ReviewFunctional significance of the rapid regulation of brain estrogen action: Where do the estrogens come from?
Introduction
Gonadal steroids produce a wide range of cellular effects that are largely, but not exclusively, mediated through intracellular receptors. These steroid hormone receptors are members of a large family of ligand-activated transcription factors that bind response elements located on the DNA and regulate the transcription of genes encoding a wide variety of proteins. These proteins include synthesis enzymes (such as tyrosine hydroxylase), transporters, receptors, signal transduction proteins (phosphatases, kinases, accessory proteins, etc.) or degradation enzymes (such as monoamine oxidases), which ultimately modify neurotransmission (Maggi et al., 2004, McEwen and Alves, 1999). These effects are relatively slow and develop with latencies ranging from 1 h to several days. The role of genomic actions of steroids in adults has been extensively documented based on studies of physiology and behavior. Steroids exert profound organizational effects on the developing brain and the increase of secretion of sex steroid hormones at puberty and their maintenance throughout the reproductive life are responsible for the activation and maintenance of secondary sex characters and behavior such as courtship, reproductive behavior, aggressive behaviors, etc. (Becker et al., 2002). Seasonal fluctuations and/or variations across the estrus cycle of circulating levels of estrogens positively correlate with variation in these reproductive responses (Ball and Balthazart, 2002, Prendergast et al., 2002, Wingfield and Silverin, 2002). A variety of effects of estrogens and other steroids on responses unrelated to reproduction have also been identified. For example, estrogens are known to influence cognitive functions, pain mechanisms, fine motor skills, mood, temperature regulation and sleep (McEwen and Alves, 1999, Wang et al., 2001).
In addition, a host of studies have also identified effects of steroids that are too rapid (seconds to minutes) to be mediated through the activation of DNA transcription and protein synthesis (Kelly and Ronnekleiv, 2002, McEwen and Alves, 1999, Moss et al., 1997). This is particularly the case for 17β-estradiol (E2) which can rapidly (within a few seconds to several minutes; see below) activate a wide variety of intracellular signaling pathways including modulations of intracellular calcium concentrations (Beyer et al., 1976, Mermelstein et al., 1996) and protein phosphorylations (Moss et al., 1997, Nethrapalli et al., 2004, Wade and Dorsa, 2003, Wade et al., 2001, Watters et al., 1997). These actions seem to be initiated primarily at the cellular membrane and lead to modulations of electrical activity (Kelly and Ronnekleiv, 2002, Moss et al., 1997) and neuronal activation (Abraham et al., 2003, Abraham et al., 2004, Gu et al., 1996, Wade and Dorsa, 2003, Zhou et al., 1996) in various brain regions (for review see Maggi et al., 2004, McEwen and Alves, 1999).
Although there is no longer any doubt about the existence of non-genomic effects, many uncertainties remain. One of the most debated questions is whether these effects are mediated by interactions of estrogens with the “classical” nuclear estrogen receptors (ERs) located in the cell nucleus or associated with the neuronal membrane and whether these effects are elicited by physiologically relevant concentrations of estrogens. In addition, the nature of the mechanism(s) able to modulate rapidly the bioavailability of estrogen (that is necessary to explain the existence of these fast effects) has rarely been questioned or even discussed, even though this represents a fundamental aspect of the rapid effects of steroids. Furthermore, while there are a plethora of data characterizing rapid, presumably non-genomic, effects of estrogens based on cellular measures of action, there is still little information concerning the significance of these effects at the organismal or behavioral level of analysis. This review will try to address these last two questions. Firstly, we will examine the potential sources of estrogen for the brain that are rapidly modulated and, secondly, we will summarize what is known about the functional significance of fast effects of estrogen for physiology and behavior. In addition, the question of the physiological relevance of doses that can activate the rapid effects of estrogens will also be discussed.
Section snippets
Physiological relevance of the fast cellular effects of steroids
Rather surprisingly, while the existence of non-genomic effects of steroids is not subject to doubt anymore, our knowledge of their implications in the regulation of physiological and behavioral processes remains quite limited. Perhaps the most progress has been made for the C21 steroids corticosterone and progesterone. In the case of corticosterone, rapid effects have been identified on various measures of sexual behavior (Moore and Orchinik, 1994) and stress (Orchinik, 1998) in amphibians and
Non-genomic effects on cell function
Fast effects of steroids were described for the first time in 1941 by Hans Selye, who observed a rapid anesthetic and sedative effect of progesterone (Selye, 1941). In the 60s and in the beginning of the 70s, several studies suggested that estrogens modulate the electrical activity of various neuronal populations (Bueno and Pfaff, 1976, Whitehead and Ruf, 1974, Yagi, 1973). The concept of fast and non-genomic action of estrogen was first introduced in 1976 by Martin Kelly who demonstrated that E
Where does estrogen come from?
Together, these observations raise the question of the mechanisms controlling the rapid fluctuations of estrogen bioavailability that are presumably needed to sustain the fast actions of the hormone. Intuitively, it can indeed be hypothesized that, for fast non-genomic actions of steroids to be biologically effective, the endogenous ligand’s availability must also change quickly. That is not to say that slow changes of steroids levels would not activate non-genomic effects. However, in this
The fast effects of estrogens: systemic or central origin of the steroid?
In both sexes, androgens such as testosterone or androstenedione can be converted into estrogens by an enzymatic process, called aromatization, which is catalyzed by the enzyme aromatase (or estrogen synthase). This enzyme is present primarily in the ovaries (but also to a lesser extent in the testes), the placenta, the bones and the brain (Naftolin and MacLusky, 1984, Sasano and Harada, 1998, Simpson et al., 2002). Under normal conditions, aromatase expression in the avian and mammalian
What is a physiological concentration of estrogen?
The fact that estrogen production is very localized in the brain suggests that high concentrations may be rapidly attained in specialized locations such as the synaptic clef in specialized synapses. These local brain concentrations may thus exceed at discrete sites the physiological concentrations of circulating estrogens. This could then explain why some (most) of the rapid effects of estrogens that have been observed in vitro can only be activated with what has been considered so far as
What terminates estrogen action in the brain?
Warner and Gustafsson also compared the effects of E2 and neurotransmitters and observed that “the changes [induced by neurostransmitters] are not only rapid, they are also transient” and “there are multiple mechanisms at the synapse to terminate neurotransmitter action and rectify intracellular ion homeostasis.” They stated that the case of E2 is different because “plasma levels do not change rapidly and transiently and no extremely rapid metabolic pathways to terminate estrogen action at the
Effects on appetitive and consummatory aspects of male sexual behavior
If rapid modulations of brain estrogen synthesis and catabolism are involved in the non-genomic control by estrogens of physiological and behavioral processes, the blockade of aromatase activity should rapidly lead to detectable changes in these responses. Accordingly, in recent experiments conducted in quail, systemic injections of a large dose of VorozoleTM, a non-steroidal aromatase inhibitor, significantly reduced most aspects of male copulatory behavior in sexually active males (gonadally
Conclusions
Besides their well-known long lasting action, mounting evidence indicates that estrogens also exert rapid effects on physiological and behavioral processes. These effects are activated within a few minutes and have been described in both sexes. Rapid effects of steroids, estrogens in particular, have been the subject of intense debates concerning namely the question of the existence and nature of the receptors involved. However, the fundamental issue of the source of rapid changes in estrogen
Acknowledgments
Research in our laboratory and preparation of this article were supported by grants NIH/NIMH R01 MH50388 to G.F.B. and FRFC 2.4562.05 to J.B. We thank all our collaborators who helped to produce the original data that are the basis of this article, in particular Drs M. Baillien and H.C. Evrard. We also thank Drs J. Bakker, M. Keller, G.E. Hoffman and M.M. McCarthy for suggesting a number of useful references and ideas that are used in this review. Finally, we thank M. Taziaux for discussion and
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