The E domain encompasses several regions, including the LBD, a dimerization domain, and a part of the nuclear localization region. It is also the site of certain posttranslational modifications. It contains a nuclear localization sequence that gets activated upon ligand binding. The D domain, also known as the hinge region, is the flexible connection between the DBD and ligand-binding domain (LBD). It is also involved in receptor dimerization and is the most conserved region of the receptor. The C domain is the DNA-binding domain (DBD) that binds to specific DNA sites called estrogen response elements (EREs). It is also responsible for several protein–protein interactions. The N-terminal transactivation domain, also called the A/B domain, includes the activation function 1 domain, which is thought to bind to the transcription complexes. They are modular proteins composed of 5 domains ( Figure 1). Nuclear ERs are members of the nuclear hormone receptor superfamily they serve as ligand-activated transcription factors (TFs) regulating gene expression. This review discusses the types and structure of estrogen receptors and signaling in fibroids, the current therapeutic options targeting estrogen receptors/signaling, and future research directions. In addition, the necessity of estrogen for leiomyoma growth represents a unique therapeutic opportunity through targeting estrogen receptors, signaling pathways, and estrogen response genes. 5 – 8 The role of estrogen in fibroid biology is complex and involves several other factors, including progesterone, growth factors, and genetic and epigenetic factors. Fibroids are considered estrogen dependent since no prepubertal cases have been described, and tumors tend to regress after menopause and on gonadotropin-releasing hormone agonists (GnRHa) treatment, which decreases ovarian estrogen production. 3 – 6Įstrogens, cholesterol-derived steroid hormones, play a vital role in the female reproductive physiology in addition to their pleiotropic effects on other body systems. These factors include steroid hormones, growth factors, cytokines, chromosomal, genetic, and epigenetic aberrations. However, several genetic, hormonal, and biologic factors have been shown to contribute to the development, growth, and maintenance of uterine fibroids. 1, 2 The underlying processes driving the transformation of a myocyte into a uterine fibroid are not completely understood. A fibroid tumor starts as a monoclonal proliferation of a single uterine smooth muscle cell. Uterine fibroids, also called leiomyomas, are the most common gynecologic tumors. In particular, epigenomics of estrogen activity and individualized (precision) medicine appear to be attractive areas for future research. Future research can identify potential targets for the development of novel treatments. Current therapeutic and research agents targeting ERs/signaling include gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, aromatase inhibitors, selective ER modulators, gene therapy, and others. Several aberrations in estrogen receptors and signaling pathways are implicated in fibroid pathobiology. Estrogen-signaling pathways in fibroids include genomic (direct and indirect) and nongenomic including Ras-Raf-MEK (MAPK/Erk Kinase)-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-phosphatidylinositol-3,4,5-trisphosphate (PIP3)-Akt (Protein kinase B)-mammalian target of rapamycin (mTOR) pathways shortly Ras-Raf-MEK-MAPK and PI3K-PIP3-Akt-mTOR pathways. In this review, we discuss the types and structure of estrogen receptors (nuclear and membrane bound, including α and β receptors and G protein-coupled estrogen receptor 1 GPER1). Understanding the role of estrogen in fibroids is not only important for understanding the pathobiology of fibroids but also for the development of successful therapeutics. Of these factors, estrogen is particularly critical since fibroids are considered estrogen dependent because no prepubertal cases have been described in the literature and tumors tend to regress after menopause. Several genetic, hormonal, and biological factors have been shown to contribute to the development and growth of fibroid tumors. Uterine fibroids are the most common gynecologic tumors with a significant medical and financial burden.
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