In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily through their cognate receptors to set off cascades of signaling pathways and enact large-scale gene expression programs. In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. This hormone imbalance leads to heightened inflammation and may also increase the pelvic pain of the disease and decrease endometrial receptivity to embryo implantation. This review focuses on the molecular mechanisms governing progesterone and estrogen signaling supporting endometrial function and how they become dysregulated in endometriosis. Understanding how these mechanisms contribute to the pelvic pain and infertility associated with endometriosis will open new avenues of targeted medical therapies to give relief to the millions of women suffering its effects.

Though endometriosis and infertility are clearly associated, the pathophysiological mechanism remains unclear. Previous work has linked endometrial ARID1A loss to endometriosis-related endometrial non-receptivity. Here, we show in mice that ARID1A binds and regulates transcription of the Foxa2 gene required for endometrial gland function. Uterine-specific deletion of Arid1a compromises gland development and diminishes Foxa2 and Lif expression. Deletion of Arid1a with Ltf-iCre in the adult mouse endometrial epithelium preserves the gland development while still compromising the gland function. Mice lacking endometrial epithelial Arid1a are severely sub-fertile due to defects in implantation, decidualization, and endometrial receptivity from disruption of the LIF-STAT3-EGR1 pathway. FOXA2 is also reduced in the endometrium of women with endometriosis in correlation with diminished ARID1A, and both ARID1A and FOXA2 are reduced in nonhuman primates induced with endometriosis. Our findings describe a role for ARID1A in the endometrial epithelium supporting early pregnancy establishment through the maintenance of gland function.

Female subfertility is highly associated with endometriosis. Endometrial progesterone resistance is suggested as a crucial element in the development of endometrial diseases. We report that MIG-6 is downregulated in the endometrium of infertile women with endometriosis and in a non-human primate model of endometriosis. We find ERBB2 overexpression in the endometrium of uterine-specific Mig-6 knockout mice (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6d/d mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6d/d mice revert to their normal expression in Mig-6d/dErbb2d/d mice. Together, our results demonstrate that ERBB2 overexpression in endometrium with MIG-6 deficiency causes endometrial progesterone resistance and a nonreceptive endometrium in endometriosis-related infertility, and ERBB2 targeting reverses these effects.

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Adenomyosis is a nonmalignant uterine disorder in which endometrial tissue exists within and grows into the myometrium. Animal models have generated limited insight into the still-unclear pathogenesis of adenomyosis, provided a platform for preclinical screening of many drugs and compounds with potential as therapeutics, and elucidated mechanisms underlying the pain and fertility issues that occur in many women with the disease. Spontaneous adenomyosis has been studied in nonhuman primates, primarily in the form of case reports. Adenomyosis is routinely experimentally induced in mice through methods such as neonatal tamoxifen exposure, pituitary engraftment, and human tissue xenotransplantation. Several studies have also reported hormonal or environmental toxicant exposures that give rise to murine adenomyosis, and genetically engineered models have been created that recapitulate the human-like condition, most notably involving alteration of β-catenin expression. This review describes the animal models for adenomyosis and their contributions to our understanding of the factors underpinning the development of symptoms. Animal models represent a unique opportunity for understanding the molecular basis of adenomyosis and developing efficacious treatment options for affected women. Herein, we assess their different potentials and limitations with regard to identification of new therapeutic interventions and reflect on future directions for research and drug validation.

Abstract The endometrium, composed of epithelial and stromal cell compartments, is tightly regulated by the ovarian steroid hormones estrogen (E2) and progesterone (P4) during early pregnancy. Through the progesterone receptor (PGR), steroid receptor coactivators, and other transcriptional coregulators, progesterone inhibits E2-induced cell proliferation and induces the differentiation of stromal cells in a process called decidualization to promote endometrial receptivity. Although interleukin-13 receptor subunit alpha-2 (Il13ra2) is expressed in the human and mouse endometrium, its potential role in the steroid hormone regulation of the endometrium has not been thoroughly examined. In this study, we employed PGR knockout mice (PRKO) and steroid receptor coactivator-1 knockout mice (SRC-1−/−) to profile the expression of Il13ra2 in the murine endometrium and determine the role of these transcriptional regulators in the hormone-responsiveness of Il13ra2 expression. Furthermore, we utilized a well-established decidualization-inducing steroidogenic cocktail and a siRNA-based knockdown of IL13RA2 to determine the importance of IL13RA2 in the decidualization of primary human endometrial stromal cells. Our findings demonstrate that Il13ra2 is expressed in the sub-epithelial stroma of the murine endometrium in response to ovarian steroid hormones and during early pregnancy in a PGR- and SRC-1-dependent manner. Furthermore, we show that knockdown of IL13RA2 before in vitro decidualization of primary human endometrial stromal cells partially compromises the full decidualization response. We conclude that Il13ra2 is a downstream target of progesterone through PGR and SRC-1 and plays a role in mediating the stromal action of ovarian steroid hormones.

Endometriosis is a prevalent gynecological condition associated with pelvic pain and infertility. Despite more than a century of research, the etiology of endometriosis still eludes scientific consensus. This lack of clarity has resulted in suboptimal prevention, diagnosis, and treatment options. Evidence of genetic contributors to endometriosis is interesting but limited; however, significant progress has been made in recent years in identifying epigenetic role in the pathogenesis of endometriosis through clinical studies, in vitro cell culture experiments, and in vivo animal models. The predominant findings include endometriosis-related differential expression of DNA methyltransferases and demethylases, histone deacetylases, methyltransferases, and demethylases, and regulators of chromatin architecture. There is also an emerging role for miRNAs in the control of epigenetic regulators in the endometrium and endometriosis. Changes in these epigenetic regulators result in differential chromatin organization and DNA methylation with consequences for gene expression independent of a genetic sequence. Epigenetically altered expression of genes related to steroid hormone production and signaling, immune regulation, and endometrial cell identity and function have all been identified and appear to play into the pathophysiological mechanisms of endometriosis as well as resulting infertility. This review summarizes and critically discusses early seminal findings, the ever-growing recent evidence of epigenetic contributions to the pathophysiology of endometriosis, and implications for proposed epigenetically targeted therapeutics.

Sirtuin 1(SIRT1) is a member of the sirtuin family that functions to deacetylate both histones and non-histone proteins. Previous studies have identified significant SIRT1 upregulation in eutopic endometrium from infertile women with endometriosis. However, SIRT1 function in the uterus has not been directly studied. Using immunochemistry analysis, we found SIRT1 to be most strongly expressed at GD4.5 and GD5.5 in decidualized cells and at GD7.5 in secondary decidual cells in mouse. To assess the role of SIRT1 in uterine function, we generated uterine Sirt1 conditional knockout mice (Pgrcre/+Sirt1f/f; Sirt1d/d). A 6-month fertility trial revealed that Sirt1d/d females were subfertile. Implantation site numbers were significantly decreased in Sirt1d/d mice compared to controls at GD5.5. Sirt1d/d implantation sites at GD4.5 could be divided into two groups, Group #1 with luminal closure and non-specific COX2 expression compared to controls (14/20) and Group #2 with an open lumen and no COX2 (6/20). In Sirt1d/d Group #1, nuclear FOXO1 expression in luminal epithelial cells was significantly decreased. In Sirt1d/d Group #2, nuclear FOXO1 expression was almost completely absent, and there was strong PGR expression in epithelial cells. At GD5.5, stromal PGR and COX2 were significantly decreased in Sirt1d/d uterine in the areas surrounding the embryo compared to controls, indicating defective decidualization. An artificially induced decidualization test revealed that Sirt1d/d females showed defects in decidualization response. All together, these data suggest that SIRT1 is important for decidualization and contributes to preparing a receptive endometrium for successful implantation.