VOL.23, 2002
VOL.22, 2001
VOL.21, 2000
VOL.20, 1999
VOL.19, 1998
VOL.18, 1997

including Psychoneuroimmunology, Neuropsychopharmacology,
Reproductive Medicine, Chronobiology
and Human Ethology, ISSN 0172–780X

NEL Vol.24 Nos.3/4, Jun-Aug 2003


Estrogen Genomic and Nongenomic Signaling Processes may Really be Working in Harmony

2003; 24:130136
pii: NEL243403E02

[ Read pdf ]


Related Articles in this issue:
1. Preface - Guest Editorial
by Stefano (below)
2. Stefano et al
| 3. Zhu et al | 4. Cho et al - Review


Estrogen Genomic and Nongenomic Signaling Processes may Really be Working in Harmony

George B. Stefano

Neuroscience Research Institute, State University of New York College at Old Westbury, Old Westbury, New York, USA;

Key words:
estrogen; gonads; invertebrate; reproduction


In recent times, estrogen has been labeled as a protective and/or destructive cellular messenger. In our review, we attempt to understand this discrepancy. In trying to rectify the differences in the risk, onset, and progression of neurodegenerative diseases between men and women, the gonadal hormone estrogen has been the primary focus of investigation for many years. Although this gender difference may encompass disparate and overlapping reasons, estrogen and signaling events mediated by its receptor have been shown to be neuroprotective in a number of neurodegenerative disease models such as Alzheimer’s, Parkinson’s, and Schizophrenia. Although data from human studies remains highly controversial, a large body of research suggests that this hormone plays a pivotal role in retarding and preventing the formation of neurodegenerative diseases through its receptor. Gaining a better understanding of these estrogen receptor mediated neuroprotective mechanisms may lead to new therapeutic strategies for the treatment of neurodegenerative diseases, which are a heterogeneous group of diseases of the nervous system that have many different etiologies. Due to the prevalence, morbidity and mortality of the neurodegenerative diseases, they represent significant medical, social, and financial burdens.

These diseases are often age associated, chronic and progressive with limited treatment modalities. It is usually noted in many epidemiological studies that premenopausal women experience greater protection from neurological diseases, but articulating the precise biological mechanisms for this gender difference in disease risk and onset has remained elusive. Although multiple complex factors may be involved, the role of the hormone estrogen and its receptor has remained one of the central focuses of investigation since postmenopausal women enjoy none of the same protection against neurological diseases as those who are premenopausal.

The significance of estrogen, as an important signaling molecule, is demonstrated by our recent findings in this issue of Neuroendocrinology Letters in that this molecule is also present in invertebrate neural tissues. We not only demonstrate 17-b-estradiol’s presence via mass spec, but also find a fragment of the estrogen receptor-b gene, exhibiting 100% sequence identity to that found in man. Here, it appears to down regulate ganglionic microglial cells after surgical insult, which normally stimulates their egress from the tissue. Additionally, 17-b- estradiol down regulates these cells following fMLP activation. These actions are antagonized by tamoxifen and L-NAME exposure, demonstrating a receptor-mediated event, as well as one involving nitric oxide release, supporting a cell surface role for estrogens action. The results show that 17-b-estradiol can down regulate invertebrate ganglionic glia cells, demonstrating a neural role transcending reproduction.

In the last report in this issue, we sought to determine if estrogen is found in Mytilus reproductive tissues. We determined the presence of 17-b-estradiol via high pressure liquid chromatography and radioimmunoassay in the animals’ gonads. This substance was further identified via nanoelectro-spray ionization quadrupole time of flight mass spectrometry. We also determined that estradiol isoforms also were present in the tissue. These data demonstrate that 17-b-estradiol, and an estradiol isoform, is present in Mytilus gonadal tissues, suggesting that they have functions related to reproduction. This further suggests that estrogen’s association with reproductive activities has a long evolutionary history and that this association began in invertebrates.

We further speculate that estrogen signaling was essential for animals, including invertebrates, because it was a messenger involved with rhythmical/cyclic regulatory patterns, involving tissue growth. It is ideally suited for this role because it has a long half-life, which allows it to reach nuclear targets, i.e., genomic processes. Here, cell surface signaling, i.e., nongenomic processes, may also be important, and part of estrogen’s signaling repertoire, since it modulates cell activation states, i.e., down regulating, so that growth can occur in an optimum microenvironment. Thus, by down regulating a cells general activity, i.e., mobility, it allows the cells to focus its "attention" on growth/reproduction when appropriate. This process would enable the genomic nature of estrogen’s signaling to take place since the cells are in a more receptive state. This action of the cell surface receptors also serves to conserve energy in order to focus energy on reproductive associated growth processes.

The finding of estrogen signaling in invertebrates highlights the molecules evolutionary significance. This, in itself, urges caution in interpreting its role in biomedical situations.

Copyright  Neuroendocrinology Letters 2003
Society of Integrated Sciences
All rights reserved. No part may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or ortherwise, without prior written permission from the Editor-in-Chief.
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