Divergent mechanisms for trophic actions of estrogens in the brain and peripheral tissues

Abstract

17β-estradiol (E2) can enhance reproductive, cognitive, and affective functions; however, the mechanisms by which E2 has these effects need to be better understood. Pleiotrophic effects of E2 can occur via traditional and novel actions at various forms of estrogen receptors (ERs). In the central nervous system, trophic effects of E2 may be related to beneficial effects of hormone replacement therapy (HRT). However, in peripheral reproductive tissues, E2's capacity to evoke growth can increase risk of cancers. This review focuses on investigations aimed at elucidating divergent mechanisms of steroids to promote trophic effects in the brain, independent of effects on peripheral reproductive tissues. First, actions of estrogens via ERα or ERβ for peripheral growth (carcinogen-induced tumors, uterine growth) and hippocampus-dependent behaviors (affect, cognition) are described. Second, factors that influence these effects of estrogens are described (e.g. experience, timing/critical windows, non-ER mechanisms). Third, effects of estrogens at ERβ related to actions of progestogens, such as 5α-pregnan-3α-ol-20-one (3α,5α-THP) are described. In summary, effects of E2 may occur via multiple mechanisms, which may underlie favorable effects in the brain with minimal peripheral trophic effects.

Non-feminizing estrogens: A novel neuroprotective therapy

“…Similarly, in estrogen-depleted APP SWE xPS1 mice, 17α-E2 attenuated the loss of neurons in CA1 and reduced microglial activation in the hippocampus (Manaye et al, 2011). When injected directly into the hippocampus of young, estrogen-depleted rats, the non-feminizing synthetic estrogen analogues, ZYC-5 and ZYC-13, increased cognitive performance to a similar extent as 17β-E2 (Walf et al, 2011), suggesting non-feminizing estrogens may have functional effects on memory in addition to their neuroprotective effects. This cognitive enhancement was observed despite no appreciable binding of ERs by ZYC-5 and ZYC-13 in the hippocampus (Walf et al, 2011).…”

Progestogens’ effects and mechanisms for object recognition memory across the lifespan

“…For example, uterine growth and carcinogen-induced mammary tumor proliferation among young, ovariectomized rats is increased by estradiol or ERα, but not ERβ, ligand administration; conversely, estradiol or ERβ ligands enhance hippocampally-mediated behaviors (e.g. elevated plus maze as an anxiety measure as well as cognitive measures) [101] and [102]. Thus, it is possible to dissociate steroids divergent trophic actions in the brain from those in the body.…”

Research Resource: Transcriptional Profiling in a Cellular Model of Breast Cancer Reveals Functional and Mechanistic Differences Between Clinically Relevant SERM and Between SERM/Estrogen Complexes

“…Depending on the promoter context of the bound receptor, and the cofactors that are recruited to the receptor in a particular cell, it can either positively or negatively regulate target gene transcription. Thus, the same ER-ligand complex can have very different activities in different cells, an observation that explains how estrogens, generally considered to be reproductive hormones, exhibit activities in bone, the cardiovascular system, and in brain that are unrelated to reproductive function (2)(3)(4).…”