Written By: IJCP Editorial Team

Published On: 06 Aug, 2022 11:39 AM | Updated On: 16 May, 2024 5:11 AM

Endometriosis Pathogenesis: New Insights into Potential Therapies

Endometriosis is an estrogen-dependent disorder defined by the presence of endometrium-like tissue in any extrauterine site, even those distant to the uterus, including the pelvic peritoneum, ovaries, and bowel, and, rarely, extra pelvic location. It usually affects women of reproductive age and its prevalence in this population is around 2–10%; accounting for almost 35–50% of women presenting for infertility and pain management. It is typically diagnosed and identified at a later stage when its metastasis or growth outside the uterus usually starts. 

Endometriosis is generally reported to cause symptoms such as pain, dysmenorrhea, dyspareunia, lower abdominal and/or back pain, and, most importantly, infertility, which is a serious consequence of this disease. Though endometriosis can initially remain asymptomatic for a long period, once aggravated, it greatly compromises the quality of life in women suffering from the disease. A key reason for delayed diagnosis is a lack of non-invasive methods for its detection. 

In terms of its pathogenesis, various mechanisms have been suggested to contribute to the onset of endometriosis, such as physical factors such as uterine tissue damage or scarring (occurring during or after surgery), remnant cells from menstrual blood, stem cells, the uterine microenvironment (conducive to tumor generation), and biochemical factors such as oxidative stress, inflammation, hormones, tumor promoting-genes and proteins, and angiogenesis. Out of all these factors, Inflammation is one of the main mechanisms that triggers cell metastasis and invasion as endometriosis involves cell proliferation and infiltration. In the uterine environment, macrophages, natural killer cells, and T cells are regulated by associated increases in the levels of proinflammatory mediators such as prostaglandins, metalloproteinases, cytokines, and chemokines. These immune molecules promote propagation and adhesion but also help in the evasion of immunosurveillance leading to the adhesion of cells in ectopic sites. Hence, in most cases, pharmacological inhibitors targeting NF-κB have been proposed as potential therapeutics against the disease. For example, Dienogest attenuates the expression of IL-8 by reducing TNFα-induced NF-κB activation and may confer a protective effect against endometriosis. Similarly, BAY 11-7085 and SN-50 are known to reduce ICAM-1 expression, and cell proliferation and increase apoptosis of endometriotic lesions, thereby diminishing their development. 

Also, inflammatory cytokines play key roles in the progression of endometriosis by promoting survival, growth, invasion, differentiation, angiogenesis, and immune evasion. Tocilizumab and other pharmacological substances antagonizing the effect of these cytokines may be effective in reducing endometriosis-associated inflammation. Apoptotic and autophagic pathways may represent promising targets for the development of novel therapeutic options against endometriosis. For example, Beclin can be induced by hypoxic conditions in the endometrium in response to an increase in progesterone levels.

Another Key factor in endometriosis progression is Epithelial-Mesenchymal Transition (EMT). EMT causes endometrial cells to develop metastatic and invasive properties. In this process, E-cadherin works to detach endometrial cells from their native site, while N-cadherin encourages the propagation, invasion, and metastasis. Logically, because of the involvement of EMT in endometriosis progression, pharmacological inhibitors that target these pathways could be beneficial to endometriosis patients such as isoliquiritigenin, fucoidan, etc.

Reference: Kapoor R, et al.,  Int J Mol Sci. 2021 Oct 28;22(21):11700.