scholarly journals Extranuclear estrogen receptor's roles in physiology: lessons from mouse models

2014 ◽  
Vol 307 (2) ◽  
pp. E133-E140 ◽  
Author(s):  
Ellis R. Levin
Keyword(s):  
Mouse Models ◽  
Sex Steroids ◽  
Steroid Receptors ◽  
Sex Steroid ◽  
Normal Cells ◽  
Receptor Localization ◽  
Selective Agonists ◽  
And Function ◽  
Receptor Pool ◽  
Made In

Steroid receptors exist and function in multiple compartments of cells in most organs. Although the functions and nature of some of these receptors is being defined, important aspects of receptor localization and signaling to physiology and pathophysiology have been identified. In particular, extranuclear sex steroid receptors have been found in many normal cells and in epithelial tumors, where they enact signal transduction that impacts both nongenomic and genomic functions. Here, I focus on the progress made in understanding the roles of extranuclear estrogen receptors (ER) in physiology and pathophysiology. Extranuclear ER serve as a model to selectively intervene with novel receptor reagents to prevent or limit disease progression. Recent novel mouse models and membrane ER-selective agonists also provide a better understanding of receptor pool cross-talk that results in the overall integrative actions of sex steroids.

scholarly journals DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors

2012 ◽  
Vol 23 (1) ◽  
pp. 188-199 ◽  
Author(s):  
Ali Pedram ◽  
Mahnaz Razandi ◽  
Robert J. Deschenes ◽  
Ellis R Levin
Keyword(s):  
Membrane Trafficking ◽  
Steroid Receptors ◽  
Protein S ◽  
Steroid Receptor ◽  
Sex Steroid ◽  
Target Cells ◽  
Sex Steroid Receptors ◽  
Receptor Localization ◽  
And Function ◽  
Pat Protein

Classical estrogen, progesterone, and androgen receptors (ERs, PRs, and ARs) localize outside the nucleus at the plasma membrane of target cells. From the membrane, the receptors signal to activate kinase cascades that are essential for the modulation of transcription and nongenomic functions in many target cells. ER, PR, and AR trafficking to the membrane requires receptor palmitoylation by palmitoylacyltransferase (PAT) protein(s). However, the identity of the steroid receptor PAT(s) is unknown. We identified the DHHC-7 and -21 proteins as conserved PATs for the sex steroid receptors. From DHHC-7 and -21 knockdown studies, the PATs are required for endogenous ER, PR, and AR palmitoylation, membrane trafficking, and rapid signal transduction in cancer cells. Thus the DHHC-7 and -21 proteins are novel targets to selectively inhibit membrane sex steroid receptor localization and function.

Sex Steroids Modify Working Memory

2000 ◽  
Vol 12 (3) ◽  
pp. 407-414 ◽  
Author(s):  
Jeri S. Janowsky ◽  
Bambi Chavez ◽  
Eric Orwoll
Keyword(s):  
Working Memory ◽  
Sex Steroids ◽  
Verbal Memory ◽  
Animal Studies ◽  
Older Men ◽  
Sex Steroid ◽  
Cortical Function ◽  
Age Related ◽  
Hippocampal Synaptogenesis ◽  
And Function

In the last ten years, numerous mechanisms by which sex steroids modify cortical function have been described. For example, estrogen replacement improves verbal memory in women, and animal studies have shown effects of estrogen on hippocampal synaptogenesis and function. Little is known about sex steroid effects on other aspects of memory, such as frontal lobe-mediated working memory. We examined the relationships between working memory and sex steroid concentrations and whether sex steroid supplementation would modify age-related loss of working memory in older men and women. Before hormone supplementation, working memory, tested with the Subject Ordered Pointing Test (SOP), was worse in older subjects than younger subjects, and there was no evidence of gender differences at either age. Testosterone supplementation improved working memory in older men, but a similar enhancement of working memory was not found in older women supplemented with estrogen. In men, testosterone and estrogen effects were reciprocal—with better working memory related to a higher testosterone to estrogen ratio. These results suggest that sex steroids can modulate working memory in men and can act as modulators of cognition throughout life.

Sex steroid receptors in rheumatoid arthritis

2004 ◽  
Vol 106 (3) ◽  
pp. 293-300 ◽  
Author(s):  
Masato ISHIZUKA ◽  
Masahito HATORI ◽  
Takashi SUZUKI ◽  
Yasuhiro MIKI ◽  
Andrew D. DARNEL ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Tissue ◽  
Relative Abundance ◽  
Sex Steroids ◽  
Steroid Receptors ◽  
Inflammatory Cells ◽  
Sex Steroid ◽  
Rt Pcr ◽  
Sex Steroid Receptors ◽  
Synovial Tissues

Rheumatoid arthritis (RA) is a disease characterized primarily by chronic inflammatory synovitis and is well-known to be associated with significant sex differences in its prevalence and clinical features. Sex steroids have been proposed to be involved in the pathogenesis of RA, but details pertaining to the expression of sex steroid receptors in RA synovial tissue have yet to be fully characterized. In the present study, we examined oestrogen receptor (ER) α, ERβ, progesterone receptor (PR) and androgen receptor (AR) mRNA expression using real-time reverse transcriptase–PCR (RT-PCR) in eight female RA synovial tissues and six female synovial tissues without inflammation, and determined immunolocalization of ERα, ERβ, PR-A, PR-B and AR using immunohistochemistry in synovial tissues obtained from 22 RA patients. Real-time RT-PCR analysis demonstrated the expression of ER, PR and AR mRNAs in both RA and non-inflamed synovial tissues. Relative abundance of ER mRNAs was significantly higher in RA synovial tissue than non-inflamed synovial tissue (P<0.05). In addition, the relative ERα/ERβ mRNA expression ratio was significantly lower in RA than non-inflamed synovial tissue (RA, 2.34±1.60; and non-inflamed, 20.7±19.1; P<0.05). There were no significant differences in relative abundance of PR mRNA. Relative abundance of AR mRNA was significantly lower in RA (P<0.05). Immunoreactivity for ERα, ERβ, PR-B and AR was detected in the lining cells, inflammatory cells and fibroblasts in all the patients examined. The labelling indices for ERβ and PR-B were more abundant in both lining cells (ERβ, 54.2±12.2%; PR-B, 73.6±18.9%) and inflammatory cells (ERβ, 74.6±16.2%; PR-B, 75.9±16.1%) than in fibroblasts (ERβ, 36.5±15.6%; PR-B, 49.4±18.0%). Labelling indices for ERα and AR were significantly higher in lining cells (ERα, 14.4±8.6%; AR, 31.2±11.3%) and fibroblasts (ERα, 12.1±7.5%; AR, 20.1±9.6%) than those in inflammatory cells (ERα, 5.7±3.3%; AR, 9.2±4.4%). There were significant differences (P<0.05) in the labelling indices for ERα, ERβ and PR-B between men and women under 50 years of age in fibroblasts of RA synovial tissues. These results indicate that sex steroid receptors are present in RA and non-inflamed synovial tissues, including inflammatory cells in RA, and suggest that sex steroids may play important roles in the regulation of inflammation of RA synovial tissue.

Sex Steroid Blockade Enhances Thymopoiesis By Modulating Notch Signaling

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 291-291 ◽  
Author(s):  
Enrico Velardi ◽  
Jennifer J Tsai ◽  
Amanda M. Holland ◽  
Natalie V Singer ◽  
Mallory L West ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Sex Steroids ◽  
Sex Steroid ◽  
Immune Recovery ◽  
Thymic Involution ◽  
Hematopoietic Stem ◽  
Thymic Function ◽  
Cell Commitment ◽  
And Function

Abstract Thymopoiesis is a complex process dependent on precise signals from the supporting thymic stromal microenvironment that orchestrates the progression of precursor T cells through well-defined maturation stages. It is well documented that the decline in thymic size and function with age is in part correlated with an increase in sex steroids. This age-related decline in function can be detrimental to the recovery of the thymus in patients receiving radio or chemo-therapy with hematopoietic stem cell transplantation (HSCT). Delayed immune reconstitution, especially in the T cell lineage, is associated with an increased risk of opportunistic infections and malignant relapses. Therefore strategies to enhance thymic reconstitution has the potential to decrease the period of T cell lymphopenia and increase overall clinical outcome. In the process of evaluating the effects of sex steroids in the decline of the thymic function, we found a decrease in the expression of the key thymopoietic factors IL-7, CCL25 and Delta-like 4 (DLL4) by thymic stromal cells after testosterone treatment (Figure 1A). We then addressed if these transcriptional changes were the result of a direct regulation by the androgen receptor (AR). Using a computational approach, and subsequently confirmed by ChIP studies, we found that AR directly bound and negatively regulated the promoter of DLL4, a critical gene involved in T cell commitment and differentiation. We and others have previously shown that sex steroid ablation (SSA) can regenerate young and aged immune system by promoting bone marrow and thymic lymphopoiesis and promoting recovery from autologous and allogeneic HSCT. However the mechanisms underlying the sex steroid-mediate thymic involution and its regeneration after SSA are poorly understood. Moreover, one of the main drawbacks to standard clinical methods of sex steroid ablation using luteinizing hormone releasing hormone (LHRH) agonists (LHRH-Ag) is the initial surge in sex steroids they cause. To address this, we employed a novel class of LHRH-antagonists (LHRH-Ant) that rapidly block the secretion of sex steroids without causing their initial surge that can be even more detrimental to thymopoiesis. Mice treated with LHRH-Ant showed a significantly faster increase in thymic cellularity compared with LHRH-Ag treated mice (Figure 1B). Given the negative regulation of DLL4 by the AR, we hypothesized that DLL4 expression would conversely increase after SSA in vivo. Indeed, we found a significant increase in DLL4 expression after SSA and also an increase in genes downstream of DLL4, such as Ptcra, Hes1 and Cd25 (Figure 1C). We next evaluated if treatment with the LHRH-Ant would provide a faster immune recovery after injury to the immune system. We found that mice treated with LHRH-Ant showed a faster thymic regeneration after total body irradiation (TBI) compared to the control irradiated mice (Figure 1D) and enhanced viral clearance (Figure 1E). Finally, we also found that LHRH-Ant enhanced thymic and peripheral reconstitution up to 3 months after allo-HSCT (Figure 1F). In conclusion, we found that down-regulation of DLL4 may represent one of the mechanisms underlying the effects of sex steroids on thymic function. We demonstrate that SSA with a novel LHRH-Ant increases DLL4 expression and enhances thymic and peripheral T cell recovery and function after immune injury. These findings suggest that the employment of a LHRH-Ant, which is already in clinical use for prostate cancer patients, represents a novel therapeutic strategy to enhance immune recovery and function in immunocompromised patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Minireview: Rapid Actions of Sex Steroids in the Endothelium

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2411-2422 ◽  
Author(s):  
Renee W. Y. Chow ◽  
David J. Handelsman ◽  
Martin K. C. Ng
Keyword(s):  
Sex Steroids ◽  
Target Genes ◽  
Steroid Receptors ◽  
Classical Model ◽  
Time Lag ◽  
Signaling Cascades ◽  
Sex Steroid ◽  
Specific Response ◽  
Steroid Administration ◽  
Steroid Signaling

The endothelium is a dynamic interface between the blood vessel and the circulating blood that plays a pivotal role in vascular homeostasis. As such, studies on sex steroid regulation of endothelial function are critical to understanding the role of sex steroids in cardiovascular health and disease. The classical model of steroid action involves liganded steroid receptors binding to specific response elements on target genes to regulate gene transcription. In whole organisms, the time lag between steroid administration and observable effects produced by newly synthesized protein is typically in the order of hours to days. And yet, some effects of steroids, such as vasodilatation, occur within seconds to minutes of steroid administration. Studies in multiple cell types have also shown that steroids can cause the rapid initiation of multiple signaling cascades and second messenger systems, prompting investigations into alternate, transcription independent mechanisms of steroid action. Studies of the endothelium over the past two decades have revealed fundamental mechanisms in rapid sex steroid signaling. In particular, endothelium-dependent vasodilatation by estradiol-induced activation of endothelial nitric oxide synthase has proven to be an uniquely informative model to study sex steroid signaling via classical sex steroid receptors localized to the cell membrane. Despite the complexity of feedback and cross talk between rapid sex steroid signaling and other modes of steroid action, recent studies in this field are facilitating the development of steroidal drugs that selectively target the ability of sex steroids to initiate signaling cascades.

Antagonism by Progesterone of Diethylstilbestrol-lnduced Pituitary Tumorigenesis in Fischer 344 Rats: Effects on Sex Steroid Receptors and Tyrosine Hydroxylase mRNA

1996 ◽  
Vol 63 (6) ◽  
pp. 530-539 ◽  
Author(s):  
Gerardo G. Piroli ◽  
Claudia A. Grillo ◽  
Monica G. Ferrini ◽  
Victoria Lux-Lantos ◽  
Alejandro F. De Nicola
Keyword(s):  
Tyrosine Hydroxylase ◽  
Steroid Receptors ◽  
Sex Steroid ◽  
Fischer 344 Rats ◽  
Fischer 344 ◽  
Sex Steroid Receptors ◽  
Pituitary Tumorigenesis

The melanocortin system

2003 ◽  
Vol 284 (3) ◽  
pp. E468-E474 ◽  
Author(s):  
Ira Gantz ◽  
Tung M. Fong
Keyword(s):  
Sexual Function ◽  
Energy Homeostasis ◽  
Melanocortin Receptors ◽  
Experimental Basis ◽  
Melanocortin System ◽  
Genetic Studies ◽  
Melanocortin Peptides ◽  
Selective Agonists ◽  
Made In

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.

Sex Steroids and Human Behavior: Implications for Developmental Psychopathology

CNS Spectrums ◽  
2001 ◽  
Vol 6 (1) ◽  
pp. 75-88 ◽  
Author(s):  
Gerianne M. Alexander ◽  
Bradley S. Peterson
Keyword(s):  
Sex Differences ◽  
Human Behavior ◽  
Sex Steroids ◽  
Developmental Psychopathology ◽  
Mammalian Species ◽  
Brain Structures ◽  
Postnatal Life ◽  
Brain Structure And Function ◽  
Atypical Development ◽  
And Function

AbstractIn a variety of mammalian species, prenatal androgens organize brain structures and functions that are later activated by steroid hormones in postnatal life. In humans, studies of individuals with typical and atypical development suggest that sex differences in reproductive and nonreproductive behavior derive in part from similar prenatal and postnatal steroid effects on brain development. This paper provides a summary of research investigating hormonal influences on human behavior and describes how sex differences in the prevalences and natural histories of developmental psychopathologies may be consistent with these steroid effects. An association between patterns of sexual differentiation and specific forms of psychopathology suggests novel avenues for assessing the effects of sex steroids on brain structure and function, which may in turn improve our understanding of typical and atypical development in women and men.

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