Neutral Effect of Hormones on Cognition in Younger Women

June 25, 2013

New data suggest that use of hormone therapy has no sustained benefit or risk to cognitive function in women aged 50 to 55 years.

These latest results come from the Women's Health Initiative Memory Study of Younger Women (WHIMSY) and were published online June 24 in JAMA Internal Medicine.

"Earlier findings in older women in the WHI (Women's Health Initiative) study showed adverse effects of hormone therapy on cognition," lead author, Mark A. Espeland, PhD, Wake Forest School of Medicine, Winston-Salem, North Carolina, explained to Medscape Medical News. "But some observational and animal studies have suggested benefits of hormonal therapy on cognition when used around the time of menopause. So we really didn't know what to expect.

"Overall, the finding of no benefit but also no harm is reassuring," he added. "I think we can say that when these drugs are used to treat menopausal symptoms there does not appear to be any long-term harm to the brain."

Author of an accompanying editorial, Francine Grodstein, ScD, Brigham and Women's Hospital, Boston, Massachusetts, pointed out that "Hormone therapy is most often needed at time of menopause and it is crucial to understand the side effects, so this is a very important study.

"These results provide some reassurance that hormone therapy does not seem to be causing complications in terms of brain health in this younger age group," she told Medscape Medical News. She added that the results will not change current recommendations but may give clinicians a bit more confidence to prescribe hormone therapy for the treatment of menopausal symptoms.

Dr. Grodstein emphasized that the decision to use hormone therapy must be made on an individual basis. Noting that hormone therapy is known to protect against osteoporosis and the growing evidence of a protective effect against heart disease in women aged 50 to 55 years, she said it will depend on each individual's risk for these and other diseases.

"There is some evidence that hormone therapy may increase stroke risk but stroke is less common than cardiac disease, so it is a complex area and all the different risks and benefits must be examined for each patient. But at least we can now have some confidence that this treatment should not affect cognitive function when used in this age group."

WHIMSY Results

The current WHIMSY study involved 1326 postmenopausal women who had participated in the WHI study of hormone therapy and started treatment when aged 50 to 55 years.

They had been randomly assigned to 0.625 mg conjugated equine estrogens (with or without 2.5 mg medroxyprogesterone acetate) or placebo for a mean of 7 years. Cognition was evaluated for another 7 years after treatment stopped with the Telephone Interview for Cognitive Status–modified (TICS-m) test, a 14-question assessment with scores ranging from 0 to 50.

Results showed that global cognitive function scores from women who had been assigned to hormone therapy were similar to those from women assigned to placebo. There were no overall differences for any individual cognitive domain.

Table. WHIMSY Cognitive Outcomes With Hormone Therapy vs Placebo

Cognitive Function Test Standardized Difference: Hormone Therapy Minus Placebo (95% Confidence Interval)
Global cognitive function 0.02 (–0.08 to 0.12)
Verbal memory 0.01 (–0.08 to 0.11)
Attention –0.06 (–0.15 to 0.03)
Executive function 0.00 (–0.10 to 0.10)
Verbal fluency –0.05 (–0.15 to 0.05)
Working memory 0.00 (–0.10 to 0.11)

Positive score indicates better cognitive function with hormone therapy.

Negative Effect of Conjugated Equine Estrogen Alone on Verbal Fluency?

Prespecified subgroup analyses found some evidence that hormone therapies may have adversely affected verbal fluency among women who had previously had hysterectomy and so were taking estrogen alone (mean treatment effect, –0.17) or among those with prior use of hormone therapy (–0.25).

The authors note that another study in similar-age women, WHISCA, has also shown slight reductions in verbal fluency in women taking estrogen alone. They write, "Although the magnitudes of these possible treatment-related differences in verbal fluency are small, the similarity in the trends across the trials raises the possibility that CEE [conjugated equine estrogen]-alone therapy may be associated with small longer-term adverse effects on verbal fluency." However, they add that this finding could also have resulted by chance.

"This small adverse signal on verbal fluency in women with a prior hysterectomy or in those just using unopposed estrogen probably wouldn't even be noticeable in an individual person, so we're not sure what it means," Dr. Espeland said. "But this was also one of the negative effects seen in older women."

The researchers did not test cognition at the start of the study, only at the end. But Dr. Espeland said the fact that the treatment and placebo groups were well balanced at baseline with regard to other factors, such as education and depressive symptoms, makes it a valid comparison. "We feel confident that our results are correct," he stated.

Dr. Espeland came up with several possible reasons that cognitive function results with hormone therapy are different in older and younger women. Noting that in the older women, the adverse effect of hormone therapy on cognition was stronger in those who already had some cognitive impairment, he suggested that it may be an effect that only exacerbates cognitive impairment once it has already started to manifest itself.

In addition, some literature raises the possibility that if a woman is off estrogen for a while, then there is an altered response when they are exposed again. "The brain appears to reset itself after the menopause," he commented.

Dr. Grodstein agreed that the difference between the effects seen in younger and older women was not that surprising. "As we age the brain becomes more vulnerable, so it is entirely possible that estrogen could have different effects at different ages," she said.

The researchers are continuing to follow the women for another couple of years and will perform further cognitive tests by telephone, so longer-term results will become available.

No "Window of Opportunity" for Dementia Prevention

In her editorial, Dr. Grodstein says that although these new data are reassuring in that regard, they may be considered disappointing because they show no evidence of substantial cognitive benefits.

She points out that much attention has been given to the "window of opportunity" hypothesis regarding the use of hormone therapy in postmenopausal women, which suggested that hormone therapy may help prevent dementia and coronary heart disease when used around the time of menopause, and that the increased risks for both dementia and heart disease found in the WHI trials were due to the older ages of women enrolled.

She says that although there is mounting evidence that a window of opportunity does indeed seem to exist for heart disease, this does not seem to be the case for dementia.

In addition to the WHIMSY results, the KEEPS trial has also suggested a neutral effect of hormone therapy on cognitive function in younger postmenopausal women, she notes. And in both the WHI trial and the Nurses' Health Study hormone therapy caused a modest increase in stroke risk regardless of the timing of its initiation, she adds.

Asked by Medscape Medical News whether she was surprised by the current results, Dr. Grodstein replied, "Hormone therapy is extremely complicated. It is hard to predict the outcome of any given study. I have learned not to have any advanced expectations in this regard."

This study was supported by the National Institute on Aging. Dr. Espeland and Dr. Grodstein have disclosed no relevant financial relationships.

JAMA Intern Med. Published online June 24, 2013. Abstract Editorial


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