Elsevier

Steroids

Volume 72, Issue 5, May 2007, Pages 381-405
Steroids

Review
Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications

https://doi.org/10.1016/j.steroids.2007.02.003Get rights and content

Abstract

Estrogen is an important hormone signal that regulates multiple tissues and functions in the body. This review focuses on the neurotrophic and neuroprotective actions of estrogen in the brain, with particular emphasis on estrogen actions in the hippocampus, cerebral cortex and striatum. Sex differences in the risk, onset and severity of neurodegenerative disease such as Alzheimer's disease, Parkinson's disease and stroke are well known, and the potential role of estrogen as a neuroprotective factor is discussed in this context. The review assimilates a complex literature that spans research in humans, non-human primates and rodent animal models and attempts to contrast and compare the findings across species where possible. Current controversies regarding the Women's Health Initiative (WHI) study, its ramifications, concerns and the new studies needed to address these concerns are also addressed. Signaling mechanisms underlying estrogen-induced neuroprotection and synaptic plasticity are reviewed, including the important concepts of genomic versus nongenomic mechanisms, types of estrogen receptor involved and their subcellular targeting, and implicated downstream signaling pathways and mediators. Finally, a multicellular mode of estrogen action in the regulation of neuronal survival and neurotrophism is discussed, as are potential future directions for the field.

Introduction

Estrogen has been one of the most studied hormones in the scientific arena. A search of PubMed using the keyword “estrogen” reveals over 113,000 citations/publications since 1934, with more than 40% of the published papers appearing in the last 10 years. Thus, the area of estrogen research has seen a relative explosion in the last decade. Much of the interest has been sparked by a desire to understand the actions and mechanisms of estrogen throughout the body, and to formulate better diagnoses and treatment for breast cancer, osteoporosis, cardiovascular and neurological disease and a multitude of postmenopausal symptoms. Classically, estrogen is considered a “reproductive” hormone, due to its well-known role in feedback signaling in the hypothalamic-pituitary-ovarian axis. The reproductive actions and roles of estrogen have been reviewed extensively previously, and the reader is referred to several excellent reviews on this subject [1], [2], [3], [4], [5]. This review will focus on the “non-reproductive” effects of estrogen in the brain, specifically on the neuroprotective and neurotrophic/synaptic plasticity actions of estrogen. Much of the work in these areas has been conducted in rodent animal models; however, there is a growing body of work in humans and non-human primates, which will also be presented and discussed in context with the findings in rodents. There is also a small but growing literature on estrogen analogues, such as the clinically relevant selective estrogen receptor modulators (SERMs), and their effects on brain plasticity and neuroprotection, which will also be discussed. A major goal of the review is to discuss potential sites and mechanisms of action for estrogen in the modulation of plasticity, cognition and neuroprotection, and project possible future directions for these important fields of research. An additional goal is to discuss current controversies in the field, and propose potential future directions for research.

Section snippets

Sex differences and neuroprotection

Indirect evidence that estrogen may be neuroprotective first arose from studies in intact animals on sex differences in brain injury. Studies on cerebral ischemia-induced brain damage in gerbils revealed that female gerbils had a lower incidence and less severe brain damage following carotid artery occlusion than male gerbils [6]. Subsequent studies in rats and mice found a similar sex difference, with young adult female rats and mice having smaller infarct volume as compared to young adult

Estrogen and memory

A growing body of evidence has accumulated over several decades that support a regulatory role for estrogen on cognition/memory. With respect to humans, this body of evidence springs from several sources, including sex differences in cognitive function, human menstrual cycle fluctuations in cognitive performance, randomized controlled trials and observational studies on effects of estrogen depletion and replacement in postmenopausal women, as well as imaging studies on estrogen and cognition.

Conclusions

This review demonstrates the remarkable body of work that has been conducted on the neuroprotective and neurotrophic actions of estrogen in the brain. Clearly much progress in our understanding of estrogen actions in the brain has been derived from this body of work that spans decades. Just as clear is the need for continued focused research in the area to resolve lingering controversies in the field and to address complex mechanisms that underlie estrogen neuroprotective and neurotrophic

Acknowledgements

This research was supported by Research Grants (HD28965 and NS050730) from the National Institute of Child Health and Human Development, and National Institutes of Neurological Disorders and Stroke, National Institutes of Health.

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