title: The effect of estrogen synthesis inhibition on hippocampal memory.
abstract: 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.
authors: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: j.bayer@uke.de.
authors: Janine
authors: J
authors: Bayer
authors: Department of Neuroanatomy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: rune@uke.de.
authors: Gabriele
authors: G
authors: Rune
authors: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: h.schultz@uke.de.
authors: Heidrun
authors: H
authors: Schultz
authors: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Radiology, Pennsylvania State University College of Medicine, Hershey, PA, USA. Electronic address: mtobia@hmc.psu.edu.
authors: Michael J
authors: MJ
authors: Tobia
authors: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: imke.mebes@endokrinologikum.com.
authors: Imke
authors: I
authors: Mebes
authors: Mammazentrum am Jerusalem Krankenhaus, Hamburg, Germany. Electronic address: katzler@mammazentrum.eu.
authors: Olaf
authors: O
authors: Katzler
authors: Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: t.sommer@uke.de.
authors: Tobias
authors: T
authors: Sommer
mesh_terms: D000368:Aged; D000077384:Anastrozole; D004958:Estradiol / Q000096:biosynthesis*; D005260:Female; D006179:Gyrus Cinguli / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D000077289:Letrozole; D017774:Long-Term Potentiation / Q000187:drug effects; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008568:Memory / Q000187:drug effects*; D008570:Memory, Short-Term / Q000187:drug effects; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology; D017698:Postmenopause; D017397:Prefrontal Cortex / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D065088:Steroid Synthesis Inhibitors / Q000494:pharmacology*; D011795:Surveys and Questionnaires; D014230:Triazoles / Q000494:pharmacology; D014706:Verbal Learning / Q000187:drug effects; D014936:Word Association Tests
chemical_list: D009570:Nitriles; D065088:Steroid Synthesis Inhibitors; D014230:Triazoles; D000077384:Anastrozole; D004958:Estradiol; D000077289:Letrozole
keywords: Aromatase inhibitors; Dual process model; Estrogen; Hippocampus; Memory