Long-term menopausal hormone therapy may affect brain volume, cognition

Two commonly used menopausal hormone therapy drugs may affect brain volume or cognitive function in older women after years of exposure, according to research published online March 21 in Neurology.  

Over the course of a seven-year randomized placebo-controlled trial, researchers analyzed the effects of two types of common menopausal hormone therapy (mHT) on the brain structure and cognition of menopausal women with good heart health.  

Participants recruited for the study were originally enrolled in KEEPS (Kronos Early Estrogen Prevention Study) at the Mayo Clinic in Rochester, Minnesota. All were 42 to 57 years of age and five to 36 months past menopause, according to the researchers. Researchers randomized the participants to one of the following groups: 0.45 mg/d oral conjugated equine estrogen (oCEE); 50 μg/d transdermal 17β-estradiol (tE2) or placebo pills and a patch for four years. The mHT groups were also given oral progesterone for 12 days each month to protect the endometrium, according to study methods.  

Researchers conducted brain MRIs on one 1.5-tesla system of study participants before randomization, at 18, 36 and 48 months during mHT, at the end of four years of mHT or placebo and three years after the end of mHT or placebo. Additionally, a subset of 68 participants underwent Pittsburgh compound B-PET scans.  

Study results included the following:  

• Ventricular volumes increased more in the oCEE group compared to placebo during the four years of mHT, but the increase in ventricular volumes was not different from the placebo group three years after the discontinuation of mHT.  

• Increase in white matter hyperintensity volume was similar in the oCEE and tE2 groups, but it was statistically significantly greater than placebo only in the oCEE group. 

• The longitudinal decline in dorsolateral prefrontal cortex volumes was less in the tE2 group compared to placebo, which correlated with lower cortical Pittsburgh compound B uptake. 

• Rates of global cognitive change in mHT groups were not different from the placebo group.  

"The effects of oCEE on global brain structure during mHT subside after oCEE discontinuation but white matter hyperintensities continue to increase; the relative preservation of dorsolateral prefrontal cortical volume in the tE2 group over seven years indicates that mHT may have long-term effects on the brain," the researchers concluded. "This study provides Class III evidence that the rates of change in global brain volumes and cognitive function in recently menopausal women receiving mHT (tE2 or oCEE) were not significantly different from women receiving placebo, as measured three years after exposure to mHT."