Early observational studies suggested that postmenopausal hormone treatment may improve cognitive functioning in women; however, studies from the Women’s Health Initiative have shown that estrogen replacement therapy started in postmenopausal women (65 years or older) did not enhance cognitive functioning nor did it decrease the risk of dementia.

What has evolved is the hypothesis that there may be a “critical window” such that hormone replacement therapy initiated near the onset of menopause may reduce future risk of developing neurodegenerative disorders and may improve cognition.

This theory is supported by the findings of a study which compared cognitive functioning in women who had undergone either unilateral or bilateral oophorectomy (what would be considered a surgical menopause) to women had not undergone oophorectomy.  In this study, women who had one or both ovaries removed before menopause were almost twice as likely to develop cognitive problems or dementia as compared to women who did not have this surgery. Furthermore, women who were younger at the time of surgical menopause were more likely to develop dementia than women who were older when their ovaries were removed. In contrast, women who had their ovaries removed before the age of 49 but received estrogen replacement therapy (at least until the age of 50) were not more likely to experience cognitive problems.

This study suggests that estrogen, while it may not enhance cognitive function in postmenopausal women, may have a protective effect on the brains of younger women and that premature estrogen deficiency – as occurs after the removal of the ovaries prior to the onset of menopause — may increase a woman’s risk of developing cognitive problems or dementia at a later age.

Much less clear is what happens to cognitive functioning in women who start hormone replacement therapy as they transition naturally into menopause.  Now we have data from the KEEPS-Cog trial, a randomized, double-blinded, placebo-controlled clinical trial designed to investigate the effects of up to four years of HRT on cognition and mood in recently postmenopausal women.

In this trial, healthy recently postmenopausal women were randomized to receive oral estrogen and progesterone (n=220), transdermal estradiol and oral progesterone (n=211), or placebo (n= 262) for up to four years. Overall cognitive health was assessed using the Modified Mini-Mental State Examination.  Depressive symptoms were assessed using the Beck Depression Inventory.

Contrary to the researchers’ hypothesis, neither HRT formulation affected cognitive function in healthy recently postmenopausal women. These findings are consistent with findings from the Women’s Health Initiative Memory Study of Younger Women (WHIMSY) and a recent meta-analysis (Hogervorst et al, 2010) suggesting that HRT use in the early postmenopausal period has no cognitive benefits. However, most studies have used the Modified Mini-Mental State Examination, which, some critics argue, may not be able to detect subtle changes in cognitive functioning.

With regard to mood, treatment with oral estrogen and progesterone was associated with statistically significant improvements in symptoms of anxiety and depression, mood symptoms commonly seen in recently postmenopausal women; however, administration of transdermal estradiol did not benefit mood.

While this study shows that hormone replacement therapy may benefit younger menopausal women in terms of depression and anxiety, we still have to contend with the fact that prolonged use of HRT may carry some risk, including increased incidence of stroke, thromboembolic events, and breast cancer.  If depression or anxiety is the most troubling symptom, we might thus consider use of an antidepressant.  Specifically the serotonergic antidepressants – SSRIs and SNRIs – may also help to treat the vasomotor symptoms that occur during the perimenopause.

Ruta Nonacs, MD PhD

Gleason CE, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS–Cognitive and Affective Study. PLOS Medicine, June 2015.

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