Estrogen Replacement Therapy and Memory

By Marina Jovanovic

 

What is Memory?

Human memory and how it works is still one of the great mysteries (or enigmas) waiting to be solved and understood, so that we may acquire more control over its intricacies and be able to help those who experience problems with it. A life without memories, where one would never be able to recognize the face or voice of a loved one, never be able to recognize a language, never be able to learn a new task (such as cooking) or remember an old one (such as writing), is an unimaginable one for most of us. In order for us to benefit from an experience, we have to be able to remember it. The Roman statesman Cicero stated many centuries ago that memory is "the treasury and guardian of all things." Thus, memory is essential to the concept of learning as well. So what exactly is memory, and how does it work? Here's some background information intended to shed some light on this inquiry.

 

The Basics of Memory and How is Works

The process by which experiences change our nervous system and inevitably our behavior is referred to as learning, and we call these changes memories. Early in the century, the German philosopher Herman Ebbinghaus (1850-1909) studied the memorization of syllables in a seemingly meaningless series. He wished to study scientifically the process of memory and rehearsal, the process of deliberate conscious awareness of certain information and its repetition. It is intended to help maintain the information in consciousness or to help store it in the memory "archives" located throughout the brain. First, he attempted to memorize a list of nonsense syllables, after which he tried to retain the list in his memory. Next, he tested his memory by seeing how many times he had to re-read the list before re-learning it perfectly. The fewer times he had to go back to the list, the more information he had retained from his original effort. Ebbinghaus called this "savings" ­ the reduction in the number of trials (or time) needed for re-learning compared to the original learning. Yet, he had no context that could help him organize the unfamiliar information in terms of something already familiar. This line of research changed dramatically in the 1950's and 1960's with the advent of the computer, which made it possible to dissect the complexity of memory into its component processes. The mind is essentially like a computer: first, input must be encoded, then stored and retained, and finally retrieved on demand.

Some of the most important discoveries concerning memory have been made in relation to studies done on those individuals who have some sort of faulty memory. Take for example the case of H.M. who was, sadly, affected by a relatively pure form of anterograde amnesia as a result of a surgical procedure aimed to treat his very severe epilepsy. The term anterograde refers to something "forward, ahead, relating to the future," and is thus used in the context of amnesia to refer to the difficulty of acquiring new information. There is also the retrograde form of amnesia where a person has difficulty remembering old information. H.M. and other individuals who suffer from this particular from of amnesia are able to remember information learned before the brain damage occurred, but are not able to form new memories following the brain damage. Thus, H.M. will always enthusiastically welcome his wife every single time she comes to visit, as if seeing her for the first time in months even though she might have just stepped out of the room for a moment. He cannot name nor identify the faces and names of people he has met since he had the operation, and he will laugh at the same joke over, and over, and over again tirelessly.

The region of H.M.'s brain that was affected by the surgical procedure was the hippocampus, a formation based on the case of H.M. and others with hippocampal damage, researchers came to the following conclusions about the hippocampus:

 

Thus, the hippocampus compares new information with information already in memory and acts as a consolidation center of sorts. It is somewhat like the "new books" shelf in a library that holds new material for a certain period of time before it is transferred elsewhere to be stored permanently. Subjects with damage to the left side of the hippocampus appear to have trouble remembering visual designs and locations, while those with right hippocampal damage have the reverse problem. Memories are not stored in one specific place. They are stored where there is brain activity.

There are several different ways that memories can be subdivided or categorized:

 

 

Other, less significant subdivisions can be made as well, but they are not relevant to this particular discussion and will not be mentioned. Sensory memory extends the availability of information acquired from the environment for a very brief time. For a long time, time iconic memory was thought to consist of only about 4.5 items, as confirmed by initial experiments. This it due to the fact that researchers had overlooked certain possible discrepancies between:

Further research conducted by George Sperling in the 1960's showed that the original hypothesis rang true only if subjects had to make a full report (on a group of nine letters that were flashed). On the other hand, if they had to give only a partial report, then their recall was close to 100 percent. Thus, Sperling finally concluded that the sensory store must hold at least nine items. If the subjects knew all of the subsets, then they must have known all of the subsets in the icon.

There are several differences between short-term and long-term memory, and one is their limitations. Short-term memory has two major limitations:

Long-term memory, as the other hand, is not characterized by these limitations. Thus, in summary:

While explicit memories appear to be processed by the hippocampus, implicit memory processing takes place in the more ancient brain regions, specifically the cerebellum. Thus, in the case of H.M., his explicit memory was affected by the surgical procedure, while his implicit memory remained intact.

With all the different ways of encoding and storing memory, and the supposedly unlimited span of our long-term memory, why are we not able to remember so many things while others stick out in our minds clear as glass? What is it about certain experiences that make them indelible in our memory? Several explanations have been offered over time. Certain memory researchers have suggested that forgetting occurs as new experiences interfere with our retrieval and the physical memory trace begins to gradually decay. The concept of a "memory trace" is hard to define, but it is based upon the changes that take place on the neuronal level in the brain when learning and memory occur. Neurons are, in a way, the building blocks of the brain and its activity, for it is their communication and interaction with each other that constitutes brain activity.

The scientist Donald Hebb offered a neural basis for learning and remembering when he proposed the concept of long-term potentiation (LTP). Hebb proposed a circuit in which a weak synapse is strengthened when it is stimulated simultaneously with the neuron firing. In numerous experiments, rapidly stimulating certain memory-circuit connections increased their sensitivity for hours and even weeks to come. This was due to the fact that the sending neuron now needed less initiative to release its neurotransmitter, and receptor sites might have increased as well. These findings may help researchers one day discover a drug that will enhance human memory, especially for those whose memory is failing them. Estrogen replacement therapy (ERT) may be the beginning of this particular journey, as recent research suggests. How does estrogen and the replacement therapy factor in when it comes to memory retention?

 

Estrogen Replacement Therapy: The Prescription for Memory "Betterment?"

There already exists evidence that certain hormones which humans produce when stimulated by stress or excitement tend to boost learning and memory. When we are greatly aroused, our stress hormones help make memories indelible by making more glucose energy available to the fuel brain activity. This hormone surge tells the brain that some significant event is taking place, and the arousal burns the experience into our mind. Emotion-triggered hormonal changes offer an explain as to why we long remember shocking or exciting events - an earthquake, a wartime ambush, or a first kiss. It appears that stress hormones are not the only ones that have this particular effect on memory the hormone estrogen seems to have a similar effect.

Many women in their post-menopausal years tend to experience a normal age-related decline in memory, while those affected by Alzheimer's Disease (AD) experience a much more rapid degeneration of their memory trace.

 

A new long-term study from the National Institute on Aging (NIA) suggests that use of estrogen replacement therapy (ERT) by post-menopausal women may help slow normal age-related decline in memory. NIA's Baltimore Longitudinal Study of Aging (BLSA) between 1978 and 1994 is the first to document the effects of estrogen on age-related changes in memory over a long period of time. By looking at estrogen use in 288 women enrolled in the study, researchers were able to examine the relationship between estrogen therapy and short-term visual memory. The investigators at the NIA collected information on ERT use during visits to the NIA for memory testing as part of the BLSA and were able to show that women who were on ERT during the memory testing period performed better than women who had never received treatment. Furthermore, some participants who began ERT between their regular visits to the NIA were able to maintain stable memory performance whereas women who never took ERT showed predicted age-associated decreases in memory over a six-year period, on average. Using the BLSA database, the researchers looked at 116 women on ERT and 172 who had never used any type of hormone replacement therapy.

On each visit to the NIA, the women in the BLSA were given the Benton Visual Retention Test (BVRT) where they were shown a series of figures for 10 seconds and then asked to reproduce each figure from memory. The BVRT uses up to 10 different figures in each testing session. "Because there is no maximum number of errors that can be scored during the BVRT, one way to evaluate performance on the test is to examine the average difference in the number of errors between the follow-up visits to the BLSA," said Dr. Susan Resnick, principal investigator of the study. "Women who were on ERT showed an average difference of about two fewer errors than women who were never treated with ERT, which is a significant difference." Previous studies have indicated that verbal memory may be affected by ERT use, but this study is one of first documenting an effect on visual memory. The effects of ERT on visual memory decline are smaller than those seen in studies on verbal memory decline and may only be evident in studies like this one that include larger numbers of subjects.

These findings, in combination with previous studies of verbal memory, suggest that ERT may influence different types of memory. "Animal studies show that estrogen can directly influence structural characteristics of neurons in the brain, particularly in regions that are important for new learning," Dr. Resnick said. "These regions are also most vulnerable to neuron loss seen in Alzheimer's Disease. Thus, lessening the effects of these changes with ERT holds promise as a drug intervention.For example, a study done with mice has shown that the hippocampal neuronal network is important when it comes to the acquisition of spatial reference memory. Another neuronal network, called the striatal system, was found to be important in non-spatial navigation during a water-maze task. The benefits of tonic ERT in improving both spatial and non-spatial memory were deduced from the fact that mice who received this treatment (as opposed to those who received a placebo) did the water-maze task much faster and with greater accuracy. Of course, ERT double-blind, controlled experiments must be conducted before anyone can advocate use of ERT to slow cognitive decline or prevent Alzheimer's disease. These trials supported by the NIA are currently being planned or are already in progress.

As part of a 9-year study in the BLSA, researchers are currently performing annual magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments to examine brain structure and function in individuals aged 55 and older. PET measurements of regional cerebral blood flow (rCBF) are obtained under three conditions: rest and verbal and figural delayed recognition memory tasks. Fifteen women receiving ERT (with or without the hormone progesterone) were compared with a matched sample of 17 untreated women. There were no significant differences between the two groups in regional brain volumes or ventricular size. However, ERT users and nonusers showed significant differences in PET-rCBF relative activation patterns during the memory tasks. ERT-users also showed better performance on neuropsychological tests of figural and verbal memory and on some aspects of the PET activation tests, although the two groups did not differ in education, overall verbal ability, or performance on other neuropsychological tests. Thus these findings confirm previous observations of the beneficial effects of ERT on figural memory.

Researchers at the National Institutes of Health in Bethesda, Maryland, and the Weizmann Institute in Rehovot, Israel, report that one type of estrogen, estradiol, "induces formation of dendritic spines (nerve pathways)" in the hippocampus. Due to the extensive and intricate role of the hippocampus in memory, hippocampal function has long been associated with the progression of Alzheimer's Disease. Researchers found that the addition of estradiol to hippocampal cells caused a temporary reduction in levels of a second chemical, called brain-derived neurotrophic factor (BDNF). Down-regulation of BDNF, in turn, led "to a twofold increase in dendritic spine density," according to the researchers. Dendritic spines form part of the network of interlocking neurologic pathways the brain uses to store and retrieve memories. Neurologists theorize, therefore, that a denser dendritic web might result in sharper memory function.

Several other studies have shown that exogenous estrogen, or estrogen not produced in the body, can lead to an improvement in verbal memory and an easier acquisition of new information in women. While short-term memory does not appear to be substantially affected by the aging process, long-term memory experiences decreases in both speed and accuracy with normal aging. Also, the extent of impairment seems to be dependent on the presence or absence of environmental cues. In other words, significant differences are present between free recall, cued recall, and recognition of information in memory. Thus, the one of the hardest types of new memories to form with increased age is those that have no environmental context. Sex differences are evident as well in cognitive functioning and memory, since men appear to excel in spatial and quantitative abilities and gross motor strength, while women have better verbal abilities, in perceptual speed and accuracy, and in fine motor skills. This may be due to the influence of sex hormones on prenatal brain organization. In general, studies focusing on the link between estrogen and memory have provided support to the hypothesis that estrogen may help maintain aspects of short-term and long-term memory with a non-significant, or perhaps even negative, effect on visual-spatial memory. Thus, these studies appear to contradict the findings in the aforementioned visual study.

What can be concluded from these studies is that the initial research seems promising in identifying estrogen as an aid in bettering memory in post-menopausal women and AD patients. Yet, further research must be conducted to make sure that the effect of estrogen is indeed as beneficial as it seems. For further information on estrogen and ERT, direct your inquires to your health-care provider.

Other Web Resources

Alzheimer's Disease Education & Referral Center

This site is sponsored by the NIA, and provides information on Alzheimer's and other memory-related diseases

The Charles A. Dana Foundation & Dana Alliance For Brain Initiatives.

This site provides information regarding the activities, publication and programs of the Foundation and Alliance, as well as information on various brain diseases and disorders.

Women's Health Connection

This site is sponsored by a consumer health educational resource network providing extensive information on women's hormone related disorders and related issues.

Society For Neuroscience

This site provides the latest information regarding neuroscientific research and centered around educating the public about issues related to neuroscience.

The Brain-Longevity Program

This site provides information on the methods and benefits of the program, as well as other educational resources related to neuroscience.

ADDvance Magazine

This site it sponsored by the magazine and is meant to be an information resource for women with ADD.

References

Carlson, N. R. (1998). Physiology of Behavior (6th ed.). Needham Heights, MA: Allyn and Bacon.

Costa, M. M., Reus, V. I., Wolkowitz, O. M., Manfredi, F., Lieberman, M. (1999, July). Biological Psychiatry. 46 (2), 182-188.

Myers, D. G. (1998). Psychology (5th ed.). New York: Worth Publishers.

Rissanen, A., Puolivaeli, J., van Groen, T., Riekkinen, Paavo Jr. (1999, April). In mice tonic estrogen replacement therapy improves non-spatial and spatial memory in a water maze task. Neuroreport: For Rapid Communication of Neuroscience Research. 10 (6), 1369-1372.

Robinson, D., Friedman, L., Marcus, R., Tinklenberg, J., et al. (1994, Sep). Estrogen replacement therapy and memory in older women. Journal of the American Geriatrics Society. 42 (9), 919-922.

Sherwin, B. B. (1997, May). Estrogen effects on cognition in menopausal women. Neurology. 48 (5, Sup 7), S21-S26.

Sherwin B. B. (1994). Estrogenic effects on memory in women. Hormonal restructuring of the adult brain: Basic and clinical perspectives, New York Academy of Sciences, New York, NY, USA, 213-231.