Hormone Therapy: No Effect on Cognition After Menopause

July 21, 2016

Hormone therapy with estradiol (with or without progestin) showed no effect on cognition in both early and late postmenopausal women in a new placebo-controlled randomized trial.

The ELITE study is the first to directly address the timing hypothesis: whether hormone therapy has different effects in early and late postmenopausal women on the progression of subclinical atherosclerosis. The cognitive part of the study — ELITE-Cog — was published online in Neurology on July 15.

"Our results show there is no cognitive benefit or harm of estradiol over a 5-year period in either early or late menopausal women," lead author, Victor W. Henderson, MD, Stanford University, California, commented to Medscape Medical News.

"It therefore should not be prescribed to women for an expectation of cognitive benefit," he said. "But if women are experiencing vasomotor symptoms or are worried about osteoporosis risk, then physicians can be reassured that they can prescribe estradiol therapy and there will not be a harmful effect on cognition."

He explained that previous trials have shown a null effect of hormone therapy on cognition in older postmenopausal women, but there aren't much data on younger postmenopausal women earlier after menopause.

"There has been some expectation that the younger group may gain a cognitive benefit from hormone therapy, based on the results of animal studies and small clinical trials with shorter durations of treatment, but our study is larger than previous ones and is the first to look specifically at timing of hormone therapy with regard to cognition."

The current study involved 567 healthy women age 41 to 84 years who were early postmenopausal (within 6 years) or late postmenopausal (10+ years).

They were randomly assigned to oral 17β-estradiol, 1 mg/d, or placebo for a mean duration of 57 months. Women with a uterus who were randomly assigned to estradiol also received a cyclic micronized progesterone vaginal gel. Cognitive tests were performed at baseline, 2.5 years, and 5 years.

The primary endpoint — verbal episodic memory — showed no significant difference between estradiol and placebo. Differences were similar in early and late postmenopausal groups.

Interactions between postmenopausal groups and differences between treatment groups were also not significant for executive function or global cognition.

"The hypothesis was that estradiol would show a benefit in cognition in early menopause but not in later menopause," Dr Henderson commented. "But this is not what we found. We found no difference between estradiol and placebo on cognitive tests at either time point, and the same result in both early and later menopausal women."

He noted that despite no approved indication for estradiol as a booster to cognition in early menopausal women, some doctors believe there may be such a benefit in this group. Thus, it is sometimes prescribed for this purpose. "But our results show there is no case for this."

Dr Henderson cautions that because women with cognitive deficits or dementia were excluded in this analysis, the study's results apply only to women with good mental skills at the time they begin treatment.

Also, the findings cannot be extrapolated to cardiovascular or other health outcomes of hormone therapy, which must be assessed individually, he said. Indeed, Dr Henderson noted that there is now some evidence that hormone therapy, initiated early, may have beneficial cardiovascular effects, while it is clear that late hormone therapy can contribute to heart disease.

On the question of whether menopause itself affects cognitive function, Dr Henderson said this is a very controversial area, but it is commonly thought that there is an adverse effect on cognition during menopause.

"My view is that this is probably the case but the effect is small and transient, and there does not appear to be a net effect in the long-term. But this is very difficult to gauge as the data is all observational," he added. "You cannot randomize women to go through the menopause — and the studies are generally small."

He added that the current results cannot be applied to the question of whether hormone therapy affects the development of dementia in later life. "This is a different question. The underlying mechanism for the role of estrogen in dementia/Alzheimer's is different to that of cognition in the menopausal years."

He explained that the large-scale Women's Health Initiative Memory Study, a randomized treatment trial, looked at dementia as one outcome and found an increase in dementia in women taking estrogen (alone or with a progestin) compared with those taking a placebo.

"This was in an older group of women. I think we can say that in older postmenopausal women, estrogen therapy does not reduce the risk of dementia."

But he noted that observational studies have suggested a reduction in dementia in women who have taken hormone therapy, and these data are mainly in younger women who have been taking hormones for menopausal symptoms.

"But these are not randomized trials, so we don't have reliable information on the effect of hormone therapy in younger women on later dementia," he concluded. "And as the mechanisms are probably different between effects on cognition in the shorter term and effects on dementia many years later, I don't think our current results affect thinking on hormones and dementia in later life."

The study was supported by the National Institutes of Health (NIH). Dr Henderson receives research support from the NIH and has received travel expense reimbursement from the NIH, the American Academy of Neurology, and the International Menopause Society.

Neurology. Published online July 15, 2016. Abstract

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