Neuroendocrinology Letters 2003; 24(3/4):128–129
pii: NEL243403E02
Preface
Estrogen Genomic and Nongenomic Signaling
Processes May Really Be Working In Harmony
George B. Stefano
Neuroscience Institute, State University of New York at Old Westbury, Old Westbury,
New York, USA;
Correspondence to: Prof. George B. Stefano, Ph.D.
Neuroscience Institute,
State University of New York at Old Westbury, Old Westbury,
New York, 11568, USA;
phone 516-876-2732; fax 516-876-2727;
email : [email protected]
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
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Neuroendocrinology Letters Nos.3/4, Jun-Aug Vol.24, 2003 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
PREFACE by George B. Stefano:
Estrogen Genomic and Nongenomic Signaling Processes May Really Be Working In Harmony
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-β-estradiol’s presence via mass
spec, but also find a fragment of the estrogen receptor-β 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-βestradiol 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-β-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-β-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-β-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.
Neuroendocrinology Letters Nos.3/4, Jun-Aug Vol.24, 2003 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
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