Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. It is caused when shed endometrial tissue travels retrograde into the lower abdominal cavity. Endometriosis is the most common cause of chronic pelvic pain in women and is associated with infertility. The underlying pathologic mechanisms in the intracavitary endometrium and extrauterine endometriotic tissue involve defectively programmed endometrial mesenchymal progenitor/stem cells. Although endometriotic stromal cells, which compose the bulk of endometriotic lesions, do not carry somatic mutations, they demonstrate specific epigenetic abnormalities that alter expression of key transcription factors. For example, GATA-binding factor-6 overexpression transforms an endometrial stromal cell to an endometriotic phenotype, and steroidogenic factor-1 overexpression causes excessive production of estrogen, which drives inflammation via pathologically high levels of estrogen receptor-β. Progesterone receptor deficiency causes progesterone resistance. Populations of endometrial and endometriotic epithelial cells also harbor multiple cancer driver mutations, such as KRAS, which may be associated with the establishment of pelvic endometriosis or ovarian cancer. It is not known how interactions between epigenomically defective stromal cells and the mutated genes in epithelial cells contribute to the pathogenesis of endometriosis. Endometriosis-associated pelvic pain is managed by suppression of ovulatory menses and estrogen production, cyclooxygenase inhibitors, and surgical removal of pelvic lesions, and in vitro fertilization is frequently used to overcome infertility. Although novel targeted treatments are becoming available, as endometriosis pathophysiology is better understood, preventive approaches such as long-term ovulation suppression may play a critical role in the future.

The transcription factor GATA2 is important for endometrial stromal cell decidualization in early pregnancy. Progesterone receptor (PGR) is also critical during decidualization but its interaction with GATA2 in regulating genes and pathways necessary for decidualization in human endometrium are unclear. RNA-sequencing (RNA-seq) was performed to compare gene expression profiles (n = 3), and chromatin immunoprecipitation followed by sequencing (ChIP-seq) using an antibody against GATA2 (n = 2) was performed to examine binding to target genes in human endometrial stromal cells undergoing in vitro decidualization (IVD including estrogen, progestin, and 3′,5′-cyclic AMP analogue) or vehicle treatment. We identified 1232 differentially expressed genes (DEGs) in IVD vs vehicle. GATA2 cistrome in IVD-treated cells was enriched with motifs for GATA, ATF, and JUN, and gene ontology analysis of GATA2 cistrome revealed pathways that regulate cholesterol storage, p38 mitogen-activated protein kinase, and the c-Jun N-terminal kinase cascades. Integration of RNA-seq and ChIP-seq data revealed that the PGR motif is highly enriched at GATA2 binding regions surrounding upregulated genes in IVD-treated cells. The integration of a mined public PGR cistrome in IVD-treated human endometrial cells with our GATA2 cistrome showed that GATA2 binding was significantly enhanced at PGR-binding regions in IVD vs vehicle. Interrogating 2 separate ChIP-seq data sets together with RNA-seq revealed integration of GATA2 and PGR action to coregulate biologic processes during decidualization of human endometrial stromal cells, specifically via WNT activation and stem cell differentiation pathways. These findings reveal the key pathways that are coactivated by GATA2 and PGR that may be therapeutic targets for supporting implantation and early pregnancy.

No abstract

No abstract

which is at increased risk for preeclampsia. The aim of this study is to determine whether differences exist in these factors in IVF pregnancies with and without ED, compared to spontaneous pregnancies. DESIGN: Case control study MATERIALS AND METHODS: Residual early second trimester maternal serum samples were available from women having prenatal screening at a single center, from 1/2015 to 12/2016. 57 third-party ED pregnancies were identified. Each ED case was matched to two control samples from spontaneously conceived pregnancies (n¼114), and one control sample from a non-ED IVF pregnancy ("IVF", n¼57). All controls were matched for gestational age and duration of freezer storage. All samples were from singleton pregnancies and had been tested for maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotropin (hCG) and inhibin A (inhA) prior to storage. Samples were retrieved from storage for measurement of PlGF and sVEGFR-1 levels via ELISA. Samples were tested in duplicate without operator knowledge of group assignment. Maternal serum levels of all markers were corrected for gestational age effects by conversion to multiples of the median (MoM). Levels of each marker were then analyzed for differences among the study groups using an analysis of variance (ANOVA) with pairwise p-values adjusted for multiple comparisons.RESULTS: SVEGFR-1 levels in ED subjects were 18.4% higher than spontaneous controls, and 16.5% higher than non-ED IVF subjects. However, these differences did not reach statistical significance (p¼0.16). No significant differences were noted in PlGF or uE3 levels when comparing the three groups. ED pregnancies were remarkable in that AFP levels were significantly elevated compared to non-IVF (p < 0.01) and IVF (p<0.05) levels. Both IVF and ED subjects had greater levels of inhA than non-IVF controls (p<0.01); and ED subjects had significantly higher levels of inhA than IVF controls (p<0.01). HCG levels were significantly elevated in ED pregnancies compared to non-IVF controls (p<0.05) however no significant difference was noted in ED vs IVF pregnancies.CONCLUSIONS: Second-trimester sVEGFR-1 and PlGF levels were not significantly altered in ED pregnancies, when compared to IVF or spontaneous pregnancies. Our data supports previous findings that ED pregnancies have significantly greater levels of AFP, inhA, and hCG-markers which have been associated with placental disease. Further study is recommended to correlate these markers with elevated rates of placental ischemia in the ED population.