March 31, 2015
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Easing Menopause: Estrogen For the Brain
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Easing Menopause: Estrogen For the Brain

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).(1)(2)(3) 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.(4)

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