Does Hormone Therapy Affect Brain Structure, Cognition in Menopause?

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The authors acknowledged that the study was limited and plan to follow the group through 4 years of treatment.

Hormone therapy may increase brain ventricular volume in women who recently entered menopause, according to data published in Neurology.

Previous research indicated that hormone therapy delivered later in menopause may promote dementia; however its effect early on in menopause are not well understood.

In this ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), researchers led by Kajal Kantarci, MD, MS, of Mayo Clinic in Rochester, MN used imaging biomarkers to determine changes in brain structure most closely associated with aging and cognitive function in women taking oral conjugated equine estrogens (CEE) and transdermal 17β-estradiol therapy.

Ultimately, 101 women (aged 42-59 years; 5-36 months from last menses) from the KEEPS trial underwent baseline MRI prior to treatment. Analysis of MRI data was conducted for 95 participants who repeated at least 1 MRI at 18, 36, or 48 months. At baseline, there were no differences in whole brain volume and cognitive performance between the treatment and placebo groups.

At 48 months, whole brain volume decreased in both the CEE (P=.004) and 17β-estradiol (P=.002) groups, but not in the placebo group (P=.09), though not statistically significant. Ventricular volumes at 48 months increased across all 3 groups; however the increase in the CEE group was greater than in the placebo group (P=.01). The percent increase in ventricular volume from baseline to 18, 36, and 48 months was greater in the CEE group compared to placebo at all time points. Notably, no change was observed in global cognitive function in any group.

The researchers found that after adjusting for age, the increase in ventricular volume did correlate with the decline in whole brain volume (r= -0.58; P≤ .001) and increase in volume of white matter hyperintensities (r= 0.27; P=.01). Additionally, the increase in ventricular volume at 18 months appeared to correlate with the initiation of treatment in relation to menopause onset in the CEE group. Those who intiated treatment later in menopause showed a greater increase in ventricular volume at 18 months (r= 0.40; P=.03).

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Acknowledging the study’s small sample size, the authors conceded that “it is possible that the women who experienced structural brain changes with hormone therapies early in menopause will develop cognitive decline during an extended follow-up, and if proven, the imaging findings would be useful early surrogates of future clinical events. On the other hand, it is possible that these brain changes will subside after cessation of hormone therapy, and women who had structural brain changes during the 4 years of postmenopausal hormone therapy will not have an increased risk of cognitive decline over a longer follow-up.”

The researchers plan to follow the participants beyond their 4 years of hormone treatment to see if structural brain changes are persistent and if women with these changes will develop clinical cognitive decline.


Kartarci K, Tosakulwong N, Lesnick TG, et al. Effects of hormone therapy on brain structure: A randomized controlled trial. Neurology. 2016; 87:1–9.