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The Molecular and Neuroanatomical Basis for Estrogen Effects in the Central Nervous System

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

	Introduction

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 
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.

	Historical overview

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 
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).

	ERs and actions in the central nervous system

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 
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.

View larger version (29K): [in this window] [in a new window]   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.

	Intracellular ERs

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

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.

	Novel estrogen actions

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 
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).

	Estrogen actions throughout the central nervous system

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 
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).

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).

	Estrogen actions on cognitive function and memory processes

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 
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 12–24 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.

	Estrogens and neuroprotection in relation to aging and dementia

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 
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 Alzheimer’s disease and protect cells from damage and destruction by free radicals and ß-amyloid protein. Moreover, the cognitive improvement seen in Alzheimer’s 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).

	Conclusions

Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 
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 Alzheimer’s 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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Top Introduction Historical overview ERs and actions in... Intracellular ERs Novel estrogen actions Estrogen actions throughout the... Estrogen actions on cognitive... Estrogens and neuroprotection in... Conclusions References

 

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