Chronic exposure to estradiol impairs some cognitive functions

Rats exposed to a steady dose of estradiol were impaired on tasks involving working memory and response inhibition, the researchers found.

Their report appears this week in the journal Behavioral Neurosciences.

The researchers made the discovery when studying the effects of estradiol on activities mediated by the prefrontal cortex, a brain region that is vital to working memory and to the ability to plan, respond to changing conditions and moderate or control one’s behavior.

Working memory is the ability to briefly remember information needed for a particular task, said Susan Schantz, a U. of I. professor of veterinary biosciences and principal investigator on the study. An example in humans is a phone number that is forgotten soon after the number is dialed.

“With working memory you’re just keeping it active until you use it,” she said.

In the new study, rats were trained to press one of two levers to obtain a food reward. Those that alternated between the levers (which were withdrawn from the rat enclosure for a few seconds between trials) received a reward. Those that hit the same lever twice in a row got no reward. Rats exposed to estradiol performed worse than their counterparts on this task, earning significantly fewer rewards.

A second set of tests measured the rats’ ability to wait before responding to a stimulus. The rats had to wait 15 seconds before pushing a lever to get a reward. Those exposed to estradiol performed worse on this task than those that were not exposed.

“That’s the test where we really saw the most striking effects with estradiol,” Schantz said. The estradiol-treated rats “were not as good at waiting,” she said.

“Rats treated with estradiol are definitely a lot more active and make a lot more lever presses,” said neuroscience graduate student Victor Wang, the lead author on the study. “That’s not conducive toward being rewarded.”

The researchers had not expected to see such pronounced results. In fact, the study had been designed to give them baseline information for a separate inquiry into the effects of soybean estrogens on cognitive function. They planned to compare the effects of chronic estradiol exposure to the effects of chronic exposure to genistein, a phytoestrogen found in soybeans. Genistein is believed to have similar effects in the body as natural or synthetic estrogens, although no study has definitively proven that it does.

Schantz and her colleagues had focused on the prefrontal cortex because it is rich in estrogen receptor beta (ER-beta), a protein that spurs gene expression and other activities in the cell when it binds to estradiol. Genistein also activates ER-beta.

Some women take genistein supplements or eat soy-based foods to reduce hot flashes or other symptoms of menopause, Schantz said.

“Women take them thinking they’ll be a safe alternative to hormone-replacement therapy and they might help hot flashes,” she said. Those who have heard that hormone replacement can improve cardiac or brain function also hope that eating soy or taking genistein supplements will have the same effects, she said.

The effects of hormone replacement therapy (HRT) are more complex – and problematic – than once thought. A recent large-scale study of HRT in post-menopausal women was stopped because of an increased risk of stroke and blood clots in women taking estrogen alone, and a higher than average incidence of breast cancer, cardiovascular disease, blood clots and stroke in women taking estrogen and progesterone.

Studies of estrogen’s effects on cognition have also had mixed results. In earlier studies, for example, psychology professor Donna Korol, a collaborator on the current project, found that estradiol enhances some abilities, such as place or spatial learning, while hindering others, such as learning that relies on stimulus-response associations, considered by some to be akin to “habit” and not fluid thought.

Performance in these tasks involves brain structures outside the prefrontal cortex.

The research indicates that multiple factors influence the effects of estradiol on the brain, Schantz said. The timing of the exposure, the types of brain functions or structures studied and the age of the test subjects can all generate different results, she said.