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Disease

Cardiovascular Disease

There is a disparity in prevalence of cardiovascular disease (CVD) between pre- and post-menopausal women, and the difference can be attributed to estrogen levels. Mutations in ERβ have been shown to influence cardiomyocytes, the cells that comprise the largest part of the heart, and can lead to an increased risk of CVD. Specifically, 17βE2 (a naturally occurring estrogen) improves cardiac metabolism by increasing myocardial ATP levels and respiratory function in the heart. In addition, it can inhibit myocyte cell death due to stress by altering various signaling pathways and can stimulate myocyte regeneration. While ERα has a more profound role in regeneration, ERβ can still increase endothelial progenitor cell activation and increase cardiac function after a myocardial infarction. The ERβ signaling pathway is also implicated in the role of vasodilation and arterial dilation, causing an increase in endothelial function and arterial perfusion. As a result, it can lead to a decrease in blood pressure and heart rate. 

Alzheimer’s Disease

Similar to CVD, post-menopausal women have an increased risk of developing Alzheimer’s disease (AD) due to a loss of estrogen, which affects proper aging of the hippocampus, neural survival and regeneration, and amyloid metabolism. As a result, genetic variation in ERβ is both sex and age dependent and ERβ polymorphism can lead to accelerated brain aging, cognitive impairment, and development of AD pathology. ERβ mRNA is highly expressed in hippocampal formation and contributes to increased neuronal survival against neurodegenerative diseases such as AD. In addition, ERβ upregulates insulin-degrading enzyme (IDE), which aids in the maintenance of β-amyloid degradation. However, in AD, lack of ERβ causes a decrease in this degradation and an increase in symptoms. ERβ also plays a role in regulating APOE, a risk factor for AD that redistributes lipids across cells. APOE expression in the hippocampus is specifically regulated by 17βE2, affecting learning and memory in individuals afflicted with AD. Thus, estrogen therapy via an ERβ-targeted approach can be used as a prevention method for AD either before or at the onset of menopause. Interactions between ERα and ERβ can lead to antagonistic actions in the brain, so an ERβ-targeted approach can increase therapeutic neural responses independently of ERα. Therapeutically, ERβ can be used in both men and women in order to regulate plaque formation in the brain. 

Neuroprotective Benefits

Synaptic Strength and Plasticity

Variations in endogenous estrogen levels cause changes in dendritic architecture in the hippocampus, with lower levels leading to decreased dendritic spines. However, treatment of 17βE2 can reverse this affect, giving it the ability to modify hippocampal structure. As a result of the relationship between dendritic architecture and long-term potentiation (LTP), ERβ can enhance LTP and lead to an increase in synaptic strength.  Furthermore, 17βE2 promotes neurogenesis in developing hippocampal neurons and neurons in the subventricular zone and dentate gyrus of the adult human brain. Specifically, ERβ increases the proliferation of progenitor cells to create new neurons and can be increased later in life through 17βE2 treatment.