What exactly is endometrial receptivity? Lessey, Bruce A.; Young, Steven L.
Fertility and sterility,
April 2019, 2019-04-00, 20190401, Letnik:
111, Številka:
4
Journal Article
Recenzirano
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Endometrial receptivity is a complex process that provides the embryo with the opportunity to attach, invade, and develop, culminating in a new individual and continuation of the species. The window ...of implantation extends 3–6 days within the secretory phase in most normal women. In certain inflammatory or anatomic conditions, this window is narrowed or shifted to preclude normal implantation, leading to infertility or pregnancy loss. Of the factors that prevent normal implantation and pregnancy, embryo and endometrial quality share responsibility. In this review, we highlight the advances in the study of implantation from the perspective of the endometrium, normally a barrier to implantation. New advances will allow the early identification of defects in endometrial receptivity and provide new avenues for treatment that promote successful establishment of pregnancy.
The endometrium maintains complex controls on proliferation and apoptosis as part of repetitive menstrual cycles that prepare the endometrium for the window of implantation and pregnancy. The ...reliance on inflammatory mechanisms for both implantation and menstruation creates the opportunity in the setting of endometriosis for establishment of chronic inflammation that is disruptive to endometrial receptivity, causing both infertility and abnormal bleeding. Clinically, there can be little doubt that the endometrium of women with endometriosis is less receptive to embryo implantation, and strong evidence exists to suggest that endometrial changes are associated with decreased cycle fecundity as a result of this disease. Here we provide unifying concepts regarding those changes and how they are coordinated to promote progesterone resistance and estrogen dominance through aberrant cell signaling pathways and reduced expression of key homeostatic proteins in eutopic endometrium of women with endometriosis.
Successful embryo implantation requires a receptive endometrium. Poor uterine receptivity can account for implantation failure in women who experience recurrent pregnancy loss or multiple rounds of ...unsuccessful in vitro fertilization cycles. Here, we demonstrate that the transcription factor Forkhead Box O1 (FOXO1) is a critical regulator of endometrial receptivity in vivo. Uterine ablation of Foxo1 using the progesterone receptor Cre (PgrCre) mouse model resulted in infertility due to altered epithelial cell polarity and apoptosis, preventing the embryo from penetrating the luminal epithelium. Analysis of the uterine transcriptome after Foxo1 ablation identified alterations in gene expression for transcripts involved in the activation of cell invasion, molecular transport, apoptosis, β-catenin (CTNNB1) signaling pathway, and an increase in PGR signaling. The increase of PGR signaling was due to PGR expression being retained in the uterine epithelium during the window of receptivity. Constitutive expression of epithelial PGR during this receptive period inhibited expression of FOXO1 in the nucleus of the uterine epithelium. The reciprocal expression of PGR and FOXO1 was conserved in human endometrial samples during the proliferative and secretory phase. This demonstrates that expression of FOXO1 and the loss of PGR during the window of receptivity are interrelated and critical for embryo implantation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Significant progress has been made in the understanding of embryonic competence and endometrial receptivity since the inception of assisted reproductive technology. The endometrium is a highly ...dynamic tissue that plays a crucial role in the establishment and maintenance of normal pregnancy. In response to steroid sex hormones, the endometrium undergoes marked changes during the menstrual cycle that are critical for acceptance of the nascent embryo. There is also a wide body of literature on systemic factors that impact assisted reproductive technology outcomes. Patient prognosis is impacted by an array of factors that tip the scales in her favor or against success. Recognizing the local and systemic factors will allow clinicians to better understand and optimize the maternal environment at the time of implantation. This review will address the current literature on endometrial and systemic factors related to impaired implantation and highlight recent advances in this area of reproductive medicine.
Objective To provide a focused review of the scientific literature pertaining to endometrial receptivity. Design Review of the literature and appraisal of relevant articles. Setting Academic teaching ...hospital. Patient(s) Women with infertility. Intervention(s) None. Main Outcome Measure(s) Critical review of the literature. Result(s) Although a consensus has been achieved regarding the existence of a temporally defined period during which embryo attachment and invasion can occur (called the “window of implantation”), reliable methods to assess “receptivity” have not been established or adequately validated. In women with certain gynecologic disorders, including endometriosis, tubal disease, and polycystic ovary syndrome, endometrial receptivity seems to be compromised, leading to infertility and pregnancy loss. The establishment of reliable biomarkers for the detection of defects in endometrial receptivity has been a long-sought goal that remains an elusive target. The validation of endometrial biomarkers will require properly designed and implemented studies based on the recognition that endometrial receptivity defects are not equally distributed in women with endometriosis or these other conditions. Conclusion(s) Rapidly advancing technologies are bringing new biomarkers to the clinical arena that promise to further reveal the complexities of the implantation process.
Objective To determine if the molecular profiles of endometriotic lesions contain informative measures of inflammation and immune dysfunction that may contribute to better understanding of the ...interplay between immune dysfunction and inflammation and their contribution to endometriosis pathogenesis. Design Immune and inflammation transcriptomic analysis with the use of the Nanostring nCounter GX Human Immunology V2 platform (579 human immune and inflammation–related genes and 15 housekeeping genes). Setting Academic university and teaching hospital. Intervention(s) None. Patient(s) Stage III–IV endometriosis patients with infertility (n = 8) and fertile disease-free control women undergoing tubal ligation (n = 8). Menstrual stage was matched to secretory phase in all participants. Main Outcome Measure(s) Immune and inflammation transcriptomics quantification from ectopic endometriotic lesions and matched eutopic endometrium from patients. Endometria of fertile women served as control subjects. Result(s) Our results displayed endometriotic lesions as molecularly distinct entities compared with eutopic endometrium and endometrium of control samples; 396 out of 579 screened immune and inflammation–related genes were significantly different in ectopic tissues compared with control endometrium. Most importantly, eutopic endometrium of the patients displayed a unique molecular profile compared with the control endometrium (91/579 genes were significantly different), particularly of genes involved in regulation of cell apoptosis and decidualization. Conclusion(s) We characterize differential expression of immune-inflammation genes in endometriosis patients, and show molecular distinction of eutopic endometrium of patients compared with control fertile women.
In two randomized trials, two different doses of the oral gonadotropin-releasing hormone antagonist elagolix significantly reduced endometriosis-related dysmenorrhea and nonmenstrual pelvic pain but ...had hypoestrogenic adverse effects.
Objective To determine the impact of endometriotic lesion removal on local and systemic inflammation. Design Multiplex cytokine analysis on samples from endometriosis patients before surgery, 2 weeks ...after surgery, and 3 months after surgery. Setting Academic teaching hospital and university. Patient(s) A total of 43 endometriosis patients before and after excision of lesions by means of laparoscopic surgery, and 25 normal women. Intervention(s) None. Main Outcome Measure(s) Plasma, eutopic and ectopic tissue, and peritoneal fluid cytokine levels. Result(s) Compared with presurgery plasma samples, levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL) 2, IL-8, and IL-10 decreased significantly by 2 weeks after surgery in endometriosis patients. Interestingly, levels began to rise at 3 months after surgery in most cases. In tissue, levels of GM-CSF and IL-15 were lower in eutopic tissue, while levels of basic fibroblast growth factor, interferon-inducible protein 10, IL-1 receptor antagonist, granulocyte colony–stimulating factor, macrophage inflammatory protein 1β, IL-7, and IL-5 were higher in eutopic than in ectopic tissue. In peritoneal fluid, levels of IL-5 and IL-12 were higher in early versus advanced stages of endometriosis. Compared with normal women, plasma from endometriosis patients had higher levels of inflammatory cytokines. Conclusion(s) Endometriotic lesion removal significantly alters the inflammatory profile both locally and systemically in women with endometriosis. Our findings indicate that ectopic lesions are the major drivers of systemic inflammation in endometriosis. The transitory nature of the change may reflect the recurrence of the condition and the influence of systemic factors in its onset.
Endometriosis is a chronic, inflammatory disease characterized by the growth of endometrial tissue in aberrant locations outside the uterus. Neoangiogenesis or establishment of new blood supply is ...one of the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. IL-17A is emerging as a potent angiogenic and proinflammatory cytokine involved in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. However, sparse information is available in the context of endometriosis. In this study, we demonstrate the potential importance of IL-17A in the pathogenesis and pathophysiology of endometriosis. The data show a differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Importantly, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations. Immunohistochemistry revealed localization of IL-17A primarily in the stroma of matched ectopic and eutopic tissue samples. In vitro stimulation of endometrial epithelial carcinoma cells, Ishikawa cells, and HUVECs with IL-17A revealed significant increase in angiogenic (vascular endothelial growth factor and IL-8), proinflammatory (IL-6 and IL-1β), and chemotactic cytokines (G-CSF, CXCL12, CXCL1, and CX3CL1). Furthermore, IL-17A promoted tubulogenesis of HUVECs plated on Matrigel in a dose-dependent manner. Thus, we provide the first evidence, to our knowledge, that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to the significant reduction in the systemic levels of IL-17A. Taken together, our data show a likely important role of IL-17A in promoting angiogenesis and proinflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions.
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