Re-Opening the Critical Window for Estrogen Therapy

Abstract

A decline in estradiol (E2)-mediated cognitive benefits denotes a critical window for the therapeutic effects of E2, but the mechanism for closing of the critical window is unknown. We hypothesized that upregulating the expression of estrogen receptor ␣ (ER␣) or estrogen receptor ␤ (ER␤) in the hippocampus of aged animals would restore the therapeutic potential of E2 treatments and rejuvenate E2-induced hippocampal plasticity. Female rats (15 months) were ovariectomized, and, 14 weeks later, adeno-associated viral vectors were used to express ER␣, ER␤, or green fluorescent protein (GFP) in the CA1 region of the dorsal hippocampus. Animals were subsequently treated for 5 weeks with cyclic injections of 17␤-estradiol-3-benzoate (EB, 10 g) or oil vehicle. Spatial memory was examined 48 h after EB/oil treatment. EB treatment in the GFP (GFP ϩ EB) and ER␤ (ER␤ ϩ EB) groups failed to improve episodic spatial memory relative to oil-treated animals, indicating closing of the critical window. Expression of ER␤ failed to improve cognition and was associated with a modest learning impairment. Cognitive benefits were specific to animals expressing ER␣ that received EB treatment (ER␣ ϩ EB), such that memory was improved relative to ER␣ ϩ oil and GFP ϩ EB. Similarly, ER␣ ϩ EB animals exhibited enhanced NMDAR-mediated synaptic transmission compared with the ER␣ ϩ oil and GFP ϩ EB groups. This is the first demonstration that the window for E2-mediated benefits on cognition and hippocampal E2 responsiveness can be reinstated by increased expression of ER␣.

Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice

“…Exogenous estrogens have long been known to regulate many types of learning and memory mediated by the hippocampus and other brain regions (see (Bean et al, 2015; Daniel et al, 2015; Duarte-Guterman et al, 2015; Ervin et al, 2015; Foster, 2012; Frick, 2015; Frick et al, 2015; Korol and Pisani, 2015; Luine, 2014) for recent reviews). The current findings provide novel insight into the functional role of brain-derived estrogens on learning and memory in rodents.…”

New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection

“…The ERs have similar distribution in female and male brains, but may differ in relative expression [77]. ER-α and ER-β expression patterns generally overlap, where ER-α is associated with reproductive behavior, whereas ER-β is associated with non-reproductive behaviors such as learning and memory [78] and anxiety-related behaviors. In hippocampus and cortical neurons, the estrogens-mainly E2 and other estrogenic ligands bind to membrane-associated and mitochondrial-associated G protein-coupled receptor (GPR 30), and activates the classical/ canonical nuclear and extranuclear orintra-cytoplasmatic ER isoforms-α and β-functioning as transcription factors [79][80][81], and a new type of nuclear ER, the orphan estrogenrelated receptor γ (ERR γ), which regulates dopaminergic neuronal phenotype [82], and IGF-1 receptor, which was recently recognized as a receptor for estrogens.…”

“…Conversely, ER-α changes are detected presynaptically in synaptic vesicles and postsynaptically in plasmalemmal and cytoplasmic regions of spine heads where protein translation occurs. In aged animals, it was demonstrated for the first time [78] that the window for E2-mediated benefits on cognition and hippocampal E2 responsiveness can be reinstated by increased expression of ER-α.…”

“…The first is regarding the benefits from the upregulation of the expression of ER-α,butnotofER-β, in the hippocampus of aged animals, in order to restore the potential of E2 treatments and rejuvenate E2-induced hippocampal plasticity [78]. The second are from the results of a multinational study [103] sustaining the beneficial effects of long-term treatment with diarylpropionitrile (DPN, 0.05 mg/kg/day, sc.…”

Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups

“…Other mechanisms are possible. Age and age-related chronic diseases change the expression of estrogen receptor-alpha and estrogen receptor-beta in the brain and how estrogen receptor-alpha responds to estrogen (30)(31)(32), which may contribute to differential effects of hormone therapy on cognition between the two cohorts. We have previously reported that the adverse impact of hormone therapy on cognitive function in the WHIMS cohort was strongest among women with lower baseline levels (2): Differences in the levels of education and the prevalence of risk factors for cognitive decline (hypertension, diabetes, cardiovascular disease) between the two cohorts may also contribute to differential hormone therapy effects.…”