scholarly journals Estrogen Response Element-Independent Estrogen Receptor (ER)-α Signaling Does Not Rescue Sexual Behavior but Restores Normal Testosterone Secretion in Male ERα Knockout Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5288-5294 ◽  
Author(s):  
Melissa A. McDevitt ◽  
Christine Glidewell-Kenney ◽  
Jeffrey Weiss ◽  
Pierre Chambon ◽  
J. Larry Jameson ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Sexual Behavior ◽  
Gene Transcription ◽  
Sexual Behaviors ◽  
Elevated Serum ◽  
Normal Male ◽  
Classical Pathway ◽  
Male Reproductive Function ◽  
Estrogen Response ◽  
Regulate Gene

Estrogen receptor (ER)-α mediates estradiol (E2) actions in the male gonads and brain and is critical for normal male reproductive function. In the classical pathway, ERα binds to estrogen response elements (EREs) to regulate gene transcription. ERα can also regulate gene transcription independently of EREs via protein-protein interactions with transcription factors and additionally signal via rapid, nongenomic pathways originating at the cell membrane. This study assessed the degree to which ERE-independent ERα signaling can rescue the disrupted masculine sexual behaviors and elevated serum testosterone (T) levels that have been shown to result from ERα gene deletion. We utilized male ERα null mice that possess a ER knock-in mutation (E207A/G208A; AA), in which the mutant ERα is incapable of binding to DNA and can signal only through ERE-independent pathways (ERα−/AA mice). We found that sexual behavior, including mounting, is virtually absent in ERα−/− and ERα−/AA males, suggesting that ERE-independent signaling is insufficient to maintain any degree of normal sexual behavior in the absence of ERE binding. By contrast, ERE-independent signaling in the ERα−/AA mouse is sufficient to restore serum T levels to values observed in wild-type males. These data indicate that binding of ERs to EREs mediates most if not all of E2’s effects on male sexual behavior, whereas ERE-independent ERα signaling may mediate E2’s inhibitory effects on T production.

1625: Role of Estrogen Receptor β in the Regulation of Sexual Behavior in Male Mice

2004 ◽  
Vol 171 (4S) ◽  
pp. 429-429
Author(s):  
Masayoshi Nomura ◽  
Naohiro Fujimoto ◽  
Donald W. Pfaff ◽  
Sonoko Ogawa ◽  
Tetsuro Matsumoto
Keyword(s):  
Estrogen Receptor ◽  
Sexual Behavior ◽  
Estrogen Receptor Β ◽  
Male Mice

scholarly journals Estrogen receptor-mediated repression of human hepatic lipase gene transcription

2002 ◽  
Vol 43 (3) ◽  
pp. 383-391 ◽  
Author(s):  
Daniel R. Jones ◽  
Robert J. Schmidt ◽  
Richard T. Pickard ◽  
Patricia S. Foxworthy ◽  
Patrick I. Eacho
Keyword(s):  
Estrogen Receptor ◽  
Gene Transcription ◽  
Hepatic Lipase ◽  
Lipase Gene ◽  
Hepatic Lipase Gene

scholarly journals Mouse Estrogen Receptor β Forms Estrogen Response Element-Binding Heterodimers with Estrogen Receptor α

1997 ◽  
Vol 11 (10) ◽  
pp. 1486-1496 ◽  
Author(s):  
Katarina Pettersson ◽  
Kaj Grandien ◽  
George G. J. M. Kuiper ◽  
Jan-Åke Gustafsson
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Estrogen Receptor Β ◽  
Estrogen Response Element ◽  
Response Element ◽  
Estrogen Response

scholarly journals Enhanced Sexual Behaviors and Androgen Receptor Immunoreactivity in the Male Progesterone Receptor Knockout Mouse

Endocrinology ◽  
2005 ◽  
Vol 146 (10) ◽  
pp. 4340-4348 ◽  
Author(s):  
Johanna S. Schneider ◽  
Carly Burgess ◽  
Nicole C. Sleiter ◽  
Lydia L. DonCarlos ◽  
John P. Lydon ◽  
...  
Keyword(s):  
Sexual Behavior ◽  
Androgen Receptor ◽  
Progesterone Receptor ◽  
Sexual Behaviors ◽  
Gene Deletion ◽  
Biological Significance ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Testicular Development ◽  
Testicular Weight

Reproductive and behavioral functions of progesterone receptors (PRs) in males were assessed by examining consequences of PR gene deletion. Basal hormone levels were measured in male progesterone receptor knockout (PRKO) mice and compared to wild-type (WT) counterparts. RIA of serum LH, testosterone, and progesterone levels revealed no significant differences. Levels of FSH were moderately but significantly lower and inhibin levels were higher in PRKOs; these differences were not accompanied by gross differences in testicular weight or morphology. PRKOs exhibited significant alterations in sexual behavior. In initial tests PRKOs exhibited reduced latency to mount, compared with WT. In second sessions, PRKOs again showed a significantly reduced latency to mount and increased likelihood of achieving ejaculation. RU486 treatment in WT produced increased mount and intromission frequency and decreased latency to intromission. In anxiety-related behavior tests, PRKO mice exhibited intermediate anxiety levels, compared with WT, suggesting that enhanced sexual behavior in PRKOs is not secondary to reduced anxiety. Immunohistochemical analysis revealed significantly enhanced androgen receptor expression in the medial preoptic nucleus and bed nucleus of the stria terminalis of PRKO. We conclude that testicular development and function and homeostatic regulation of the hypothalamic-pituitary testicular axis are altered to a lesser extent by PR gene deletion. In contrast, PR appears to play a substantial role in inhibiting the anticipatory/motivational components of male sexual behavior in the mouse. The biological significance of this inhibitory mechanism and the extent to which it is mediated by reduced androgen receptor expression remain to be clarified.

scholarly journals Differential activation by xenoestrogens of ER alpha and ER beta when linked to different response elements

1998 ◽  
Vol 158 (3) ◽  
pp. R11-R14 ◽  
Author(s):  
WD Pennie ◽  
TC Aldridge ◽  
AN Brooks
Keyword(s):  
Estrogen Receptor ◽  
Luteinizing Hormone ◽  
Molecular Basis ◽  
Estrogen Response Element ◽  
Differential Activation ◽  
Response Elements ◽  
Estrogen Response ◽  
Cell Tissue ◽  
Different Response ◽  
Er Alpha

The discovery of a second estrogen receptor (ER beta) has significant implications for our understanding of the molecular basis for the diverse actions of estrogen. Here we report the differential activation by natural and xenobiotic estrogens of ER alpha and ER beta when linked to different response elements. Receptor mediated activation of reporter constructs containing either the estrogen response element (ERE) from the vitellogenin (Vit) gene or from the luteinizing hormone beta (LH) gene were examined in transiently transfected Cos-1 cells. ER beta preferentially activated the consensus Vit ERE whereas ER alpha showed greater activation at the divergent LH ERE. This differential activation was observed for a number of ligands including estradiol, estrone, bisphenol A, octylphenol and diethystilbestrol. These findings show that the nature of the ERE, as well as the ratio of ER subtypes in a particular cell/tissue, will influence whether particular estrogen responsive genes are activated in the presence of natural or xenobiotic estrogens.

scholarly journals Aromatase: Contributions to Physiology and Disease in Women and Men

Physiology ◽  
2016 ◽  
Vol 31 (4) ◽  
pp. 258-269 ◽  
Author(s):  
Jennifer Blakemore ◽  
Fredrick Naftolin
Keyword(s):  
Human Physiology ◽  
Estrogen Receptor ◽  
Aromatase Inhibitors ◽  
Reproductive System ◽  
Short Review ◽  
Estrogen Response Element ◽  
Comprehensive Overview ◽  
Response Element ◽  
Estrogen Response ◽  
Health And Disease

Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.

Selective estrogen receptor modulators: mechanism of action and clinical experience. Focus on raloxifene

2001 ◽  
Vol 13 (4) ◽  
pp. 331 ◽  
Author(s):  
Daniel Thiebaud ◽  
Roberta J. Secrest
Keyword(s):  
Estrogen Receptor ◽  
Clinical Trial Data ◽  
Selective Estrogen Receptor Modulators ◽  
Ligand Complex ◽  
Tissue Specific ◽  
Estrogen Receptor Modulators ◽  
Estrogen Response ◽  
Cellular Factors ◽  
Estrogen Antagonist ◽  
Receptor Modulators

Selective estrogen receptor modulators (SERMs) are a diverse group of compounds that bind with specific, high-affinity binding to the estrogen receptor (ER). Depending on the tissue, SERMs can act as either ER agonists or antagonists. Recent advances in ER biology have provided insight into possible mechanisms by which SERMs elicit these tissue-specific estrogen agonist and estrogen antagonist activities. The estrogen response pathway has been shown to differ among target tissues depending on various tissue and cellular factors, such as the ER subtype, the structure of the bound receptor–ligand complex, and the tissue-specific cellular transcriptional machinery. Clinically available SERMs include clomiphene, tamoxifen and toremifene, which are triphenylethylenes, and raloxifene, a benzothiophene. Raloxifene has estrogen agonist effects on bone, serum lipids, and arterial vasculature, and estrogen antagonist effects in breast and uterus. Clinical trial data for raloxifene is used to illustrate some of the mechanisms by which SERMs exert their tissue-specific estrogen agonist and estrogen antagonist effects. The complex pharmacology surrounding the tissue selectivity of SERMs is discussed.

scholarly journals The High Mobility Group Protein 1 Enhances Binding of the Estrogen Receptor DNA Binding Domain to the Estrogen Response Element

1998 ◽  
Vol 12 (5) ◽  
pp. 664-674 ◽  
Author(s):  
Lorene E. Romine ◽  
Jennifer R. Wood ◽  
LuAnne A. Lamia ◽  
Paul Prendergast ◽  
Dean P. Edwards ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Dna Binding ◽  
High Mobility ◽  
High Mobility Group ◽  
Estrogen Response Element ◽  
Dna Binding Domain ◽  
High Mobility Group Protein ◽  
Response Element ◽  
Estrogen Response ◽  
Group Protein

Abstract We have examined the ability of the high-mobility group protein 1 (HMG1) to alter binding of the estrogen receptor DNA-binding domain (DBD) to the estrogen response element (ERE). HMG1 dramatically enhanced binding of purified, bacterially expressed DBD to the consensus vitellogenin A2 ERE in a dose-dependent manner. The ability of HMG1 to stabilize the DBD-ERE complex resulted in part from a decrease in the dissociation rate of the DBD from the ERE. Antibody supershift experiments demonstrated that HMG1 was also capable of forming a ternary complex with the ERE-bound DBD in the presence of HMG1-specific antibody. HMG1 did not substantially affect DBD-ERE contacts as assessed by methylation interference assays, nor did it alter the ability of the DBD to induce distortion in ERE-containing DNA fragments. Because HMG1 dramatically enhanced estrogen receptor DBD binding to the ERE, and the DBD is the most highly conserved region among the nuclear receptor superfamily members, HMG1 may function to enhance binding of other nuclear receptors to their respective response elements and act in concert with coactivator proteins to regulate expression of hormone-responsive genes.

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