Extended Periods of Estrogen Deprivation Increases Risk of Stroke

According to a recent study, estrogen deprivation for an extended period of time radically diminishes the number of brain receptors for the hormone, along with its capability to prevent strokes.

The damage, however, can be averted if estrogen replacement takes place closely following the plunge in hormone levels.

"This is further evidence of a critical window for estrogen therapy, either right before or right after menopause," reported the corresponding author of the study, Dr. Darrell W. Brann, Chief of Georgia Health Science University’s Developmental Neurobiology Program.

Brann’s research follows a previous, well-known study, the Women’s Health Initiative (WHI), which followed 161,808 women between the ages of fifty and seventy-nine for twelve years, eventually finding that hormone therapy actually increased rather than decreased stroke risk.

Critics of the WHI study stated that one issue with the research findings was that many of the women involved went years without hormone replacement, which bolstered the theory that timing is essential.

This new study, which was performed on rats, found that the unused receptors become targets for elimination in the aged rat subjects. Surprisingly, the receptor loss did not take place in the uterus, which remained sensitive to estrogen.

The researchers also found that, after long periods of estrogen deprivation had passed, an enzyme known as CHIP—carboxyl terminus of Hsc70 interacting protein—increased binding with estrogen receptor alpha, a major brain receptor for neuroprotection. The CHIP levels remained unaltered, but the increased binding resulted in the destruction of roughly 50% of the receptors.

"We think this is the mechanism for how the receptor gets degraded," Brann said.

When the researchers treated the aged rats with estrogen at a later date, their findings correlated with the WHI findings in that there was a spike in mortality of the rat subjects.

"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 stated. The protection against stroke the brain was able to provide when estrogen was administered to the rats earlier suggests that there is a "critical window" of time. Further, when CHIP activity was obstructed, so was the receptor destruction.

Brann stated that the next steps consist of treating those rats where CHIP-related destruction is blocked with estrogen in order to see if salvaged receptors will react, as well as examining the same process in other regions of the brain.

"We think the estrogen receptor decrease is why the sensitivity decreases," concluded Brann. "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."

This study is published in the journal Proceedings of the National Academy of Sciences.