Hippocampal volumes are larger in postmenopausal women using estrogen therapy compared to past users, never users and men: A possible window of opportunity effect

Center for Studies on Human Stress, Douglas Hospital Research Center, McGill University, 6875 boul. Lasalle, Verdun, Que. H4H 1R3, Canada.
Neurobiology of aging (Impact Factor: 5.01). 02/2008; 29(1):95-101. DOI: 10.1016/j.neurobiolaging.2006.09.001
Source: PubMed


Considerable evidence suggests that estrogen can have neuroprotective effects. However, recent results raised important questions regarding the conditions under which hormone therapy (HT) following menopause can be beneficial. It has been suggested that variables such as time of initiation and duration of HT use are of critical importance for beneficial cognitive effects to be observed. The aim of the present study was to investigate the potential neuroprotective effects of estrogens in aging on brain regions with high levels of estrogen receptors, namely the hippocampus (HC) and the amygdala (AG). In order to better characterize the punctual and long-term effects of estrogens, we tested postmenopausal women currently using estrogen therapy alone (ET), past HT users, never users, and men. Age at menses, age at menopause, HT duration and age were included as covariates in the analysis. Results demonstrate that women using ET had larger left and right HC volumes compared to men, and larger right HC volumes compared to past users and never users. Importantly, we found a significant negative relationship between ET duration and HC volume in this group. The observed effects were region-specific since no significant differences could be observed for the AG. In summary, these findings support a treatment duration dependent neuroprotective role of estrogen on HC volume in aging.

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    • "The discrepancies between these studies may be explained by the critical window theory, which posits that a positive effect on hippocampal structure will be limited to HT taken around the onset of menopause. Moreover, one study reported that duration of HT was negatively associated with hippocampal volume, pointing to a treatment duration effect (Lord, et al., 2008). "
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    ABSTRACT: Observational studies support a neuroprotective role of hormone therapy (HT) in the perimenopause, with hippocampal size being a widely used biomarker. We investigated the effect of HT started before the onset of menopause and lasting for at least 3 years on hippocampal volume and shape in 80 postmenopausal women and 80 controls matched on age and intracranial volume taken from a large community-based sample (Nord-Trøndelag Health Study-magnetic resonance imaging). The main effect of hormone group showed a statistically significant difference in hippocampal volumes (p = 0.028). Both the right (3.2%) and left (2.8%) hippocampal volumes were larger in the HT group but only significant for the right hippocampus (p = 0.023). Shape analysis revealed significant regional sparing of the medial aspect of the right hippocampal head and lateral aspect of the body extending to the tail, corresponding to the cornu ammonis, including part of the subiculum, in the HT group. A similar nonsignificant pattern was observed in the left hippocampus. The present study provides support for the critical window theory demonstrating that HT initiated in the perimenopause has neuroprotective properties. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neurobiology of Aging 06/2015; 474(9). DOI:10.1016/j.neurobiolaging.2015.05.023 · 5.01 Impact Factor
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    • "In women, MRI data show that menopause is associated with a decline in hippocampal volume that cannot be attributed to age-related changes (Goto et al., 2011). In addition, postmenopausal women using hormone therapies (HT) to treat menopause-related symptoms have larger hippocampi compared to age-matched non-users and men (Erickson et al., 2010; Lord et al., 2008). Changes in hippocampal volume have also been described across the menstrual cycle and correlate with fluctuations in hormone levels (Protopopescu et al., 2008). "
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    ABSTRACT: In estrogen-induced synaptic plasticity, a correlation of structure, function and behavior in the hippocampus has been widely established. 17ß-estradiol has been shown to increase dendritic spine density on hippocampal neurons and is accompanied by enhanced long-term potentiation and improved performance of animals in hippocampus-dependent memory tests. After inhibition of aromatase, the final enzyme of estradiol synthesis, with letrozole we consistently found a strong and significant impairment of long-term potentiation (LTP) in female mice as early as after six hours of treatment. LTP impairment was followed by loss of hippocampal spine synapses in the hippocampal CA1 area. Interestingly, these effects were not found in male animals. In the Morris water maze test, chronic administration of letrozole did not alter spatial learning and memory in either female or in male mice. In humans, analogous effects of estradiol on hippocampal morphology and physiology were observed using neuroimaging techniques. However, similar to our findings in mice, an effect of estradiol on memory performance has not been consistently identified/observed. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 05/2015; 74. DOI:10.1016/j.yhbeh.2015.05.008 · 4.63 Impact Factor
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    • "The most frequently studied measure has been HC volume, with some inconsistent findings (Eberling et al., 2003; Greenberg et al., 2006; Raz et al., 2004). A Canadian study reported that 16 women currently using HT had significantly larger right HC volume than 10 past users and 15 women who had never used HT (Lord et al., 2008). However, they also reported that, among current users, increased duration of treatment was associated with smaller total HC volume. "
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    ABSTRACT: Structural imaging studies suggest gender differences in brain volumes; however, whether hormone treatment (HT) can protect against age-related structural changes remains unknown, and no prior neuroimaging study has investigated potential interactions between HT and estrogen receptor (ESR) polymorphisms. Magnetic resonance imaging was used to measure gray and white matter, hippocampal volume, corpus callosum, cerebrospinal fluid (CSF), total intracranial volume (ICV) and white matter lesions (WML) in 582 non-demented older adults. In multivariable analysis, when compared to women who had never used HT, men and women currently on treatment, but not past users, had significantly smaller ratios of gray matter to ICV and increased atrophy (CSF/ICV ratio). Hippocampal and white matter volume as well as the corpus callosum area were not significantly different across groups. ESR2 variants were not significantly associated with brain measures, but women with the ESR1 rs2234693 C allele had significantly smaller WML. Furthermore this association was modified by HT use. Our results do not support a beneficial effect of HT on brain volumes in older women, but suggest the potential involvement of ESR1 in WML.
    Neurobiology of aging 10/2013; 35(3). DOI:10.1016/j.neurobiolaging.2013.09.026 · 5.01 Impact Factor
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