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      Decidualization of the human endometrium

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          Abstract

          Background

          Decidualization of the human endometrium, which involves a dramatic morphological and functional differentiation of human endometrial stromal cells ( ESCs), is essential for the establishment of a successful pregnancy. Decidualization results from a complex interplay of transcription factors, morphogens, cytokines, cell cycle regulators, and signaling pathways.

          Methods

          Based on a literature review, the regulation of, and the molecular mechanisms involved in, the decidualization of the endometrium are described.

          Main findings

          Progesterone, together with proteins that are regulated by progesterone and/or cyclic adenosine monophosphate, including homeobox A10, forkhead box O1, signal transducers and activators of transcription, and heart and neural crest derivatives expressed transcript 2, forms a critical network for ESC decidualization and is a prerequisite to successful implantation. Decidualized ESCs contribute to the microenvironment at the feto–maternal interface and its direct or indirect influence on extracellular matrix remodeling, regulation of the local immune response, anti‐oxidative stress, and angiogenesis (vascular maturation). Impairment of this process is associated with a variety of pregnancy disorders, including infertility, recurrent miscarriages, and uteroplacental disorders.

          Conclusion

          A deeper understanding of the process of decidualization is expected to provide new insights into the fields of reproductive biology and reproductive medicine.

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          Most cited references84

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          Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.

          Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell-specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mouse. An Ang1 relative, termed angiopoietin-2 (Ang2), was identified by homology screening and shown to be a naturally occurring antagonist for Ang1 and Tie2. Transgenic overexpression of Ang2 disrupts blood vessel formation in the mouse embryo. In adult mice and humans, Ang2 is expressed only at sites of vascular remodeling. Natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.
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            Cyclic decidualization of the human endometrium in reproductive health and failure.

            Decidualization denotes the transformation of endometrial stromal fibroblasts into specialized secretory decidual cells that provide a nutritive and immunoprivileged matrix essential for embryo implantation and placental development. In contrast to most mammals, decidualization of the human endometrium does not require embryo implantation. Instead, this process is driven by the postovulatory rise in progesterone levels and increasing local cAMP production. In response to falling progesterone levels, spontaneous decidualization causes menstrual shedding and cyclic regeneration of the endometrium. A growing body of evidence indicates that the shift from embryonic to maternal control of the decidual process represents a pivotal evolutionary adaptation to the challenge posed by invasive and chromosomally diverse human embryos. This concept is predicated on the ability of decidualizing stromal cells to respond to individual embryos in a manner that either promotes implantation and further development or facilitates early rejection. Furthermore, menstruation and cyclic regeneration involves stem cell recruitment and renders the endometrium intrinsically capable of adapting its decidual response to maximize reproductive success. Here we review the endocrine, paracrine, and autocrine cues that tightly govern this differentiation process. In response to activation of various signaling pathways and genome-wide chromatin remodeling, evolutionarily conserved transcriptional factors gain access to the decidua-specific regulatory circuitry. Once initiated, the decidual process is poised to transit through distinct phenotypic phases that underpin endometrial receptivity, embryo selection, and, ultimately, resolution of pregnancy. We discuss how disorders that subvert the programming, initiation, or progression of decidualization compromise reproductive health and predispose for pregnancy failure.
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              Endocrine regulation of menstruation.

              In women, endometrial morphology and function undergo characteristic changes every menstrual cycle. These changes are crucial for perpetuation of the species and are orchestrated to prepare the endometrium for implantation of a conceptus. In the absence of pregnancy, the human endometrium is sloughed off at menstruation over a period of a few days. Tissue repair, growth, angiogenesis, differentiation, and receptivity ensue to prepare the endometrium for implantation in the next cycle. Ovarian sex steroids through interaction with different cognate nuclear receptors regulate the expression of a cascade of local factors within the endometrium that act in an autocrine/paracrine and even intracrine manner. Such interactions initiate complex events within the endometrium that are crucial for implantation and, in the absence thereof, normal menstruation. A clearer understanding of regulation of normal endometrial function will provide an insight into causes of menstrual dysfunction such as menorrhagia (heavy menstrual bleeding) and dysmenorrhea (painful periods). The molecular pathways that precipitate these pathologies remain largely undefined. Future research efforts to provide greater insight into these pathways will lead to the development of novel drugs that would target identified aberrations in expression and/or of local uterine factors that are crucial for normal endometrial function.
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                Author and article information

                Contributors
                hokada@hirakata.kmu.ac.jp
                Journal
                Reprod Med Biol
                Reprod. Med. Biol
                10.1111/(ISSN)1447-0578
                RMB2
                Reproductive Medicine and Biology
                John Wiley and Sons Inc. (Hoboken )
                1445-5781
                1447-0578
                01 February 2018
                July 2018
                : 17
                : 3 ( doiID: 10.1111/rmb2.2018.17.issue-3 )
                : 220-227
                Affiliations
                [ 1 ] Department of Obstetrics and Gynecology Kansai Medical University Osaka Japan
                Author notes
                [*] [* ] Correspondence

                Hidetaka Okada, Department of Obstetrics and Gynecology, Kansai Medical University, Hirakata, Japan.

                Email: hokada@ 123456hirakata.kmu.ac.jp

                Author information
                http://orcid.org/0000-0002-7932-6999
                Article
                RMB212088
                10.1002/rmb2.12088
                6046526
                30013421
                c0ca63e0-0c7f-4c45-8c8b-5c13fce1ea03
                © 2018 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 06 December 2017
                : 03 January 2018
                Page count
                Figures: 2, Tables: 0, Pages: 8, Words: 6736
                Funding
                Funded by: Japan Society for the Promotion of Science KAKENHI
                Award ID: 17K11260
                Award ID: 15K20169
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                rmb212088
                July 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:16.07.2018

                decidualization,endometrial stromal cells,endometrium,heart and neural crest derivatives expressed 2,progesterone

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