Abstract. Endometriosis is a common type of chronic inflammatory disease with an immunological background. In this review, we aimed to explore the contemporary literature on the infection and sterile inflammation that support the pathogenesis of endometriosis. This article reviews the English-language literature on inflammatory, environmental, immunological and oxidative factors associated with endometriosis in an effort to identify factors that cause a predisposition to endometriosis. Intrauterine microbes may be critical for the initiation of endometriosis; the initial activation of pathogen recognition receptors by microbial stimuli results in the activation of proinflammatory pathways and innate immunity. In addition to their response to various exogenous pathogen-associated molecular patterns, Toll-like receptors (TLRs) also recognize a wide range of endogenous danger-associated molecular patterns (DAMPs). The increased expression levels of DAMPs may be involved in the subsequent process of nuclear transcription factor-κB-dependent sterile inflammation. Oxidative stress, secondary to the influx of iron during retrograde menstruation, is involved in the progression of endometriosis. DAMP-mediated danger signals and oxidative stress are bidirectional during sterile inflammation (danger signal spiral). This review supports the hypothesis that there are at least two distinct phases of endometriosis development: The initial wave of TLR activation in modulating innate immune responses would be followed by the second big wave of sterile inflammation.

Abstract. The association between endometriosis and malignant transformation has often been described in the medical literature. A search was conducted between 1966 and 2010 through the English language literature (online Medline PubMed database) using the keywords endometriosis combined with malignant transformation. The search revealed an increase in reports describing endometriosis and malignancy. Approximately 1.0% of women with endometriosis have lesions that undergo malignant transformation. The malignant processes that are associated with endometriosis may be classified into three groups: i) epithelial ovarian cancers (endometrioid adenocarcinoma and clear cell carcinoma), ii) other Müllerian-type tumors, including Müllerian-type mucinous borderline tumor and serous borderline tumor and iii) sarcomas such as adenosarcoma and endometrial stromal sarcoma in the female pelvic cavity. Persistent oxidative stress induced by endometriosis-dependent hemorrhage may be associated with carcinogenesis. In conclusion, the malignant transformation of endometriosis has multiple pathways of development and may share a common pathogenic mechanism; iron-induced oxidative stress derived from repeated hemorrhage.

The histogenesis of endometriosis and endometriosis-associated ovarian cancer is one of the most mysterious aspects of pathology. To better understand the histogenesis of endometriosis and endometriosis-associated ovarian cancer, we analyzed the possibility of a link of endometrium, ovarian surface epithelium, and a cortical inclusion cyst to ovarian endometriosis and endometriosis-associated ovarian cancer by immunohistochemistry using the epithelial membrane antigen (an epithelial marker), calretinin (a mesothelial marker), and hepatocyte nuclear factor (HNF)-1β (a clear cell carcinoma-specific transcription factor). During ovarian surface epithelium invagination, cortical inclusion cyst epithelial cells may, in some cases, undergo mesothelial-epithelial transition and subsequently differentiate into endometriosis. This case of endometriosis that has undergone Müllerian metaplasia arises from the HNF-1β-negative cells. The remaining endometriosis may develop from the late secretory and menstrual endometria, with HNF-1β-positive staining, by retrograde menstruation. Endometrioid adenocarcinoma and clear cell carcinoma arise from the HNF-1β-negative and HNF-1β-positive epithelial cells of endometriosis, respectively. It has been proposed that clear cell and endometrioid-type adenocarcinomas arise from distinct types of endometriosis with different cells of origin.

HNF-1β in endometriosis might be a factor that controls the cell cycle and DNA damage checkpoints.