Regulation of progesterone receptor messenger ribonucleic acid in the rat medial preoptic nucleus by estrogenic and antiestrogenic compounds: an in situ hybridization study.

Progesterone receptor (PR) messenger RNA (mRNA) is concentrated in neurons of the preoptic area and other regions of the rat hypothalamus where it is colocalized with the estrogen receptor and regulated by changes in the steroid hormonal milieu. To date, little is known about the regulation of PR mRNA by estrogens and whether antiestrogenic compounds are capable of modulating its expression. The present studies used in situ hybridization to ascertain the time course of PR mRNA regulation in the medial preoptic nucleus by 17beta-estradiol, determine the effective dose required to elicit a response, and compare the efficacy of 17beta-estradiol with a variety of estrogenic or antiestrogenic compounds. The first series of studies revealed that the treatment of ovariectomized rats with 17beta-estradiol resulted in an increase in PR expression within 2 h, after which it remained elevated until 10 h postinjection and then returned to baseline levels. When ovariectomized rats were injected with 25-1000 ng/kg of 17beta-estradiol and euthanized 6 h later, a dose-dependent increase in the level of PR mRNA was observed, with a maximal response at 1000 ng/kg and an EC50 of 93.5 ng/kg. Subsequent studies evaluated the efficacy of a variety of estrogenic and antiestrogenic compounds in the rat preoptic nucleus. 17Beta-estradiol, diethylstilbestrol, and 17alpha-estradiol all significantly increased the level of PR mRNA, although the degree of induction varied with each compound. The injection of tamoxifen, raloxifene, toremifene, droloxifene, clomiphene, GW 5638, or ICI 182,780 had no significant estrogenic effect on PR gene expression at the dose evaluated. In contrast, when tamoxifen or raloxifene, but not ICI 182,780, was administered in the antagonist mode, a significant dose-related decrease in the estradiol-induced level of PR mRNA was seen in the preoptic area. The results of these studies clearly demonstrate that PR mRNA expression in the rat preoptic area is rapidly stimulated by a small dose of 17beta-estradiol. Moreover, the present report has also shown that the estrogenic nature of compounds such as tamoxifen, raloxifene, toremifene, droloxifene, clomiphene, and GW 5638 cannot be predicted by their activity in peripheral tissues. Together, the results of these studies provide important information about the central activity of estrogens and provide evidence for their tissue-specifc actions in the rat.

[1]  S. McKenna,et al.  An assessment of agonist/antagonist effects of tamoxifen in the female mouse brain , 1992, Hormones and Behavior.

[2]  J. Blaustein,et al.  Cytoplasmic progestin-receptors in guinea pig brain: Characteristics and relationship to the induction of sexual behavior , 1979, Brain Research.

[3]  D. H. Olster,et al.  Gonadal Steroid Hormone Receptors and Social Behaviors , 1989 .

[4]  M. Tzukerman,et al.  Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. , 1994, Molecular endocrinology.

[5]  R. Turner,et al.  Tamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats. , 1988, Endocrinology.

[6]  P. Shughrue,et al.  In situ hybridization analysis of the distribution of neurokinin‐3 mRNA in the rat central nervous system , 1996, The Journal of comparative neurology.

[7]  J. Pike,et al.  Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. , 1995, Molecular endocrinology.

[8]  V. Jordan.  243. Antitumour activity of the antiestrogen ICI 46,474 (Tamoxifen) in the dimethylbenzanthracene (DMBA)—induced rat mammary carcinoma model , 1974 .

[9]  K. Mayo,et al.  Transient expression of progesterone receptor messenger RNA in ovarian granulosa cells after the preovulatory luteinizing hormone surge. , 1991, Molecular endocrinology.

[10]  A. M. Etgen.  Antiestrogens: Effects of tamoxifen, nafoxidine, and CI-628 on sexual behavior, cytoplasmic receptors, and nuclear binding of estrogen , 1979, Hormones and Behavior.

[11]  C. Redmond,et al.  A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. , 1989, The New England journal of medicine.

[12]  M. Sar,et al.  Neurons of the Hypothalamus Concentrate [3H]Progesterone or Its Metabolites , 1973, Science.

[13]  Fredi Kronenberg,et al.  Hot Flashes: Epidemiology and Physiologya , 1990, Annals of the New York Academy of Sciences.

[14]  R. Simerly,et al.  Ovarian Steroid Regulation of Estrogen and Progesterone Receptor Messenger Ribonucleic Acid in the Anteroventral Periventricular Nucleus of the Rat , 1996, Journal of neuroendocrinology.

[15]  D. Pfaff,et al.  Sex difference in estradiol regulation of progestin receptor mRNA in rat mediobasal hypothalamus as demonstrated by in situ hybridization. , 1991, Neuroendocrinology.

[16]  P. Shughrue,et al.  Comparative distribution of estrogen receptor‐α and ‐β mRNA in the rat central nervous system , 1997, The Journal of comparative neurology.

[17]  R. Love,et al.  Symptoms associated with tamoxifen treatment in postmenopausal women. , 1991, Archives of internal medicine.

[18]  K. Grandien,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors � and � , 2022 .

[19]  H. Bryant,et al.  Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  A. D. Mayer,et al.  Effects of brain antiestrogen implants on maternal behavior and on postpartum estrus in pregnant rats. , 1987, Neuroendocrinology.

[21]  S. Robinson,et al.  Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. , 1988, Cancer research.

[22]  K. Korach,et al.  Responses in the brain of estrogen receptor alpha-disrupted mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  F Kronenberg,et al.  Hot flashes: epidemiology and physiology. , 1990, Annals of the New York Academy of Sciences.

[24]  V. Jordan.  Biochemical pharmacology of antiestrogen action. , 1984, Pharmacological reviews.

[25]  B. Katzenellenbogen,et al.  Cloning of the rat progesterone receptor gene 5'-region and identification of two functionally distinct promoters. , 1993, Molecular endocrinology.

[26]  C. Arnaud,et al.  A controlled trial of raloxifene (LY139481) HCl: Impact on bone turnover and serum lipid profile in healthy postmenopausal women , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[27]  A. Wakeling,et al.  Use of pure antioestrogens to elucidate the mode of action of oestrogens. , 1995, Biochemical pharmacology.

[28]  J. Meredith,et al.  ICI 182,780: a pure antiestrogen that affects behaviors and energy balance in rats without acting in the brain. , 1993, The American journal of physiology.

[29]  P. Chambon,et al.  The N-terminal region of the chicken progesterone receptor specifies target gene activation , 1988, Nature.

[30]  D. Pfaff,et al.  Antagonism of sexual behavior in female rats by ventromedial hypothalamic implants of antiestrogen. , 1987, Neuroendocrinology.

[31]  C. Barraclough,et al.  Suppression of spontaneous LH surges in estrogen-treated ovariectomized rats by microimplants of antiestrogens into the preoptic brain , 1989, Brain Research.

[32]  B. Komm,et al.  The distribution of estrogen receptor-β mRNA in the rat hypothalamus , 1996, Steroids.

[33]  R. J. Barfield,et al.  Antagonism of central estrogen action by intracerebral implants of tamoxifen , 1984, Hormones and Behavior.

[34]  J.,et al.  Responses in the brain of estrogen receptor a-disrupted mice , 1997 .

[35]  A. Jolivet,et al.  Progesterone receptor immunoreactivity in aromatic L‐amino acid decarboxylase‐containing neurons of the guinea pig hypothalamus and preoptic area , 1996, The Journal of comparative neurology.

[36]  M. Warembourg.  Uptake of 3H labeled synthetic progestin by rat brain and pituitary. A radioautography study , 1978, Neuroscience Letters.

[37]  S. Birge.  Is There a Role for Estrogen Replacement Therapy in the Prevention and Treatment of Dementia? , 1996, Journal of the American Geriatrics Society.

[38]  L. Moore,et al.  3-[4-(1,2-Diphenylbut-1-enyl)phenyl]acrylic acid: a non-steroidal estrogen with functional selectivity for bone over uterus in rats. , 1994, Journal of medicinal chemistry.

[39]  P. Lomax,et al.  Postmenopausal hot flushes and their management. , 1993, Pharmacology & therapeutics.

[40]  J. Gustafsson,et al.  Cloning of a novel estrogen receptor expressed in rat prostate and ovary , 2022 .

[41]  D. Pfaff,et al.  The temporal relationship between estrogen-inducible progestin receptors in the female rat brain and the time course of estrogen activation of mating behavior. , 1980, Endocrinology.

[42]  E. Milgrom,et al.  Immunohistochemical evidence of the presence of estrogen and progesterone receptors in the same neurons of the guinea pig hypothalamus and preoptic area , 1989, Brain Research.

[43]  P. Webb,et al.  Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. , 1995, Molecular endocrinology.

[44]  D. Pfaff,et al.  Expression and estrogen regulation of progesterone receptor mRNA in neurons of the mediobasal hypothalamus: an in situ hybridization study. , 1989, Molecular endocrinology.

[45]  V. Jordan,et al.  Suppression of mouse mammary tumorigenesis by long-term tamoxifen therapy. , 1991, Journal of the National Cancer Institute.

[46]  L. Heisler,et al.  In vitro labeling of gonadal steroid hormone receptors in brain tissue sections , 1995, Steroids.

[47]  A. M. Etgen,et al.  Regulation of estrogen-stimulated lordosis behavior and hypothalamic progestin receptor induction by antiestrogens in female rats , 1986, Hormones and Behavior.

[48]  R. Turner,et al.  Tamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[49]  D. Pfaff,et al.  Progestin receptors with and without estrogen induction in male and female hamster brain. , 1987, Neuroendocrinology.

[50]  I. Wickelgren.  Estrogen Stakes Claim to Cognition , 1997, Science.

[51]  J. Raynaud,et al.  Estrogen-sensitive progestin-binding sites in the female rat brain and pituitary , 1979, Brain Research.

[52]  R. Nicholson,et al.  The effect of synthetic anti-oestrogens on the growth and biochemistry of rat mammary tumours. , 1975, European journal of cancer.

[53]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[54]  J. Turcotte,et al.  Immunocytochemical localization of estrogen-induced progestin receptors in guinea pig brain , 1988, Brain Research.

[55]  J. Turcotte,et al.  Estradiol-induced progestin receptor immunoreactivity is found only in estrogen receptor-immunoreactive cells in guinea pig brain. , 1989, Neuroendocrinology.

[56]  J. Kato.  Progesterone Receptors in Brain and Hypophysis , 1985 .

[57]  M. Sar,et al.  Topographic distribution of progestin target cells in hamster brain and pituitary after injection of [3H]R5020 , 1983, Brain Research.

[58]  K.,et al.  A new derivative of triphenylethylene: effect on implantation and mode of action in rats. , 1967, Journal of reproduction and fertility.

[59]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[60]  M. Sar.  Distribution of progestin-concentrating cells in rat brain: colocalization of [3H]ORG.2058, a synthetic progestin, and antibodies to tyrosine hydroxylase in hypothalamus by combined autoradiography and immunocytochemistry. , 1988, Endocrinology.

[61]  J. Kato,et al.  Distribution of cells containing progesterone receptor mRNA in the female rat di- and telencephalon: an in situ hybridization study. , 1992, Brain research. Molecular brain research.