No Cognitive Difference Between Early, Late Estrogen Therapy

Miriam E. Tucker

October 19, 2014

NATIONAL HARBOR, Maryland — Oral estradiol therapy neither improves nor harms cognitive function in menopausal women, regardless of time since menopause.

Wendy Mack, PhD, of the Keck School of Medicine, University of Southern California, Los Angeles, presented those findings from the Early versus Late Intervention Trial with Estradiol (ELITE) here at the North American Menopause Society (NAMS) 2014 Annual Meeting.

ELITE aims to test the "critical window" hypothesis that use of hormone therapy in younger menopausal women may offer benefit, whereas use in older women (>65 years) will not. The primary aim of the study is to test the hypothesis with regard to atherosclerosis, and those findings are scheduled to be presented at the upcoming American Heart Association meeting.

In terms of cognitive function, which is a secondary outcome, the study showed no effect on early vs late treatment. Oral estradiol therapy initiated within 6 years of menopause did not affect the primary (verbal memory) or secondary (global cognitive, executive functions) outcome differently than therapy initiated 10 or more years after menopause.

According to Dr Mack, "ELITE-cog" is the only study thus far to look at the relationship of hormone therapy to cognitive function during the span of a woman's postmenopausal lifetime, and it is the only one adequately powered to detect differences, with 643 patients initially enrolled and 445 remaining at 5 years in the two-by-two trial.

Results of previous studies looking at the effect of hormone therapy on memory and other aspects of cognitive function have conflicted, with some showing harm and others benefit. Those studies have varied with regard to hormone regimens, study duration, and the ages and time since menopause of the women enrolled, Dr Mack said.

ELITE enrolled healthy, postmenopausal women who were either within 6 years or past 10 years of menopause. They were randomly assigned to receive either 1 mg of oral 17ß-estradiol daily plus 4% progesterone gel on the last 10 days of each month for those participants with a uterus or placebos of both.

The researchers tested participants' verbal memory, executive function, and global cognition at baseline and at 2.5 and 5 years. For all three measures, at 5 years, there were no differences, either by treatment group or by early vs late menopause group (P = 0.33 and 0.88, respectively), for a composite score of 0.61 for verbal memory and 0.21 for executive function, and 0.7 and 0.25 for global cognition composite score.

"ELITE did not provide any support for a critical window hypothesis on cognitive function, and it remains unique as the only trial specifically designed and powered to test the critical window hypothesis," Dr Mack concluded in her presentation.

Lila Nachtigall, MD, professor of obstetrics and gynecology at New York University–Langone Medical Center, New York City, told Medscape Medical News that the findings surprised her because the lack of cognitive benefit in younger menopausal women conflicts with her clinical experience. Another audience member said the same thing during the question-and-answer period.

"Anecdotally, in our practice, we see the young [menopausal] woman who says she has brain fog, she can't remember nouns, can't say people’s names.... When we treat with estrogen, those women who complain of that seem to get better. I have never done a double-blind study, but I know that it happens all the time."

Dr Nachtigall postulated that the difference may be that ELITE did not select participants on the basis of symptoms. Some did have symptoms, but having symptoms was not among the study criteria.

Dr Nachtigall told Medscape Medical News that overall, it was a good study, and she does not doubt the findings.

"The message is that it didn't matter whether you start early or late, you really didn't get a brain benefit.... I know anecdotally it does, but I think the study had good numbers, and they did follow them for 5 years. I think in that [study] group, they really didn't see an improvement. But they weren't women complaining about cognitive loss.... For women who come to me and say they have brain fog, I would still [prescribe estrogen]. I would watch and see. If they say they're better, they're better."

She also pointed out that the study's findings provide reassurance regarding the lack of cognitive harm in the older group especially, tracing back to the trend seen in the Women’s Health Initiative.

She told Medscape Medical News that although she usually does not start older women on estrogen, it is still an option for some who are still having hot flashes. "You have to individualize [treatment]."

The study was supported by the National Institute on Aging. Dr Mack and Dr Nachtigall have disclosed no relevant financial relationships.

North American Menopause Society (NAMS) 2014 Annual Meeting. Presented October 17, 2014. Abstract S-12.

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