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Estrogen: Rejuvenation for the Aging Brain

Published October 4, 2015

By Dr. Bryan Warner

Most people think of estrogen as the female sex hormone, but it’s also a vitally important brain hormone. In fact, it’s essential for a woman’s brain to function at peak efficiency.

If you’re a woman entering perimenopause (which begins with the period leading up to menopause), you may find yourself experiencing more than hot flashes. You may become memory-brainuncharacteristically forgetful and have increasing episodes of “brain fog” ― that is, lack of focus and mental clarity. Words or names may hover on the tip of your tongue, but don’t quite materialize in speech. Purpose may slip from the mind before you can walk from one room to another. The car keys mysteriously disappear.

Some women find that, when they become post-menopausal, these symptoms lessen and their brains resume more normal functioning, but for others they persist. And, sadly, estrogen deficiency has also been associated with Alzheimer’s disease, which destroys not only memory and cognition but the victim’s very persona.

Research in neurophysiology has made considerable progress in locating where certain functions and processes occur in the brain. Researchers have also focused on determining how diminishing gonadal steroids ― the major sex steroid hormones estradiol, progesterone and testosterone ― affect the central nervous system, causing not only memory loss and fuzzy thinking but also mood changes.

While women can’t avert menopause, they can avoid the gradual loss of its effects on the brain. They have the choice of whether or not their bodies will be deprived of estrogen in the years following menopause. So, for women approaching that time of life, the question becomes whether or not to supplement.

Is Estrogen Therapy Right for You?

You may remember: In 2002, the National Institutes for Health halted the Women’s Health Initiative (WHI) study prematurely, setting off alarm bells for many women who were on hormone replacement therapy (HRT). Panicked by the findings of a higher incidence of breast cancer, heart attacks and stroke among women taking Prempro, a combination of estrogen and progestin, millions of women quit the drug cold turkey. And the millions who opted to continue with HRT lived in fear of the consequences.

In subsequent years, criticism of the WHI’s methodology mounted, and the study’s findings were clarified to show that the synthetics Premarin and Provera did not apply well to natural human hormones. The new understanding? Not only does human estrogen supplementation protect against heart disease and stroke, but it relieves menopausal symptoms, improves vaginal dryness, helps prevent osteoporosis and decreases cholesterol (when given topically) ― and, very importantly, it improves memory and lowers the risk of Alzheimer’s disease.

To be clear, Prempro, the drug used in the WHI study, is a synthetic drug made from progestin and conjugated equine estrogen (CEE), which comes from the urine of pregnant mares. Not even counting the cruelty to which donor mares are subjected in making the drug, there are problems with this product. For one, the estrogen has to bind with a receptor, and it’s questionable how well CEEs bind to human receptors. That’s one reason that, in our practice, we use natural estrogen (estradiol) derived from plants that is “bioidentical” with human-produced estrogen. Studies using estradiol have proved more reliable than those conducted with CEE, which contains only a small fraction of the hormone used in estradiol-only tests.

How Does Estrogen Reduction Affect Memory?

Estrogen is highly active in the brain. It protects brain neurons, stimulates neuronal growth, helps repair damaged neurons and connects with receptors on neurons to influence brain activity.  It increases neurotransmitters such as serotonin, dopamine and norepinephrine, which are needed for normal functioning, along with the number of receptors for these transmitters. In addition, it increases blood supply, which is essential for the brain to function.

When estrogen production is diminished by age or surgical removal of ovaries, neuronal connectivity is impaired. As a result, neurotransmitters are reduced and blood supply is diminished. The brain doesn’t have what it needs to function well.

Around 85% of perimenopausal women have hot flashes, a sudden feeling of heat in the upper body. Although these sensations are not well understood, they begin in the brain and are thought to be caused by low estrogen levels (though progesterone and testosterone contribute as well). But it’s a mistake to think that hot flashes are just an annoyance. They may, in fact, signal neurologic problems. For instance, they correlate with memory impairment in women whose ovaries have been removed. Moreover, it is thought that hot flashes aren’t just symptomatic of estrogen loss but rather actually contribute to aging and degeneration of the brain, especially in the hippocampus, which is the center for memory and cognition.

The good news? Estrogen replacement therapy (ERT) with estradiol can relieve hot flashes and reestablish normal blood flow and functioning in the brain.

Around the age of 50, as perimenopause advances and estrogen diminishes, women’s brains begin to shrink. This occurs primarily in the hippocampus and parietal lobe, which are the areas most associated with memory and cognition, and may account for the brain fog, short-term memory problems and verbal memory problems that women in this stage of life commonly report. Men don’t experience a comparable loss in brain size for approximately another ten years.

Again, ERT can help forestall brain atrophy.

The Cholinergic Hypothesis

Acetylcholine, the first neurotransmitter discovered, has a number of functions, but one of the most important is its key role in learning and memory formation. Cholinergic (acetylcholine-producing) neurons in the basal forebrain are nerve cells that send messages through acetylcholine to the hippocampus.

With age and/or the onset of Alzheimer’s disease (AD), this process declines, impairing the ability to form and recall memories.

More than 25 years ago, several influential studies set forth the idea that, by affecting cholinergic neurons, estrogens could influence cognitive performance. Since then, research has documented conclusively that estrogen-stimulated cholinergic projections to the cerebral cortex play a key role in memory, attention, perception, awareness, thought, language, and consciousness. And, in the hippocampus, they promote memory formation.

It has also been shown that, when deprived of estrogen, cholinergic processes begin to shut down. Without compensating estrogen therapy, the result is a gradual march to impaired thinking, faulty memory and possibly dementia.

Can Estrogen Therapy Really Prevent and Treat Cognitive Decline?

As the years tick by, most of us reach a point at which old age looks more and more like a reality. And for many of us, the possibility that we might lose our ability to think, remember and function normally hangs over our heads like a sword of Damocles. But take heart. We are lucky to be living in our time when researchers have reached a level of understanding of the brain that enables us to take preventive action.

A recent study showed that women who embarked upon estrogen therapy for two to three years shortly after the onset of menopause reduced their risk of cognitive impairment by 64%.

Another study followed women with a mean age of 74.4 years who had previously used estrogen therapy and compared them to women who had not. Those with past estrogen use had a significantly lower risk of developing Alzheimer’s. What’s more, the longer these women continued therapy, the lower their risk became.

These and other studies add up to good news for women who have yet to go through menopause, or who are currently in the perimenopause stage: If you begin estrogen therapy around the time of menopause and continue it for several years, you will likely enjoy long-term protection against cognitive impairment. And, according to another study, you will also lower your risk of developing Alzheimer’s by around 65 percent.

On the other hand, your ability to benefit from estrogen therapy and protect against Alzheimer’s progressively diminishes the longer you wait after menopause to start. The reason? To achieve a protective effect, you need to start receiving estradiol before your ability to produce cholinergic projections begins to deteriorate.

Is It Time to Plan for Your Postmenopausal Life?

We buy insurance. We invest and save for the future. In other words, we wisely look ahead and plan in many ways to make our future lives as secure and productive as possible as we age. But is anything more important than protecting your brain’s ability to function well?

Helping women understand what happens in menopause and the risks that can come with hormonal changes is an important part of our practice ― as is helping them reduce those risks by designing a customized ERT program tailored to their body’s unique needs.

We’ll be glad to talk with you about what you can do to reduce your risk of mental decline as you transition to a new life phase. Just call us at 314-735-0780 for an appointment.


Daniel, J. & Donanich, G. Acetylcholine Mediates the Estrogen-Induced increase in NMDA Receptor Binding in CA1 of the Hippocampus and the Associated Improvement in Working Memory. Journal of Neuroscience. September 1, 2001, 21(17):6949-6956. full.pdf. Accessed: September 14, 2015.

Garbe, E. and Suissa, S. Issues to debate on the Women’s Health Initiative (WHI) study.

Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies. Human Reproduction. (2004) 19 (1): 8-13. doi: 10.1093/humrep/deh022. Accessed September 17, 2015.

Gibbs, R. Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis. Endocrine Reviews, 2010 Apr; 31(2):224-253. Published online: December 17, 2009. Accessed: September 15, 2015.

Shepherd, J. Effects of Estrogen on Cognition, Mood, and Degenerative Brain Diseases. Journal of the American Pharmacists Association. 2001; 41(2). Accessed: September 15, 2015.

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  • My husband and I have been going to Dr. Warner for about three years now.  I started mainly because I felt I had a hormone imbalance.  I had gone through menopause just a few years before.  My blood pressure, which had been great my entire life, went high, my hair was falling out, incontinence, sleep problems, and just normal aging…Read More
  • In August 2010, my husband and I became patients of Dr. Bryan Warner. I was so excited about the appointment. I had been studying about Bioidential Hormone Therapy. I had many issues i.e., low energy, weight gain, sleeplessness and night sweats.  Dr. Warner has been a tremendous blessing to me and my husband. He has a wealth of knowledge. Dr.…Read More
  • My aging body loves BHRT and what it can do.  With Dr. Warner, I find that no subject is off limits and I'm very comfortable discussing any hormonal, health or aesthetic needs.  I so appreciate that I don't have to sign up for expensive concierge service and he still willing to deal with my unusual issues.  Also, I am very…Read More



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