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Abstract
Endometriosis is a chronic inflammatory disorder characterized by the presence of endometrial-like tissue growing outside of the uterus. Although the cause is unknown, retrograde menstruation leads to deposition of endometrial cells into the peritoneal cavity. Lack of disease recognition and long diagnostic delays (6–10 years) lead to substantial personal, social and financial burdens, as well as delayed treatment. A non-invasive diagnostic for endometriosis is a major unmet clinical need. Here, we assessed whether differences in menstrual effluent-derived stromal fibroblast cells (ME-SFCs) from women with and without endometriosis provide the basis for a non-invasive diagnostic for endometriosis. In addition, we investigated whether treatment of control ME-SFCs with inflammatory cytokines (TNF and IL-1β) could induce an endometriosis-like phenotype. ME-SFCs from laparoscopically diagnosed endometriosis patients exhibit reduced decidualization capacity, measured by IGFBP1 production after exposure to cAMP. A receiver operating characteristic (ROC) curve developed using decidualization data from controls and endometriosis subjects yielded an area under the curve of 0.92. In addition, a significant reduction in ALDH1A1 gene expression and increased podoplanin surface expression were also observed in endometriosis ME-SFCs when compared to control ME-SFCs. These endometriosis-like phenotypes can be reproduced in control ME-SFCs by exposure to inflammatory cytokines (TNF and IL-1β) and are associated with increased cell migration. These results are consistent with the hypothesis that chronic intrauterine inflammation influences the development of endometriosis lesions following retrograde menstruation. In conclusion, the analysis of ME-SFCs can provide an accurate, rapid, and non-invasive diagnostic for endometriosis and insight into disease pathogenesis.
Highlights
Endometriosis is a common, complex, and chronic inflammatory disorder associated with debilitating pelvic pain, dysmenorrhea, and infertility [1, 2]
Consistent with the differences in the eutopic endometrium of women with and without endometriosis, we have previously shown distinct differences in menstrual effluent (ME) and menstrual effluent-derived stromal fibroblast cells (ME-SFCs) obtained from a small cohort of women with endometriosis compared to healthy controls, including impaired stromal cell decidualization and reduced expression of Aldehyde dehydrogenase 1 family member A1 gene (ALDH1A1) and other genes associated with the retinoic acid pathway [21]
In a paired analysis of ME-SFCs isolated from control subjects, we clearly show a reduction in dibutyryladenosine- 3′ (cAMP)-induced decidualization (i.e., insulin growth factor binding protein 1 (IGFBP1) production) on day 7 following tumor necrosis factor (TNF) exposure on days 1 and 3, when compared to control MESFCs exposed to vehicle on the same days (Figure 3A, P < 0.01)
Summary
Endometriosis is a common, complex, and chronic inflammatory disorder associated with debilitating pelvic pain, dysmenorrhea, and infertility [1, 2]. It is defined by the growth of endometriallike tissues containing epithelial glands and stromal cells outside of the uterus, primarily in the peritoneal cavity. The exact cause(s) of endometriosis are not known, a commonly accepted theory is based on a causative role of retrograde menstruation [3], whereby endometrial tissue containing stromal cells is shed and delivered to the peritoneal cavity. Chronic endometritis, a poorly diagnosed condition characterized by persistent endometrial inflammation, is a significant risk factor for endometriosis [17, 18] and highlights the potential role of chronic endometrial inflammation in endometriosis
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