Elsevier

Psychoneuroendocrinology

Volume 56, June 2015, Pages 213-225
Psychoneuroendocrinology

The effect of estrogen synthesis inhibition on hippocampal memory

https://doi.org/10.1016/j.psyneuen.2015.03.011Get rights and content

Highlights

  • Estradiol depletion specifically impaired hippocampus-dependent memory.

  • Estradiol depletion tended to decrease memory-related hippocampal activity.

  • Estradiol depletion increased memory-related activity in prefrontal areas.

  • The increased prefrontal activity reflects most likely a compensatory mechanism.

Summary

17-Beta-estradiol (E2) facilitates long term-potentiation (LTP) and increases spine synapse density in hippocampal neurons of ovariectomized rodents. Consistent with these beneficial effects on the cellular level, E2 improves hippocampus-dependent memory. A prominent approach to study E2 effects in rodents is the inhibition of its synthesis by letrozole, which reduces LTPs and spine synapse density. In the current longitudinal functional magnetic resonance imaging (fMRI) study, we translated this approach to humans and compared the impact of E2 synthesis inhibition on memory performance and hippocampal activity in post-menopausal women taking letrozole (n = 21) to controls (n = 24). In particular, we employed various behavioral memory paradigms that allow the disentanglement of hippocampus-dependent and -independent memory. Consistent with the literature on rodents, E2 synthesis inhibition specifically impaired hippocampus-dependent memory, however, this did not apply to the same degree to all of the employed paradigms. On the neuronal level, E2 depletion tended to decrease hippocampal activity during encoding, whereas it increased activity in the anterior cingulate and the dorsolateral prefrontal cortex. We thus infer that the inhibition of E2 synthesis specifically impairs hippocampal functioning in humans, whereas the increased prefrontal activity presumably reflects a compensatory mechanism, which is already known from studies on cognitive aging and Alzheimer's disease.

Introduction

Since the observation that hippocampal synapse density covaries with oestrus-cycle-dependent changes in 17-beta-estradiol (E2) concentrations, it has been known that E2 also influences non-reproductive brain circuits (Woolley et al., 1990). For example, the experimental administration of E2 and its precursors increases spine synapse density, promotes spine maturation and enhances the magnitude of long-term potentiation (LTP; Li et al., 2004, Smith et al., 2009). Interestingly, these effects on hippocampal plasticity are not mainly mediated by E2 derived from the gonads (Fester et al., 2006, Rune et al., 2006, Kretz et al., 2004). Instead, the de novo synthesis of E2 by hippocampal neurons is essential to the maintenance of hippocampal synapses (Kretz et al., 2004). Hippocampal E2 levels can actually exceed serum E2 levels (Hojo et al., 2004, Kato and Kawato, 2013). Systemic application of the aromatase inhibitor letrozole, i.e. the decrease of endogenous E2 levels, reduces spine synapse density and impairs LTP, even in the hippocampus of ovariectomized female mice, i.e. in the absence of E2 synthesized in the ovaries (Vierk et al., 2012, Zhou et al., 2010).

Consistent with the cellular actions of E2, a positive association between E2 and hippocampus-dependent spatial memory has been described in rodents (Gibbs et al., 2004, Harburger et al., 2007). In humans, the effects of E2 on memory have mostly been explored in the context of hormone therapies (HT), where E2 is primarily exogenously applied to treat osteoporosis and other menopause-related health problems. Based on the different HT regimens with respect to the hormonal compounds, doses and time of onset after menopause, the observed effects of HT on memory are highly inconsistent (Hogervorst and Bandelow, 2010).

Contrary to the effects of exogenous E2 treatment employed in the HT-studies, we explored the understudied influence of endogenously synthesized E2 in postmenopausal women. In particular, we characterized the effect of letrozole – which is used for neoadjuvant treatment of estrogen receptor positive breast cancer – on memory and hippocampal activity. We focused on postmenopausal women as they have low peripheral E2 baseline levels, similar to the ovariectomized rodents that showed reduced hippocampal plasticity in response to letrozole treatment (Fester et al., 2012, Zhou et al., 2010). A longitudinal design was employed in which a cohort of postmenopausal women with an indication for letrozole treatment was tested prior to, and 3–6 months after onset of aromatase inhibition, and this cohort was then compared to an age-matched control group.

To characterize the impact of E2 depletion on neural plasticity in the hippocampus (Zhou et al., 2010), we studied brain activity during episodic memory formation using fMRI. In particular, we employed an established paradigm (Staresina and Davachi, 2006), in which hippocampal activity during encoding correlates with subsequent memory performance. We hypothesized a relative decline in memory-related hippocampal activity in the AI compared to the control group.

Episodic memory can be based on hippocampus-dependent, but also on hippocampus-independent processes. Whereas the hippocampus is critically involved in retrieving an item together with associated contextual information (associative memory or recollection), recognizing an item without any associated information (item memory or familiarity) can be based purely on the parahippocampal cortices (Davachi, 2006). Behaviorally, we therefore employed three process-specific memory tests to disentangle the effect of E2 depletion on hippocampus-dependent and -independent forms of episodic memory. Such process-specific memory tests are highly sensitive to subtle changes in memory performance and allow a more specific inference to the underlying neural substrates, i.e. the hippocampus vs. parahippocampal cortices (Yonelinas, 2002). We hypothesized that there is a specific decline in hippocampus-dependent but not in parahippocampus-dependent memory processes, i.e. in recollection but not familiarity. Additionally, standard neuropsychological tests and questionnaires were applied to identify potential confounding variables between participants of the AI and control group.

Section snippets

Participants and general procedure

Participants of the ‘Aromatase Inhibition group’ (AI group) were recruited during the breast cancer consulting hour at the University Medical-Center of Hamburg Eppendorf and at the Mammazentrum of the Jerusalem Hospital in Hamburg. Participants for the control group (C group) were recruited during the breast consulting hour and through advertisements.

Twenty-three postmenopausal participants aged between 56 and 75 years (M = 67.39, SD = 4.70) with receptor-sensitive breast cancer stage I to stage

Sample

Table 1 summarizes characteristics of the participants included in statistical analyses. Experimental groups did not significantly differ with respect to age, delay between measurement points, the number of years since menopause, the use of HT, the number of nulliparous women or years of education (Table 1).

Questionnaires

Means, standard deviations and p-values of statistical analyses for the questionnaires are summarized in Table 2, Table 3. Questionnaires were used to assess potential confounds such as

Discussion

E2 depletion specifically decreased hippocampus-dependent recollection in the two verbal memory paradigms, i.e. the verbal source-memory task and the German equivalent of the Rey auditory verbal learning test. Performance in the visual memory task showed a similar pattern, but group differences reached only trend-level statistical significance. This is, to our knowledge, the first evidence that E2 depletion in postmenopausal women specifically impairs hippocampus-dependent memory and modulates

Role of the funding source

The study was funded by the German Research Foundation [DFG SO 952/2-1 and DFG SO 952/6-1].

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgement

None.

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