Brain structure and cognition 3 years after the end of an early menopausal hormone therapy trial

Abstract

Objective: The effects of 2 frequently used formulations of menopausal hormone therapy (mHT) on brain structure and cognition were investigated 3 years after the end of a randomized, placebo-controlled trial in recently menopausal women with good cardiovascular health.

Methods: Participants (aged 42-56 years; 5-36 months past menopause) were randomized to one of the following: 0.45 mg/d oral conjugated equine estrogen (oCEE); 50 μg/d transdermal 17β-estradiol (tE2); or placebo pills and patch for 4 years. Oral progesterone (200 mg/d) was given to mHT groups for 12 days each month. MRIs were performed at baseline, at the end of 4 years of mHT, and 3 years after the end of mHT (n = 75). A subset of participants also underwent Pittsburgh compound B-PET (n = 68).

Results: Ventricular volumes increased more in the oCEE group compared to placebo during the 4 years of mHT, but the increase in ventricular volumes was not different from placebo 3 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 placebo.

Conclusions: 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 7 years indicates that mHT may have long-term effects on the brain.

Classification of evidence: 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 3 years after exposure to mHT.

Figure 1. Changes in brain structure and global cognitive function

Longitudinal change in global brain structure and global cognitive function ([A] whole brain, [B] ventricle, [C] WMH, [D] global cognition) in the tE2, oCEE, and placebo groups during mHT (0–48 months) and during the 3 years after mHT (48–84 months). Shaded panels represent the clinical trial phase. mHT = menopausal hormone therapy; oCEE = oral conjugated equine estrogen; tE2 = transdermal 17β-estradiol; WMH = white matter hyperintensity.

Figure 2. Longitudinal change in dorsolateral prefrontal cortex volumes by 7 years

(A) Location of the superior and middle frontal gyri regions of interest (i.e., dorsolateral prefrontal cortex) is shown on a 3-dimensional surface render of the template brain. (B) Log Jacobian values for the annualized change in superior and middle frontal gyri cortical volumes are displayed in box-and-whisker plots. DLPF = dorsolateral prefrontal; oCEE = oral conjugated equine estrogen; tE2 = transdermal 17β-estradiol.

Figure 3. Correlations between PiB SUVR (i.e., β-amyloid) deposition and reduction of cortical volume in superior and middle frontal gyri

Correlation of global cortical PiB SUVR with the log Jacobian values of the annualized change in superior and middle frontal gyri cortical volumes 7 years after randomization in the (A) oCEE (n = 17), (B) tE2 (n = 21), and (C) placebo (n = 30) groups. Participants who were APOE ε4 positive are plotted with red circles. A correlation was observed in the tE2 (r = −0.51; p = 0.02), but not in the oCEE and placebo groups. Removal of the outlier in the tE2 group strengthened the correlation but did not change the findings (r = −0.74; p ≤ 0.001). The correlations were not modified by APOE ε4. oCEE = oral conjugated equine estrogen; PiB = Pittsburgh compound B; SUVR = standard unit value ratio; tE2 = transdermal 17β-estradiol.