Elsevier

Hormones and Behavior

Volume 31, Issue 3, June 1997, Pages 232-243
Hormones and Behavior

Regular Article
Estrogen Receptor Function as Revealed by Knockout Studies: Neuroendocrine and Behavioral Aspects

https://doi.org/10.1006/hbeh.1997.1390Get rights and content

Abstract

Estrogens are an important class of steroid hormones, involved in the development of brain, skeletal, and soft tissues. These hormones influence adult behaviors, endocrine state, and a host of other physiological functions. Given the recent cloning of a second estrogen receptor (ER) cDNA (the ERβ), work on alternate spliced forms of ERα, and the potential for membrane estrogen receptors, an animal with a null background for ERα function is invaluable for distinguishing biological responses of estrogens working via the ERα protein and those working via another ER protein. Data generated to date, and reviewed here, indicate that there are profound ramifications of the ERα disruption on behavior and neuroendocrine function. First, data on plasma levels of estradiol (E2), testosterone (T), and luteinizing hormone (LH) in wild-type (WT) versus ERαmice confirm that ERα is essential in females for normal regulation of the hypothalamic–pituitary gonadal axis. Second, ovariectomized female ERαmice do not display sexual receptivity when treated with a hormonal regime of estrogen and progesterone that induces receptivity in WT littermates. Finally, male sexual behaviors are disrupted in ERαanimals. Given decades of data on these topics our findings may seem self-evident. However, these data represent the most direct test currently possible of the specific role of the ERα protein on behavior and neuroendocrinology. The ERαmouse can be used to ascertain the specific functions of ERα, to suggest functions for the other estrogen receptors, and to study indirect effects of ERα on behavior via actions on other receptors, neurotransmitters, and neuropeptides.

References (78)

  • B.S. McEwen

    Non-genomic and genomic effects of steroids on neural activity

    Trends Pharmacol. Sci.

    (1991)
  • S. Mosselman et al.

    ERβ: identification and characterization of a novel human estrogen receptor

    FEBS Lett.

    (1996)
  • I. Motelica-Heino et al.

    Testosterone levels in plasma and testes of neonatal mice

    J. Steroid Biochem.

    (1988)
  • I. Motelica-Heino et al.

    Intermale aggression in mice: Does hour of castration after birth influence adult behavior?

    Physiol. Behav.

    (1993)
  • A.A. Nunez et al.

    The effects of testosterone, estradiol, and dihydrotestosterone on male mouse (Mus musculus

    Horm. Behav.

    (1978)
  • J. Nyby et al.

    Intracranial androgenic and estrogenic stimulation of male-typical behaviors in house mice (Mus domesticus

    Horm. Behav.

    (1992)
  • J.G. Nyby et al.

    Nonaromatizable androgens may stimulate a male mouse reproductive behavior by binding estrogen receptors

    Physiol. Behav.

    (1987)
  • S. Ogawa et al.

    Reproductive functions illustrating direct and indirect effects of genes on behavior

    Horm. Behav.

    (1996)
  • V.D. Ramirez

    Characterization of membrane action of steroids

    Neuroprotein

    (1992)
  • J.A. Resko et al.

    Brain steroids synthesis and metabolism

    Neuroprotein

    (1992)
  • P.J. Shughrue et al.

    The distribution of estrogen receptor β mRNA in the rat hypothalamus

    Steroids

    (1996)
  • R.B. Simerly

    Hormonal control of neuropeptide gene expression in sexually dimorphic olfactory pathways

    Trends Neurosci.

    (1990)
  • J.T. Watson et al.

    Activation of sexual behavior by implantation of testosterone propionate and estradiol benzoate into the preoptic area of the male Japanese quail

    Horm. Behav.

    (1989)
  • B.E. Wee et al.

    Hormonal restoration of masculine sexual behavior in long-term castrated B6D2F1 mice

    Physiol. Behav.

    (1988)
  • E. Zyzek et al.

    Short-term effect of estrogen on release of prolactin by pituitary cells in culture

    Biochem. Biophys. Res. Commun.

    (1981)
  • S.M. Aronica et al.

    Estrogen action via the cAMP signalling pathway: Stimulation of adenylate cyclase and cAMP-regulated gene transcription

    Proc. Natl. Acad. Sci. USA

    (1994)
  • R.J. Auchus et al.

    The oestrogen receptor

    Balliere's Clinical Endocrinology and Metabolism: Hormones, Enzymes and Receptors

    (1994)
  • M.J. Baum et al.

    Copulation in castrated male rats following combined treatment with estradiol and dihydrotestosterone

    Science

    (1973)
  • M.J. Baum et al.

    Steroidal control of behavioral neuroendocrine and brain sexual differentiation: Studies in a carnivore, the ferret

    J. Neuroendocrinol.

    (1990)
  • Y. Berthois et al.

    Estradiol membrane binding sites on human breast cancer cell lines

    J. Steroid Biochem.

    (1986)
  • J.D. Blaustein et al.

    Gonadal steroid hormone receptors and social behaviors

  • M. Byers et al.

    Estrogen receptor β mRNA expression in rat ovary: down-regulation by gonadotrophins

    Mol. Endocrinol.

    (1997)
  • N.J. Charest et al.

    A frameshift mutation destabilizes androgen receptor messenger RNA in the Tfm mouse

    Mol. Endocrinol.

    (1991)
  • L.W. Christensen et al.

    Intrahypothalamic implants of testosterone or estradiol and resumption of masculine sexual behavior in long-term castrated male rats

    Endocrinology

    (1974)
  • L.W. Christensen et al.

    Blockage of testosterone-induced mounting behavior in the male rat with intracranial application of the aromatization inhibitor, androst-1,4,6-triene-3,17-dione

    Endocrinology

    (1975)
  • J.F. Couse et al.

    Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene

    Mol. Endocrinol.

    (1995)
  • J.F. Couse et al.

    Disruption of the mouse oestrogen receptor gene: resulting phenotypes and experimental findings

    Biochem. Soc. Trans.

    (1995)
  • S. K. Das, J. A. Taylor, K. S. Korach, B. C. Paria, S. K. Dey, D. B. Lubahn, Estrogenic responses in estrogen receptor...
  • Cited by (177)

    View all citing articles on Scopus

    M. C. ShepperdP. M. Stewart, Eds.

    1

    To whom correspondence should be addressed at Department of Biology, Gilmer Hall, University of Virginia, Charlottesville, VA 22903. E-mail: [email protected].

    View full text