Is brain estradiol a hormone or a neurotransmitter?

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Mounting evidence indicates that, besides their well-known hormonal mode of action at the genetic level, estrogens such as 17β-estradiol also influence brain function by direct effects on neuronal membranes. Experimentally induced rapid changes in estradiol bioavailability in the brain have been shown to alter the expression of male sexual behavior significantly within minutes – probably too quickly to be accounted for by conventional genetic mechanisms. In parallel, recent studies indicate that aromatase, the enzyme that converts testosterone to estradiol in the brain, is expressed in presynaptic terminals and modulated within minutes by Ca2+-dependent phosphorylation. In this article, we develop the hypothesis that brain estrogens display many, if not all, functional characteristics of neuromodulators or even neurotransmitters.

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Introduction: neurotransmitters versus hormones

Chemical communication between cells is fundamental to neural function. Categorizing chemical messengers present in the brain is necessary when trying to organize the seemingly endless complexity of the CNS. One categorical distinction established nearly 100 years ago is that between hormones and neurotransmitters [1], but the validity of this distinction continues to be challenged. Our focus here is on the steroid hormone 17β-estradiol (E2) and its identity as a chemical messenger. Hormones

Fast actions of estrogens on cell function

It has been known for many years that estrogens such as E2 mediate some of their effects via nuclear receptors that act as transcription factors to modulate gene transcription, and that they also mediate other, more rapid effects in the brain that do not involve genomic mechanisms (or do so only indirectly) 3, 4, 5. For example, estrogens can change the electrophysiological activity of various populations of neurons with latencies of a few seconds [6], or reduce within minutes Ca2+ currents in

Control of aromatase transcription in the brain by steroids

It was discovered in the early 1970s that estrogens are synthesized in the brain by aromatization of androgens such as testosterone [11]. Estrogens locally produced in the preoptic area have a key role in the activation of sexual behavior in various vertebrate species [12]. Preoptic aromatase activity is, in contrast to aromatase expressed in ovarian or adipose tissues, regulated by genomic actions of sex steroids 13, 14. Testosterone treatment of castrated birds 15, 16 and mammals [17]

Cellular localization of aromatase and its physiological significance

Aromatase-expressing cells are distributed in a relatively small number of discrete brain regions primarily in the diencephalon. However, fibers originating from these cells are much more widespread and can be detected in a relatively large number of brain areas 30, 31. Within cells, a significant fraction of aromatase activity appears to be located in presynaptic boutons. This enzymatic activity is enriched in synaptosomes prepared from zebra finch or rat brain 32, 33, and dense aromatase

Effects on appetitive and consummatory aspects of male sexual behavior

Although rapid effects of estrogens on cell function have been widely identified, few studies have investigated rapid E2 effects on whole-organism responses in behavior and physiology. One study on rats identified effects of estradiol injections on male sexual behavior after latencies of 20–30 min [42]. Rapid membrane actions of E2 were also shown to enhance the genomic effects of this steroid on lordosis behavior (i.e. taking up a sexually receptive position that allows mounting and

What is the cellular basis for these rapid effects on behavior?

During the past decade, E2 has been shown to have short-latency effects on many cellular and biochemical events associated with various neural messenger systems. This topic has been reviewed extensively (e.g. 5, 6, 57, 58) and is beyond the scope of this paper. The mechanisms mediating these cellular actions of estrogens are good candidates to explain the behavioral effects already described. For example, rapid changes in E2 availability in neuronal perikaya could modulate the activity of

Does E2 meet the criteria for a neurotransmitter, and why is that important?

The concept of neurosecretion and associated ideas about the unity of action of the nervous and endocrine systems have been articulated in some form for decades, but assumptions that endocrine and neural signaling are respectively mediated by hormones and neurotransmitters can hinder scientific thinking. Subsequent to the discovery of neurosecretion, it was established that some hormones, in particular testosterone, are actually pro-hormones that must be transformed at target sites into more

Concluding remarks

The recently identified rapid changes in aromatase activity address in part the conceptual gap between the well-documented rapid non-genomic effects of estrogens in the brain and the apparent lack of mechanisms to modify estrogen availability rapidly in specific brain areas [10]. Experiments mimicking the activation or inactivation of aromatase, by acute injection of E2 or an aromatase inhibitor respectively, rapidly affect the expression of sexual behavior or the reaction to noxious stimuli,

Acknowledgements

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 C.A. Cornil. We thank the following individuals for discussion and comments on the manuscript: Drs Julie Bakker, Claudio Carere, Jean-Pierre Bourguignon, Lucien Bettendorf and Margaret M. McCarthy.

References (75)

  • N.W. Hoffman

    Whole-cell recordings of spontaneous synaptic currents in medial preoptic neurons from rat hypothalamic slices: mediation by amino acid neurotransmitters

    Brain Res.

    (1994)
  • A. Foidart

    Critical re-examination of the distribution of aromatase-immunoreactive cells in the quail forebrain using antibodies raised against human placental aromatase and against the recombinant quail, mouse or human enzyme

    J. Chem. Neuroanat.

    (1995)
  • C.A. Cornil

    Estradiol rapidly activates male sexual behavior and affects brain monoamine levels in the quail brain

    Behav. Brain Res.

    (2006)
  • C.A. Cornil

    Rapid effects of aromatase inhibition on male reproductive behaviors in Japanese quail

    Horm. Behav.

    (2006)
  • I. Ceccarelli

    Estrogen and μ-opioid receptor antagonists counteract the 17 β-estradiol-induced licking increase and interferon-γ reduction occurring during the formalin test in male rats

    Pain

    (2004)
  • R.M. Craft

    Sex differences in pain and analgesia: the role of gonadal hormones

    Eur. J. Pain

    (2004)
  • N.J. Liu et al.

    Prolonged ovarian sex steroid treatment of male rats produces antinociception: identification of sex-based divergent analgesic mechanisms

    Pain

    (2000)
  • H.C. Evrard et al.

    Aromatization of androgens into estrogens reduces response latency to a noxious thermal stimulus in male quail

    Horm. Behav.

    (2004)
  • E.J. Filardo et al.

    GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release

    Trends Endocrinol. Metab.

    (2005)
  • G.P. Cardona-Gomez

    Synergistic interaction of estradiol and insulin-like growth factor-I in the activation of PI3K/Akt signaling in the adult rat hypothalamus

    Mol. Brain Res.

    (2002)
  • O.K. Ronnekleiv et al.

    Diversity of ovarian steroid signaling in the hypothalamus

    Front. Neuroendocrinol.

    (2005)
  • I.M. Abraham et al.

    Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo

    Neuroscience

    (2005)
  • E-E. Baulieu et al.

    Neurosteroids: A new brain function?

    J. Steroid Biochem. Mol. Biol.

    (1990)
  • J. Balthazart

    Rapid changes in production and behavioral action of estrogens

    Neuroscience

    (2006)
  • R.J.M. Timmers

    Estrogen-2-hydroxylase in the brain of the male African catfish, Clarias gariepinus

    Gen. Comp. Endocrinol.

    (1988)
  • J. Balthazart

    Distribution and regulation of estrogen-2-hydroxylase in the quail brain

    Brain Res. Bull.

    (1994)
  • Y. Osawa

    Multiple functions of aromatase and the active site structure; aromatase is the placental estrogen 2-hydroxylase

    J. Steroid Biochem. Mol. Biol.

    (1993)
  • D.E. Baranano

    Atypical neural messengers

    Trends Neurosci.

    (2001)
  • G.W. Harris

    Neural Control of the Pituitary Gland

    (1955)
  • S.H. Snyder et al.

    Novel neurotransmitters and their neuropsychiatric relevance

    Am. J. Psychiatry

    (2000)
  • B.S. McEwen et al.

    Estrogen actions in the central nervous system

    Endocr. Rev.

    (1999)
  • B.S. McEwen

    Invited review: estrogens effects on the brain: multiple sites and molecular mechanisms

    J. Appl. Physiol.

    (2001)
  • P.G. Mermelstein

    Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor

    J. Neurosci.

    (1996)
  • Y. Zhou

    Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain

    Endocrinology

    (1996)
  • N. Linford

    The rapid effects of estrogen are implicated in estrogen-mediated neuroprotection

    J. Neurocytol.

    (2000)
  • E.R. Simpson

    Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis

    Endocr. Rev.

    (1994)
  • T. Steimer et al.

    Androgen increases formation of behaviourally effective oestrogen in dove brain

    Nature

    (1981)
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