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Horm Metab Res 2012; 44(08): 563-568
DOI: 10.1055/s-0032-1311605
Review
© Georg Thieme Verlag KG Stuttgart · New York

Steroid Hormone Receptors: Long- and Short-term Integrators of the Internal Milieu and the External Environment

J. D. Blaustein
1   Neuroscience and Behavior Program and Center for Neuroendocrine Studies, University of Massachusetts, Amherst, MA, USA
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Publication History

received 15 December 2011

accepted 28 March 2012

Publication Date:
27 April 2012 (online)

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Abstract

Many of the influences of estrogens and progestins on the brain and behavior are mediated by estrogen receptors and progestin receptors, acting as transcriptional regulators. The homologous and heterologous regulation of the concentrations of these receptors by cognate hormones is well established. However, although they were discovered and characterized based on their binding to cognate hormone and their role in transcriptional regulation, steroid hormone receptors have a more complex role and serve many more functions than originally suspected. First, besides being regulated by steroid hormones, the intracellular concentrations of brain steroid hormone receptors are regulated by neurotransmitters, a pathway by which stimuli from the environment, including from conspecific animals, can modulate the concentration of particular steroid hormone receptors in subsets of cells. Further, besides being activated by cognate steroid hormones, the receptors can be activated by a variety of neurotransmitters and phosphorylation pathways, providing a route through which environmental stimulation can activate steroid-receptor-dependent functions in specific cells. In addition, the transcription factor, estrogen receptor-α, produced from the estrogen receptor-α gene, can be modified to be targeted to membranes, where it can signal via kinase pathways. Finally, developmental experiences, such as particular stressors during the pubertal period, can permanently remodel the brain’s response to ovarian hormones, most likely by long-term changes in regulation of the receptors mediating those responses. In addition to their function in responding to cognate ligand, it is now more appropriate to think of steroid hormone receptors as integrators of a wide variety of signaling pathways.

Key words

estradiol - progesterone - behavior - neuroendocrinology - estrogen receptor - progestin receptor
 

  • References

  • 1 Jensen EV, Jacobson HI. Fate of steroid estrogens in target tissues. In: Pincus G, Vollmer E. (eds.). Biological Activities of Steroids in relation to cancer. New York: Academic Press; 1960: 161-174
    Google Scholar
  • 2 Sherman MR, Corvol PL, O’Malley BW. Progesterone-binding components of chick oviduct. I Preliminary characterization of cytoplasmic components. J Biol Chem 1970; 245: 6085-6096
    PubMedGoogle Scholar
  • 3 Pfaff DW. Uptake of 3H-estradiol by the female rat brain. An autoradiographic study. Endocrinology 1968; 83: 1149-1155
    PubMedGoogle Scholar
  • 4 Stumpf WE. Estradiol-concentrating neurons: topography in the hypothalamus by dry mount autoradiography. Science 1968; 162: 1001-1003
    CrossrefPubMedGoogle Scholar
  • 5 Zigmond RE, McEwen BS. Selective retention of oestradiol by cell nuclei in specific brain regions of the ovariectomized rat. Journal of Neurobiology 1969; 17: 889-899
    PubMedGoogle Scholar
  • 6 Michael RP. Estrogen-Sensitive Neurons and Sexual Behavior in Female Cats. Science 1962; 136: 322-323
    CrossrefPubMedGoogle Scholar
  • 7 McEwen BS, Davis PG, Parsons B, Pfaff DW. The brain as a target for steroid hormone action. Ann Rev Neurosci 1979; 2: 65-112
    CrossrefPubMedGoogle Scholar
  • 8 Kuiper GGJM, Enmark E, Peltohuikko M, Nilsson S, Gustafsson JA. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996; 93: 5925-5930
    CrossrefPubMedGoogle Scholar
  • 9 Jensen EV, Suzuki T, Kawasima T, Stumpf WE, Jungblut PW, de Sombre ER. A two-step mechanism for the interaction of estradiol with rat uterus. Proc Natl Acad Sci USA 1968; 59: 632-638
    CrossrefPubMedGoogle Scholar
  • 10 O’Malley BW, Means AR. Female steroid hormones and target cell nuclei. Science 1974; 183: 610-620
    CrossrefPubMedGoogle Scholar
  • 11 King WJ, Greene GL. Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature 1984; 307: 745-747
    CrossrefPubMedGoogle Scholar
  • 12 Welshons WV, Lieberman ME, Gorski J. Nuclear localization of unoccupied oestrogen receptors. Nature 1984; 307: 747-749
    CrossrefPubMedGoogle Scholar
  • 13 O’Malley BW. Coregulators: from whence came these “master genes”. Mol Endocrinol 2007; 21: 1009-1013
    CrossrefPubMedGoogle Scholar
  • 14 MacLusky NJ, McEwen BS. Oestrogen modulates progestin receptor concentrations in some rat brain regions but not in others. Nature 1978; 274: 276-278
    CrossrefPubMedGoogle Scholar
  • 15 Blaustein JD, Feder HH. Cytoplasmic progestin receptors in guinea pig brain: Characteristics and relationship to the induction of sexual behavior. Brain Res 1979; 169: 481-497
    CrossrefPubMedGoogle Scholar
  • 16 Moguilewsky M, Raynaud JP. The relevance of hypothalamic and hypophyseal progestin receptor regulation in the induction and inhibition of sexual behavior in the female rat. Endocrinology 1979; 105: 516-522
    CrossrefPubMedGoogle Scholar
  • 17 Blaustein JD, Feder HH. Cytoplasmic progestin receptors in female guinea pig brain and their relationship to refractoriness in expression of female sexual behavior. Brain Res 1979; 177: 489-498
    CrossrefPubMedGoogle Scholar
  • 18 Brown TJ, Blaustein JD. Loss of hypothalamic nuclear-bound progestin receptors: Factors involved and the relationship to heat termination in female guinea pigs. Brain Res 1985; 358: 180-190
    CrossrefPubMedGoogle Scholar
  • 19 Blaustein JD, Feder HH. Nuclear progestin receptors in guinea pig brain measured by and in vitro exchange assay after hormonal treatments that affect lordosis. Endocrinology 1980; 106: 1061-1069
    CrossrefPubMedGoogle Scholar
  • 20 Warembourg M. Radioautographic study of the brain and pituitary after [3H]progesterone injection into estrogen-primed ovariectomized guinea pigs. Neuroscience Letts 1978; 7: 1-5
    PubMedGoogle Scholar
  • 21 Meredith JM, Auger CJ, Blaustein JD. Down-regulation of estrogen receptor immunoreactivity by 17 beta-estradiol in the guinea pig forebrain. J Neuroendocrinol 1994; 6: 639-648
    CrossrefPubMedGoogle Scholar
  • 22 Lauber AH, Romano GJ, Mobbs CV, Pfaff DW. Estradiol regulation of estrogen receptor messenger ribonucleic acid in rat mediobasal hypothalamus – an in situ hybridization study. J Neuroendocrinol 1990; 2: 605-611
    CrossrefPubMedGoogle Scholar
  • 23 Malik KF, Feder HH, Morrell JI. Estrogen receptor immunostaining in the preoptic area and medial basal hypothalamus of estradiol benzoate- treated and prazosin- treated female guinea-pigs. J Neuroendocrinol 1993; 5: 297-306
    CrossrefPubMedGoogle Scholar
  • 24 Blaustein JD, Brown TJ. Progesterone decreases the concentration of hypothalamic and anterior pituitary estrogen receptors in ovariectomized rats. Brain Res 1984; 304: 225-236
    CrossrefPubMedGoogle Scholar
  • 25 Attardi B. Facilitation and inhibition of the estrogen-induced luteinizing hormone surge in the rat by progesterone: Effects on cytoplasmic and nuclear estrogen receptors in the hypothalamus-preoptic area, pituitary, and uterus. Endocrinology 1981; 108: 1487-1496
    CrossrefPubMedGoogle Scholar
  • 26 Smanik EJ, Young HK, Muldoon TG, Mahesh VB. Analysis of the effect of progesterone in vivo on estrogen receptor distribution in the rat anterior pituitary and hypothalamus. Endocrinology 1983; 113: 15-22
    CrossrefPubMedGoogle Scholar
  • 27 Cardinali DP, Nagle CA, Rosner JM. Control of estrogen and androgen receptors in the rat pineal gland by catecholamine transmitter. Life Sci 1975; 16: 93-106
    CrossrefPubMedGoogle Scholar
  • 28 Nock BL, Blaustein JD, Feder HH. Changes in noradrenergic transmission alter the concentration of cytoplasmic progestin receptors in hypothalamus. Brain Res 1981; 207: 371-396
    CrossrefPubMedGoogle Scholar
  • 29 Thompson MA, Woolley DE, Gietzen DW, Conway S. Catecholamine synthesis inhibitors acutely modulate [3H]estradiol binding by specific brain areas and pituitary in ovariectomized rats. Endocrinology 1983; 113: 855-865
    CrossrefPubMedGoogle Scholar
  • 30 Gietzen DW, Hope WG, Woolley DE. Dopaminergic agonists increase [3H]estradiol binding in hypothalamus of female rats, but not of males. Life Sci 1983; 33: 2221-2228
    CrossrefPubMedGoogle Scholar
  • 31 Woolley DE, Hope WG, Gietzen DW, Thompson MT, Conway SB. Bromocriptine increases 3H-estradiol uptake in brain and pituitary of female, but not of male, gonadectomized adrenalectomized rats. Proc West Pharmacol Soc 1982; 25: 437-441
    PubMedGoogle Scholar
  • 32 Blaustein JD, Turcotte J. Small apomorphine-induced increase in the concentration of cytosol estrogen receptors in female rat hypothalamus and pituitary. Brain Res Bull 1987; 18: 585-590
    CrossrefPubMedGoogle Scholar
  • 33 Blaustein JD. The a1-noradrenergic antagonist prazosin decreases the concentration of estrogen receptors in female hypothalamus. Brain Res 1987; 404: 39-50
    CrossrefPubMedGoogle Scholar
  • 34 Blaustein JD, Letcher B. Noradrenergic regulation of cytosol estrogen receptors in female hypothalamus: Possible role of alpha2-noradrenergic receptors. Brain Res 1987; 404: 51-57
    CrossrefPubMedGoogle Scholar
  • 35 Blaustein JD, Brown TJ, McElroy JF. Some catecholamine inhibitors do not cause accumulation of nuclear estrogen receptors in rat hypothalamus and anterior pituitary gland. Neuroendocrinology 1986; 43: 143-149
    CrossrefPubMedGoogle Scholar
  • 36 Blaustein JD, Brown TJ, Swearengen ES. Dopamine-b-hydroxylase inhibitors modulate the concentration of functional estrogen receptors in female rat hypothalamus and pituitary gland. Neuroendocrinology 1986; 43: 150-158
    CrossrefPubMedGoogle Scholar
  • 37 Nock B, Feder HH. α1-Noradrenergic regulation of hypothalamic progestin receptors and guinea pig lordosis behavior. Brain Res 1984; 310: 77-85
    CrossrefPubMedGoogle Scholar
  • 38 Lauber AH, Whalen RE. Muscarinic cholinergic modulation of hypothalamic estrogen binding sites. Brain Res 1988; 443: 21-26
    CrossrefPubMedGoogle Scholar
  • 39 Tetel MJ, Blaustein JD. Immunocytochemical evidence for noradrenergic regulation of estrogen receptor concentrations in the guinea pig hypothalamus. Brain Res 1991; 565: 321-329
    CrossrefPubMedGoogle Scholar
  • 40 Cohen-Parsons M, Roy EJ. Social stimuli augment estrogen receptor binding in preoptic area of female prairie voles. Brain Res 1989; 476: 363-366
    CrossrefPubMedGoogle Scholar
  • 41 Cohen-Parsons M, Carter CS. Males increase progestin receptor binding in brain of female voles. Physiol Behav 1988; 42: 191-197
    CrossrefPubMedGoogle Scholar
  • 42 Cohen-Parsons M, Carter CS. Males increase serum estrogen and estrogen receptor binding in brain of female voles. Physiol Behav 1987; 39: 309-314
    CrossrefPubMedGoogle Scholar
  • 43 Power RF, Mani SK, Codina J, Conneely OM, O’Malley BW. Dopaminergic and ligand independent activation of steroid hormone receptors. Science 1991; 254: 1636-1639
    CrossrefPubMedGoogle Scholar
  • 44 Mani SK, Allen JMC, Clark JH, Blaustein JD, O’Malley BW. Convergent pathways for steroid hormone- and neurotransmitter-induced rat sexual behavior. Science 1994; 265: 1246-1249
    CrossrefPubMedGoogle Scholar
  • 45 Mani SK, Blaustein JD, Allen JM, Law SW, O’Malley BW, Clark JH. Inhibition of rat sexual behavior by antisense oligonucleotides to the progesterone receptor. Endocrinology 1994; 135: 1409-1414
    CrossrefPubMedGoogle Scholar
  • 46 Mani SK, Allen JMC, Lydon JP, Mulac-Jericevic B, Blaustein JD, DeMayo FJ, Conneely O, O’Malley BW. Dopamine requires the unoccupied progesterone receptor to induce sexual behavior in mice. Mol Endocrinol 1996; 10: 1728-1737
    CrossrefPubMedGoogle Scholar
  • 47 Beyer C, Gonzalez-Flores O, Gonzalez-Mariscal G. Progesterone receptor participates in the stimulatory effect of LHRH, prostaglandin E2, and cyclic AMP on lordosis and proceptive behaviours in rats. J Neuroendocrinol 1997; 9: 609-614
    PubMedGoogle Scholar
  • 48 Chu HP, Morales JC, Etgen AM. Cyclic GMP may potentiate lordosis behaviour by progesterone receptor activation. J Neuroendocrinol 1999; 11: 107-113
    CrossrefPubMedGoogle Scholar
  • 49 Mani SK, Allen JMC, Rettori V, McCann SM, O’Malley BW, Clark JH. Nitric oxide mediates sexual behavior in female rats. Proc Natl Acad Sci USA 1994; 91: 6468-6472
    CrossrefPubMedGoogle Scholar
  • 50 Acosta-Martinez M, Gonzalez-Flores O, Etgen AM. The role of progestin receptors and the mitogen-activated protein kinase pathway in delta opioid receptor facilitation of female reproductive behaviors. Horm Behav 2006; 49: 458-462
    CrossrefPubMedGoogle Scholar
  • 51 Blaustein JD. Neuronal steroid hormone receptors: they’re not just for hormones anymore. Endocrinology 2004; 145: 1075-1081
    PubMedGoogle Scholar
  • 52 Cenni B, Picard D. Ligand-independent activation of steroid receptors: New roles for old players. Trends Endocrinol Metab 1999; 10: 41-46
    CrossrefPubMedGoogle Scholar
  • 53 Rajendren G, Dudley CA, Moss RL. Role of the vomeronasal organ in the male-induced enhancement of sexual receptivity in female rats. Neuroendocrinology 1990; 52: 368-372
    CrossrefPubMedGoogle Scholar
  • 54 Auger AP, Moffatt CA, Blaustein JD. Progesterone-independent activation of rat brain progestin receptors by reproductive stimuli. Endocrinology 1997; 138: 511-514
    CrossrefPubMedGoogle Scholar
  • 55 Blaustein JD, Farrell S, Ghavami G, Laroche J, Mohan G. Non-intromissive mating stimuli are sufficient to enhance sexual behaviors in ovariectomized female rats. Horm Behav 2009; 55: 404-411
    CrossrefPubMedGoogle Scholar
  • 56 Lonstein JS, Greco B, De Vries G, Stern JM, Blaustein JD. Maternal behavior stimulates c fos activity within estrogen receptor alpha-containing neurons in lactating rats. Neuroendocrinology 2000; 72: 91-101
    CrossrefPubMedGoogle Scholar
  • 57 Olesen KM, Auger CJ, Auger AP. Regulation of progestin receptor expression in the developing rat brain by a dopamine d1 receptor antagonist. J Neuroendocrinol 2007; 19: 481-488
    CrossrefPubMedGoogle Scholar
  • 58 Olesen KM, Jessen HM, Auger CJ, Auger AP. Dopaminergic activation of estrogen receptors in neonatal brain alters progestin receptor expression and juvenile social play behavior. Endocrinology 2005; 146: 3705-3712
    CrossrefPubMedGoogle Scholar
  • 59 Micevych PE, Chaban V, Ogi J, Dewing P, Lu JK, Sinchak K. Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures. Endocrinology 2007; 148: 782-789
    PubMedGoogle Scholar
  • 60 Murakami G, Tanabe N, Ishii HT, Ogiue-Ikeda M, Tsurugizawa T, Mukai H, Hojo Y, Takata N, Furukawa A, Kimoto T, Kawato S. Role of cytochrome p450 in synaptocrinology: endogenous estrogen synthesis in the brain hippocampus. Drug Metab Rev 2006; 38: 353-369
    CrossrefPubMedGoogle Scholar
  • 61 Ishii H, Tsurugizawa T, Ogiue-Ikeda M, Asashima M, Mukai H, Murakami G, Hojo Y, Kimoto T, Kawato S. Local production of sex hormones and their modulation of hippocampal synaptic plasticity. Neuroscientist 2007; 13: 323-334
    CrossrefPubMedGoogle Scholar
  • 62 Saldanha CJ, Remage-Healey L, Schlinger BA. Synaptocrine signaling: steroid synthesis and action at the synapse. Endocr Rev 2011; 32: 532-549
    CrossrefPubMedGoogle Scholar
  • 63 Ramirez VD, Zheng JB, Siddique KM. Membrane receptors for estrogen, progesterone, and testosterone in the rat brain: Fantasy or reality. Cell Mol Neurobiol 1996; 16: 175-198
    CrossrefPubMedGoogle Scholar
  • 64 Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER. A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem 2007; 282: 22278-22288
    CrossrefPubMedGoogle Scholar
  • 65 Hammes SR, Levin ER. Minireview: recent advances in extranuclear steroid receptor actions. Endocrinology 2011; 152: 4489-4495
    CrossrefPubMedGoogle Scholar
  • 66 Brown TJ, Blaustein JD. Inhibition of sexual behavior in female guinea pigs by a progestin receptor antagonist. Brain Res 1984; 301: 343-349
    CrossrefPubMedGoogle Scholar
  • 67 Rissman EF, Wersinger SR, Taylor JA, Lubahn DB. Estrogen receptor function as revealed by knockout studies: Neuroendocrine and behavioral aspects. Horm Behav 1997; 31: 232-243
    CrossrefPubMedGoogle Scholar
  • 68 Kow LM, Pfaff DW. The membrane actions of estrogens can potentiate their lordosis behavior-facilitating genomic actions. Proc Natl Acad Sci USA 2004; 101: 12354-12357
    CrossrefPubMedGoogle Scholar
  • 69 Blaustein JD, Lehman MN, Turcotte JC, Greene G. Estrogen receptors in dendrites and axon terminals in the guinea pig hypothalamus. Endocrinology 1992; 131: 281-290
    CrossrefPubMedGoogle Scholar
  • 70 Blaustein JD. Estrogen receptors in neurons: new subcellular locations and functional implications. Endocrine Journal 1994; 2: 249-258
    PubMedGoogle Scholar
  • 71 Milner TA, McEwen BS, Hayashi S, Li CJ, Reagan LP, Alves SE. Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J Comp Neurol 2001; 429: 355-371
    CrossrefPubMedGoogle Scholar
  • 72 Hart SA, Snyder MA, Smejkalova T, Woolley CS. Estrogen mobilizes a subset of estrogen receptor-alpha-immunoreactive vesicles in inhibitory presynaptic boutons in hippocampal CA1. J Neurosci 2007; 27: 2102-2111
    CrossrefPubMedGoogle Scholar
  • 73 Kurian JR, Olesen KM, Auger AP. Sex differences in epigenetic regulation of the estrogen receptor-alpha promoter within the developing preoptic area. Endocrinology 2010; 151: 2297-2305
    CrossrefPubMedGoogle Scholar
  • 74 Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ. Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor alpha expression in the medial preoptic area of female offspring. Endocrinology 2006; 147: 2909-2915
    CrossrefPubMedGoogle Scholar
  • 75 Laroche J, Gasbarro L, Herman JP, Blaustein JD. Reduced behavioral response to gonadal hormones in mice shipped during the peripubertal/adolescent period. Endocrinology 2009; 150: 2351-2358
    PubMedGoogle Scholar
  • 76 Ismail N, Garas P, Blaustein JD. Long-term effects of pubertal stressors on female sexual receptivity and estrogen receptor-alpha expression in CD-1 female mice. Horm Behav 2011; 59: 565-571
    CrossrefPubMedGoogle Scholar
  • 77 Laroche J, Gasbarro L, Herman JP, Blaustein JD. Enduring influences of peripubertal/adolescent stressors on behavioral response to estradiol and progesterone in adult female mice. Endocrinology 2009; 150: 3717-3725
    CrossrefPubMedGoogle Scholar
  • 78 Olesen KM, Ismail N, Merchasin ED, Blaustein JD. Long-term alteration of anxiolytic effects of ovarian hormones in female mice by a peripubertal immune challenge. Horm Behav 2011; 60: 318-326
    CrossrefPubMedGoogle Scholar
  • 79 Molenda-Figueira HA, Williams CA, Griffin AL, Rutledge EM, Blaustein JD, Tetel MJ. Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats. Horm Behav 2006; 50: 383-392
    CrossrefPubMedGoogle Scholar
  • 80 Tetel MJ. Modulation of steroid action in the central and peripheral nervous systems by nuclear receptor coactivators. Psychoneuroendocrinology 2009; 34 (Suppl. 01) S9-S19
    CrossrefPubMedGoogle Scholar
  • 81 Jensen EV, de Sombre ER. Estrogen-receptor interaction. Science 1973; 182: 126-134
    CrossrefPubMedGoogle Scholar