Research shows estradiol does not affect cognition post-menopause

Hormone replacement therapy in the form of estradiol did not affect memory, global cognition or executive function, regardless of the treatment’s timing in randomised trial.

Vaginal oestrogen could improve the quality of life for a subset of women, without the high levels of systemic hormones. In the image, close-up of an elderly woman

A new study has thrown into doubt the popular belief that a woman’s memory can be affected by the timing of her menopause and when menopausal hormone replacement therapy (HRT) is started — known as the “timing hypothesis”.

Led by Victor Henderson, professor of neurology and neurological sciences at Stanford University’s school of medicine in California, researchers randomised 567 healthy post-menopausal women, aged 41–84 years, to receive a daily 1mg dose of 17b-estradiol or placebo.

The women were split into two groups: the early group, comprising patients who were all within six months of their final period or had undergone a surgical menopause; and the late group, which was made up of patients who experienced a natural or surgical menopause at least ten years ago.

The cognitive ability of all participants was tested at the outset and again after two-and-a-half and five years, after which time the researchers discovered that, compared with baseline scores, verbal memory and global cognition composite scores improved in both treatment groups.

The team also found that there was no difference in the cognitive function of patients given estradiol within six years of menopause compared with those who begun therapy ten years after the menopause.

Reporting their findings in Neurology
(online, 15 July 2016), the authors conclude that the results of the trial failed to confirm the “timing hypothesis” for cognitive outcomes in healthy post-menopausal women.

“These results indicate that post-menopausal women near the time of menopause – in addition to women further from the time of menopause – should not expect [HRT] to enhance cognition,” the researchers say, adding that “healthy, younger post-menopausal women considering [HRT] for approved indications need not be overly concerned that treatment adversely affects these cognitive abilities over a five-year period”.

For verbal memory, the mean difference in composite scores (-0.06, 95% confidence interval [CI] -0.22 to 0.09) was not significant (P=0.33). The differences were similar in early and late post-menopause groups.

Interactions between post-menopause groups and mean standardised differences between treatment groups were also not significant when they looked at executive function (the brain’s ability to organise and act on information) and global cognition.

They also found that interactions were not significant when time since a patient’s menopause was analysed (for verbal memory P=0.80; for executive functions P=0.60; and for global cognition P=0.76).

Commenting on the study, Nuttan Tanna, pharmacist consultant in women’s health and older people at Northwick Park menopause clinical and research unit in Harrow, north west London, says: “This study is interesting but highlights [the] need for further research to gain an understanding of the physiological and metabolic processes in play for functions such as memory, cognitive function, dementia and how hormone replacement therapy (HRT) and oestrogen replacement therapy affects these processes.”

She adds that current practice and advice to patients considering HRT should include the risks and benefits as per the National Institute for Health and Care Excellence (NICE)’s clinical guidance – for example, the risks and benefits for various conditions, such as stroke, breast cancer and osteoporosis. “NICE’s guidance also states that the likelihood of HRT affecting risk of dementia is unknown,” Tanna adds.


[1] Henderson VW, St. John JA, Hodis HN et al. Cognitive effects of estradiol after menopause. A randomized trial of the timing hypothesis. Neurology 2016;87:1–10. doi: 10.1212/WNL. 0000000000002980

Last updated
The Pharmaceutical Journal, Research shows estradiol does not affect cognition post-menopause;Online:DOI:10.1211/PJ.2016.20201473

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