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      Toll-Like Receptor Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhea

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          Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC).

          Patients and Methods

          Fifty-six women aged 16–35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL–1β) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs.


          The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI −4.69, −0.09) increase in IL–1β release when compared with pain-free participants across both days.


          This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea.

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          Most cited references 42

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          The prevalence and risk factors of dysmenorrhea.

          Dysmenorrhea is a common menstrual complaint with a major impact on women's quality of life, work productivity, and health-care utilization. A comprehensive review was performed on longitudinal or case-control or cross-sectional studies with large community-based samples to accurately determine the prevalence and/or incidence and risk factors of dysmenorrhea. Fifteen primary studies, published between 2002 and 2011, met the inclusion criteria. The prevalence of dysmenorrhea varies between 16% and 91% in women of reproductive age, with severe pain in 2%-29% of the women studied. Women's age, parity, and use of oral contraceptives were inversely associated with dysmenorrhea, and high stress increased the risk of dysmenorrhea. The effect sizes were generally modest to moderate, with odds ratios varying between 1 and 4. Family history of dysmenorrhea strongly increased its risk, with odds ratios between 3.8 and 20.7. Inconclusive evidence was found for modifiable factors such as cigarette smoking, diet, obesity, depression, and abuse. Dysmenorrhea is a significant symptom for a large proportion of women of reproductive age; however, severe pain limiting daily activities is less common. This review confirms that dysmenorrhea improves with increased age, parity, and use of oral contraceptives and is positively associated with stress and family history of dysmenorrhea.
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            Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4).

            Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-)-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-)-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-)-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-)-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-)-opioid agonists suppress pain.
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              Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients.

              The association between lesion type, disease stage and severity of pain was studied in a large group of women with endometriosis to verify whether endometrial implants at different sites determine specific complaints and to evaluate the validity of the current classification system in women with symptomatic disease. A total of 1054 consecutive women with endometriosis undergoing first-line conservative or definitive surgery were included. Data on age at surgery, disease stage according to the revised American Fertility Society (AFS) classification, anatomical characteristics of endometriotic lesions, and type and severity of pain symptoms were collected and analysed by multiple logistic regression. Minimal endometriosis was present in 319 patients, mild in 139, moderate in 292 and severe in 304. A significant inverse relationship was demonstrated between age at surgery and moderate-to-severe dysmenorrhoea, dyspareunia and non-menstrual pain. A strong association was found between posterior cul-de-sac lesions and pain at intercourse [Wald chi (2) = 17.00, P = 0.0001; odds ratio (OR) = 2.64, 95% confidence interval (CI) = 1.68-4.24]. A correlation between endometriosis stage and severity of symptoms was observed only for dysmenorrhoea (Wald chi (2) = 5.14, P = 0.02) and non-menstrual pain (Wald chi (2) = 5.63, P = 0.018). However, the point estimates of ORs were very close to unity (respectively, 1.33, 95% CI = 1.04-1.71, and 1.01, 95% CI = 1.00-1.03). The association between endometriosis stage and severity of pelvic symptoms was marginal and inconsistent and could be demonstrated only with a major increase in study power.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                09 March 2020
                : 13
                : 503-516
                [1 ]Adelaide Medical School, University of Adelaide , Adelaide, South Australia, Australia
                [2 ]Faculty of Health Science, University of Adelaide , Adelaide, South Australia, Australia
                [3 ]Statistical Revelations , Melbourne, Victoria, Australia
                [4 ]Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide , Adelaide, South Australia, Australia
                [5 ]Robinson Research Institute, School or Pediatrics and Reproductive Health, University of Adelaide , Adelaide, South Australia, Australia
                [6 ]School of Medicine, University of Adelaide , Adelaide, South Australia, Australia
                Author notes
                Correspondence: Susan F Evans Tel +61 418 849 895 Email susan.evans@adelaide.edu.au
                © 2020 Evans et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 3, References: 51, Pages: 14
                The study was part-funded by the Australia New Zealand College of Anaesthetists (ANZCA) Research Foundation (Grant 15/013). Its contents are solely the responsibility of the authors and the funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Original Research


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