Trends in Neurosciences
OpinionThe dual action of estrogen hypothesis
Section snippets
Neuroestrogens versus ovarian estrogens
Estrogens are steroid hormones that were initially isolated and characterized in the late 1920s by Adolf Butenandt (Nobel laureate for this discovery) and Edward A. Doisy [1]. They are present in all vertebrates and some invertebrates, and are traditionally considered to be the primary female sex hormone because they are produced by the ovary, released into the blood, and play a key role in the control of female reproduction. Estrogens are secreted in the developing ovarian follicles by
The dual control of estrogen synthesis
Ovarian and brain estrogens have exactly the same chemical structure and are produced by the same enzyme, aromatase. Two fundamentally different controls of brain AA have been identified that operate in distinct time-domains. In the long term, steroids increase transcription of the aromatase gene, resulting in increased enzyme concentration and thus activity (genomic control). In a shorter timescale, post-translational modifications of the enzymatic protein drastically modify its activity
Fast versus slow actions of estrogens
As other steroid hormones, estrogens are classically considered to exert their biological effects by binding to their cognate nuclear receptors [i.e., estrogen receptor α (ERα) and estrogen receptor β (ERβ)], which then act as ligand-activated transcription factors to regulate transcription of specific genes associated with an estrogen-responsive element (ERE) or other types of response elements (e.g., AP1, Sp1, NF-κB) [8]. These biological effects are thus mediated via transcription of genes,
Distinct controls of behavioral motivation and performance
This distinction was confirmed and reinforced by more recent experiments during which brain estrogen bioavailability was pharmacologically manipulated by intracerebroventricular (ICV) injections. For these studies, castrated male quail that were chronically treated with exogenous T (subcutaneous Silastic™ implant) were implanted with an ICV cannula in the third ventricle, and then were used as their own controls in successive behavior trials after injections of aromatase inhibitors or various
Towards a generalization?
We think that the dual action hypothesis has wide applicability. It is hard to be certain at present because investigators studying estrogen actions in other behavioral systems have not designed their studies to address questions related to the dual action view as we have done. However, consideration of some other examples of E2 action on motivated behaviors is illustrative.
Three studies identified rapid effects of estrogens on male sexual behavior in rodents (rats 14, 19 and mice [16]). In all
Multiple neuroanatomical targets
The separation of estrogen effects on motivation and performance may possibly relate to a neuroanatomical specificity in the site of steroid action on sexual behavior in quail and other vertebrates. Several studies that we previously reviewed [42] have indeed suggested dissociations between the neuronal circuits underlying the expression of ASB reflecting motivation, and consummatory sexual behavior (CSB) indicative of performance.
In quail, detailed analysis of the extent of stereotaxic lesion
The different estrogen receptors
The two types of behavioral effects of estrogens could also be potentially differentiated based on the different receptors mediating the responses (Box 3). Several studies have implicated the receptors ERα and ERβ in the control of sexual behavior by nuclear mechanisms, but there is no published study on the type of estrogen receptor mediating rapid membrane-initiated effects on male sexual behavior. One study recently reported that the Gq-protein-coupled membrane ER (Gq-mER) does not seem to
Concluding remarks: the dual action of estrogen hypothesis
The dual action theory of estrogen action provides a useful way to organize recent somewhat surprising findings about estrogens, their regulation of behavior, and their mechanisms of action. We were among those who had previously proposed that brain estrogens should be considered more as a neurotransmitter than as a traditional hormone 55, 56. These observations stimulated additional research on the various modes by which estrogens can act on behavior. These data in turn stimulated the posing
Acknowledgments
Research in our laboratories mentioned here and the preparation of this review were supported by National Institutes of Health grant RO1 MH50388. C.A.C. is a Fonds de la Recherche Scientifique (FRS)–Fonds National de la Recherche Scientifique (FNRS) Research Associate. We thank Dr Margaret M. McCarthy for useful comments on an earlier version of this article.
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