Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu, rich in inflammatory markers and pain-inducing prostaglandins PGE2/PGF2α and lipid peroxides, and the endometriotic tissue is innervated with nociceptors. Our clinical study showed the abundance of oxidatively-modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively-modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (i) the detection of lipoprotein derived oxidation-sensitive pain molecules, (ii) the ability of such molecules to induce nociception, and (iii) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins similar to that seen in the PF. The oxidatively-modified lipoproteins induced hypothermia (intra-cerebroventricular) in CD-1 mice and nociception in the Hargreaves paw-withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin-E and N-acetylcysteine and the NSAID, indomethacin suppressed the pain inducing ability of oxidatively-modified lipoproteins. Treatment of human endometrial cells with oxidatively-modified lipoproteins or PF from women with endometriosis showed up-regulation of similar genes belonging to the opioid and inflammatory pathways. Our finding that oxidatively-modified lipoproteins can induce nociception has a broader impact not only in the treatment of endometriosis-associated pain but also in other diseases associated with chronic pain.

Mitochondria are a major player in cellular energetics, oxidative stress and programmed cell death. Mitochondrial dynamics regulates and integrates these functions. Mitochondrial dysfunction is involved in cardiac hypertrophy, hypertension and myocardial ischemia/reperfusion injury. Reactive oxygen species generation is modulated by the fusion-fission pathway as well as key proteins such as sirtuins that act as metabolic sensors of cellular energetics. Mitochondrial redox status has thus become a good target for therapy against cardiovascular diseases. Recently, there is an influx of studies garnered towards assessing the beneficial effects of mitochondrial targeted antioxidants, drugs modulating the fusion-fission proteins, sirtuins, and other mitochondrial processes as potential cardio-protecting agents.

An estimated 10%-15% of women of reproductive age suffer from endometriosis and can be plagued with one or many forms of pain. It is no mystery that endometriosis is an extremely complex disease, with several factors leading to the predominant symptoms of infertility and pain. Although there are currently multiple options available for treating endometriosis-associated pain, none have the ability to completely relieve the symptoms. This review both highlights the current trends in treatment of endometriosis-associated pain and explores some novel options available for therapy directed towards oxidative stress, inflammation and nociceptive mechanisms of pain. A PubMed search was conducted to identify the most recent publications on the topic of pain associated with endometriosis, and further research was performed to clarify the mechanism by which current treatments target pain. Lastly, the authors include a review of pharmacological options at the forefront of endometriosis research. A more comprehensive understanding of the mechanisms behind endometriosis-associated pain will ultimately lead to more effective treatments and improved prognoses for patients.

Endometriosis is a clinical condition affecting young women. Cells from the endometrium appear and flourish outside the uterus, often causing pain. Typically viewed as a hormonal disorder, new studies suggest that endometriosis may be an epigenetic disease. The major objective of this study was to investigate if epigenetic‐mediated changes play a role in endometriosis‐associated pain. Peritoneal fluid (PF) from women with and without endometriosis (n=6) were used to treat endometrial cells (EM‐42 and Ishikawa) for 48 hours. Global Histone modification changes were detected using Western blots. The mRNA expression of nociceptors such as cycloxygenase‐2 (COX‐2) and transient receptor potential channel TRPV1 was detected using quantitative real‐time polymerase chain reaction (qPCR). Our results indicated changes in Histone 3 and Histone 4 modifications depending on the presence or absence of endometriosis‐associated pain. There was >;25‐fold induction in the pain‐associated genes in endometriotic tissue. Human miRNome array showed significant differences in over 30 miRNAs in endometrial tissue from endometriosis patients compared to controls. Our findings provide evidence for epigenetic changes in patients with endometriosis‐associated pain.