August 31, 2005
Estrogen Lowers Free Radical Production In Female Rats

Estrogen's effect of lowering free radical production might explain why pre-menopausal women are at lower risk of stroke than same age men.

Estrogen’s role as an inhibitor of toxic free radicals in cerebral blood vessels may be a key reason why premenopausal women have a lower stroke risk than men.

According to UC Irvine School of Medicine researchers, estrogen has a powerful and positive influence on women’s health by increasing the energy production efficiency of mitochondria – the tiny power plants that provide cells the energy they need to function. And in doing so, the hormone inhibits the mitochondrial production of free radical oxygen molecules. Previous studies have shown that excessive amounts of these radical elements in the body, through a process called oxidative stress, can damage blood vessels and lead to stroke or degenerative disease.

In the UCI study, Dr. Vincent Procaccio of the Center for Molecular and Mitochondrial Medicine and Genetics and colleagues discovered estrogen receptors in vascular mitochondrial cells. To see how mitochondria functioned with deficient estrogen levels, they removed the ovaries from test rats, which suppressed any hormone influence, and identified a significant increase in radical oxygen molecule levels and a decline in the capacity for mitochondria to produce energy. In rats treated with doses of estrogen, however, vascular mitochondria produced energy more efficiently with lower amounts of damaging free radicals.

This effect is probably a product of natural selection. But why? Why would estrogen have been selected for to cause this effect? Why wouldn't testosterone cause the same effect? Or why wouldn't mitochondria always work more efficiently and produce less free radicals even without hormones present?

“We want to find out more how estrogen can protect blood vessels in the brain,” said Procaccio, also an assistant professor of pediatrics. “And when we gain a fuller understanding, we hopefully can figure out how best to realize potential benefits of hormone replacement therapies. Also, learning the mechanisms by which estrogen is beneficial to brain circulation may give us new ideas about how to protect against stroke.”

Spurred by recent findings of the Women’s Health Initiative, there is growing debate over the effects of estrogen and the risk of cardiovascular disease and stroke. While women aged 30 to 50 have about five times less risk of stroke than men, this difference disappears when women reach menopause. Research studies show that estrogen protects animals from experimental stroke, but recent clinical trials with certain hormone replacement therapies in older women did not show protection from stroke.

Study results appear on the online version of Molecular Pharmacology. Chris Stirone, Sue P. Duckles and Diana N. Krause of the UCI Department of Pharmacology assisted with the study. The National Institutes of Health provided support.

Another question: If women live with less free radical production until they hit menopause then why do they catch up with men on stroke rates? They should have less total accumulated free radical damage by the time they lose the estrogen that keeps free radical production down. If that is the mechanism by which stroke risk is lower in women then shouldn't their stroke risk remain lower due to less accumulated damage? Even once they start accumulating damage at the same rate as men they still have less damage accumulated and hence their total accumulated damage should continue to lag.

The KEEPS study just getting underway will investigate whether early estrogen supplementation can prevent the increase in heart disease due to menopause.

New Haven, Conn. -- Researchers at Yale School of Medicine and seven other national institutions are recruiting patients to participate in the Kronos Early Estrogen Prevention Study (KEEPS) to look at the effects of estrogen on heart disease prevention.

The study will explore whether beginning hormone therapy in women during the menopausal transition (ages 42 to 58) protects against atherosclerosis, the major cause of heart attacks. Results from a prior study of older women called the Women's Health Initiative (WHI) estrogen plus progestin trial suggested there were few benefits of estrogen on atherosclerosis. The National Institutes of Health halted the study in 2002, but KEEPS will explore issues raised by WHI. Women in WHI were postmenopausal, with a mean age of 62.7, yet most women begin hormone treatment much younger, at the onset of menopausal symptoms.

"Once atherosclerosis is present, it is already too late to prevent it," said Yale principal investigator Hugh Taylor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale. "We think estrogen can help to prevent the disease if started early enough."

Prior to the WHI, most data suggested that hormone replacement therapy was associated with a high degree of protection (30 to 50 percent reductions) against coronary heart disease, mortality and osteoporotic fractures, in addition to a small increase in breast cancer risk.

Once effective anti-cancer treatments are developed the trade-offs of hormone replacement therapies will shift much more clearly toward use of hormone replacements. Also, future cheap DNA testing will allow more accurate predictions of the relative risk of cardiovascular diseases and cancers. Those with lower cancer risk and higher heart disease and stroke risk will be the best candidates for hormone replacement.

But my preferred future solution to the increased risk of heart disease and stroke with age would be to use cell therapies and/or gene therapies to repair the circulatory system. Make the circulatory system young again.

Update: As Sheila reminds me in the comments, a previous post of mine reported evidence that estrogen might not continue to benefit blood vessels in old age. See my post "Estrogen Becomes Vasoconstrictor In Old Age". But perhaps an increase in arginine in the diet could restore the vasodilation effect of estrogen as I discuss in that post.

Share |      Randall Parker, 2005 August 31 02:01 AM  Aging Studies

Sheila said at August 31, 2005 3:15 PM:

And how does all this mesh with your previous post about estrogen becoming a vasoconscrictor in old age? Seems like that would be relevant to stroke risk.

Randall Parker said at August 31, 2005 3:49 PM:


Thanks for reminding me about that. I do not know the answer to your question. We need a study that looks at arginine supplementation in old age to see if the vasoconstriction effect could get cancelled out.

As I said in that previous post, hormone replacement therapies are problematic. Decreased hormone levels might serve adaptive purposes in aged bodies. Hence my general skepticism about using hormon replacement therapies today. Though for women going through particularly tough menopause transitions I can certainly understand why some choose to run the risks.

Robert Nelson,M.D. said at March 16, 2006 9:06 PM:

I am a gynecologist and have been treating menopausal women for 43 years. It is my understanding that after menopause, there is a progressive decrease in the number of estrogen receptors [ alpha and beta?] in all tissues, including coronary arteries. cerebral vessels,etc. If this is so, then it would at least partially explain the conflicting data from years of observational studies showing a significant protection from cardiovascular disease and dementia and WHI data which showed no benefit for either . As a gynecologist, I generally start my patients on HT with the onset of menopause ,not age 63 as in WHI.
I would appreciate your comments and insight on these issues.
Thank you

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