Three individuals were excluded due to artifacts in the MRI data. This left a sample size of 62 individuals who had used HT. In a multiple regression analysis with age, years of education, hormone status (current or past hormone use), hormone type (unopposed CEE, CEE with MPA, or PE), age at menopause, duration of therapy, and D entered, the overall ANOVA model was significant for the left (F (7,54) = 2.43; p<.03) and marginally significant for the right (F (7,54) = 2.10; p<.06) hippocampus. As predicted, there was a significant negative relationship between the interval between menopause and hormone initiation (D) and hippocampal volume for both left (T=−2.33; β=−.32; p<.02) and right hemispheres (T=−2.14; β=−.31; p<.03), after controlling for the variance in hippocampal volume associated with age, years of education, hormone status (current or prior), type of hormone, duration of therapy, and age at menopause. Thus, our effect can be considered statistically independent from these confounding factors. This result is clearly in line with a window of opportunity hypothesis and indicates that shorter intervals between menopause and hormone initiation are associated with larger hippocampi (see ). There were non-significant trends for age, years of education, and age at menopause in relation to hippocampal volume (p<.20) while hormone status (current, past), hormone type, and duration of therapy were unrelated to volume (both p>.60). Furthermore, we removed the one individual with the longest period between hormone initiation and menopause from the analysis to examine whether one individual was driving the observed effect. With this one individual removed, all of the effects of D as described above remained significant.
Figure 1 A scatterplot of hippocampal volume averaged across left and right hemispheres for each participant as a function of the number of years between menopause and hormone treatment initiation. Left and right hemisphere volumes were highly correlated (r = (more ...)
We next examined whether initiating hormone therapy coincidentally with the time of menopause was associated with larger hippocampal volumes compared to women who had never reported taking hormone therapy. For both the left and right hemispheres, those that initiated HT at the time of menopause (N=38) had larger hippocampal volumes than those that had never used HT (N=37; left: T=2.66; p<.009; right: T=2.73; p<.008) suggesting that HT use at or near the time of menopause might be associated with sparing of hippocampal volume (see ). On the other hand, there were no reliable differences between those that had never used HT and the group that initiated HT between one and eighteen years after menopause (N=24; left: T=.06; p<.95; right: T=.95; p<.34).
Figure 2 We examined whether those that initiated hormone treatment coincidentally with age at menopause or those that initiated hormone treatment between one and eighteen years post-menopause differed in hippocampal volume from those women who had never reported (more ...)
We applied the regression models used for the hippocampus to assess the left and right amygdala and caudate nucleus volumes. In a multiple regression analysis with age, years of education, hormone status (current or past hormone use), hormone type (unopposed CEE, CEE with MPA, or PE), age at menopause, duration of therapy, and D entered, the overall ANOVA model was not significant for either the left (F (7,54) = 0.44; n.s.) or the right (F (7,54) = 0.36; n.s.) amygdala. Furthermore, the beta coefficients for D were not significant for either the left or right amygdala. The volume of the left (F (7,54) = 1.12; n.s.) and right (F (7,54) = 0.63; n.s.) caudate nucleus was also unrelated to D. Finally, in a secondary analysis of these brain structures when comparing those that had never used HT to those that had initiated HT at the time of menopause or between 1–18 years post-menopause, we found no reliable differences between the groups (all p>.05).
In the analyses described above, we included women in the HT group (N=5) who reported receiving PE as treatment for menopausal symptoms. However, the impact of phytoestrogens on the central nervous system in humans remains a topic of debate. Therefore, to examine whether these five women were influencing the pattern of results described above, we re-ran all analyses while excluding women who had received PE (N=57). When these five women were removed, all results described above remained unchanged.
To test whether hippocampal volume, amygdala volume, caudate nucleus volume or D was related to spatial memory performance we conducted a series of multiple regression analyses in which age, years of education, hormone status, hormone type, duration of therapy, and age at menopause were entered as covariates of no interest and either brain volume for each region or D as a factor of interest with spatial memory performance (% correct) as a dependent variable. There was no relationship between D and any of the three spatial memory set sizes (all p>.05) indicating that the interval between menopause and initiation of HT was not related to memory performance in this task (see ). However, although not significant, the β values for the comparison between D and spatial memory performance were negative indicating that higher accuracy rates were related to shorter intervals between menopause and HT initiation. Age, years of education, hormone status, hormone type, duration of therapy, and age at menopause were also unrelated to spatial memory performance (all p > .05 for all memory set sizes). In an ANOVA to determine if spatial memory performance differed between those that had never used HT versus women who had initiated hormone use at the time of menopause, we found that there were no differences between the groups for either of the three set-sizes (all p >.05). Finally, neither the hippocampus, amygdala, nor caudate nucleus volumes were related to performance for any of the three memory set sizes (all p >.05).
Table 2 Summary of spatial memory accuracy rates broken down by the interval between menopause and hormone initiation (D = age at hormone initiation – age at menopause) for each set-size (1-item, 2-item, 3-item), and for never users. There were no statistically (more ...)