by Maureen Miller Pelletier, MD and Deborah S. Romaine
Do you sometimes believe that you're losing your mind -- or feel that you've finally found it? Women at midlife often find themselves at one extreme or the other, and wondering if maybe, just maybe, they can blame it all on hormones. According to the latest research, the answer may be more complex than a simple 'yes' or 'no' affords. Here's what we know so far..
How oestrogen affects your brain
A healthy, normally functioning brain contains numerous biochemical receptors that respond to, and trigger, various actions. These receptors regulate the manufacture, duration, and destruction of substances called neurotransmitters - the chemicals that make it possible for neurons to communicate with each other. Key among the neurotransmitters believed responsible for many aspects of cognitive function and memory are serotonin, norepinephrine, and acetylcholine. Estrogen affects these neurotransmitters as well as their receptors in the brain.[1]
Low levels of serotonin and norepinephrine are linked to depression and to reduced cognitive abilities; raising them relieves these symptoms. Estrogen appears to stimulate serotonin and norepinephrine receptors in the brain, causing them to increase production. Estrogen also appears to slow the breakdown of serotonin and norepinephrine, keeping them active longer. Acetylcholine appears to have a key role in neurocommunication related to cognition (thinking patterns as well as intellectual functions) and memory. Estrogen seems to raise acetylcholine levels, improving both cognition and memory at least temporarily.
As well, oestrogen appears to function as a mild vasodilator to increase blood flow within the brain. Studies employing high-tech imaging such as PET (photon emission tomography) have allowed researchers to visualize and track vascular changes in the brain following oestrogen administration. This, researchers believe, increases the flow of oxygen and nutrients to brain cells, helping them to function more efficiently.
Researchers have also been able to "map" changes in functions within certain parts of the brain, such as the parietal lobe, which handles analytical thinking, as a woman transitions through menopause, documenting differences in the actions of oestrogen on neurotransmitters and receptors in the brain. These changes are most pronounced during the years a woman is moving through the menopause transition. It appears that certain processes and functions make permanent shifts after menopause, giving rise to the belief that many women become more creative later in life because the parts of their brains that handle creativity become more active. But does this come at a cost?
Midlife, menopause and memory
"Foggy" or "fuzzy" thinking emerged as a term of reference in the 1990s to describe the sometimes-confused thought processes that many women experience at menopause and midlife. It's been variously attributed to physical changes in the brain, emotional disturbances, stress, and hormonal shifts, among other factors.
At first women joked about foggy thinking amongst themselves, sometimes complaining about it to their doctors. Some women and their medical practitioners believed that a woman's memory and cognitive abilities seemed to improve when the woman started taking oestrogen replacement therapy (oestrogen alone) or hormone replacement therapy (oestrogen and progestin). A number of preliminary studies done in lab animals seemed to support such anecdotal reporting and the hypothesis that oestrogen improved memory and cognitive abilities. Even some early studies involving small samples of post-menopausal women seemed to affirm the link.[2]
ERT falls short
Researchers began asking whether oestrogen, prescribed to alleviate hot flashes and other menopausal symptoms, was also the ticket to preserving mental acuity. Recently there has been an attempt to quantify the relation between oestrogen replacement therapy and midlife cognition with clinical evidence. So far these studies have failed to show conclusive evidence of improved cognition or memory with oestrogen supplementation.
Human studies, such as the large-scale Atherosclerosis Risk in Communities (ARIC) Study undertaken at Johns Hopkins University in Baltimore, Maryland, included a component to evaluate oestrogen replacement therapy and cognitive functioning in menopausal women. The ARIC study first tested more than 2,800 women participants between the ages of 48 and 67 in 1990-1992, subjecting them to a battery of memory tests involving word recall and fluency.
ARIC was unable to establish any correlation between oestrogen supplementation and cognitive function, neither negative nor positive. When this longitudinal study retested just over 2,000 participants in 1998, the results were similar. The researchers concluded that there was no evidence to support the view that ERT decreased the rate of age-related cognitive decline.[3]
While the relation between ERT and cognition proved insubstantial, researchers took another tack and began investigating a possible link between oestrogen and dementia, particularly in relation to Alzheimer's disease.
Alzheimer's disease
Estimates are that three in ten people in North America over age 65 have Alzheimer's disease and related dementias. By age 85, the number leaps to five in ten. Because women tend to live longer than men, Alzheimer's is a particular health concern for women, who not only are more likely than men to live long enough to get Alzheimer's but also to live longer with the disease and thus experience the severe and debilitating symptoms that occur in the more progressive stages of the disease. Alzheimer's disease takes a terrible toll on those who have it, those who care for them, and the health care system overall.
A big part of the challenge is that researchers don't entirely know what causes Alzheimer's disease. There is clear evidence that the presence and function of neurotransmitters such as acetylcholine become altered, but it is not clear whether this is a cause or result. Two defining anatomical characteristics in the brains of people with Alzheimer's are the presence of amyloid plaques (an insoluble protein fragment) that ultimately fill the spaces between neurons and an entanglement of neuron structures. These changes undoubtedly affect the processes through which neurons communicate with each other. However, the precise mechanisms of the interference remain a mystery. So does any role that oestrogen might play in them.
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Alzheimer's disease is the most common, and most debilitating, age-related dementia. Health experts estimate that it affects one in ten people over age 65 and half of those over age 85. Although memory loss is perhaps the best-known symptom and consequence of this progressive and incurable disease, people with Alzheimer's disease gradually lose all cognitive function. Researchers don't fully understand why or how Alzheimer's disease develops. They believe neurons, or nerve cells, in the brain become deformed into convoluted tangles, which prevents them from functioning.
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More inconclusive data: ERT and Alzheimer's
To date, the few studies done to explore the connection between oestrogen treatment and Alzheimer's disease have failed to establish that ERT might delay or prevent the disease, at least when clinical signs of Alzheimer's already exist. One such study, reported in the Journal of the American Medical Association[4], gave oestrogen to 120 women, average age 75, who were already showing signs of mild to moderate Alzheimer's. The randomized double-blind study divided participants into three groups: placebo, high-dose Premarin (conjugated estrogens), and low-dose Premarin.
At the end of the 12-month study there was no difference in the rate of decline among those who received oestrogen and those who did not. Another study conducted at the University of Southern California reported similar findings among its participants -- also women who already had Alzheimer's disease.[5]
It's important to note that these were studies in which the groups were quite small and narrowly defined. The larger question of whether oestrogen has the ability to prevent the onset of Alzheimer's is a separate issue, and one now being explored in larger studies. Among them are the Women's Health Initiative Memory Study (WHIMS) and the Women's Health Initiative Study of Cognitive Aging, both sponsored by the National Institutes of Health (U.S.), and the Women's International Study of Long Duration Oestrogen After Menopause. Results will be produced over the next four years (see their website http://www.nih.gov for updates and information).
Although many researchers believe that they will find a connection between oestrogen and random Alzheimer's, the form of the disease that afflicts the vast majority of people, it's particularly unlikely that estrogen treatment would have any effect on familial Alzheimer's disease, sometimes referred to as early onset Alzheimer's. Although this is the more rare form, accounting for perhaps 2 percent to 5 percent of all Alzheimer's cases, it is the most devastating because it generally strikes in the 30s or 40s and progresses quickly to severe debilitation.
Researchers believe nearly all familial Alzheimer's can be traced to defects in three genes on three chromosomes. Environmental factors, including oestrogen, appear to have little, if any, role in triggering or alleviating familial Alzheimer's.
Estrogen: just one piece of the puzzle
And what about oestrogen and brain function in men? Of course, men have small amounts of oestrogen in their bodies as well. Will taking oestrogen improve their brain function and head off memory loss and Alzheimer's disease? So far no one is suggesting this. Because a man's oestrogen levels don't drop off dramatically in midlife, as they do in women, researchers believe other factors have primary responsibility for the development of Alzheimer's disease in men -- and may indeed in women as well. Even in women, there is no evidence, nor do researchers suggest that oestrogen alone is the triggering factor for Alzheimer's. Rather, it is clear that the causes of Alzheimer's disease are multiple and interrelated, and undoubtedly envelope both genetic and environmental factors. Estrogen is just one of these factors.
At this point, clear clinical evidence that taking oestrogen improves brain function or prevents Alzheimer's disease is lacking, despite the potential promise of early observational studies and continued anecdotal reports.
Weighing the risks
Research over the past decade has taught us much about the potential risks of taking oestrogen after menopause. It is not so much a question of whether oestrogen is safe but if the benefits outweigh the risks. One key concern for women and their doctors is the prospect of an increased risk for certain cancers, namely endometrial and breast cancer.
Estrogen causes the lining of a woman's uterus to grow, as it did during her normal cycles in her fertile years. Because of this, doctors almost always prescribe oestrogen in combination with progestin to curtail this growth. Researchers believe taking progestin along with oestrogen negates any potential increase in risk for endometrial cancer in women who take oestrogen.
Whether progestin does anything to negate an increased risk for breast cancer is less certain. Indeed, there is some evidence to suggest that progesterone might increase a woman's risk for breast cancer. Statistically, a woman's risk for developing breast cancer goes up the longer her body is exposed to oestrogen. Women who start menstruating early (before age 12) and enter menopause late (after age 55) have a slightly higher risk of developing breast cancer, according to the National Cancer Institute (NCI). Early studies suggest that taking oestrogen after menopause further increases this risk.
According to the NCI, numerous studies conducted over the past 25 years are not conclusive but support the early findings. The Collaborative Group on Hormonal Factors in Breast Cancer conducted one of the largest surveys of study findings, involving 160,000 women and found that breast cancer risk did indeed increase among women taking oestrogen therapy. But the increase diminishes after a woman stops taking oestrogen therapy, and returns to normal levels five years after stopping the oestrogen.
All other factors being equal, a woman has about a 1 and 8 chance of developing breast cancer in her lifetime. Because all other factors seldom are equal, however, a woman's risk for breast cancer is quite personal and something she should discuss with her physician before taking oestrogen for any reason.
Creativity at midlife: finding your inner artist
Changes take place in your brain at menopause whether or not you choose to take oestrogen. Many women enjoy the outcome of these changes, which tend to result in a shift in perspective and thinking processes that are more creative and less structured than what they experienced before menopause. Sometimes we refer to this as a shift from left-brain thinking - the linear thought processes most useful for dealing with many of the functions we associate with cognitive abilities such as calculations and detail-orientation - to right-brain thinking - the non-linear thought processes typically associated with creativity in art, music, writing, and other areas that we don't usually consider as cognitive functions. This perhaps accounts, at least in part, for the surge of creative output from women in midlife and beyond.
Some women who take oestrogen and find that their cognitive abilities and memory improve tend to notice less of a change in their creativity, suggesting that returning the biochemistry of the brain closer to its premenopausal structure inhibits the changes women might otherwise welcome. Clearly there are no easy or obvious answers to these matters. Menopause remains a very unique and personal experience for each woman.
Maureen Miller Pelletier, M.D. and Deborah S. Romaine coauthored The Complete Idiot's Guide to Menopause (Alpha Books, 2000). Dr. Pelletier is board-certified in OB-GYN and practices gynaecology specializing in menopause, PMS, and pelvic pain in Cincinnati, Ohio and Northern Kentucky. She received her medical degree from Tufts University School of Medicine. Her website is http://www.pelletierintegrativemd.com
Ms. Romaine is a writer specializing in health and lifestyle topics. She has authored or coauthored over a dozen books, among them Syndrome X: Managing Insulin Resistance (coauthored with Jennifer B. Marks, M.D.), Beef Busters (coauthored with Marissa Cloutier, RD, MS, and Eve Adamson), and a number of titles in Alpha Books' The Complete Idiot's Guide series. She lives in Tacoma, Washington.
This article first appeared in A Friend Indeed (Mar/Apr 2002), the newsletter for women in menopause and midlife.
For more information
Web sites:
Books:
- Healing Mind, Healthy Woman. Alice Domar and Henry Dreher, 1997,
- Hormones and the Mind. Edward L. Klaiber, 2001.
- In Praise of the Crone: A Celebration of Feminine Maturity. Dorothy Morrison, 1999.
- Menopause and the Mind: The Complete Guide to Coping With Cognitive Effects of Perimenopause and Menopause, Including Memory Loss, Foggy Thinking, and Verbal Slips. Claire L. Warga, 2000.
- The 12 Secrets of Highly Creative Women: A Portable Mentor. Gail McMeekin, 2000.
