Dr. Merchenthaler is a Professor, Department of Epidemiology and Public Health and Anatomy & Neurobiology, University of Maryland, School of Medicine, Baltimore, MD; and Dr. Prokai is the Robert A. Welch Professor, Department of Molecular Biology & Immunology, University of North Texas Health Science Center, Fort Worth, TX.

For many women going through menopause, hormone replacement therapy (HRT) can be a godsend. Made popular in 1966 by Robert Wilson’s book, Feminine Forever, HRT use rose hugely in the following decades, as it was shown to offer some much-needed relief from many physical, psychological, and cognitive symptoms of menopause — from hot flashes and fatigue to incontinence and insomnia. HRT can also offer the body some important protective benefits, like helping prevent osteoporosis.

But where HRT really flexes its muscles, so to speak, is in the brain. The effects of HRT — of estrogen therapy (ET), in particular — on the central nervous system (CNS) cannot be denied.

Among estrogen’s many benefits in the brain, it also seems to prevent or delay memory and cognitive decline, including diseases like Alzheimer’s and Parkinson’s.

If you think about it, the symptoms of menopause are largely neurological in origin, which many women may not realize. Insomnia, hot flashes, dizziness, anxiety, depression, and fatigue are all originate in the CNS — and all are thought to occur when there is too little estrogen circulating in it. Menopausal symptoms can range from bothersome to debilitating for some women. Among estrogen’s many benefits in the brain, it also seems to prevent or delay memory and cognitive decline, including diseases like Alzheimer’s and Parkinson’s.

But despite its advantages and popularity, hormone therapies are also some of the most controversial treatments out there, as more research comes in about the long-term health implications. As much as we want estrogen to correct symptoms of the CNS, we don’t want too many hormones roaming around the rest of the body. Certain forms of HRT have been shown to increase a woman’s risk of cardiovascular disease, including stroke, as well as some forms of cancer, like uterine and certain breast cancers, although this is still controversial. For these reasons, it’s not completely clear whether the benefits to the brain outweigh the risks to the body for current estrogen therapies.

However, there is a lot of good evidence that safer forms of estrogen are indeed possible, and will exist in the near future. This article will outline the current thoughts on how ET can best be used. Is there a certain window of time when ET should be started to have the most benefits with the least risk? How can we harness the power of ET for the protective and restorative benefits to the brain without harming other tissues of the body? Researchers are still working on many of these questions, but there is already some very strong evidence that we are on the way to developing safe and effective forms of ET.

What Early Studies Taught Us about Estrogen — And Why We Need to Rethink Them

A 1998 study called Heart and Estrogen/Progestin Replacement Study (HERS) showed us that there were some serious heart risks associated with HRT. The study revealed that not only was the risk higher in the first year of using HRT, but there were continued heart risks even years down the road. Then, in 2002, researchers conducted the largest randomized clinical trial of HRT, the Women's Health Initiative (WHI) trial and the WHI Memory Study (WHIMS). Estrogen was shown to decrease the risk of hip fracture and colorectal cancer, as well as prevent hot flashes but increased the incidence of breast cancer, stroke, pulmonary embolism, and coronary heart disease.

Both studies utilized a form of [estrogen made from the urine of pregnant mares]…and a synthetic form of progesterone… These are not the forms of estrogen or progesterone that the human ovary produces.

But unlike HRT, ET by itself had no effect on breast cancer risk. The ET in the WHI study was actually stopped because of the increased risk of stroke that was occurring without any benefit in the prevention of heart disease. These studies led researchers to conclude that though it clearly offers some benefits, the heightened risk of cardiovascular disease was enough to outweigh those benefits.

Findings Based on Estrogen from Horses, Not People
In spite of — or perhaps because of — all the questions the studies raised, researchers realized that the results of these studies may need to be interpreted differently. For example, both studies utilized a form of ET called Premarin®, which is essentially estrogen collected from pregnant mare urine and a synthetic form of progesterone, called medroxyprogesterone acetate (MPA). These are not the forms of estrogen or progesterone that the human ovary produces. There are also many other variables that could affect the results of using ET, like the doses used and methods of administration (patch, orally, or by injection), how long a woman stays on hormone therapy, and the age when she begins the therapy in relation to her age at menopause.
The Timing of ET Matters, Too

In fact, one of the most important issues with ET seems to be the timing of it. Some newer studies that have reanalyzed the WHI data have actually found that if a woman takes ET within 10 years of beginning menopause, she has no more risk of developing breast cancer than anybody else. Moreover, ET in this age group provides certain protection against breast cancer. This is good news. Conversely, if a woman begins ET later than 10 years of beginning menopause, her risk of developing breast cancer does seem to increase. Findings like this show that there is a lot of value to reanalyzing old studies.

However, stroke, probably due to the elevated coagulation and inflammation caused by estrogen, remains a serious risk, regardless of the time from the onset of menopause or the form of HT.

Some newer research has also shown that ET — if started around the time of menopause — can reduce the cognitive decline that comes with age. If it’s started decades later, however, ET does not seem to offer the same protective benefits to mental health. So, it seems that this "critical window" may prevent multiple health problems, in both the body and the brain. In fact, some studies have shown that estrogen has a "healthy cell bias": in other words, it has more potential in preventing problems than for fixing them after they have occurred. This observation also seems to be true in the prevention of memory loss and certain neurodegenerative diseases, including Alzheimer’s.

Despite all the health benefits when hormones are started at the right time, however, stroke is still a serious risk. This is probably due to the fact that estrogen increases inflammation and coagulation (clotting) in the body’s blood vessels, including those of the brain. The risk of stroke with hormone therapy is considerable, too, regardless of when a woman starts therapy, or the form that she uses (ET alone or HRT).

Because the brain is one of the most important targets for ET and its side effects mainly occur in the body’s other organs (uterus, breast, blood and heart/vessels), researchers are very interested in discovering new forms of ET that will provide the greatest benefits to the CNS without causing unwanted side effects in the rest of the body. Doing so would reduce the most disturbing menopausal symptoms (hot flashes, cognitive and memory loss, sleep disturbances, depression, and anxiety), while helping reduce risk for neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease, traumatic brain and spinal cord injury and cerebrovascular stroke. And it would do all this without having the adverse effects in the rest of the body, like the forms of cancer mentioned earlier.

How Estrogen Affects — and Protects — the Brain

Among estrogen’s many benefits, it offers powerful "neuroprotection", which as you might guess literally translates as "protection of the neurons," the cells of the brain and spinal cord. This is, of course, important for women before the onset of menopause, and it’s the reason that estrogen therapy can improve women’s health in so many ways during and after menopause. Estrogen’s neuroprotective benefits work in a variety different ways, most of which are too complicated to get into here, but include both genomic and non-genomic mechanisms.

It is thought that estrogen may actually rescue or prevent neurons from cell death.

For example, estrogen may take part in cell signaling and communication, in maintaining healthy mitochondria (cells’ key energy source), and in promoting overall cellular health by packing a punch to free radicals (tiny molecules that can damage cells’ DNA). In fact, many neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, amyotropic lateral sclerosis [ALS), stroke, etc. are thought to be due to damage by free radicals and aging. Estrogen may help take care of free radicals by actively scavenging for them directing or by helping to boost other endogenous substances that do the same.

Rescuing Cells from Certain Death
Another way that estrogen protects the brain is by regulating how cells live — and die. Estrogen can promote cell survival and the formation of neurons (neurogenesis) through a variety of avenues, like nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophins, and insulin-like growth factor 1 (IGF-1). As mentioned, estrogen can also affect the life-cycle of the cell by staving off cell death. A process called apoptosis (a.k.a. "cell suicide") is a regulated form of cell death that removes unneeded or damaged cells and is key to cells’ development and general well-being. It is thought that estrogen may actually rescue or prevent neurons from cell death. Though cell death is sometimes considered necessary, when neurons die, they are typically not replaced; therefore, it behooves the brain to lose as few neurons as possible.

Preventing Inflammation
Estrogen has also been shown to help reduce inflammation, which can lead to a host of health problems. In the rest of the body, inflammation can cause heart disease and type 2 diabetes, and in the brain it is linked to multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, stroke, brain and spinal injury and sepsis. Specifically, estrogen can reduce not only the expression of "neuroinflammatory" compounds in the brain but the selective permeability of the blood-brain barrier — if this sounds complicated, it is! But the end-goal is that inflammation in the CNS is reduced. Not surprisingly, estrogen actually works in multiple ways to prevent inflammation in the nervous system, and lead to better brain health.
Going Forward: Targeting Estrogen Receptors in the Brain, Soy And Other New Approaches

Early studies (albeit in rodents) gave researchers great hope for using certain kinds of estrogens to treat diseases that affected the brain. The second type of estrogen receptor, called ERβ, was discovered fifteen years ago, which is present at high concentrations in certain areas of the brain but not in the rest of the body. For instance ERβ seemed to be involved in the development of Alzheimer's disease, dementia, and depression. But the receptor was expressed only low concentrations or absent in the uterus, pituitary gland, and breast — and it is these areas of the body that we don’t want estrogen to go, because of the increased risk of bleeding and cancer. Therefore, developing an estrogen that would "prefer" to bind to this ERβ receptor would be a great boon for menopause research and menopausal women alike.

Newer research on ERβ has led to promising results. For example, it has been found to play a crucial role in how estrogen fights degeneration in the brain, as well as boosts learning and memory. In addition, researchers suspect that ERβ could be a powerful tool to fight an array of conditions including brain disorders likes anxiety Though there are some differences in the ways that ERβ is distributed throughout the body in rodents vs. humans (and much of the initial research was on rodents), researchers are still very optimistic about the potential for using estrogens that target ERβ in the brain specifically.

Estrogens from Plants: Can Soy Really Help?
Many women may have heard of the potential benefits of eating soy products to help with menopause symptoms. Though the research on soy has been mixed, there is some evidence that soy may mimic the effects of estrogen in the body. Soy is a phytoestrogen, which is a weaker form than the estrogen that animals produce. It is thought that phytoestrogens like soy may be behind the finding that Asians, of both sexes, have lower incidences of sex hormone-related disorders (like prostate cancer in men and breast cancer and hot flashes in women), compared to Westerners.

Soy is a phytoestrogen, which is a weaker form than the estrogen that animals produce. It is thought that phytoestrogens like soy may be behind the finding that Asians, of both sexes, have lower incidences of sex hormone-related disorders.

The high intake of soy foods has also been linked to the low rate of Alzheimer’s disease in Asia compared to the Western world, though studies on this topic have led to mixed results. One reasons for this is the evidence that the GI tracts of many Asian people produce a certain end-product from soy, called equol (an isoflavone), which Westerners are less likely to produce. And it may be this difference that is key in Asians’ lower incidence of menopause symptoms and other hormone-related diseases. If this is the case, it would mean that just adding soy to the diet would not necessarily have the desired effect. But some studies have found that women who are actually administered the compound equol do have some improvements in menopause symptoms (depression, anxiety, and fatigue), but more research will need to be done to fully understand the link between soy and estrogen.

Are There Other Estrogen "Mimics" We Can Take Advantage of?
Another way to retain estrogen’s beneficial brain effects while avoiding the adverse organ effects is to come up with "estrogen-like" compounds. These molecules do not function exactly like the parent hormone, estrogen, but they behave in similar ways. Sometimes these are called non-feminizing estrogens (though this is a bit of a misnomer), and they should technically avoid all the side effects of chronic estrogen therapy, which affect the uterus, breast, liver, and other organs. They can also be used in both women and men, in certain circumstances.

It has been difficult, however, to create good estrogen-like compounds because they need to behave in very specific ways. Must research has been devoted to designing these molecules to retain all the neuroprotective effects of estrogen, by tweaking the molecular structure in various ways, for example. Some have looked promising when they were tested in rats, but because the compounds were ultimately large and attracted too much to fat, they would not have been appropriate to move forward with drug development. Still, there is research being devoted to the development of good mimics, and researchers remain optimistic about their potential.

Precursors to Estrogen: The Prodrugs
Another method for getting estrogen to the brain without affecting the rest of the body is to give women a compound that’s not quite estrogen — yet. In other words, a precursor of estrogen, or a prodrug, can be converted into estrogen after it is inside the body. Therefore, the prodrug is not an active form, and only becomes so once it’s fully converted by the body (and this should theoretically occur in the area of the body that the drug is meant to affect). Studies have found that using prodrugs can actually boost the effectiveness of a parent drug.

Though there’s still a ways to go, researchers are very encouraged by the results of studies so far, and women — menopausal or not — should be encouraged, too.

Researchers especially like the idea of prodrugs because there is not a lot of cost or risk associated with their development. There has been a good amount of research devoted to developing estrogen prodrugs, not only for the treatment of menopause symptoms, but also for treatment of other diseases, like Alzheimer’s disease and stroke. Some prodrugs are particularly good at gaining access to and remaining in the brain, which is not an easy thing to do — this is because of a tight "blood-brain barrier", which is meant to keep toxins and other unwanted molecules in the blood stream rather than the brain.

Though there have been some hurdles to developing estrogen prodrugs, researchers are still hopeful about using this class of drugs for treating a variety of menopause symptoms. In fact, one promising drug, called estrogen-derived para-quinol, has been shown to act primarily in the brain, and even better, it does not seem to give off any toxic by-products. Experiments in rats have shown encouraging results, and hopefully more research will explore estrogen prodrugs for use in humans.

Is There Hope for Effective Estrogen Therapies? Absolutely!

To recap, though early studies raised some concerns about using estrogen safely, when researchers looked deeper into these findings, they saw trends that would allow them to develop better ones in the future. Some of the important variables seemed to be what kinds of hormones were being used (estrogen vs. combination), how it was administered, and the age the woman started on hormones relative to her age at menopause (the "critical window").

We want estrogen to work in the brain and the rest of the nervous system, not in the organs of the body. The nervous system needs it to function smoothly — when estrogen is missing, this is where the symptoms of menopause begin (hot flashes, fatigue, muscle weakness, depression, anxiety, and insomnia). And researchers are working hard to discover new and clever ways to get estrogen to our nervous systems without letting it affect the rest of the body. Some of these methods — phytoestrogens, estrogen "mimics" and the prodrugs — are looking like powerful prospects. The prodrug approach seems particularly promising and powerful as it can be administered not only to women but to men — yes, even men may benefit from treating their brain selectively with estrogens for conditions ranging from Alzheimer’s disease to sexual disfunctions. Though there’s still a ways to go, researchers are very encouraged by the results of studies so far, and women — menopausal or not — should be encouraged, too.

Acknowledgments

The authors’ research in this subject has been supported in part by grants (AG031535 to I.M. and L.P., NS044765 to L.P.) from the National Institutes of Health and by a grant to I.M. from Ausio Pharmaceuticals. L.P. acknowledges endowment (BK-0031) from the Welch Foundation.