HRT & the Brain

Does hormone replacement protect the brain?

by Tabitha M. Powledge

Does hormone replacement protect the brain? Never mind the equivocal results of clinical trial data, animal researchers say yes, definitely. The conclusions of recent clinical trials may be confusing and controversial, but Phyllis Wise and her colleagues consistently report that very low levels of estrogen replacement reduce injury from stroke in animals.

In studies at the University of Kentucky in Lexington and the University of California at Davis, the researchers have shown that 17-beta-estradiol - the estrogen produced in the human ovary - protects animal brains by changing the expression of several genes, thereby altering the level of neurogenesis.

There is agreement from Robert Gibbs, a reproductive physiologist at the University of Pittsburgh, that animal studies clearly demonstrate that hormone replacement helps prevent age-related cognitive decline. "Definitely yes," he said.

However, this view contrasts with the most recently published data from the large Women's Health Initiative, which suggests that not only does combination hormone replacement therapy have no obvious neuroprotective benefit for women, but it even seems to increase their risk of stroke.

There are several reasons for the apparent discrepancy, say researchers. Wise explains the differences between the latest clinical trial and her lab's results this way: "This was hormone replacement, not estrogen replacement, and the estrogen is not estradiol 17-beta but a combination of multiple estrogens made in horses," she told BioMedNet News.

"Also, what we're looking at is not the risk of stroke, but injury after you have a stroke," she added. Gibbs, among others, suggests there may be a window of opportunity in which hormone replacement must be initiated in order to be effective, and that the size of the estradiol dose matters.

In a recent unpublished study, researchers in Wise's lab showed that estrogen increases proliferation of cells in the dorsal sub-ventricular zone of the brain, and that a significant proportion of the cells created were neural precursors. However, what subsequently happens to these precursors is still a mystery, she says. "We don't know whether they go on to become neurons," she said.

Many of the animal studies in the Wise lab are designed to mimic comparisons of postmenopausal women on hormone replacement therapy and women not taking hormones. In one, ovariectomized rats were given both low and high physiological levels of estradiol for a week before occlusion of their cerebral arteries. In the rats that got estradiol, the volume of the resulting infarct was significantly lower than it was in control rats treated with oil, she says.

But different brain regions responded differently to estradiol. Injury size was reduced overall and in the cortex, but not in the striatum, says Wise. Protection was not due to alterations in cerebral blood flow that permitted more nutrients to reach the brain, she says. And estradiol protected even middle-aged animal brains. "To our surprise, it was very efficacious in the cortex," said Wise.

Estrogen protects the brain in several different ways, depending on the type of injury, the brain region affected, and the hormone dose. Wise and her colleagues believe that low, physiological levels of estradiol protect the brain from stroke injury by upregulating estrogen receptor mRNA, thus preventing downregulation of expression of estrogen receptor (ER) genes in the cerebral cortex. They also found that estradiol does not protect against injury in tissue explants treated with an ER antagonist.

With the help of two kinds of knockout mice, one lacking ER-alpha and the other without ER-beta, the researchers showed that physiological levels of estradiol reduced the volume of stroke injury both in the ER-beta- knockouts and wild-type mice, but not in the ER-alpha-knockouts. Wise concludes that only the ER-alpha receptor is critical to preventing ischemic injury., 6/03

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