Running head: ESTROGEN AND THE EFFECTS ON COGNITION

Estrogen and the Effects on Cognition Debra Franckowiak Walden University

ESTROGEN AND THE EFFECTS ON COGNITION Estrogen and the Effects on Cognition Over the past decade, numerous studies have been conducted to ascertain hormonal influences on cognition. In particular, estrogen levels have been hypothesized to have an effect upon cognition while aging and additional research indicates that estrogen levels may increase a persons risk for dementia or Alzheimers disease (Janicki & Schupf, 2010, p. 359). Despite the contrasting research, there does appear to be plausible biological mechanisms by which estrogen might lead to improved cognition, reduced risk for dementia, or improvement in the severity of dementia (Yaffe, Sawaya, Lieberburg, & Grady, 1998, p. 688).

Since the life expectancy of a woman is longer than it was over 100 years ago, it is fair to assume that women will live more than half of their lives after menopause. As a peri-menopausal woman, I have already experienced some small cognitive differences as compared to five years ago. Clearly, the deficits are small but they are worrisome nonetheless. This paper will describe estrogen receptors and the potential impact on cognitive function, the components of cognition, and the impact of hormone replacement therapy (HRT) on cognition. Historical Roots of Estrogen Mapping In order to explain the mechanical process that estrogen takes within the brain, it is important to review the historical roots of estrogen mapping within the brain. Although gonadal estrogen was mapped in the late 1960s, estrogen receptors (ERs) located in the hypothalamus and the pituitary gland, was not discovered until the 1980s (Pfaff, 1980). Soon after, researchers identified ERs in the hippocampus, cerebral cortex, midbrain, and brainstem (Sherwin, 2003, p. 133). Presently, computerized tomography (CT) scans and magnetic resonance imaging (MRI) have allowed researchers to localize certain functions and diseases to specific areas of the brain

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(Shepard, 2001, para. 7). We are now aware of two types of intracellular estrogen receptors, ER and ER (McEwen & Alves, 1999). Structure and Pathway of Estrogen in Brain Since ERs are widely distributed throughout the brain, the estrogen actions are also widely distributed and affect many neurotransmitter systems. Some of these neurotransmitter systems include the catecholaminergic, serotonergic, cholinergic, and -aminobutyric acidergic systems (McEwen, 2002). Two examples of actions of estrogen are the increase dendritic spine density on CA1 pyramidal neurons in the hippocampus within 24-72 hours after acute administration (Gould, Woolley, Frankfurt, & McEwen, 1990, p. 1287) and estrogen increases the concentration of choline acetytransferase, a neurotransmitter that has been flagged in memory functions and have been severely reduced in Alzheimers disease (Sherwin, 2003, p. 134). Although these samples are only two ways in which estrogen can influence structures and functions of the brain, there are numerous clinical hypothesis based upon biological research findings that maintain that estrogen impacts some aspects of cognition, particularly in women (McEwen, 2002, p. 357). Structure of Brain and Action of Estradiol Cognition is a very broad term used to describe human information processing. More specifically, cognition includes functions such as attention, pattern recognition, memory, learning, language processing, problem solving, abstract reasoning, and psychomotor skills (Sherwin, 2003, p. 134). Among these functions, memory, is one of the largest components of cognition and is thought of as a system that stores and retrieves information that has been acquired through the senses (Sherwin, 2003, p. 134).

ESTROGEN AND THE EFFECTS ON COGNITION Based on findings that estrogen induces cyclic changes in synapse formation and spine density of the hippocampus, (Gould et al., 1990, p. 1291) it might be said that estrogen would have a profound effect on hippocampally dependent cognitive functions such as memory and learning, which involve the acquisition, encoding, and consolidation of new information (Sternberg & Sternberg, 2012). Estrogen is a neuroactive hormone with the largest concentrations of ER receptors located in the hippocampus (Shughrue & Merchenthaler, 2000, p. 97), hypothalamus, and in the amygdala; and the neurotransmitter that estrogen up-regulates is acetylcholine (Luine, 1985, p. 486). Additionally, the hippocampus has been shown to be the critical area for declarative memory. When one synthesizes this information, it may be likely that estrogen would have its most profound effect on memory (Sherwin, 2003, p. 135). The hippocampus is involved in episodic, declarative, contextual, spatial learning, and memory. It also serves as the command center of autonomic and vegetative functions such as

ACTH secretion (Phillips & LeDoux, 1992).The hippocampus is susceptible to damage by stroke and head trauma and vulnerable to damage during aging and repeated stress (Sapolsky, 1992). According to Daniel (2006), there is evidence that supports the hypothesis that estrogen affects performance on tasks of learning and memory by influencing the cognitive strategy that will be used by an animal to solve a task (p. 791). Research Findings It would seem that since research indicates the level of estrogen in the hippocampus may impact the performance of learning and memory, a hormone replacement therapy (HRT) may be especially beneficial to those with cognitive difficulties. However, this is not the case. Clinical trials of HRT in women that were younger than 65 years old demonstrated that estrogen alone

ESTROGEN AND THE EFFECTS ON COGNITION either enhances or has not effect on verbal memory in short-term follow up and in women 65

years old or older demonstrated a neutral result (Janicki & Schupf, 2010, p. 361). Actual studies in women have substantial methodological problems and have produced conflicting results. There is evidence that estrogen therapy improves cognitive performance in recently menopausal women, but no evidence of beneficial effect in asymptomatic women (Yaffe et al., 1998, p. 694). In fact, an observational study conducted in Cache County Utah, evaluated 1,866 women with a mean average age of 74.4 years (Zandi et al., 2002, p. 2123).The findings suggested that past use of estrogen therapy showed a significant reduction in the risk of developing Alzheimers Disease (Gibbs, 2010, p. 844). Essentially, this study showed that after menopause, estrogen therapy used for 3, 10, and > 10 years helped to protect women from Alzheimers disease. The bonus factor in this study was that those women who had only taken estrogen therapy for three years post menopause received the same protection benefits as the ten year user. Another study reported that women who received estrogen therapy for 2-3 years around menopause had less risk of cognitive impairment than women who received placebos (Bagger, Tanko, Alexandersen, Quin, & Christiansen, 2005, p. 12). In both of these studies, the researchers have observed that there is a critical period in which estrogen therapy must be administered in order to reduce the risk of age-related cognitive impairment. The Critical Period Hypothesis has been utilized in many studies and unfortunately the definitive evidence of this critical period is lacking despite results showing that short-term estrogen therapy begun around the time of menopause may in fact, provide protection against cognitive decline in women (Rodgers, Bohacek, & Daniel, 2010, p. 1194). According to Gibbs (2010), there are several brain mechanisms which may account for the positive effects of estrogen therapy. For instance, the neurons found in the forebrain and that

ESTROGEN AND THE EFFECTS ON COGNITION project to the hippocampus and frontal cortex, become compromised as we age. Apparently, estradiol increases the function of the projections in the hippocampus and increases the

connectivity of the neurons in the hippocampus. Both of these actions have direct positive effects upon learning, memory, and attention span (Baxter & Chiba, 1999, p. 179). Even though many studies support the hypothesis that estrogen helps in certain aspects of attention and memory (especially in peri-menopausal women), there are certain ERs that appear to be associated with the risk in developing cognitive impairment (Newhouse et al., 2010, p. 860). Additionally, the Womens Health Initiative Memory Study (WHIMS), established that non-demented participants assigned to treatment had a 40% elevation in their risk of substantial cognitive decline (Rapp, Espeland, & Shumaker, 200, p. 2663). The Nurses Health Study, a prospective cohort begun in 1976, found that for long-term users of estrogen therapy or combined with progestin, had an increased risk of significant decline on most cognitive tasks. This decline was worse in women who initiated hormone replacement therapy at an older age (Kang, Weuve, & Grodstein, 2004, p. 101). Despite these negative findings, it is important to note that most studies continue to have important methodological limitations. Limitations of Hormone Therapy Research on Cognition In all of these studies, there were some limitations which produced mixed results. For example, when comparing the Womens Health Initiative Memory Study (WHIMS) and the Heart and Estrogen/Progestin Replacement Study (HERS), there are differences due to confounding variables. For instance, women who choose to take hormone therapy are often healthier than women who choose not to take hormones (Matthews, Kuller, Wing, Meilahn, & Plantinga, 1996, p. 971) which may have impacted the outcome as investigators may have underestimated the harms of hormone usage in the earlier studies. The second limiting factor,

ESTROGEN AND THE EFFECTS ON COGNITION and I believe the most crucial one, is the timing of the administration of the hormone therapy. In almost all of the studies I have read, the hormone replacement occurred well after menopause occurred which leads me to the belief that the critical window theory is even more important to

the outcomes of these studies. If the majority of the research shows that hormone therapy in later life contributes to dementia but no research is done on women using hormone therapy in premenopause, we cannot know what the long-term effect of the hormone therapy is on cognition later in life. In addition, I think the length of time a woman uses hormone therapy is probably another variable that may contribute to the mixed results of hormone therapy and cognition. In most randomized clinical trials of hormone therapy, women tended to be older when they were assigned to hormone therapy. Some studies indicated that the average age was around 67 while other studies indicated the average age was 72. Another factor which contributes to the mixed results is related to the variation of mental states of the women in the studies. Some women were depressed and were being treated for depression and were appropriately categorized in the study and yet, other studies indicated that this variation was not accounted for. Lastly, studies intentionally introduced variables (social stress factors to test cognition) that researchers knew could not be replicated or repeated. All of these factors contribute to the mixed outcomes of hormone replacement therapy research. Additional Research Suggestions There appears to be ample evidence to suggest that estrogen influences neuroanatomical and neurophysiological aspects of cognition. Additionally, there seems to be evidence to support the idea that estrogen would have a beneficial effect on cognition in women. The difficulty in interpreting the current research findings is that most of the work on estrogen and cognition has been completed in postmenopausal women whose ovaries have atrophied. Another concern is

ESTROGEN AND THE EFFECTS ON COGNITION that in these studies, there are significant methodological limitations. Most researchers have indicated that there does appear to be a critical period during the immediate postmenopausal years in which hormone therapy would help to protect cognition (Sherwin, 2003, p. 146) but non-observational studies have not been conducted to confirm this hypothesis. Because of these factors, I would recommend that controlled studies that address the biases that are inherently found in the study of postmenopausal women be conducted. Perhaps a more structured method of documenting and stratifying the use of other drugs that may impact the central nervous system (anti-anxiety drugs for instance)could be utilized to strengthen an experimental study and eliminating the use of inappropriate measuring instruments and the variety of doses of estrogen formulations would help to strengthen future studies. Summary There is sufficient evidence to suggest that hormone therapy, estrogen in particular, has positive effects on memory and cognition when it is administered to non-surgical menopausal women shortly after the cessation of the menstrual cycle. The literature seems to suggest that hormone therapy given to older women (the age has not really been defined) does very little to help in improving cognitive function and in some cases, may in fact even be detrimental. The variability of hormone therapy effects and cognition is directly related to a womans

age and the timing of the hormone therapy treatment although the timing of the initiation has not been studied thoroughly (and is recommended by me). This particular aspect of study would help us to learn if the critical period is related to the neurons decreased ability to absorb estrogen as a woman ages or if there is a way to reverse brain dysfunction between the time menopause occurred and hormone therapy began.

ESTROGEN AND THE EFFECTS ON COGNITION Regardless of the future studies, we do know that estrogen is essential to optimal brain function. This hormone has been shown to increase cerebral blood flow, decrease inflammatory changes, and increase neuronal synapses in the brain (Shepard, 2001, p. 1). The ability to stall disabling diseases such as Alzheimers disease, allows the aging woman to have a better quality of life and could in fact, decrease the health care costs associated with long-term illnesses. It is important to remember that despite the variations in study outcomes, the research does show that there is a link between estrogen and cognitive function. Further studies will be needed to determine the effects of estrogen on cognitive function at various stages of the aging process; with replacement therapy and without replacement therapy. It does appear that current literature supports the notion that HRT after menopause is not recommended as it will not improve cognitive function so future studies should focus on structured methodological studies that are non-observational and that focus on a specific time-frames (such as immediately post menopause through three years) in order to evaluate the impact of hormone therapy and cognitive function. As a side note, the measurement tool utilized to assess cognitive function needs to be one that can be easily repeated and replicated in order to add credibility to the future study.

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References Bagger, Y. Z., Tanko, L. B., Alexandersen, P., Quin, G., & Christiansen, C. (2005). Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause, 12, 12-17. Baxter, M. G., & Chiba, A. A. (1999). Cognitive functions of the basal forebrain. Current Opinion Neurobiology, 9, 178-183. Daniel, J. M. (2006). Effects of estrogen on cognition: What have we learned from research? Journal of Neuroendocrinology, 18, 787-796. Gibbs, R. B. (2010, March). Does short-term estrogren therapy produce lasting benefirs in brain? Endocrinology, 151(3), 843-845. doi: 10.1210/en.2009-1453 Gould, E., Woolley, C. S., Frankfurt, M., & McEwen, B. S. (1990). Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J Neurosceince, 10, 1286-1291. Janicki, S. C., & Schupf, N. (2010). Hormonal influences on cognition and risk for Alzheimer disease. Curr Neurol neurosci Rep, 10(5), 359-366. doi: 10.1007/s11910-010-0122-6 Janicki, S. C., & Schupf, N. (2010, September). Hormonal influences on cognition and risk for alzheimer disease. Curr Neurol Neurosci Rep, 10(5), 359-366. doi: 10.1007/sl1910-0100122-6 Kang, J. H., Weuve, J., & Grodstein, F. (2004). Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women. Neurology, 63, 101-109. doi: 10.1212/01.WNL.0000132522.13574.67

ESTROGEN AND THE EFFECTS ON COGNITION Luine, V. N. (1985). Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol, 89, 484-490.

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Matthews, K. A., Kuller, L. H., Wing, R. R., Meilahn, E. N., & Plantinga, P. (1996). Prior to use of estrogen replacement therapy, are users healthier than non users? American Journal of Epidemiology, 143, 971-978. McEwen, B. S. (2002). Estrogen action throughout the brain. Recent Prog Hom Res, 57, 357384. McEwen, B. S., & Alves, S. H. (1999). Estrogen actions in the central nervous system. Endocr Rev, 20, 279-307. Newhouse, P. A., Umas, J., Wilkins, H., Coderre, E., Sites, C. K., Naylor, M.,...Young, S. N. (2010). Estrogen treatment impairs cognitive performance following psychosocial stress and monoamine depletion in postmenopausal women. Menopause, 17(4), 860-873. doi: 10.1097/gme.0b013e3181e15df4 Pfaff, D. W. (1980). Estrogen and Brain Function. New York: Springer-Verlag. Phillips, R. G., & LeDoux, J. E. (1992). Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci, 106, 274-285. Rapp, S. R., Espeland, M. A., & Shumaker, S. A. (2003). Effect of estrogen plus progestin on global cognitive function in postmenopausal women; the Womens Health Initiative Memory Study: a randomized controlled trial. JAMA, 289, 2663-2672. Rodgers, S. P., Bohacek, J., & Daniel, J. M. (2010). Transient estradiol exposure during middle age in ovariectomized rats exerts lasting effects on congitive function and the hippocampus. Endocrinology, 151, 1194-1203.

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Sapolsky, R. (1992). Stress, the Aging and the Mechanisms of Neuron Death. Cambridge:: MIT Press. Shepard, J. E. (2001). Effects of estrogen on cognition, mood, and degenerative brain diseases. J AM Pharm Assoc, 41(2). Sherwin, B. B. (2003). Estrogen and cognitive functioning in women. Endocrine Reviews, 24(2), 133-151. doi: 10.1210/er.2001-0016 Shughrue, P. J., & Merchenthaler, I. (2000). Estrogen is more than just in sex hormones; novel sites for estrogen action in the hippocampus and cerebral cortex. Front Neuroendocrinol, 21, 95-101. Sternberg, R. J., & Sternberg, K. (2012). Cognitive Psychology (Sixth ed.). Belmont, CA: Wadsworth: Cengage Learning. Yaffe, K., Sawaya, G., Lieberburg, I., & Grady, D. (1998). Estrogen therapy in postmenopausal women. JAMA, 279(9), 688-695. Zandi, P. P., Calson, M. C., Plassman, B. I., Welsh-Bohmer, K. A., Mayer, L. S., Steffens, D. C., & Breitner, J. C. (2002). Hormone replacement therapy and incidence of Alzheimer disease in older women: the cache county study. JAMA, 288, 2123-2129.