Researchers discovered that long periods of estrogen deprivation in aging rats have a severe impact on reducing the number of brain receptors for the hormone and increases stroke risk.
According to a study in Proceedings of the National Academy of Sciences, the impairment is forestalled if estrogen replacement starts shortly after hormone levels drop.
Dr. Darrell W. Brann, Chief of GHSU's Developmental Neurobiology Program and the study's corresponding author writes:
"This is further evidence of a critical window for estrogen therapy, either right before or right after menopause."
According to the results of a 12-year study of 161,808 women between the ages of 50-79 of the widely publicized Women's Health Initiative, hormone therapy generally increased the risk of stroke as well as other health problems. The study was criticized because many women, like Brann's aged rats, had gone years without hormone replacement, supporting the case that timing is vital.
Brann's earlier studies in the hippocampus, a center for cognition, learning and memory, also displayed a reduction in hormone receptors in younger rodents that were models of surgical menopause; however, questions remained about why the loss happened and if it occurs naturally with aging.
The new study reveals this loss by discovering that inactive receptors become targets for elimination in rats mimicking 60-65 year olds, about a decade past menopause; however, the receptor loss did not affect the uterus which continued to remain sensitive to estrogen.
Researchers detected, after prolonged periods of estrogen starvation, that an enzyme called CHIP - carboxyl terminus of Hsc70 interacting protein - increased binding with estrogen receptor alpha, a major brain receptor for neuroprotection. Although CHIP levels remain unaltered, the increased binding results in approximately half the receptors getting hauled to the cell's proteosome to be chopped up and degraded. Brann said, "We think this is the mechanism for how the receptor gets degraded."
When researchers later treated the aged rats with estrogen, they found what the Women's Health Initiative showed: increased mortality.
"So it did not seem to do anything good and maybe it did some harm in older rats and that is similar to what the WHI found," Brann said. The brain protection afforded by estrogen when given earlier to the rats, suggested the "critical window."
Additionally when CHIP activity was blocked, so was the receptor destruction.
Researchers who treated the aged rats with estrogen at a later time confirmed what the Women's Health Initiative displayed: increased mortality.
"So it did not seem to do anything good and maybe it did some harm in older rats and that is similar to what the WHI found. The brain protection afforded by estrogen when given earlier to the rats, suggested the "critical window."
It also revealed that when CHIP activity was blocked, so was the receptor destruction.
Subsequent research includes treating those rats with estrogen where CHIP-related destruction is blocked to establish whether salvaged receptors will respond, as well as determining what processes occur in other areas of the brain.
Brann, who also is Associate Director of GHSU's Institute of Molecular Medicine and Genetics said:
"We think the estrogen receptor decrease is why the sensitivity decreases. If the hormone is gone long enough it is logical there would be decreased sensitivity as normal feedback between the receptor and hormone is reduced."
Written by Grace Rattue