The Molecular and Neuroanatomical Basis for Estrogen Effects in the Central Nervous System
Bruce S. McEwen
Harold and Margaret Milliken Hatch Laboratory of
Neuroendocrinology, Rockefeller University, New York, New York
10021
Address all correspondence and requests for reprints to: Dr. Bruce S. McEwen, Laboratory of Neuroendocrinology, Rockefeller University, 1230 York Avenue, New York, New York 10021. E-mail:mcewen{at}rockvax.rockefeller.edu
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Introduction
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With increasing life expectancy during the 20th
century, women are likely to live a substantial part of their lives in
a state of estrogen deficiency. Hot flushes are for many women the most
dramatic and noticeable consequence of loss of ovarian hormones. Loss
of bone calcium and osteoporosis, developing much more gradually, is
another consequence that has led many women to take estrogen
replacement therapy (ERT) at the menopause. Likewise, the loss of
protection of the coronary arteries, leading postmenopausal women to
increased risk for cardiovascular disease, is another result of
estrogen deficiency that has reinforced the value of ERT. Yet, it is
only quite recently that medical science has recognized that the brain
is one of the organs of the body that suffers from the loss of this
circulating hormone.
This has happened despite studies over more than 30 yr indicating that
estrogens target the brain of experimental animals (for summary, see
Ref. 1). However, most of the animal studies have focused on estrogen
actions on the hypothalamus affecting ovulation and reproductive
behavior, and only recently has it become apparent that estrogens exert
many actions outside of the reproductive function, including actions on
brain areas that are important for learning and memory, emotions and
affective state, as well as motor coordination and pain sensitivity.
Indeed, some women experience at surgical or natural menopause
difficulties in remembering names and other information important for
daily life as well as deficits in fine motor coordination and reaction
times and feelings of depression and anxiety (2). These effects reflect
the actions of estrogens on a large number of brain areas outside of
the hypothalamus. The problem in these brain regions has been to
recognize the receptors and mechanisms by which estrogens produce their
effects. This brief review will focus on two aspects: first, the
cellular and molecular mechanisms by which estrogens produce their
diverse effects on the brain; and second, the brain regions and cell
types in which estrogens produce their effects, emphasizing new
knowledge regarding estrogen actions outside of the hypothalamus and
pituitary gland. Finally, a brief discussion will summarize the
potential clinical applications of this information, particularly in
relation to cognitive function and dementia.
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Historical overview
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In the early 1960s, putative DNA-binding estrogen receptors (ERs)
were identified as proteinaceous binding sites for tritiated estradiol
in the tissue cytosol and cell nuclear compartment (3). Found initially
in reproductive tract, putative ERs were subsequently identified by
in vitro cytosol binding and in vivo uptake and
cell nuclear retention in the pituitary gland and hypothalamus (1). At
first, only ERs in the hypothalamus and pituitary gland were studied
because they were the most obvious and also the most obviously related
to estrogen actions on reproduction. Gradually, however, nerve cells
containing putative ERs were recognized in brain regions such as the
hippocampus, cerebral cortex, midbrain, and brain stem. The
introduction of antibodies to ERs and the cloning of ERs permitted more
direct measurements of the receptor themselves or their messenger
ribonucleic acids (mRNAs) by immunocytochemistry and in situ
hybridization histochemistry, and these newer tools generally confirmed
the older localization of ERs based upon tritiated estrogen binding and
steroid autoradiography. The classical intracellular ER is called the
ER
(see Ref. 2 for summary). Recently, a new form of the
intracellular ER, the ERß, was cloned, and mapping studies are
underway in the brain and other tissues and organs, as summarized
below. The localization of this receptor to new cell types will
undoubtedly extend the list of tissue, organs, and brain regions that
are capable of responding to estrogens with a regulation of gene
expression.
At the same time that progress with intracellular ERs has accelerated,
other investigations of the functional effects of estrogens on nerve
cell activity and neuroprotection have uncovered rapid actions of these
hormones that cannot involve activation or repression of gene
expression, because of either their extreme rapidity or their
structure-activity profile in relation to the specificity of known
intracellular ERs. These nongenomic actions of estrogens operate in
many cases on the cell surface and affect the excitability of nerve
cells and smooth muscle cells and the movement of the sodium, potassium
and calcium ions that create a nerve impulse and modulate the internal
state of neurons. However, we know very little about the molecular
characteristics and the mechanism of action of these nongenomic
receptors in cell membranes. Nevertheless, the effects that they
mediate are of sufficient interest to make them an essential component
of a review of estrogen action in brain. We shall now discuss these
issues in greater depth, using a figure and a number of summary tables
to cover material that the reader may find in more detail in another
review (2).
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ERs and actions in the central nervous system
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The variety of estrogen effects has been expanded to include rapid
actions on excitability of neuronal and pituitary cells, the activation
of cAMP- and mitogen-activated protein kinase (MAP kinase) pathways,
effects on calcium channels and calcium ion entry, and protection of
neurons from damage by excitotoxins and free radicals (Table 1
and Fig. 1
). These estrogen actions occur through
at least two types of intracellular receptors as well as a number of
other mechanisms involving receptors that have not been characterized.
Indeed, for a number of processes, there are conflicting reports, based
upon estrogen structure-activity studies and the actions of estrogen
antagonists, that intracellular receptors may not be involved. Thus, as
summarized in Table 1
, for estrogen actions on some aspects of calcium
homeostasis, certain aspects of second messenger systems and some
features of neuroprotection, a novel receptor mechanism is implicated,
in which stereospecificity for 17ß- over 17
-estradiol is replaced
by a broader specificity for the 3-hydroxyl group on the A ring. Such
findings suggest that there are novel receptor mechanisms not involving
the classical intracellular ER. However, before discussing these
receptors, we shall consider the intracellular ER.

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Figure 1. Schematic diagram of intracellular estrogen
action via ER and ERß as well as possible cell surface effects of
putative membrane ERs that produce neuroprotection (top)
or affect intracellular signaling (bottom) via the cAMP
and MAP kinase pathways. Top panel, Estradiol exerts its
effects intracellularly via two principal receptor types, ER and
ERß, and these are characterized by a distinct specificity for
17 -estradiol over 17ß-estradiol. Estrogens also exert
neuroprotective effects in part via a mechanism in which
17 -estradiol has equal or greater potency than 17ß-estradiol.
Bottom panel, Estradiol acts either via cell surface
receptors or an intracellular ER to activate two different second
messenger pathways, one involving the MAP kinase cascade and the other
involving cAMP. Both pathways result in activation of gene
transcription via at least three possible response elements: cAMP
response element, steroid response element, and AP-1. Note that
in the case of intracellular second messengers, there is some
uncertainty concerning the involvement of ER and ERß in the
signaling process vs. the roles of other, as yet
uncharacterized, receptors (see text). AC, Adenylate cyclase; CREB-P,
phosphorylated form of cAMP response element-binding protein;
ras, ras oncogene; MAPK, MAP kinase; MAPKK, MAP kinase
kinase; fos-jun, Fos-Jun heterodimer. This figure was reprinted from
Ref. 2; please see this reference for details.
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Intracellular ERs
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ER
shows a characteristic distribution in the nervous system,
with high levels in the pituitary, hypothalamus, the hypothalamic
preoptic area and amygdala and much lower levels, and a more scattered
distribution, in other brain regions. The discovery and cloning of
ERß (4, 5, 6) radically changed the view of estrogen action and
provided, among other things, a basis for understanding how the
knockout of ER
(
ERKO) (7, 8) could have resulted in a viable
organism and in the continued actions of estrogens on many tissues. The
deletion of the ERß gene was described recently (9), and ßERKO
animals are remarkably normal and are even able to reproduce, although
they show some reduction in litter size. This is in contrast to the
ERKO mice, which are sterile and show altered sexual and other
behaviors (see Ref. 2 for summary).
Measurements of messenger RNA (mRNA) for ER
and ERß reveal
distributions in the body that differ quite markedly from each other,
with moderate to high expression of ER
mRNA in pituitary, kidney,
epididymus, and adrenal; moderate to high expression of ERß mRNA in
prostate, lung, bladder, and brain; and overlapping high expression in
ovary, testis, and uterus (10). Isoforms of ERß have been identified
(see Ref. 2 for summary). The best characterized of these variants has
been termed ERß2. Compared to the originally designated ERß1, this
isoform has a lower affinity for estrogens (11), presumably due to an
18-amino acid insertion in the ligand-binding domain (12).
In brain, the distribution of ER
is well established, but there is
less certainty and more controversy surrounding the localization of
ERß. The autoradiographic maps of [3H]estradiol uptake
and retention in brain (13, 14) are presumed to reflect binding to all
forms of the ER, particularly the ER
and the ERß1 isoforms, which
have similar affinities for 17ß-estradiol (10). In situ
hybridization data suggest widespread distribution of ERß mRNA
throughout much of the brain, including olfactory bulbs, cerebellum,
and cerebral cortex (15, 16), whereas results from immunocytochemical
studies for ERß indicate a more restricted localization of detectable
protein, although the antisera that are currently available do not
always provide specific signals in some brain areas (see Ref. 2 for
discussion). Thus, it remains a likely, but unproved, assumption that
the presence of ERß mRNA indicates the presence of some functional
ERß receptor protein, even if the [3H]estradiol
autoradiography, mentioned above, has shown very little in the way of
functional ER in some of the brain regions where ERß mRNA is
expressed. The possible presence of low levels of intracellular ER, not
detectable by either autoradiography or immunocytochemistry, remains
one of the thorniest issues affecting progress in understanding the
molecular mechanisms of estrogen action in the nervous system.
ER
and ERß are similar not only in affinity for a number of
estrogens and estrogen antagonists (10), but also in their ability to
regulate genes in which the estrogen response element is the primary
site of interaction (17). The major differences between ER
and ERß
concern their ability to regulate transcription via the activating
protein-1 (AP-1) response element. With AP-1, 17ß-estradiol activated
transcription with ER
, whereas it failed to activate transcription
with ERß; in contrast, with AP-1, antiestrogens activated
transcription with ERß as well as with ER
(17). ER
and ERß
can form heterodimers when expressed in the same cells, thus giving
rise to additional possible variants as far as gene regulation (6). To
date, colocalization of ER
with ERß has been demonstrated in the
hypothalamic preoptic area, bed nucleus of the stria terminalis, and
medial amygdaloid nucleus (18), and the two ER forms probably coexist
in cells of other brain regions.
It has been known for some time that estrogen antagonists produced
agonist-like effects on some parameters in the brain and antagonize
other estrogen actions, and the heterogeneity of these effects has
implications for the therapeutic use of these substances. This has been
studied in some detail for one antagonist, CI-628, a tamoxifen-like
estrogen antagonist. The antagonistic effects of CI-628 were first seen
by its blockade of estrogen induction of both progestin receptors and
lordosis behavior (19, 20), whereas the agonist-like effects of CI-628
were seen for induction of choline acetyltransferase, a key enzyme in
acetylcholine formation, in basal forebrain and repression of type A
monoamine oxidase in amygdala (21). Recently, CI-628 was shown to block
estrogen-induced synapse formation in the hippocampus (see below)
without having any agonist-like effects (22). One important implication
of these findings is that nonsteroidal antiestrogens, such as CI-628,
and possibly also related compounds, such as tamoxifen and raloxifene,
will not have uniformly agonistic or antagonistic effects on the
diversity of actions that estrogens normally produce in the brain. This
has implications for the therapeutic applications of such agents and
requires a careful study of the actions of these agents on each end
point of estrogen action and on integrative neural processes, such as
cognition and affective state, in the event that these substances may
be antagonistic to estrogens on some processes and exert estrogen-like
effects on others. At the same time, the diverse actions of estrogens
and estrogen antagonists in brain must be explored in terms of the
emerging molecular framework of ERs and response elements, as described
above.
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Novel estrogen actions
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Membrane ERs have been reported on pituitary, uterine, ovarian
granulosa cell, and liver cell membranes, but these have been only
partially characterized in binding studies and have not yet been shown
to be linked to signal transduction mechanisms (Table 1
) (see Ref. 2
for review). Whereas some of these receptors have a specificity for
estrogens that differs from that of the intracellular ER, there is
evidence (23, 24) that a portion of the intracellular ER can be
expressed on the surface of some cells and participate in second
messenger-related effects. Besides the binding of estrogens to cell
surface sites or the expression of ER on the membrane, there are
reported effects of estrogens on neuronal excitability and second
messenger systems that have been difficult to connect with either novel
receptor mechanisms or genomic receptors. One reason for these
difficulties is a lack, in many cases, of structure-activity studies
that would rule in or rule out the participation of intracellular ER.
However, in a few cases where such studies have been carried out, there
is evidence for novel types of receptors with a pattern of specificity
that does not discriminate between 17
- and 17ß-estradiol (see
Table 1
and Fig. 1
) (2).
Noteworthy among these novel actions of estrogens is the activation of
phosphorylation of the transcription regulator, cAMP response
element-binding protein (25, 26), and of the MAP kinase pathway
(27), which represent novel ways in which estrogens can interact with
signaling pathways involving cell surface receptors and thereby
participate in cellular events also regulated by growth factors and
neurotransmitters. These processes (summarized in Table 1
and Fig. 1
)
are often interrelated at the level of intracellular signaling, and
thus, studies of these individual estrogen effects may some day
converge when more is known about each of the mechanisms.
Also important, but equally puzzling for lack of mechanistic details,
are the novel ways in which estrogenic compounds protect nerve cells
from damage by excitotoxins and free radicals (Table 1
) (see Ref. 2 for
review). In this realm, there are neuroprotective effects that are
mediated via classical genomic receptors that can be blocked by
estrogen antagonists, but there are also other actions that are not
blocked by estrogen antagonists and which appear to involve a novel
mechanism in which 17
-estradiol is as potent as 17ß-estradiol.
These actions of estrogens appear to reduce the production or actions
of free radicals in cause cell damage and promoting cell death through
apoptosis (for examples, see Table 1
).
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Estrogen actions throughout the central nervous system
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We now know that ovarian steroids have numerous effects on the
brain throughout life, beginning during gestation and continuing on
into senescence. Estrogens participate in the sexual differentiation of
the brain during early embryonic or neonatal life, and these effects
undoubtedly involve the intracellular ERs described above. The process
of sexual differentiation involves the secretion of testosterone in
fetal or early neonatal life and the actions of testosterone, either
through androgen receptors or via aromatization to estrogen, in the
defeminization and masculinization of brain structures and function
(28, 29). Although initially believed to be confined to the
hypothalamus, structural and functional sex differences have been found
in higher cognitive centers and in sensory and autonomic ganglia as
well as in structures of the limbic system of the brain, midbrain,
brain stem, and basal forebrain structures (see Ref. 2 for review).
Estrogens affect areas of the brain that are not primarily involved in
reproduction, such as the basal forebrain cholinergic system,
hippocampus, cerebral cortex, caudate-putamen, midbrain raphe and brain
stem locus coeruleus, and spinal cord (Table 2
). These systems are involved in a
variety of estrogen actions on mood, locomotor activity, pain
sensitivity, vulnerability to epilepsy, and attentional mechanisms and
cognition (Table 3
; in each of these
tables, key examples are given with references).
Despite the paucity of ER
outside the hypothalamus, hypothalamic
preoptic region, and amygdala, estrogens have effects on many other
brain regions and neurochemical systems involved in a host of
nonreproductive brain functions. The expression of ERß mRNA in many
of these brain regions has raised the possibility that functional ER
may be expressed in these brain areas (see discussion above). At the
same time, the presence of a few ER
-containing nerve cells has led
to the discovery, for example in the hippocampus, that these few nerve
cells can have powerful transsynaptic effects on neighboring neurons
(see below). In addition, the rapidity and structure-activity profile
of some of these effects have raised questions about the possible
nontraditional and even nongenomic actions of estrogens in some brain
regions.
Treatment of ovariectomized rats with 17ß-estradiol induces certain
hippocampal neurons to form new synaptic connections with other nerve
cells. These estrogen effects appear to be attributable to
intracellular ERs in inhibitory interneurons that can influence
thousands of pyramidal neurons in their vicinity, although the role of
ERß in synapse formation has not been ruled in or out (see Ref. 2 for
summary). Yet, the actions of estrogens in the basal forebrain, corpus
striatum, and nucleus accumbens on dopaminergic activity appear to be
mediated by membrane actions, as there is no indication for the
expression of either ER
or ERß in these brain regions. On the
other hand, estrogen actions on cholinergic, noradrenergic,
serotonergic, and hypothalamic dopaminergic systems are probably
mediated at least in part by known intracellular ER
or ERß that
are expressed in these brain areas (see Ref. 2 for summary). The spinal
cord also has intracellular ER
and ERß, but the reported effects
on nociception and analgesia do not directly relate to those receptor
sites in enkephalin-expressing spinal neurons (see Ref. 2 for
summary).
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Estrogen actions on cognitive function and memory
processes
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Among the most novel and fascinating effects of estrogen are those
on cognitive function, and there are at least four aspects of estrogen
and progesterone action in brain that are especially relevant to memory
processes and their alterations during aging and neurodegenerative
diseases (for details, see Ref. 2).
First, as noted above, studies of female rats show that estrogens and
progestins regulate synaptogenesis in the hippocampus, a brain region
important in spatial and declarative learning and memory. During the
estrous cycle of a female rat, these synapses are formed under the
influence of estrogens and are then broken down after the proestrus
surge of progesterone (30). In ovariectomized rats, formation of new
excitatory synapses is induced by estradiol and involves the
participation of a neurotransmitter, glutamic acid, acting through
NMDA receptors (31); progesterone administration then triggers
the disappearance of the newly formed synapses within 1224 h.
Inhibitory interneurons that innervate thousands of adjacent pyramidal
neurons express ER
and are the most likely transsynaptic regulator
of synapse formation on the pyramidal neurons.
Second, there are developmentally programmed sex differences in
hippocampal structure that may help to explain differences in the
strategies that male and female rats use to solve spatial navigation
problems. Males use global spatial cues more effectively than females
to locate food in a radial arm maze or to find a hidden platform in a
Morris water maze. An analogous sex difference in spatial
problem-solving ability is reported in humans (32). During the period
of development when testosterone is elevated in the male, aromatase
activity and ERs are transiently expressed in hippocampus (33, 34), and
recent data on behavior and synapse induction strongly suggest that
this pathway is involved in the masculinization or defeminization of
hippocampal structure and function (35, 36).
Third, ovarian steroids have widespread effects throughout the brain,
including brain stem and midbrain catecholaminergic neurons, midbrain
serotonergic pathways, midbrain dopaminergic activity, and the basal
forebrain cholinergic system (see Table 2
). Whereas basal forebrain
cholinergic function is involved in attention, noradrenergic function
is involved in arousal, serotonin is involved with mood and affect, and
dopamine is involved with reward (2). Regulation of the serotonergic
system appears to be mediated in part by the presence of estrogen- and
progestin-sensitive neurons in the midbrain raphe and leads to the
induction of tryptophan hydroxylase and the regulation of serotonin
transporters and serotonergic receptor subtypes (37), whereas the
ovarian steroid influence on cholinergic function occurs in basal
forebrain neurons that express intracellular ER and leads to the
induction of choline acetyltransferase and acetylcholinesterase
according to a sexually dimorphic pattern (38, 39). Noradrenergic and
dopaminergic systems also show sex differences and both direct and
indirect effects of estrogens via conventional ER and by nongenomic
mechanisms. Because of the widespread projections of these systems in
the forebrain, these various neuronal systems have important global
effects on arousal and attentional mechanisms as well as more specific
actions related to learning and remembering, particularly of verbal
information. Thus, it is not so surprising that ovarian steroids have
measurable effects on those aspects of cognition and also on mood and
affect and motor coordination; these effects are evident after
ovariectomy and during the decline of estrogens that occurs after the
menopause and with aging (2). However, as noted above, one of the
fundamental questions is the mechanism by which these effects occur,
whether by traditional intracellular receptors or by the novel,
nongenomic mechanisms that are referred to above, and as noted, we have
seen that the diversity of mechanisms and uncertainties about receptor
identity leave us still somewhat in the dark about the exact molecular
events.
Fourth, estrogen effects on memory have been reported in animal models
and in studies on humans (2). The memories affected are ones in which
the hippocampus plays a role along with the basal forebrain cholinergic
system; in rats, the sensitive memories are related to spatial
information (40, 41, 42, 43), whereas in humans, it is verbal memory that is
particularly sensitive (44, 45, 46). Yet, there is some contradiction in
terms of the time course of the effects and the types of memory
affected between the reported estrogen actions and the known cellular
processes, such as estrogen-induced synaptogenesis. For example,
estrogen-induced synaptogenesis in the rat hippocampus occurs within
several days, yet the effects of estrogen on cognitive function in rats
and humans noted above take a number of weeks to be fully manifested.
Moreover, the more rapid actions of estrogens in both rats and humans
(i.e. over the time course of a few days) seem to be
associated with impairment of spatial memory (47, 48). Thus, much more
research is needed to reconcile morphological and neurochemical changes
with the behavioral data. It cannot be overemphasized that rather than
one estrogen-regulated process or one brain region, many types of
estrogen action on a number of neurochemical and neuroanatomical
substrates and a number of molecular mechanisms are likely to underlie
the actions of estrogens on cognition and other aspects of behavior,
such as mood, pain perception, and nociception.
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Estrogens and neuroprotection in relation to aging and
dementia
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There is growing evidence that estrogens not only have reversible
effects to improve memory, affect, and motor coordination in women who
suffer from estrogen deficiency after the menopause, but they also
appear to have a neuroprotective effect for Alzheimers disease and
protect cells from damage and destruction by free radicals and
ß-amyloid protein. Moreover, the cognitive improvement seen in
Alzheimers disease patients after treatment with the cholinesterase
blocker, tacrine, is reported to be most evident in women also
receiving ERT (49).
There are at least two ways in which estrogens appear to be able to
protect the brain from neurodegeneration. First, as discussed above and
summarized in Table 2
, estrogens maintain function of key neural
structures, such as the hippocampus and basal forebrain, and the widely
projecting dopaminergic, serotonergic, and noradrenergic systems. As
estrogen levels decline over the menopause, these systems and the
cognitive and other behavioral processes that depend upon them also
decline, as least functionally; yet, they appear to respond to estrogen
replacement. It is conceivable that estrogens not only maintain
function but also confer resilience against neural damage by various
agents due to their ability to maintain synaptic connections and
promote the activities of these important neural systems.
The second type of neuroprotective effect of estrogens is a more direct
involvement in blocking the actions of neurotoxic agents or inhibiting
their generation. As noted above and in Table 1
, the A ring of the
estrogen molecule appears to have special properties with respect to
the formation of free radicals and special protective effects on cells
in culture that are deprived of serum or exposed to free radical
generators (2). In this regard, in vivo studies of
estrogen-mediated neuroprotection have reported successful reduction of
lesion size by SILASTIC brand implants (Dow Corning Corp.,
Midland, MI) of 17ß-estradiol in male rats subjected to middle
cerebral artery occlusion (50). In another study, a single injection of
17ß-estradiol reduced damage to hilar neurons in the hippocampal
dentate gyrus of female rats caused by kainic acid treatment (51). In
addition, estrogen treatment of cultured nerve decreases formation of
the toxic form of the ß-amyloid protein (52). Moreover, estrogen
treatment interferes with the toxic effects of the ß-amyloid protein
(53) and the human immunodeficiency virus coat protein, gp120 (54),
both of which act via free radical generation.
Besides neurons, the glial cells of the brain are implicated in aspects
of oxidative energy metabolism, brain plasticity, brain aging, and
neuroprotection (see Ref. 2 for more details). Glial cells and vascular
epithelium play a role in the adult brain in relation to glucose uptake
and energy metabolism, and ovarian steroids regulate the ability of the
female brain to use glucose as its primary energy source. For example,
in studies of postmenopausal women with or without ERT, there were
significant enhancing effects of estrogen on verbal and figural memory
tests as well as enhancements of cerebral blood flow during the memory
tasks (55). Moreover, glial cells are affected by estrogens in
vivo and in vitro, and they express a number of
proteins that are regulated by estrogens, including apolipoprotein E
and glial fibrillary acidic protein; apolipoprotein E is implicated in
membrane formation and structural plasticity, whereas glial fibrillary
acidic protein expression increases throughout the brain as it ages (2, 56). Astroglia play a role in synaptic retraction during the ovulatory
cycle in the adult hypothalamic arcuate nucleus. During the
preovulatory and ovulatory phases of the female rat estrous cycle,
there is a transient disconnection of inhibitory synaptic inputs to
arcuate nucleus neurons, and this remodeling is mediated in part by
soluble factors, such as insulin-like growth factor I (IGF-I) (57).
Moreover, there seems to be a reciprocal interaction between IGF-I and
estrogen, and one speculation is that estrogens may act in arcuate
nucleus neurons to regulate the production of a factor, possibly
-aminobutyric acid that, in turn, regulates the expression of IGF-I
by astroglia (tanycytes) in the arcuate nucleus region (57). The
mechanisms of estrogen action on glial cell function remain unclear,
but they may involve some limited expression of both ER
and ERß
within astrocytes, oligodendrocytes, and/or microglia (2).
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Conclusions
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Many regions of the central nervous system respond to estrogens,
and we are rapidly gaining insights into their diverse cellular and
molecular mechanisms of action. Although there is no proof at this time
that estrogens are truly neuroprotective and capable of slowing down
Alzheimers disease, they are perhaps the most promising agents yet
devised for this purpose. ERT is already strongly supported as therpay
for osteoporosis and cardiovascular protection, and protection of the
brain, along with benefits in terms of memory, motor coordination, and
affect, would add additional reasons for using ERT.
The question of whether males would also benefit from ERT is also very
important, but to date has not been adequately explored. Likewise, the
actions of androgens on the male brain deserve much more study,
particularly with regard to possible neuroprotection as well as
beneficial neurocognitive effects. Sex differences in the brain do not
preclude the efficacy of ERT in males, but they do indicate the need
for careful and systematic studies of estrogen actions in men as well
as women. The development of novel compounds with specific estrogenic
activities, such as the selective estrogen response modulators, offers
new hope for benefiting both men and women. However, based upon the
diversity of sites and molecular mechanisms of action of estrogens in
the brain, each novel compound needs to be carefully evaluated in terms
of what it does to a variety of neural estrogen effects in the central
nervous system.
Received January 27, 1999.
Revised March 10, 1999.
Accepted March 15, 1999.
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