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1.  Medical Management of Endometriosis: Emerging Evidence Linking Inflammation to Disease Pathophysiology 
Minerva ginecologica  2013;65(2):199-213.
Progesterone action normally mediates the balance between anti-inflammatory and pro-inflammatory processes throughout the female reproductive tract. However, in women with endometriosis, endometrial progesterone resistance, characterized by alterations in progesterone responsive gene and protein expression, is now considered a central element in disease pathophysiology. Recent studies additionally suggest that the peritoneal microenvironment of endometriosis patients exhibits altered physiological characteristics that may further promote inflammation-driven disease development and progression. Within this review, we summarize our current understanding of the pathogenesis of endometriosis with an emphasis on the role that inflammation plays in generating not only the progesterone-resistant eutopic endometrium but also a peritoneal microenvironment that may contribute significantly to disease establishment. Viewing endometriosis from the emerging perspective that a progesterone resistant endometrium and an immunologically compromised peritoneal microenvironment are biologically linked risk factors for disease development provides a novel mechanistic framework to identify new therapeutic targets for appropriate medical management.
PMCID: PMC3718308  PMID: 23598784
Endometriosis; inflammation; progesterone resistance
2.  Dietary fish oil supplementation inhibits formation of endometriosis-associated adhesions in a chimeric mouse model 
Fertility and sterility  2012;99(2):543-550.e1.
To examine whether dietary fish oil supplementation reduces development of spontaneous endometriosis-associated adhesions using an established model.
Laboratory-based study.
Medical center research laboratory.
Disease-free women of reproductive age and nude mice.
Women were not provided any intervention. Mice were randomized to receive fish oil supplementation or control diet.
Main Outcome Measure(s)
Experimental endometriosis was established in mice via injection of human endometrial tissue within 16 hours of ovariectomy. Mice were provided standard or menhaden fish oil–supplemented diets for ≥2 weeks before initiation of experimental endometriosis and until killing them 1 week later. At necropsy, mice were examined for the presence and extent of adhesions and endometriotic-like lesions. Tissues were excised and morphologically characterized.
Adhesions/lesions were reduced in mice provided with dietary fish oil compared with control animals. Leukocytes were more numerous within the adhesions/lesions of the mice maintained on the standard diet compared with animals provided with fish oil. As indicated by staining intensity, collagen deposition was greater at adhesion sites within control mice compared with fish oil–supplemented animals.
Wound-healing associated with surgery created an inflammatory peritoneal microenvironment that promoted the development of both experimental endometriosis and adhesions in a murine model. Targeting excessive inflammation with fish oil may be an effective adjuvant therapy to reduce the development of postsurgical adhesions related to endometriosis.
PMCID: PMC3582352  PMID: 23103017
Omega-3 fatty acids; adhesions; endometriosis; mice; inflammation
3.  Immune interactions in endometriosis 
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.
PMCID: PMC3204940  PMID: 21895474
chemokines; cytokines; dioxin; endocrine-disrupting chemicals; endometriosis; estrogen; immune–endocrine interactions; inflammation; peritoneum; progesterone; TCDD
4.  Development and Prevention of Postsurgical Adhesions in a Chimeric Mouse Model of Experimental Endometriosis 
Fertility and sterility  2010;95(4):1295-1301.e1.
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).
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.
Medical School Research Center
Endometrial biopsies for experimental studies described herein were provided by normally cycling women without a medical history indicative of endometriosis or adhesions.
Main Outcome Measure
Examination of the development of endometriosis-related adhesions in an experimental model.
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.
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.
PMCID: PMC3038191  PMID: 20934690
Adhesions; Endometriosis; Surgery; Mice
5.  Do Molecular Signals from the Conceptus Influence Endometrium Decidualization in Rodents? 
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.
PMCID: PMC2844778  PMID: 19551814
6.  The Conceptus Increases Secreted Phosphoprotein 1 Gene Expression in the Mouse Uterus During the Progression of Decidualization Mainly Due to It’s Effects on Uterine Natural Killer Cells1 
Reproduction (Cambridge, England)  2007;133(6):1213-1221.
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.
PMCID: PMC2613481  PMID: 17636175
7.  Effect of the Conceptus on Uterine Natural Killer Cell Numbers and Function in the Mouse Uterus During Decidualization1 
Biology of reproduction  2006;76(4):579-588.
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.
PMCID: PMC2275212  PMID: 17151350

Results 1-7 (7)