ESTROGEN THERAPY IMPROVES COGNITION; MAY PROTECT BRAIN, SPINAL CORD
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ESTROGEN THERAPY IMPROVES COGNITION; MAY PROTECT BRAIN, SPINAL CORD.
ORLANDO, Monday, Nov. 4 - Administering estrogen appears to have positive effects on cognition and may even protect the brain and spinal cord from the effects of stroke or injury, research shows.
Estrogen is the primary female sex hormone and is manufactured mostly in the ovaries. Although it is derived from testosterone, the primary male sex hormone, and is present in men in small quantities, estrogen accounts for many of the differences between the sexes. But estrogen interacts with cells and systems throughout the body, including the brain. The new studies were reported today during the 32nd annual meeting of the Society for Neuroscience.
Sanjay Asthana, MD, of the University of Wisconsin-Madison Medical School, found that healthy postmenopausal women who took estrogen or estrogen combined with another hormone, progesterone, outperformed women given a placebo on the Stroop Test, measuring attention and concentration (in the Stroop Test, the name of a color is written in a color other than what it is; the individual's task is to report the color in which the word is written). On average, women receiving estrogen or the combination of estrogen and progesterone improved their ability to concentrate by about 30 percent.
Over a 12-week period 30 women between the ages of 53 and 80 randomly were assigned to receive a daily dose of estrogen and a placebo, estrogen plus progesterone (opposed estrogen), or two placebo tablets.
"Not only did estrogen alone have a beneficial effect on cognitive abilities, but our results suggest that combined hormone replacement therapy does not detract from this benefit," Asthana says. "It's generally believed that administration of progesterone can induce depression and worsen memory. But our results show that treatment with
opposed estrogen does not have an adverse effect on reasoning ability."
Animal studies provide the basis for the cognition-enhancing effect of estrogen. Results of several trials suggest that several mechanisms are involved, such as the modulation of long-term potentiation, augmentation of neurotransmitter activity, development of new synaptic connections, increase in cerebral blood flow or antioxidant activity.
The next step, Asthana says, is to replicate these new human findings in a study that includes many more women and hormone replacement therapy of longer duration. It's also crucial, he adds, to see if different forms of estrogen exhibit differential effects on the cognitive abilities of healthy, older women.
In another study, data from a non-human primate model show that estrogen affects the number of synapses in the hippocampus and also increases the number of synapses in the area of the cerebral cortex that plays a role in many of the more complex aspects of cognition, such as memory storage, attention and planning. The hippocampus is a seahorse-shaped brain structure involved in learning, memory and emotion.
In the study, the researchers removed the ovaries of 10 young and 10 older Rhesus monkeys (equivalent to humans in their 20s and 60s). Half of the experimental population received an estrogen replacement injection once every three weeks, which approximated their natural state.
"We looked for the presence of spinophilin, a protein present in dendritic spines, which are pointed projections along the tree-like extension of a neuron cell body," says John Morrison, PhD, of the Mount Sinai School of Medicine in New York City. "These are the parts of the nerve cell likely to mediate the brain's ability to form new connections
involved in learning and memory.
"We assessed the number of spines quantitatively and were able to show that the animals that had estrogen replacement therapy had a 36 percent increase in the number of spines in Layer 1 of the prefrontal cortex," he says. The prefrontal cortex is the site of the highest level of intellectual function in humans. It is known to be susceptible to functional decline and exhibits structural changes with aging. It is one of the areas devastated in Alzheimer's disease.
These findings are important, Morrison explains. "First, they reveal for the first time that the hippocampus is not the only region of the brain associated with memory and cognition that is likely to be affected by estrogen. These results also may have implications for a protective effect of estrogen against Alzheimer's disease as well as the hormone's ability to counter a cognitive decline that occurs with normal aging," he says.
The next step in this research will involve determining the precise biochemical and synaptic changes brought about by estrogen in the prefrontal cortex and the hippocampus, as well as understanding how these changes modify information processing. Some of this research will involve animals who have undergone behavioral testing, which will allow the scientists to examine the neurobiological basis of behavioral enhancement due to estrogen replacement.
"Once we understand the behavioral, biochemical and structural effects of estrogen in these areas of the brain, we will be able to test new and more specific methods of administration, dosage effects and new estrogen receptor agonists designed to affect these brain regions in a manner that carries less risk to other organ systems," says Morrison.
Researchers also have found a crucial association in understanding how low levels of administered estrogen protect neurons in the brain from the effects of low blood flow that occurs with stroke.
Phyllis Wise, PhD, of the University of California at Davis and her colleagues surgically removed the ovaries of young and middle-aged rodents, inducing a state of menopause and eliminating estrogen production. The rodents then were divided into two groups, one of which received low "natural" doses of estradiol while the other group received placebo. One week later, the scientists then induced strokes by blocking blood flow in a major brain artery.
"This and other studies allowed us to uncover fundamental mechanisms by which estradiol acts to protect the brain against stroke injury," says Wise. "First, estradiol slows the progression of cell injury and diminishes the extent of cell death in the brain that occurs during the later phases of injury. Estradiol also diminishes the extent of programmed cell death so more cells survive, especially in the cerebral cortex. Our most recent finding is that estradiol also has a positive effect on the birth of new cells, and may diminish proliferation of cells that mediate the inflammatory response following stroke."
"Some of our earlier work had shown that an estrogen receptor called ER-alpha must be present for estradiol, the major type of estrogen made by the body, to exert its protective effect," says Wise.
Our studies clearly establish, too, that estradiol replacement accelerates and amplifies the expression of the ER alpha receptor, she explains. By binding to this receptor, estradiol activates survival genes, suppresses harmful genes and/or influences cell proliferation.
"We recently proved the ER alpha receptor is absolutely essential in protecting the brain from the injurious effects of stroke by using knockout mice that lack this receptor," Wise says. "Estradiol failed to protect the brains of these mice when strokes were induced."
These pivotal findings point to the need for developing estrogens that target the ER alpha receptor to promote protection against certain brain conditions, Wise says.
Scientists also are investigating estrogen's use as protective against damage due to spinal cord injury.
A team of investigators in Korea and at the University of Maryland School of Medicine in Baltimore have found that estrogen given to rats with spinal cord injuries reduced the expression of programmed cell death (a process known as apoptosis) and improved hind-limb motor function.
"Severe spinal cord injury initiates a complex series of cellular and molecular events that induce apoptosis of a massive number of cells, leading to permanent neurologic deficits," says Tae Oh, PhD, of the University of Maryland School of Medicine. "The synthetic steroid methylprednisolone is the only drug currently available for reducing these deficits."
But estradiol, which also is a steroid, is known to have a positive effect on certain neurodegenerative diseases and decreases the amount of cell death in animal models of stroke. Thus, Oh and his colleagues hypothesized that it would assist in recovery from spinal cord injury.
"One of the promising signs we saw in rats given estradiol after spinal cord injury was improved hind-limb motor function," says Oh. "Thirty days following the injury, scores that assessed motor function were significantly higher in the eight injured rats treated with estradiol than in the eight rats in the placebo control group."
After assessing motor function, the scientists analyzed tissue from the rats' spinal cords. "We saw that estradiol significantly reduced the size of lesions within the spinal cord following injury," he says. "In addition, treatment with estradiol after injury significantly decreased the activity of an enzyme called caspase-3, a macromolecule we know is instrumental in apoptosis. It also significantly increased the expression of a protein called bcl-2, which we know also inhibits apoptosis."
Oh says he and his colleagues currently are investigating the precise mechanisms by which estradiol exerts these protective effects, as well as the optimal dose of estradiol for treating spinal cord injury in rats. Eventually, this research may lead to the development of a therapeutic agent that would reduce apoptosis and subsequent neurologic deficits in humans following spinal cord injury.