PTGS2, HAS2 and GREM1 gene expression correlates to morphological and physiological characteristics and provides a novel approach to predict human embryo development. Ultimately, with better predictors of follicular and embryonic health, higher quality embryos can be selected and transferred, reducing higher order pregnancy rates.

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Decidualization is a complex process involving cellular proliferation and differentiation of the endometrial stroma that is required to establish and support pregnancy. Progesterone acting via its nuclear receptor, the progesterone receptor (PGR), is a critical regulator of decidualization and is known to interact with certain members of the activator protein-1 (AP-1) family in the regulation of transcription. In this study, we identified the cistrome and transcriptome of PGR and identified the AP-1 factors FOSL2 and JUN to be regulated by PGR and important in the decidualization process. Direct targets of PGR were identified by integrating gene expression data from RNA sequencing with the whole-genome binding profile of PGR determined by chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) in primary human endometrial stromal cells exposed to 17β-estradiol, medroxyprogesterone acetate, and cAMP to promote in vitro decidualization. Ablation of FOSL2 and JUN attenuates the induction of 2 decidual marker genes, IGFBP1 and PRL. ChIP-seq analysis of genomic binding revealed that FOSL2 is bound in proximity to 8586 distinct genes, including nearly 80% of genes bound by PGR. A comprehensive assessment of the PGR-dependent decidual transcriptome integrated with the genomic binding of PGR identified FOSL2 as a potentially important transcriptional coregulator of PGR via direct interaction with regulatory regions of genes actively regulated during decidualization.

Endometriosis is considered as an estrogen-dependent inflammatory disease but its etiology is unclear. To date, a mechanistic role for steroid receptor coactivators (SRCs) in endometriosis progression has not been elucidated. An SRC-1−/− mouse model reveals that the SRC-1 gene plays an essential role in endometriosis progression. Notably, a novel 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from endometriosis patients. Tnf−/− and Mmp9−/− mice with surgically induced endometriosis reveal that activation of TNFα-induced MMP9 activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α-mediated apoptosis in human endometrial epithelial cells upon TNF-α treatment and causes the epithelial-mesenchymal transition and invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the novel TNF-α/MMP9/SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.

Early embryo miscarriage is linked to inadequate endometrial decidualization, a cellular transformation process that enables deep blastocyst invasion into the maternal compartment. Although much of the cellular events that underpin endometrial stromal cell (ESC) decidualization are well recognized, the individual gene(s) and molecular pathways that drive the initiation and progression of this process remain elusive. Using a genetic mouse model and a primary human ESC culture model, we demonstrate that steroid receptor coactivator-2 (SRC-2) is indispensable for rapid steroid hormone-dependent proliferation of ESCs, a critical cell-division step which precedes ESC terminal differentiation into decidual cells. We reveal that SRC-2 is required for increasing the glycolytic flux in human ESCs, which enables rapid proliferation to occur during the early stages of the decidualization program. Specifically, SRC-2 increases the glycolytic flux through induction of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3), a major rate-limiting glycolytic enzyme. Similarly, acute treatment of mice with a small molecule inhibitor of PFKFB3 significantly suppressed the ability of these animals to exhibit an endometrial decidual response. Together, these data strongly support a conserved mechanism of action by which SRC-2 accelerates the glycolytic flux through PFKFB3 induction to provide the necessary bioenergy and biomass to meet the demands of a high proliferation rate observed in ESCs prior to their differentiation into decidual cells. Because deregulation of endometrial SRC-2 expression has been associated with common gynecological disorders of reproductive-age women, this signaling pathway, involving SRC-2 and PFKFB3, promises to offer new clinical approaches in the diagnosis and/or treatment of a non-receptive uterus in patients presenting idiopathic infertility, recurrent early pregnancy loss, or increased time to pregnancy.

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Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, the liver receptor homolog-1 (Lrh-1, NR5A2), is an orphan nuclear receptor that regulates metabolism and hormone synthesis1. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents2 and humans. Germline ablation of the Lrh-1 gene in mice is embryo-lethal at gastrulation3. Depletion of Lrh-1 in the ovarian follicle demonstrates that it regulates genes required for both steroid synthesis and ovulation4. To study the effects of Lrh-1 on mouse gestation, we disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation, and fetal death. Lrh-1 is expressed in the mouse and human endometrium. In a human model of primary culture of endometrial stromal cells, depletion of Lrh-1 by siRNA abrogated decidualization. These findings demonstrate that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for placental formation. It therefore plays multiple, indispensible roles in establishing and sustaining pregnancy.