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.
(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.
(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.
(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.
(2003). Estrogen Stimulates Postsynaptic Density-95 Rapid Protein Synthesis via the Akt/Protein Kinase B Pathway.
J. Neurosci.. 23(6), 2333 - 2339.
(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."
(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.
(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 https://blackboard.uic.edu/bbcswebdav/institution/web/news/podcasts/PdCs...
(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.
(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.
(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.
(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.
(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.
 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.
 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.
(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.
(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.
(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.
(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.
(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.
(2004). ENVIRONMENTAL ENRICHMENT REDUCES THE MNEMONIC AND NEURAL BENEFITS OF ESTROGEN.
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.
(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.
(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.
(2007). Interactive effects of fitness and hormone treatment on brain health in postmenopausal women.
Neurobiology of Aging. 28(2), 179 - 185.
Hormone therapy for men
Hormone therapy for prostate cancer can produce temporary cognitive impairment
A new study finds men treated with hormone therapy for prostate cancer may experience temporary cognitive changes in visual memory of figures and recognition speed of numbers. No other cognitive areas were affected. The degree of cognitive change was related to the magnitude of decline in the level of estradiol (a form of estrogen in men).
Salminen, E.K., Portin, R.I., Koskinen, A., Helenius, H. & Nurmi, M. 2005. Estradiol and Cognition during Androgen Deprivation in Men with Prostate Carcinoma. CANCER; Published Online: February 28, 2005 (DOI: 10.1002/cncr.20962); Print Issue Date: April 1, 2005.
Estrogen boosts memory in men with prostate cancer
A new study suggests that high doses of estrogen may improve long-term memory and decrease feelings of confusion in men whose testosterone levels have been lowered to treat advanced prostate cancer. The findings suggest that hormone deprivation, prostate cancer or a combination of the two significantly impair verbal memory, while estrogen therapy significantly improves verbal memory performance. Hormone deprivation appears to slow working memory performance, but did not affect accuracy. Supplementation with estrogen did not affect working memory.
Beer, T.M. & Janowsky, J. 2004. High dose estrogen may enhance memory in men with prostate cancer. Presented at the American Society for Clinical Oncology annual meeting in New Orleans, La. on June 6.
Elevated testosterone kills nerve cells
Testosterone is the main male hormone and plays a crucial role in neuronal function. However, a new study has found that high levels of testosterone triggered programmed cell death in nerve cells in culture. Increased loss of brain cells has been associated with several neurological illnesses, such as Alzheimer disease and Huntington disease. The findings point to another potential danger of steroid use.
 Elevated testosterone induces apoptosis in neuronal cells.
The Journal of Biological Chemistry. 281(35), 25492 - 25501.
Testosterone deprivation makes men forget
A study of men undergoing testosterone deprivation therapy for prostate cancer has found that verbal memory is significantly affected. While initial learning of words is unaffected, such testosterone-deprived men show marked forgetting after two minutes. This rapid drop in memory suggests the lack of testosterone affects the function of the hippocampus. Healthy older men, on average, have about a 40% loss in their normal levels of testosterone as they age, from the ages of 20 or 30, to 70.
Paper presented at the 34th Society for Neuroscience annual meeting in San Diego in late October 2004.
Older men with higher testosterone levels performed better on cognitive tests
A study of the levels of estrogen and testosterone in 300 older men enrolled in a larger study of risk factors for osteoporosis in men found that a higher level of testosterone was associated with better performance on various cognitive tests. The level of estrogen had no apparent effect. The study looked only at natural levels of hormones, and it is too soon to say whether testosterone supplements would help prevent cognitive decline. Although some previous studies have suggested that testosterone might benefit the brain, most of these studies have been of younger men.
 Sex Hormones and Cognitive Function in Older Men.
Journal of the American Geriatrics Society. 50(4), 707 - 712.