Estradiol Blunts Drug-Induced Memory Impairment in Young Postmenopausal Women

Marlene Busko

March 27, 2008

March 27, 2008 (Orlando, Florida) — Estradiol pretreatment significantly attenuated anticholinergic drug–induced memory impairment in younger postmenopausal women, but it increased the impairment in older postmenopausal women, in a recent study.

These results, by Julie A. Dumas, MD, from the University of Vermont College of Medicine, in Burlington, and colleagues, were presented in a poster here at the American Association for Geriatric Psychiatry 21st Annual Meeting and were recently published (Dumas J et al. Horm Behav. 2008;53:159-169).

"We think that estrogen is working through the cholinergic system," Dr. Dumas told Medscape Psychiatry. "When you are younger, your cholinergic system is intact, and you can see good effects of estrogen. When you age, your cholinergic system is more impaired, and there start to be no benefits. . . . This is the first experimental evidence in humans to show this critical idea."

Cognitive changes in postmenopausal women have been widely reported, but whether or not estrogen can reverse or prevent this decline is controversial, the group writes. Studies have shown beneficial effects of estrogen on cognition in women younger than 65 years but not in women older than 65 years. Animal studies have shown that an intact cholinergic system is necessary to see a beneficial effect of estrogen.

Previously, the researchers showed that 3 months of low-dose (1-mg/day) estradiol administered to postmenopausal women reduced the impairment induced by 2 anticholinergic drugs — the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine — in tests of attention and speed.

The current study sought to investigate how 2-mg/day estradiol interacts with the cholinergic system to affect verbal memory in younger and older postmenopausal women.

The study recruited 22 cognitively normal postmenopausal women ages 50 to 81 years. The subjects were stratified into 2 age groups:

  • 11 younger women (mean age 55.8 ± 4.3 years; range, 50 to 62 years).

  • 11 older women (mean age 74.3 ± 3.7 years; range, 70 to 81 years).

Subjects were randomly assigned to receive 17-beta estradiol (1 mg/day for 1 month followed by 2 mg/day for 2 months) or placebo for 3 months. The subjects then completed 3 days of drug challenges (scopolamine, mecamylamine, or placebo) with cognitive testing of verbal episodic memory. After this, the women were switched to the other treatment (estradiol or placebo) for 3 months followed by 3 challenges.

Estradiol pretreatment significantly reduced the drug-induced impairment on a test of episodic memory (the Buschke Selective Reminding Task) for the younger women, but it increased the impairment in this test in the older women.

These data suggest that part of the reason several prior studies have not seen significant effects on cognitive performance in the early postmenopausal period with estrogen therapy may be the lack of significant cholinergic impairment at this age, the group writes.

"Critical Period," "Optimal Time" for Estrogen Therapy

"As the cholinergic system ages, the ability of [estradiol] to provide sustained benefit may decline and thus not only may there be a critical period for initiation and administration of [estradiol], but there may be an optimal length of time," the group concludes, adding that this time remains to be determined in further research.

In a related poster, Paul A. Newhouse, MD, from the University of Vermont College of Medicine, and colleagues showed that preliminary data suggest that the addition of progesterone to estradiol appears to partially or completely counteract the ability of estrogen to enhance psychomotor speed, reaction time, and verbal memory after cholinergic blockade.

"It looks like estradiol improves cholinergic functioning to some extent, and progesterone tends to block that, which isn't totally surprising, because estrogen and progesterone have opposite effects in some tissues, Dr. Newhouse told Medscape Psychiatry. Using a pharmacologic challenge enables the researchers to see a response that they might otherwise miss in younger postmenopausal women, he added. "By temporarily 'aging' the cholinergic system with these drugs, which you can do for a few hours, now all of a sudden the estrogen benefit can get expressed," he added.

American Association for Geriatric Psychiatry 21st Annual Meeting: Posters 26 and 27. March 14-17, 2007.


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