Long periods of estrogen deprivation jeopardize brain receptors,stroke protection

Prolonged estrogen deprivation in aging rats dramatically reducesthe number of brain receptors for the hormone as well as itsability to prevent strokes , researchers report. However the damage is forestalled if estrogen replacement beginsshortly after hormone levels drop, according to a study publishedin the journal Proceedings of the National Academy of Sciences . “This is further evidence of a critical window for estrogentherapy, either right before or right after menopause ,” said Dr. Darrell W. Truck Mounted Crane

Brann, Chief of GHSU’s DevelopmentalNeurobiology Program and the study’s corresponding author. The surprising results of the much-publicized Women’s HealthInitiative – a 12-year study of 161,808 women ages 50-79 – foundhormone therapy generally increased rather than decreased strokerisk as well as other health problems. Critics said one problemwith the study was that many of the women, like Brann’s aged rats,had gone years without hormone replacement, bolstering the casethat timing is everything. Brann’s earlier work in the hippocampus, a center for cognition,learning and memory, also showed a reduction in hormone receptorsin younger rodents that were models of surgical menopause but leftquestions about why the loss occurred and whether it occurrednaturally with aging. China Knuckle Boom Truck Crane

The new study documents that loss as unusedreceptors become targets for elimination in rats mimicking 60-65year olds, about a decade past menopause. Interestingly, thereceptor loss did not occur in the uterus, which remained sensitiveto estrogen. After long periods without estrogen, researchers found that anenzyme called CHIP – carboxyl terminus of Hsc70 interacting protein- increased binding with estrogen receptor alpha, a major brainreceptor for neuroprotection. While CHIP levels remain unchanged,the increased binding results in about half the receptors gettinghauled to the cell’s proteosome to be chopped up and degraded. “Wethink this is the mechanism for how the receptor gets degraded,”Brann said. China Wrecker Tow Truck

When researchers later treated the aged rats with estrogen, theyfound what the Women’s Health Initiative showed: increasedmortality. “So it did not seem to do anything good and maybe it didsome harm in older rats and that is similar to what the WHI found,”Brann said. The brain protection afforded by estrogen when givenearlier to the rats, suggested the “critical window.” Additionallywhen CHIP activity was blocked, so was the receptor destruction. Next steps include estrogen-treating those rats where CHIP-relateddestruction is blocked to see if salvaged receptors will respondand looking at the process in other areas of the brain. “We think the estrogen receptor decrease is why the sensitivitydecreases,” said Brann, who also is Associate Director of GHSU’sInstitute of Molecular Medicine and Genetics.

“If the hormone isgone long enough it is logical there would be decreased sensitivityas normal feedback between the receptor and hormone is reduced.” Collaborators include scientists at Hebei United University inChina and the University of Texas Health Sciences Center at SanAntonio. Dr. Quan-guang Zhang, Research Scientist in Brann’s lab,is the study’s first author. Aged rats were obtained from theNational Institute on Aging and studies were funded by the NationalInstitutes of Health and American Heart Association. Additional References Citations.

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