Endometriosis is a common, complex gynecologic disorder characterized by the presence of endometrial glands and stroma at extrauterine (ectopic) sites. In women who develop this disease, alterations in specific biological processes involving both the endocrine and immune systems have been observed, which may explain the survival and growth of displaced endometrial tissue in affected women. In the past decade, a considerable amount of research has implicated a role for alterations in progesterone action at both eutopic and ectopic sites of endometrial growth which may contribute to the excessive inflammation associated with progression of endometriosis; however, it remains unclear whether these anomalies induce the condition or are simply a consequence of the disease process. In this article, we summarize current knowledge of alterations within the immune system of endometriosis patients and discuss how endometrial cells from women with this disease not only have the capacity to escape immunosurveillance, but also use inflammatory mechanisms to promote their growth within the peritoneal cavity. Finally, we discuss evidence that exposure to an environmental endocrine disruptor, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, can mediate the development of an endometrial phenotype that exhibits both reduced progesterone responsiveness and hypersensitivity to proinflammatory stimuli mimicking the endometriosis phenotype. Future studies in women with endometriosis should consider whether a heightened inflammatory response within the peritoneal microenvironment contributes to the development and persistence of this disease.

Objective

To examine the impact of a recent surgery on development of endometriosis-related adhesions in a chimeric model and to determine the therapeutic efficacy of pioglitazone (PIO).

Design

Human endometrial biopsies were maintained in estradiol (E) with or without PIO for 24 hrs prior to intraperitoneal injection into immunocompromised mice at multiple timepoints following peritoneal surgery. The presence and extent of adhesions was examined in animals relative to the initial establishment of experimental endometriosis.

Setting

Medical School Research Center

Patients

Endometrial biopsies for experimental studies described herein were provided by normally cycling women without a medical history indicative of endometriosis or adhesions.

Interventions

None

Main Outcome Measure

Examination of the development of endometriosis-related adhesions in an experimental model.

Results

Without therapeutic intervention, injection of E-treated human endometrial tissue into mice near the time of peritoneal surgery resulted in multiple adhesions and extensive endometriotic-like disease. In contrast, PIO treatment reduced adhesive disease and experimental endometriosis related to surgical injury.

Conclusions

The presence of human endometrial tissue fragments in the peritoneal cavity of mice with a recent surgical injury promoted development of both adhesive disease and experimental endometriosis. Targeting inflammation and angiogenesis with PIO therapy limited the development of postsurgical adhesions associated with ectopic endometrial growth.

A critical period in establishing pregnancy occurs after the onset of implantation but before placental development. Evidence strongly suggests that abnormalities occurring during this period can result in pregnancy termination or in pre-eclampsia; the latter may lead to small-for-gestational-weight offspring that are likely to be unhealthy. Clearly, events occurring in the endometrium during the implantation process are crucial for proper fetal development and for optimal offspring health. In several mammalian species bi-directional communication between the conceptus and endometrium during implantation is required for successful pregnancy. Although different implantation and placentation modes occur in different mammalian species, common aspects of this bi-directional signaling may exist. The molecular signals from the trophoblast cells of the conceptus, which direct endometrial changes during implantation progression, are well known in some non-rodent species. Currently, we know little about such signaling in rodents during implantation progression, when the endometrium undergoes decidualization. This review focuses on data that support the hypothesis that paracrine signals from the rodent conceptus influence decidualization. Where possible, these findings are compared and contrasted to information currently known in other species that exhibit different implantation modes.

Within the mouse endometrium, secreted phosphoprotein 1 gene expression is mainly expressed in the luminal epithelium and some macrophages around the onset of implantation. However, during the progression of decidualization it is expressed mainly in the mesometrial decidua. To date, the precise cell types responsible for the expression in the mesometrial decidua has not been absolutely identified. The goal of the present study was to assess the expression of secreted phosphoprotein 1 in uteri of pregnant mice (decidua) during the progression of decidualization and compared it to those undergoing artificially-induced decidualization (deciduoma). Significantly (P< 0.05) greater steady-state levels of secreted phosphoprotein 1 mRNA were seen in the decidua compared to deciduoma. Further, in the decidua, the majority of the secreted phosphoprotein 1 protein (SPP1) was localized within a subpopulation of granulated uterine natural killer (uNK) cells but not co-localized to their granules. However, in addition to being localized to uNK cells, SPP1 protein was also detected in another cell type(s) that were not EGF-like containing mucin-like hormone receptor-like sequence 1 protein (EMR1)-positive immune cells which are known to be present in the uterus at this time. Finally, decidual SPP1 expression dramatically decreased in uteri of interleukin-15-deficient mice which lack uNK cells. In conclusion, SPP1 expression is greater in the mouse decidua compared to the deciduoma after the onset of implantation during the progression of decidualization. Finally, uNK cells were found to be the major source of SPP1 in the pregnant uterus during decidualization. SPP1 might play a key role in uNK killer cell functions in the uterus during decidualization.

Uterine natural killer (uNK) cells are the most abundant lymphocyte in the uterus during early pregnancy that plays a role in spiral arteriole modifications. In this study, we determined if uNK cell populations differed between mouse decidua and deciduoma. Histochemical staining using Dolichos biflorous agglutinin (DBA) lectin was used to identify uNK cells and classify their stage of maturation. We found a difference in the pattern of localization and density of uNK cells between the decidua and deciduoma at Days 2–4 after the onset of decidualization. Cells were more distributed and the densities were significantly greater in the mesometrial region of the decidua compared to that of the deciduoma. Using double labeling for both DBA lectin binding and bromodeoxyuridine incorporation, we found that the greater number of uNK cells in the decidua were not due to an increase in uNK cell proliferation. Western blot analyses revealed that the increase in uNK cell number was accompanied by a significant increase in both the levels of interferon-gamma (IFNG) and pro-interleukin-18 when a conceptus was present. Vascular morphometry revealed that modifications of the spiral arterioles occurred in the mesometrial decidua but not the deciduoma, which could be attributed to the differences observed in uNK cell number and IFNG production. The present study demonstrates that differences exist in uNK cell populations between decidua and deciduoma, providing evidence that the conceptus provides signals which regulate uNK cell number and function in the uterus during implantation.