., Zilberman, J. & Cerezo, G.H. 2011. The association between metabolic syndrome, inflammation and cognitive decline. Presented at the European Society of Hypertension (ESH) 2011: 21st European Meeting on Hypertension, June 17 - 20, Milan, Italy.

[733] Thompson, P. M., Raji C. A., Ho A. J., Parikshak N. N., Becker J. T., Lopez O. L., et al.
(2010).  Brain structure and obesity.
Human Brain Mapping. 31(3), 353 - 364.

The very large and long-running Women's Health Initiative study surprised everyone when it produced its finding that hormone therapy generally increased rather than decreased stroke risk as well as other health problems. But one explanation for that finding might be that many of the women only received hormone replacement therapy years after menopause. There are indications that timing is crucial.

This new rat study involved female rats equivalent to human 60-65 year olds, about a decade past menopause.  An enzyme called CHIP (carboxyl terminus of Hsc70 interacting protein) was found to increase binding with estrogen receptors, resulting in about half the receptors getting hauled to the cell's proteosome to be chopped up and degraded. When some of the aged rats were later treated with estrogen, mortality increased. When middle-aged rats were treated with estrogen, on the other hand, results were positive.

In other words, putting in extra estrogen after the number of estrogen receptors in the brain has been dramatically decreased is a bad idea.

While this study focused on mortality, other research has produced similar conflicting results as to whether estrogen therapy helps fight age-related cognitive impairment in women (see my report). It’s interesting to note that this effect only occurred in the hippocampus — estrogen receptors in the uterus were unaffected.

Recent rodent studies add to our understanding of how estrogen affects learning and memory. A study found that adult female rats took significantly longer to learn a new association when they were in periods of their estrus cycle with high levels of estrogen, compared to their ability to learn when their estrogen level was low. The effect was not found among pre-pubertal rats. The study follows on from an earlier study using rats with their ovaries removed, whose learning was similarly affected when given high levels of estradiol.

Human females have high estrogen levels while they are ovulating. These high levels have also been shown to interfere with women's ability to pay attention.

On the other hand, it needs to be remembered that estrogen therapy has been found to help menopausal and post-menopausal women. It has also been found to be detrimental. Recent research has suggested that timing is important, and it’s been proposed that a critical period exists during which hormone therapy must be administered if it is to improve cognitive function.

This finds some support in another recent rodent study, which found that estrogen replacement increased long-term potentiation (a neural event that underlies memory formation) in young adult rats with their ovaries removed, through its effects on NMDA receptors and dendritic spine density — but only if given within 15 months of the ovariectomy. By 19 months, the same therapy couldn’t induce the changes.

Last month I reported on a finding that estrogen acts through calpain, a protein crucial to learning and memory, that acts as a neurotransmitter in the brain. Now a new study has found that BDNF activates calpain, and when it does, the spine structure changes in ways similar to those that occur during learning. When activation was blocked with calpain inhibitors, the addition of BDNF had no effect. All this implies that all the great benefits of BDNF for learning and memory are in fact due to calpain.

Older news items (pre-2010) brought over from the old website

How does estrogen affect cognition?

Estrogen levels affect hippocampal wiring

Many studies have established the role of estrogen in female cognition. A rat study has now revealed the reason. It appears that the "wiring" in the hippocampus expands and retracts in relation to the amount of estrogen present during the estrous/menstrual cycle. The findings also suggest that “the brain's capacity for growth is well beyond anything we considered in the past”.
Routtenberg, A. 2005. Presented at the Society for Neuroscience's 35th Annual Meeting in Washington, D.C.

How estrogen affects the brain

A new study involved cultured rat neurons has revealed how estrogen affects learning and memory. It appears that, in females, estrogen can activate particular glutamate receptors within the hippocampus. Glutamate is the primary excitatory neurotransmitter in the brain, allowing for fast communication between neurons.
[271] Boulware, M. I., Weick J. P., Becklund B. R., Kuo S. P., Groth R. D., & Mermelstein P. G.
(2005).  Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein.
J. Neurosci.. 25(20), 5066 - 5078.

Estrogen effect on memory influenced by stress

The question of whether estrogen helps memory and cognition in women has proven surprisingly difficult to answer, with studies giving conflicting results. Now it seems the answer to that confusion is: it depends. And one of the things it depends on may be the level of stress the woman is experiencing. A rat study has found that the performance of female rats in a water maze was affected by the interaction of hormone level (whether the rat was estrous or proestrous) with water temperature (a source of physical stress). Those rats with high hormone levels did better when the water was warm, while those with low hormone levels did better when the water was cold. The researchers suggest both timing and duration of stress might be factors in determining the effect of hormones on cognition.
[384] Rubinow, M. J., Arseneau L. M., Beverly L. J., & Juraska J. M.
(2004).  Effect of the Estrous Cycle on Water Maze Acquisition Depends on the Temperature of the Water..
Behavioral Neuroscience. 118(4), 863 - 868.

Estrogen combines with stress to impair memory

A rat study has found that male and female rats performed equally well on a task involving the prefrontal cortex when under no stress, and when highly stressed, both made significant memory errors. But importantly, after exposure to a moderate level of stress, females were impaired, but males were not. When investigated further, it was found that female rats only showed this sensitivity when they were in a high-estrogen phase of their estrus cycle. The estrogen effect was confirmed in a further study using female rats who had had their ovaries removed, thus enabling the researchers to compare the effects of estrogen versus a placebo. These results suggest that high levels of estrogen can act to enhance the stress response, causing greater stress-related cognitive impairments, while providing reassurance that estrogen appears to have no effect on cognitive performance under non-stressful conditions.
[746] Shansky, R. M., Glavis-Bloom C., Lerman D., McRae P., Benson C., Miller K., et al.
(2003).  Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction.
Mol Psychiatry. 9(5), 531 - 538.

Why estrogen helps memory

Estrogen has been implicated as having a role in memory in a number of studies, although findings have been mixed as to the value of HRT for improving memory in post-menopausal women. A new study helps us understand why estrogen might be helpful. The study details how nerve cells in the hippocampus "grow in complexity" when exposed to estrogen, increasing connections among the nerve cells. It may be that, without estrogen, the connections that are there might not work as efficiently in storing and recalling certain types of memories. Previous studies have shown that the ability of women to remember word lists varies during their normal monthly cycle.
[1005] Akama, K. T., & McEwen B. S.
(2003).  Estrogen Stimulates Postsynaptic Density-95 Rapid Protein Synthesis via the Akt/Protein Kinase B Pathway.
J. Neurosci.. 23(6), 2333 - 2339.
[880] Znamensky, V., Akama K. T., McEwen B. S., & Milner T. A.
(2003).  Estrogen Levels Regulate the Subcellular Distribution of Phosphorylated Akt in Hippocampal CA1 Dendrites.
J. Neurosci.. 23(6), 2340 - 2347.

Estrogen may dictate the problem-solving strategy chosen

Several studies have suggested estrogen may be beneficial for cognitive functioning in women. New research using rats suggests estrogen may be very specific in what types of learning it helps - and what types it may impair. In rats, it appeared to enhance place-learning, at the expense of response learning. It is suggested that postmenopausal women may experience a shift into a problem-solving mode more common to men. "Women may actually get better at performing a task from a different approach, but they are not used to doing it that way, so they view the change as an impairment."
[831] Korol, D. L., & Kolo L. L.
(2002).  Estrogen-induced changes in place and response learning in young adult female rats..
Behavioral Neuroscience. 116(3), 411 - 420.

Are you likely to develop cognitive problems in menopause?

Menopause transition may cause trouble learning

A four-year study of over 2,300 women, aged 42 to 52, has found evidence suggesting that during the early and late perimenopause women do not learn as well as they do during other menopause transition stages. Processing speed improved with repeated testing during premenopause, early perimenopause (menstrual irregularity but no "gaps" of 3 months), and postmenopause (no period for 12 months), but scores during late perimenopause (no period for three to 11 months) did not show the same degree of improvement. Improvements in processing speed were considerably reduced in late perimenopause, and improvement in verbal memory performance was reduced during both early and late perimenopause (and indeed almost non-existent during late perimenopause). These findings are consistent with self-reported memory difficulties — 60% of women state that they have memory problems during the menopause transition. The good news is that the effect seems to be temporary. Interestingly, although taking estrogen or progesterone hormones before menopause helped verbal memory and processing speed, taking them after the final period had a negative effect. This is consistent with other research indicating that the timing of hormone therapy is crucial to its effects.
[554] Greendale, G. A., Huang M. - H., Wight R. G., Seeman T., Luetters C., Avis N. E., et al.
(2009).  Effects of the menopause transition and hormone use on cognitive performance in midlife women.
Neurology. 72(21), 1850 - 1857.

Hot flashes underreported and linked to forgetfulness

In the first study to explore the relationship between objectively measured hot flashes in menopausal women and memory performance, it’s been found that women dramatically underreport the number of hot flashes they experience (by about 43%), and that, with a clear measure of hot flashes, an association between number of hot flashes and poor verbal memory is evident. There was no relationship between the number of hot flashes women thought they had and memory performance. The average number of objective hot flashes was 19.5 per day. Unsurprisingly, poor sleep also predicted poorer memory, but it was also affected by the number of hot flashes during the night when a woman was sleeping. The researchers recommend treating women for their vasomotor symptoms.
An extended interview as MP3 audio file is at
[1128] Maki, P. M., Drogos L. L., Rubin L. H., Banuvar S., Shulman L. P., & Geller S. E.
(2008).  Objective hot flashes are negatively related to verbal memory performance in midlife women.
Menopause (New York, N.Y.). 15(5), 848 - 856.

Memory problems at menopause

Findings from a study of 24 women approaching menopause have confirmed an earlier study involving over 800 women that found such women are no more likely than anyone else to suffer from memory retrieval problems. However, they did find that the women who complained more about problems with forgetfulness had a harder time learning or "encoding" new information, although they didn’t have actually have an impaired ability to learn new information. Although a larger study is needed to explore this link in more detail, the researchers suggest that stress and emotional upheaval may be responsible for attention failures that mean information isn’t encoded. The researchers did find that most of the women in their study had some sort of mood distress, including symptoms of depression or anxiety (note that this was not a random group, but women who were worried about their memory).
The study was reported at the annual meeting of the International Neuropsychological Society in Boston.

Since 1996, 803 African American and white women aged 40 to 55 have been tested annually for loss of brain function. Performance was compared annually for women in premenopausal, during menopause, and postmenopausal groups. Small but significant increases in performance were found over time during the premenopausal and perimenopausal phases, leading the authors to conclude that transition through menopause is not accompanied by a decline in working memory and perceptual speed.
[1201] Meyer, P. M., Powell L. H., Wilson R. S., Everson-Rose S. A., Kravitz H. M., Luborsky J. L., et al.
(2003).  A population-based longitudinal study of cognitive functioning in the menopausal transition.
Neurology. 61(6), 801 - 806.

Does estrogen help cognition?


Hormone replacement therapy may improve visual memory of postmenopausal women
A study of 10 postmenopausal women (aged 50-60) found that those taking combined estrogen-progestin hormone therapy for four weeks showed significantly increased activity in the prefrontal cortex when engaged in a visual matching task, compared with those on placebo.
[1409] Smith, Y. R., Love T., Persad C. C., Tkaczyk A., Nichols T. E., & Zubieta J-K.
(2006).  Impact of combined estradiol and norethindrone therapy on visuospatial working memory assessed by functional magnetic resonance imaging.
The Journal of Clinical Endocrinology and Metabolism. 91(11), 4476 - 4481.

Estrogen improves verbal memory in postmenopausal women

A study involving 60 postmenopausal women aged 32.8 to 64.9, found those receiving daily estrogen treatment (conjugated equine estrogens — Premarin) showed improved oral reading and verbal memory performance, compared to those receiving a placebo. This is consistent with brain imaging date indicating estrogen produces brain activations in the inferior parietal lobule, a region sensitive to phonological demands and implicated in reading.
[374] Shaywitz, S. E., Naftolin F., Zelterman D., Marchione K. E., Holahan J. M., Palter S. F., et al.
(2003).  Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen.
Menopause (New York, N.Y.). 10(5), 420 - 426.

Hormone replacement therapy may have cognitive benefits for older women

A study of more than 2,000 women 65 or older, found that those who underwent hormone replacement therapy after menopause appeared to enjoy better mental functioning. Women 85 and older did especially well. The improvements were seen only in women free from dementia. However, the sample does not reflect the general population - most of the participants were Mormon, and the prohibition of alcohol and tobacco might be a significant factor.
[213] Carlson, M. C., Zandi P. P., Plassman B. L., Tschanz JA. T., Welsh-Bohmer K. A., Steffens D. C., et al.
(2001).  Hormone replacement therapy and reduced cognitive decline in older women: The Cache County Study.
Neurology. 57(12), 2210 - 2216.

The positive effects of estrogen on memory

Postmenopausal women who take estrogen and young college-aged women performed more consistently on memory tests compared with postmenopausal women not taking the hormone. Consistency differs from overall memory ability and is a relatively new area in research about the neuropsychology of aging. Consistency measures memory capability on multiple administrations of the same test or on several related tests in a short period of time.
The study involved 48 postmenopausal women (aged 60 - 80), and 16 younger women (18 - 30). The older women were divided into three groups: 16 non-hormone users, 16 estrogen-users and 16 estrogen and progesterone-users. Younger women and older women taking estrogen performed more consistently than the older women not taking the hormone, as well as having higher overall memory scores. Women taking a combination of estrogen and progesterone did not perform as consistently as the estrogen-only users. This finding suggests progesterone may block some of the beneficial effects of taking estrogen alone.
Wegesin, D.J., Friedman, D., Varughese, N. & Stern, Y. 2001. Effects of estrogen-use and aging on intraindividual variability in recognition memory. Paper presented to the annual Society for Neuroscience meeting in San Diego, US.


Combined hormone therapy doesn't boost memory

A study of 180 recently menopausal women found no effect of hormone therapy (a combination of estrogen and progesterone) on cognitive function. Previous research has indicated a positive benefit of estrogen on cognition, so it is speculated that progestin may counteract these positive effects.

[917] Maki, P. M., Gast M. J., Vieweg A. J., Burriss S. W., & Yaffe K.
(2007).  Hormone therapy in menopausal women with cognitive complaints: A randomized, double-blind trial.
Neurology. 69(13), 1322 - 1330.

Removing ovaries before menopause increases risk of cognitive impairment

A very long-running study of some 1,500 women who underwent the removal of one or both ovaries for non-cancer-related reasons, has found that women who had one or both ovaries removed before menopause were nearly two times more likely to develop cognitive problems or dementia compared to women who did not have the surgery. In addition, those women who were younger when their ovaries were removed were more likely to develop dementia than women who were older when their ovaries were removed. This finding adds to other research suggesting that there may be a critical age window for the protective effect of estrogen on the brain in women.

[1291] Rocca, W. A., Bower J. H., Maraganore D. M., Ahlskog J. E., Grossardt B. R., de Andrade M., et al.
(2007).  Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.
Neurology. 69(11), 1074 - 1083.

Estrogen-alone hormone therapy could increase risk of dementia in older women

A new report from the Women's Health Initiative Memory Study suggests that older women using estrogen-alone hormone therapy could be at a slightly greater risk of developing dementia, including Alzheimer's disease (AD), than women who do not use any menopausal hormone therapy. Among 10,000 women using conjugated equine estrogens, 37 could be expected to develop dementia, compared to 25 in 10,000 women using the placebo. Previous reports from the Study found a greater risk with hormone therapy involving both estrogen plus progestin: among 10,000 women over age 65 using estrogen plus progestin there might be 45 cases of dementia compared to 22 cases in 10,000 older women on placebo.
It was also reported that beginning estrogen-alone hormone therapy after age 65 can have a small negative effect on overall cognitive abilities and that this negative effect may be greater in women with existing cognitive problems.
[871] Lewis, C. E., Masaki K., Coker L. H., for the Women's Health Initiative Memory Study, Shumaker S. A., Legault C., et al.
(2004).  Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women: Women's Health Initiative Memory Study.
JAMA. 291(24), 2947 - 2958.
[1309] Hays, J., Johnson K. C., Coker L. H., Dailey M., Bowen D., Rapp S. R., et al.
(2003).  Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial.
JAMA. 289(20), 2663 - 2672.

For women over 65, Combined Hormone Therapy increases risk of dementia

Much to the researchers’ surprise and disappointment, a four-year experiment involving 4,532 women at 39 medical centers, has found that combined hormone therapy (involving both estrogen and progestin) doubles the risk of Alzheimer's disease and other types of dementia in women who began the treatment at age 65 or older, although the risk is still small : for every 10,000 women 65 and older who take hormones, 23 of the predicted 45 cases of dementia a year, will be attributable to the hormones. The study also found that the combined hormone therapy produced no improvement in general cognitive function, and in fact had adverse effects on cognition among some women. This supports an earlier study suggesting that, while estrogen is helpful to cognitive function in postmenopausal women, the benefits can be cancelled out by progestin / progesterone. The study also confirmed previous research showing that the combination therapy increased the risk of stroke - previous research has indicated that risk factors for stroke are also risk factors for cognitive decline.
[918] Jackson, R. D., Morley Kotchen J., Wassertheil-Smoller S., Wactawski-Wende J., Shumaker S. A., Legault C., et al.
(2003).  Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial.
JAMA. 289(20), 2651 - 2662.
[1309] Hays, J., Johnson K. C., Coker L. H., Dailey M., Bowen D., Rapp S. R., et al.
(2003).  Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial.
JAMA. 289(20), 2663 - 2672.
[1194] Rossouw, J. E., Aragaki A., Safford M., Stein E., Laowattana S., Mysiw J. W., et al.
(2003).  Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women: The Women's Health Initiative: A Randomized Trial.
JAMA. 289(20), 2673 - 2684.

When is estrogen therapy helpful?

Cognitive benefit of estrogen minimal for the highly educated?
A mouse study sheds light on the mixed results coming from investigations into the cognitive effects of hormone replacement therapy. The study found no beneficial effect of estrogen in female mice who were raised in a stimulating environment. On the other hand, mice raised in standard conditions showed significant spatial and object memory improvement when treated with a high dose of estrogen (following removal of their ovaries). Among mice not treated with estrogen, an enriched environment alone significantly improved spatial memory. These results might help to explain why studies of hormone replacement therapy do not show beneficial effects for all women. Most studies of HRT use very well-educated women.
[1229] GRESACK, J. E., & Frick K. M.
Neuroscience. 128(3), 459 - 471.

New insights into hormone therapy highlight when estrogen best aids brain

Several studies have been exploring some of the many variables that may be important in determining the effect of hormone replacement therapy.
A mouse study compared the effects of receiving daily estrogen injections (“continuous treatment”) with the effects of receiving it every four days (“cyclical treatment”). The treatment lasted three months. Ovariectomized mice receiving the continuous treatment performed better on memory tasks than those receiving cyclical treatment.
Another mouse study compared the brains of ovariectomized mice treated with continuous estrogen for 47 days with those not so treated, and found that, after five days on estrogen, estrogen-treated mice produced more of the proteins important for neuron repair and neuronal function. However, with prolonged, continuous estrogen treatment, this effect diminished, and by day 47 the estrogen-treated mice were similar to the non-estrogen-treated mice in levels of the repair proteins. Mice that did not receive estrogen showed an elevation of a brain protein associated with the negative aspects of brain aging, while estrogen-treated mice did not.
A rat study examined the effects of progesterone (a component of many hormone therapies), and found that ovariectomized rats receiving progesterone exhibited deficiencies in learning and memory, supporting the hypothesis that progesterone negatively affects memory during aging. It’s suggested that the negative outcome of several studies evaluating combined estrogen/progesterone HT may be due, in part, to unfavorable effects of progesterone.
Other rat studies have found that two established protective actions of estrogen with relevance to Alzheimer's are negatively affected by the presence of progesterone.
Another study using neurons in culture demonstrated the importance of timing. Neurons exposed to estrogen prior to exposure to beta-amyloid (the protein implicated in Alzheimers) had a significantly greater rate of survival than those exposed to estrogen after being exposed to beta-amyloid. The results are consistent with clinical studies in which women who received estrogen hormone therapy at the time of menopause, before cognitive degeneration becomes apparent, have a lower risk of developing Alzheimer's disease than women who never receive any sort of HT, while for women in their 60s and 70s, hormone therapy may make things worse.
Papers presented at the 34th Society for Neuroscience annual meeting in San Diego in late October 2004.

Dangers of hormone therapy

Getting the benefits of estrogen without the downside

We know estrogen helps learning and memory, but estrogen therapy also increases cancer risk. That’s why the results of a mouse study are exciting. The study found that estrogen acts through calpain, a protein crucial to learning and memory, and like adrenalin (which acts like a hormone in most of the body but as a neurotransmitter in the brain), it does so as a neurotransmitter, modulating synaptic transmission. The findings suggest drugs that target calpain directly may provide the same cognitive benefits of estrogen therapy, without the medical risks.
[299] Zadran, S., Qin Q., Bi X., Zadran H., Kim Y., Foy M. R., et al.
(2009).  17-β-Estradiol increases neuronal excitability through MAP kinase-induced calpain activation.
Proceedings of the National Academy of Sciences. 106(51), 21936 - 21941.

Other aids to help memory in menopausal women

Less cognitive impairment seen in women taking raloxifene

Raloxifene modulates the activity of the hormone estrogen and is one of the most widely prescribed drugs for the treatment of osteoporosis. A 3-year worldwide clinical trial involving 7705 postmenopausal women with osteoporosis found that those taking 120mg of raloxifene had a 33% less chance of developing mild cognitive impairment. There was no cognitive benefit from a 60mg dose. Note that, of the 5386 women participating in the cognitive part of this trial, only 3.4% had mild cognitive impairment, and 1% had dementia.
[757] Yaffe, K., Krueger K., Cummings S. R., Blackwell T., Henderson V. W., Sarkar S., et al.
(2005).  Effect of Raloxifene on Prevention of Dementia and Cognitive Impairment in Older Women: The Multiple Outcomes of Raloxifene Evaluation (MORE) Randomized Trial.
Am J Psychiatry. 162(4), 683 - 690.

The estrogen drug raloxifene may help prevent cognitive decline in women over 70

The designer estrogen drug raloxifene has been prescribed to millions of postmenopausal women for osteoporosis, but its effects on the aging brain are unclear. A new study shows that although raloxifene does not affect the cognitive performance of most women, it may help prevent decline among women older than 70 and women whose cognitive performance is declining regardless of age.
Yaffe, K. et al. 2001. Cognitive Function in Postmenopausal Women Treated with Raloxifene. New England Journal of Medicine, 344, 1207-1213.Yaffe, K. et al. 2001. Cognitive Function in Postmenopausal Women Treated with Raloxifene. New England Journal of Medicine, 344, 1207-1213.

Fitness counteracts cognitive decline from hormone-replacement therapy

A study of 54 postmenopausal women (aged 58 to 80) suggests that being physically fit offsets cognitive declines attributed to long-term hormone-replacement therapy. It was found that gray matter in four regions (left and right prefrontal cortex, left parahippocampal gyrus and left subgenual cortex) was progressively reduced with longer hormone treatment, with the decline beginning after more than 10 years of treatment. Therapy shorter than 10 years was associated with increased tissue volume. Higher fitness scores were also associated with greater tissue volume. Those undergoing long-term hormone therapy had more modest declines in tissue loss if their fitness level was high. Higher fitness levels were also associated with greater prefrontal white matter regions and in the genu of the corpus callosum. The findings need to be replicated with a larger sample, but are in line with animal studies finding that estrogen and exercise have similar effects: both stimulate brain-derived neurotrophic factor.
[375] Erickson, K. I., Colcombe S. J., Elavsky S., McAuley E., Korol D. L., Scalf P. E., et al.
(2007).  Interactive effects of fitness and hormone treatment on brain health in postmenopausal women.
Neurobiology of Aging. 28(2), 179 - 185.