Endometriosis is an enigmatic disease affecting up to 10% of reproductive-aged women causing pain and infertility. Up to 50% of women with endometriosis are infertile, and agreement about treatment options has been difficult to establish. The association between endometriosis and infertility is derived from comparisons of fertile and infertile women, animal models, donor sperm studies, and in vitro fertilization results. Diagnostic approaches based on endometrial changes associated with endometriosis are also providing insights into possible mechanisms of infertility, especially in women with milder forms of the disease. Treatment of endometriosis, including surgical ablation or resection, is cost-effective and offers the potential for improvement in cycle fecundity. Medical management of endometriosis-associated infertility has not been proven outside of in vitro fertilization.
Objective To evaluate endometrial leukemia inhibitor factor (LIF) expression as a marker of endometrial receptivity in women with unexplained infertility (UI). Design Prospective case-control study. Setting University-associated infertility clinics. Patient(s) Women with UI for more than 1 year and healthy control women. Intervention(s) Endometrial biopsy. Main Outcome Measure(s) Time to pregnancy was compared between patients with UI who were evaluated for endometrial LIF protein as well as ανβ3 integrin expression. Endometrium was evaluated using immunohistochemistry (IHC) and messenger RNA by real time reverse transcriptase–polymerase chain reaction (PCR) (quantitative real-time reverse transcriptase–PCR) in samples from women with UI as well as healthy control women. Result(s) Leukemia inhibitor factor was expressed in epithelial cells in a cyclic fashion in controls, and overall expression in the secretory phase was similar between controls and women with UI, whereas ανβ3 integrin expression was reduced. However, using quantitative real-time PCR, LIF messenger RNA abundance was 4.4-fold lower in women with low levels of ανβ3 integrin expression compared with samples with normal integrins. By immunohistochemistry, ανβ3 integrin expression was always lacking when the histology was out of phase, whereas LIF expression was only negative in a subset of those samples. Reduced endometrial LIF expression was strongly associated with poor reproductive outcomes. Conclusion(s) Endometrial LIF expression peaks in the midsecretory phase and is reduced in some women with UI. The use of LIF in combination with ανβ3 integrin as biomarkers appears to be superior to integrin testing alone when evaluating endometrial receptivity, primarily because of its earlier pattern of expression during the secretory phase.
The extravillous trophoblast (EVT) cell lineage is a key feature of placentation and critical for spiral artery remodeling and successful pregnancy. Our knowledge of transcriptional regulation driving EVT cell development is limited. Here, we mapped the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem (TS) cells and their transition into the differentiated EVT cell lineage. Chromatin accessibility in intergenic regions was more extensive in EVT cells than in TS cells in the stem state, which is consistent with increased enhancer-driven gene regulation. Using reference epigenome annotation, we noted that 18% of the chromatin landscape in EVT cells was uncharted. We linked regulatory regions to their cognate target genes and characterized the three-dimensional organization of the TS cell functional genome by high throughput chromosome conformation capture. Integration of chromatin accessibility, long-range chromatin interactions, transcriptomic, and transcription factor binding motif enrichment enabled identification of transcription factors and regulatory mechanisms associated with EVT cell lineage development. Subsequent analyses elucidated functional roles for TFAP2C, SNAI1, and EPAS1 in the regulation of EVT cell lineage development. EPAS1 was identified as an upstream regulator of key EVT cell transcription factors, including ASCL2 and SNAI1 and together with its target genes, was linked to diseases of pregnancy, including idiopathic recurrent pregnancy loss and low birth weight. Collectively, we have revealed activation of a dynamic regulatory network that provides a framework for understanding EVT cell specification in trophoblast cell lineage development and human placentation.
Purpose The aim of this study was to investigate if there is a higher incidence of endometriosis in patients with polycystic ovary syndrome (PCOS), compared with normal fertile controls. Material and methods Women with PCOS according to Rotterdam criteria, with infertility and/or pelvic pain, were identified (n = 104), and together with fertile women seeking bilateral tubal ligation (n = 111), they were submitted to laparoscopy at the Greenville Hospital System or the University of North Carolina at Chapel Hill. A biopsy was performed in 40 patients with PCOS to confirm or not endometriosis. Results Age was similar in both groups (control: 29.7 ± 0.5 years; PCOS: 29.6 ± 0.4). The incidence of suspected endometriotic lesions in controls and PCOS patients was 12.6% (95% confidence interval [95% CI], 7.6%-20%) and 74% (95% CI, 64.8%-81.5%), respectively; with an odds ratio of 19.7 (95% CI, 9.6-40.2) of finding endometriosis in PCOS (p<0.0001). Our results were similar when endometriosis was confirmed by pathology report. Of the PCOS patients with endometriosis, 76% had endometriosis stage I or II, according to the revised American Society for Reproductive Medicine criteria. Conclusions In this case-control study, a significant association between endometriosis and women with PCOS with pelvic pain and/or infertility was found. The majority of endometriotic lesions (76%) were stage I or II.
Recurrent pregnancy loss (RPL) is defined by two or more failed pregnancies and accounts for only 1-5% of pregnancy failures. Treatment options for unexplained RPL (uRPL) are limited. Previous studies suggest a link between delayed implantation and pregnancy loss. Based on this, a timely signal for rescue of the corpus luteum (CL) using human chorionic gonadotrophin (HCG) could improve outcomes in women with uRPL. This retrospective cohort study included 98 subjects with uRPL: 45 underwent 135 monitored cycles without HCG support; and 53 underwent 142 cycles with a single mid-luteal HCG injection. Based on Log-rank Mantel-Cox survival curves, miscarriage rate and time to pregnancy decreased in the HCG group (P = 0.0005). Women receiving luteal HCG support had an increased chance of an ongoing pregnancy compared with those not receiving it (RR = 2.4; 95% CI 1.4-3.6; number need to treat (NNT) = 7; 95% CI 4-18). Subjects receiving HCG support had a significant absolute risk reduction (ARR) of miscarriage (P < 0.001; ARR = 11.5%; 95% CI 3.6-19.5; NNT = 9(5-27). These data suggest restoration of synchrony and CL support improves outcomes in women with RPL. Further randomized controlled trials of luteal-phase HCG in women with RPL appears warranted.
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