AUGUSTA, Ga. – For estrogen replacement to provide stroke
protection, it likely must be given soon after levels drop because
of menopause or surgical removal of the ovaries, scientists report
in the Journal of Neuroscience.
Animal studies indicate a "critical period" for estrogen
replacement and that when therapy is delayed, estrogen receptors on
brain cells are significantly diminished along with the
neuroprotection estrogen typically conveys, according to scientists
from the Medical College of Georgia, North China Coal Medical
University and the University of Texas Health Sciences Center at
San Antonio.
"We looked at the controversy over whether estrogen is going to
be beneficial after long periods without it and found the answer
appears to be 'no,'" says Dr. Darrell W. Brann, chief of MCG's
Developmental Neurobiology Program and the study's corresponding
author.
The controversy he's referencing resulted from the Women's
Health Initiative, a 12-year study of 161,808 women ages 50-79 that
examined the health benefits of hormone replacement therapy. Among
the surprising findings was that estrogen and estrogen plus
progesterone therapies, actually increased stroke risk rather than
reduced it. Critics said one problem with the study was that many
of the women had gone years without hormone replacement.
The animal studies indicate that they may be right, at least in
terms of estrogen's ability to protect the brain. The studies
focused on the hippocampus, a center of learning and memory, where
scientists showed that estrogen was strongly protective against
stroke in rats that got estrogen one week after surgical removal of
their ovaries. When replacement therapy was delayed by 10 weeks
after removal – equivalent to a couple of years of human life
– estrogen was essentially useless.
A closer examination of the rats who went 10 weeks without
estrogen showed alpha receptors, believed to mediate
neuroprotective effects of estrogen, were decreased by 50 percent
or more.
"That is why the receptors could not respond," says Dr. Brann,
who also is associate director of MCG's Institute of Molecular
Medicine and Genetics. "That seems to the fit the data that there
is something estrogen is doing that is necessary to maintain the
receptor at the proper levels."
Interestingly estrogen receptors were still intact and receptive
in the uterus, another important estrogen target. "We are trying to
figure out why there is a tissue difference," Dr. Brann says.
But inside the brain, there were other signs of collateral
damage from estrogen deficits. CA3, an area of the hippocampus that
tends to be stroke resistant, became vulnerable to stroke in rats
that went long term without estrogen. "Estrogen must be doing
something that is very critical for the protection of CA3 and we
think it's suppressing NADPH oxidase production," Dr. Brann says.
NADPH oxidase, the enzyme which makes the free radical superoxide,
is found in high levels in the nearby CA1 region, but in low levels
in CA3. Both regions, he notes, are critical to learning and
memory.
When a stroke happens, estrogen helps suppress free radical
production in CA1, which can become deadly to cells at further
increased levels. The studies showed CA1 and CA3 regions were
equally vulnerable to stroke in animals that went long periods
without estrogen.
"If this is also true in humans, just using surgical menopause
as an example, most women would be fine unless they came upon a
severe stress," Dr. Brann, noting that stress could be not just a
stroke but even severe emotional stress or simple aging. It may
also explain why women who undergo surgical menopause are at
increased risk of cognitive loss and dementia. "That is what we are
thinking based on this data," Dr. Brann says.
Next steps include studying the state of estrogen receptors in
the brains of naturally older rats – equivalent to about age
70 in humans – to see what happens with normal age-related
estrogen loss, waiting a while, then putting estrogen back to see
if there is any benefit.
They also want to examine the neuroprotective benefits of
estrogen made locally in the brain compared with that made by
ovaries, the largest estrogen source. In the past decade,
scientists have learned that neurons and the supportive glia cells
in the brain locally produce estrogen via the enzyme aromatase.
Both men and women have estrogen receptors in the brain and the
scientific consensus is that men's brains also produce
estrogen.
SOURCE