Women self-report many cognitive symptoms in perimenopause and menopause. Symptoms such as word-finding difficulty, difficulty paying attention, difficulty concentrating, needing to use memory aids, and feeling like they are in a brain fog. In the Seattle Midlife Women’s Health Study, out of 230 women aged 33 to 55, 60 percent reported they had an unfavorable memory change (Sullivan Mitchell & Fugate Woods, 2001). Perimenopausal women were 1.4 times more likely to report forgetfulness than were premenopausal women (Greendale, Derby & Maki, 2011). The research is accumulating that links perimenopausal symptoms associated with brain function and regulation, such as hot flashes, with cognitive symptoms associated with menopause. However, even these results are inconsistent.

Estrogen And The Female Brain

Greendale et al. (2011) investigated the direct and indirect effects of estrogen on the brain. The indirect effects include how fluctuating levels of estrogen impact mood, sleep, and hot flashes. Research links fluctuating estrogen levels with mood changes, sleep disorders, and an increased incidence of hot flashes.

Direct effects are how estrogen can cause cognitive symptoms such as word-finding difficulty. The brain has many receptors for estrogen. Detailed analysis even shows which parts of the brain have the highest number of receptors. However, the studies showing a direct link between decreased estrogen levels and cognitive symptoms have had mixed results.

A recent study using estriol, a form of estrogen, in women who have relapsing-remitting multiple sclerosis, showed a direct link between estrogen levels and brain function. Estriol is a female sex hormone that is only increased in pregnancy. Women with multiple sclerosis have fewer relapses of their symptoms when they are pregnant. Dr. Rhonda Voskuhl and her colleagues recently completed a study in which estriol was given to women with multiple sclerosis who were not pregnant. The results were promising. They are now working to determine if estriol could also affect cognitive symptoms in perimenopausal women as well.

A Potential Link Between Estrogen, Mood, And Cognitive Symptoms

The Study of Women’s Health Across the Nation (SWAN), The Seattle Midlife Women’s Health Study, and the Penn Ovarian Aging Study have examined the changes in a woman’s brain function from premenopause through menopause into post-menopause. These studies showed that a decline in memory function, attention, word-finding, and other cognitive difficulties could not be attributed to age, depression, anxiety, vasomotor symptoms, or sleep disturbances (Greendale et al., 2010).

Depressive and anxiety symptoms were associated with cognitive symptoms potentially through the effect of estrogen on serotonin, a neurotransmitter in the brain that is highly involved in regulating mood. In a clinical trial in which researchers gave perimenopausal women estrogen supplements and depleted their tryptophan (a precursor to serotonin), they found that neither increasing estrogen nor decreasing tryptophan influenced visuospatial learning. Therefore, it would appear estrogen levels do not influence visuospatial learning.

However, estrogen therapy exerted a protective effect on verbal memory and verbal fluency. When tryptophan levels were depleted, mood worsened (this makes sense, as serotonin levels would also decrease), but it improved when estrogen was given the next day. This implies a relationship between estrogen and tryptophan and possibly shows a link between estrogen and mood.

Finally, they found that the longer it had been since a woman had her last period, the lower her verbal memory performance (Amin et al., 2006).

This research shows that there is a relationship between estrogen levels, tryptophan, mood, and cognition. The question is, is it a causative relationship or a correlation? In other words, does a decrease in estrogen, through its influence on tryptophan, negatively affect cognition, or is there another factor at play here?

The Relationship Between Hot Flashes And Cognitive Symptoms In Menopause

Several investigations have not found an association between self-reported hot flashes and changes in cognitive symptoms. However, in a small study with 29 women, researchers used a hot flash monitor and showed that highly symptomatic women under-reported the number of hot flashes they experienced by 43 percent. They found that verbal memory performance is significantly related to the objective number of hot flashes women have, but not the subjective number they report (Maki et al., 2008).

Cortisol, a stress hormone, increases after a hot flash and may be the missing link between hot flashes, depressive or anxiety symptoms, and decreases in cognitive performance during perimenopause. In studies on premenopausal women, young women showed fewer increases in cortisol levels after being exposed to laboratory stimuli than did young men. This suggests that estrogen may also buffer the stress response (Greendale, Derby & Maki, 2011).

What Happens To Cognitive Performance When Premenopausal Women Are Given Estrogen Blockers?

Fifteen premenopausal women were assessed using event-related functional magnetic resonance (MRI) at baseline and eight weeks after receiving a gonadotropin-releasing hormone analogue to block estrogen secretions from the ovary. Fifteen matched wait-listed volunteers served as the control group. The results showed that blocking estrogen resulted in problems with encoding memory but not in retrieving it. Brain function returned to normal once estrogen levels were restored (Craig et al., 2007).

Estrogen also has significant effects on the hippocampus, a brain structure actively involved in the memory process. Functional MRI was used to study two groups of women, one group started hormone therapy in the perimenopause period, and the other did not use hormone therapy. The women had an average age of 60 years. The women were asked to do the following tasks:

• A delayed work list task for verbal memory
• Wait 15 minutes
• A retrieval task

The women who received early estrogen therapy had enhanced verbal memory and enhanced function of the hippocampus (Greendale, Derby & Maki, 2011).

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The Timing Of Estrogen Therapy And Cognitive Symptoms In Menopause

There is also increasing evidence that the timing of estrogen therapy is a significant factor when using it to support cognitive function. Roberta Diaz Brinton (2005) states that the timing of estrogen therapy must also be considered when women are weighing the health benefits of estrogen therapy. She divides studies on estrogen and brain function into two groups, those in which estrogen is used in women with normal healthy brain function who were subsequently exposed to some neurodegenerative insult, such as blocking estrogen production, and women who have already passed through and beyond menopause with no estrogen therapy.

Studies on women with healthy brains and nerve cells show the protective effect of estrogen. Studies on women who may have already had some changes in nerve function show mixed results. Brinton explains that the data would seem to indicate that there is a continuum of nerve cell health that progresses from healthy to unhealthy. If nerve cell and brain health are good at the time when estrogen therapy is started, then estrogen therapy is beneficial for both nerve function and survival. On the other hand, if nerve cells and the brain are unhealthy, estrogen therapy worsens the problem over time (Brinton, 2005). These findings are supported by other studies that demonstrate the negative impact of hormone therapy on women whose cognitive performance is already compromised (Greendale, Derby & Maki, 2011).

So, What Does This All Mean?

First, and most importantly, if you have any cognitive changes, it is essential that you undergo a thorough history and physical exam by your physician to rule out any medical or neurological disorder as the cause. Cognitive changes associated with menopause are subtle, and therefore a more significant change is cause for concern.

Both the stage of menopause and the symptoms women notice, such as hot flashes, seem to influence the cognitive changes women may see. The SWAN study provides reassurance that though tests on processing speed were significantly lower in perimenopausal women when compared to premenopausal women, they rebounded after the transition was complete. The Penn Ovarian Aging Study, on the other hand, showed that memory declined significantly in the transition from premenopause to post-menopause. Depressive symptoms and anxiety associated with menopause also affect cognition by slowing processing speed. Self-reported hot flashes were not associated with changes in cognitive performance. However, objective measurements of hot flashes were. More research is clearly needed in this area.

Read More: The Truth About PostMenopausal Brain Fog

In older women who are more than ten years or so past their last menstrual cycle, hormone therapy seems to have no or a minimum effect on cognition. Three randomized clinical trials also found no sustained cognitive benefit or risk from using estradiol (an estrogen hormone) to treat cognitive symptoms associated with menopause (NAMS, 2019, p 101). The finding that there was no risk associated with using estradiol in these trials is reassuring.

What’s Changed?

It appears that the research so far is inconclusive on whether estrogen therapy may help with the cognitive symptoms associated with menopause. When the life expectancy for women and the average age of menopause were both 50 years or so, studies on estrogen therapy would not have been relevant. Today, women can expect to live well into their 80s, but the average age of menopause remains in their early 50s. This means that approximately 40 percent of the lifespan of an average woman who lives to age 40 is postmenopausal.

As you may know, the pendulum for and against using hormone therapy has swung back and forth over the decades. Prior to the Women’s Health Initiative study in 2003, cumulative scientific evidence was in favor of estrogen therapy. The Women’s Health Initiative, the largest randomized clinical trial on hormone replacement at the time, concluded that hormone therapy did not improve cognitive function in perimenopausal and postmenopausal women and it potentially increased the risk of dementia in women over age 65. Since these studies were completed, newer studies have separated women into perimenopausal and early menopausal from late post-menopausal groups to better understand some of the conflicting results (Morrison et al., 2006).

A randomized clinical trial enrolled 140 women from November 2014 to February 2015. Women in the experimental group took estrogen and progesterone along with calcium and vitamin D for four months. Women in the control group took calcium and vitamin D for four months. The women were tested using the Montreal Cognitive Assessment (MoCA) and Green Climacteric Scale. The test result showed that women in the experimental group had improvement in all domains in the MoCA except orientation after receiving four months of hormone therapy (Moradi et al., 2019).

Estriol And Cognition

In 2011, a clinical trial led by Dr. Rhonda Voskuhl from the University of California, Los Angeles, began enrolling women with multiple sclerosis (MS) to study cognition. Approximately half of people diagnosed with multiple sclerosis develop problems with cognition. There are currently no FDA-approved treatments to help. Women with relapsing-remitting MS have 80 percent fewer relapses during late pregnancy than at other times. Estriol is an estrogen that is only elevated during pregnancy. Estriol levels start at undetectable before pregnancy, increase during pregnancy, and reach their highest levels late in pregnancy. The clinical trial description reports that estrogen therapy has had favorable effects in animal models for other neurological diseases.

The trial enrolled 64 women between the ages of 18 and 55 who were randomly assigned to the treatment or control group. Participants in the control group received 8 mg daily of estriol and starting at month 6 and at months 9 and 12, progestin along with their MS drug regimen. Participants in the control group received a placebo for the estriol and the progestin, but continued their MS medications. The primary outcome from the trial was a change in baseline cognitive function when assessed by the Paced Serial Addition Test (PASAT) after a year.

Dr. Voskuhl explains that we have known for decades that pregnancy has a protective effect in MS. In the clinical trials, Dr. Voskuhl and associates found that adding estriol to the MS drug Copaxone had a dramatic effect. The women who received the combination of estriol and Copaxone had a 50 percent reduction in their MS symptoms and a significant improvement in cognition. Dr. Voskuhl explained how her research on MS and estriol could be extended to menopause and the cognitive symptoms associated with menopause at the Americas Committee for Treatment and Research in Multiple Sclerosis meeting.

Cleopatrarx: What Is It?

CleopatraRX.com is a patented dosepak for estriol. Estriol is taken daily each morning, and then progesterone is taken before bed each night on the last 12 days of a 28-day cycle. This combination mimics the typical pattern of hormone release in premenopausal women. Progesterone is included as estrogen alone increases the risk of uterine cancer and uterine hyperplasia in women who have not had a hysterectomy.

As the North American Menopause Society and The Endocrine Society have indicated, a shared decision-making approach is necessary to weigh the risks and benefits of estrogen replacement therapy. It is important to fully disclose your past medical history, family history, current medications, and any symptoms you are experiencing. At that point, an assessment can be made on whether a prescription for CleopatraRX is safe and appropriate for you.

DISCLAIMER

While we strive to always provide accurate, current, and safe advice in all of our articles and guides, it’s important to stress that they are no substitute for medical advice from a doctor or healthcare provider. You should always consult a practicing professional who can diagnose your specific case. The content we’ve included in this guide is merely meant to be informational and does not constitute medical advice. 

References

1. Sullivan Mitchell, E., & Fugate Woods, N. (2001). Midlife women’s attributions about perceived memory changes: observations from the Seattle Midlife Women’s Health Study. Journal of women’s health & gender-based medicine, 10(4), 351–362. https://doi.org/10.1089/152460901750269670
2. Greendale, G. A., Derby, C. A., & Maki, P. M. (2011). Perimenopause and cognition. Obstetrics and gynecology clinics of North America, 38(3), 519–535. https://doi.org/10.1016/j.ogc.2011.05.007
3. Greendale, G. A., Wight, R. G., Huang, M. H., Avis, N., Gold, E. B., Joffe, H., Seeman, T., Vuge, M., & Karlamangla, A. S. (2010). Menopause-associated symptoms and cognitive performance: results from the study of women’s health across the nation. American Journal of epidemiology, 171(11), 1214–1224. https://doi.org/10.1093/aje/kwq067
4. Amin, Z., Gueorguieva, R., Cappiello, A., Czarkowski, K. A., Stiklus, S., Anderson, G. M., Naftolin, F., & Epperson, C. N. (2006). Estradiol and tryptophan depletion interact to modulate cognition in menopausal women. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 31(11), 2489–2497. https://doi.org/10.1038/sj.npp.1301114
5. 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. https://www.scholars.northwestern.edu/en/publications/objective-hot-flashes-are-negatively-related-to-verbal-memory-per
6. Craig, M. C., Fletcher, P. C., Daly, E. M., Rymer, J., Cutter, W. J., Brammer, M., Giampietro, V., Wickham, H., Maki, P. M., & Murphy, D. G. (2007). Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women. Psychoneuroendocrinology, 32(8-10), 1116–1127. https://doi.org/10.1016/j.psyneuen.2007.09.009
7. Brinton R. D. (2005). Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Annals of the New York Academy of Sciences, 1052, 57–74. https://doi.org/10.1196/annals.1347.005
8. The North American Menopause Society (NAMS). Crandall, C. [Ed].  (2019). Menopause Practice. A Clinician’s Guide 6^th Edition. https://www.menopause.org
9. Morrison, J. H., Brinton, R. D., Schmidt, P. J., & Gore, A. C. (2006). Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women. The Journal of neuroscience : the official journal of the Society for Neuroscience, 26(41), 10332–10348. https://doi.org/10.1523/JNEUROSCI.3369-06.2006
10. Moradi, F., Jahanian Sadatmahalleh, S., & Ziaei, S. (2019). The effect of hormone replacement therapy on cognitive function in postmenopausal women: An RCT. International journal of reproductive biomedicine, 16(12), ijrm.v16i12.3682. https://doi.org/10.18502/ijrm.v16i12.3682

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