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Different molecular mechanisms mediate the diverse biological effects of estrogens. The classical genomic mechanism is based on the function of the ER as a ligand-dependent transcription factor that binds to estrogen-response elements (EREs) in promoters of target genes to initiate gene expression. These direct genomic effects play a prominent role in the regulation of reproductive function. In contrast, nongenomic effects mediated by the classical ER have been demonstrated to activate PI3K, leading to the activation of endothelial NOS (eNOS) and hence vasorelaxation. Pathway-selective ER ligands might represent a novel option for hormone replacement therapy. Here we describe the identification and in vitro characterization of tool compounds that bind the ER reasonably well but exhibit low transcriptional activity on ERE-driven promoters. However, these compounds behave as potent stimulators of PI3K/Akt activation in vitro and lead to aortic vessel relaxation, a mechanism that is thought to be driven by nongenomic ER action. In a second set of experiments, we analyze how the in vitro pathway selectivity translates into the in vivo situation. We examine our tool compounds in comparison to estradiol and estren in the following paradigms: bone protection, uterine growth assays, and mammary gland assays. [ABSTRACT FROM AUTHOR]

It has now been over 10 years since Jan-Ake Gustafsson revealed the existence of a second form of the estrogen receptor (ERβ) at a 1996 Keystone Symposium. Since then, substantial success has been made in distinguishing its potential biological functions from the previously known form (now called ERα) and how it might be exploited as a drug target. Subtype selective agonists have been particularly useful in this regard and suggest that ERβ agonists may be useful for a variety of clinical applications without triggering classic estrogenic side effects such as uterine stimulation. These applications include inflammatory bowel disease, rheumatoid arthritis, endometriosis, and sepsis. This manuscript will summarize illustrative data for three ERβ selective agonists, ERB-041, WAY-202196, and WAY-200070. [ABSTRACT FROM AUTHOR]

Androgens are known regulators of the growth and differentiation of the prostate gland and are effective during development and maturity as well as in disease. The role of estrogens is less well characterized, but dual direct and indirect actions on prostate growth and differentiation have been demonstrated, facilitated via both ERα and ERβ. Previous studies using animal models to determine the role of ERβ in the prostate have been problematic due to the centrally mediated responses to estrogen administration via ERα that can lower androgen levels and lead to epithelial regression, thereby masking any direct effects on the prostate mediated by ERβ. Our alternate approach was to use the estrogen-deficient aromatase knockout (ArKO) mouse and the method of tissue recombination to provide new insight into estrogen action on prostate growth and pathology. Firstly, utilizing homo- and heterotypic tissue recombinants, we demonstrate that stromal aromatase deficiency results in the induction of hyperplasia in previously normal prostatic epithelium and that this response is the result of local changes to the paracrine interaction between stroma and epithelium. Secondly, using tissue recombination and an ERβ-specific agonist, we demonstrate that the activation of ERβ results in an anti-proliferative response that is not influenced by alterations to systemic androgen levels or activation of ERα. Finally, using intact ArKO mice this study demonstrates that the administration of an ERβ-specific agonist abrogates existing hyperplastic epithelial pathology specifically in the prostate but an ERβ-specific agonist does not. Therefore, in the absence of stromal aromatase gene expression, epithelial proliferation, leading to prostatic hypertrophy and hyperplasia, may result from a combination of androgenic stimulation of proliferation and failed activation of ERβ by locally synthesized estrogens. These data demonstrate essential and beneficial effects of estrogens that are necessary for normal growth of the prostate and distinguish them from those that adversely alter prostate growth and differentiation. This indicates the potential of antiandrogens and SERMS, as opposed to aromatase inhibitors, for the management of prostate hyperplasia and hypertrophy. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a chronic disabling disease affecting at least 1% of the population on a worldwide basis. Research aimed at understanding the pathogenesis of this disease led to the identification of TNFα as a major pro-inflammatory cytokine expressed in the inflamed joints of patients with rheumatoid arthritis. Subsequently, in vitro studies provided evidence to suggest that TNFα played an important role in driving the expression of additional pro-inflammatory cytokines, such as IL-1, GM-CSF, IL-6, and IL-8, in synovial cell cultures. Another important finding that confirmed the pathological significance of TNFα was that mice genetically engineered to overexpress TNFα spontaneously developed arthritis. Subsequently, the therapeutic effect TNFα blockade was tested in animal models prior to clinical trials in human patients, which provided unequivocal verification of the validity of TNFα as a therapeutic target. Anti-TNFα therapy is now accepted as a fully-validated treatment modality for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Gender differences in the development of cardiovascular disease suggested for a protective function of estrogens in heart disease. The negative or neutral outcome of clinical trials on hormone replacement therapy provides clear evidence that the role of female sex hormones in the cardiovascular system is more complex than previously thought. In particular, the function of estrogens can not be understood without detailed knowledge on the specific function of both estrogen receptor subtypes in the heart and in the vasculature. In here, we review recent studies on subtype selective ERα and ERβ agonists in different animal models of hypertension, cardiac hypertrophy and vascular inflammation. The results indicate that the activation of specific ER subtypes confers specific as well as redundant protective effects in hypertensive heart disease that might ultimately translate into novel treatment options for hypertensive heart disease. [ABSTRACT FROM AUTHOR]

Whereas hormonal replacement/menopause therapy (HRT) in postmenopausal women increases coronary artery disease risk, epidemiological studies (protection in premenopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of estrogens is thus required. The atheroprotective effect of E2 is absent in mice deficient in mature T and B lymphocytes, demonstrating the crucial role of the endothelium/immune system pair. The immunoinflammatory system appears to play a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas E2 favors an anti-inflammatory effect in vitro (cultured cells), it elicits in vivo a pro-inflammation at the level of several subpopulations of the immunoinflammatory system, which could contribute to plaque destabilization. Endothelium appears to be an important target for E2, since it potentiates endothelial NO and prostacyclin production, thus promoting beneficial effects such as vasorelaxation and inhibition of platelet aggregation. Prostacyclin, but not NO, appear to be involved in the atheroprotective effect of E2, which also accelerates endothelial regrowth, thus favoring vascular healing. Finally, most of these E2 effects are mediated by estrogen receptor α and are independent of estrogen receptor β. In summary, a better understanding of the mechanisms of estrogens on the normal and atheromatous arteries is required and should help to optimize the prevention of cardiovascular disease after menopause. These mouse models should help to screen existing and future selective estrogen receptor modulators (SERMs). [ABSTRACT FROM AUTHOR]

Models of estrogen insufficiency have revealed new and unexpected roles for estrogens in males as well as females. These models include natural mutations in the aromatase gene in humans, as well as mouse knock-outs of aromatase and the estrogen receptors, and one man with a mutation in the ERα gene. These mutations, both natural and experimental, have revealed that estrogen deficiency results in a spectrum of symptoms. These include loss of fertility and libido in both males and females; loss of bone in both males and females; a cardiovascular and cerebrovascular phenotype; development of a metabolic syndrome in both males and females, with truncal adiposity and male-specific hepatic steatosis. Most of these symptoms can be reversed or attenuated by estradiol therapy. Thus estrogen is involved in the maintenance of general physiological homeostasis in both sexes. [ABSTRACT FROM AUTHOR]

The multiple actions of estrogen in mammalian physiology are brought about, on a molecular level, by several signaling pathways, and mediated by at least two receptors-estrogen receptor (ER) α and β. Analysis of knock-out mice devoid of either or both receptor isoforms revealed the essential function of estrogen receptor α in female reproduction, as ERα deficiency leads to a complex endocrine phenotype, severe disturbances in several reproductive organs, and infertility. This reflects the many actions of estrogen in female reproductive endocrinology. To carry the understanding of estrogen action to a cellular resolution, modern genetic technologies can be employed, including artificial chromosome-based transgenesis and conditional gene targeting. The combination of these techniques yields mouse models that lack ERα in specific cell types of the body. Using cell-type-specific ERα mutants, it could be shown that ERα in neurons is essential for the luteinizing hormone (LH) surge that triggers ovulation. Studies using ERα and ERβ-selective agonists reveal that ERα activation is sufficient to induce an ovulatory hormonal stimulus. Thus, genetic analysis and selective pharmacological tools can complement each other in the molecular and cellular dissection of hormone receptor function in vivo. [ABSTRACT FROM AUTHOR]