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Adenomyosis is associated with dysmenorrhea and chronic pelvic pain; however, the triggering mechanisms of painful stimuli and the role of uterine nerve fibers in the manifestation of pain remain poorly understood. The objective of this study was to systematically review the role of uterine nerve fibers' presence and density in the occurrence of pain in patients with adenomyosis. An electronic search was performed using the Embase, PubMed/Medline, and Cochrane databases. We included all studies from inception to November 2023. A total of ten studies that compared uterine biopsies samples of women with and without adenomyosis were included. The biomarker antiprotein gene product 9.5 was decreased or absent in the endometrium of most included women with adenomyosis. None of the included studies observed a difference in neurofilament (NF) staining between the adenomyosis and non-adenomyosis groups. Studies that assessed nerve growth factor (NGF) staining were heterogeneous in design. One study reported no difference in immunohistochemistry staining in any endometrial layer between the adenomyosis and non-adenomyosis groups, while another reported increased staining in the adenomyosis functional endometrial layer, and a third study reported overexpression of NGF, synaptophysin (SYN), and microtubule-associated protein 2 mRNA in focal adenomyosis alone. Preliminary data from poor-quality studies suggest an increase in the uterine density of nerve fibers in patients with adenomyosis. Well-designed studies are essential to assess the cause-and-effect relationship between uterine nerve fibers and pain in patients with adenomyosis.

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Endometriosis's pathophysiology remains incompletely understood, with evidence pointing towards a dysregulated immune response. Regulatory T (Treg) cells, pivotal in maintaining self-tolerance, may facilitate the survival of ectopic endometrial cells within the abdominal cavity, thereby contributing to endometriosis development. This study aimed to assess the prevalence of CD39+CD73+ suppressor Treg cell subsets in the peripheral blood of endometriosis patients. This research focuses on the pivotal role of regulatory T-cells (Tregs), which are essential for maintaining immune tolerance and preventing autoimmune diseases. A case-control study was conducted, including 32 women diagnosed with endometriosis and 22 control subjects. The frequency of peripheral blood CD39+CD73+ suppressor Treg cells was quantified using flow cytometry. No significant differences were observed in the frequency of CD3+CD4+CD25High cells (Median [M]: 10.1; Interquartile Range [IQR]: 6.32‒18.3 vs. M: 9.72; IQR: 6.22-19.8) or CD3+CD4+CD25HighCD39+Foxp3+ cells (M: 31.1; IQR: 19.7-44.0 vs. M: 30.55; IQR: 18.5-45.5) between controls and patients. However, a significantly lower frequency of CD3+CD4+CD25HighCD39+CD73+ cells was observed in the endometriosis group compared to controls (M: 1.98; IQR: 0.0377-3.17 vs. M: 2.25; IQR: 0.50-4.08; p = 0.0483), suggesting a reduction in systemic immune tolerance among these patients. This finding highlights the potential role of CD39 and CD73 expression on Treg cells as biomarkers for assessing disease severity and progression. Furthermore, elucidating the mechanisms driving these alterations may unveil new therapeutic strategies to restore immune equilibrium and mitigate endometriosis symptoms.

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Establishing objective criteria to assess endometriosis symptoms is crucial in defining therapeutic strategies. The visual analogue scale (VAS) is the most used system to enhance the accuracy and reduce the subjectivity of pain assessment, and symptoms of endometriosis are considered severe when the VAS score is ≥ 7 cm. Pain symptoms can significantly impact patients' quality of life, resulting in psychological and social distress. The aim of this study is to evaluate whether a VAS cut-off point of 7 cm for each pain symptom correlates with a diminished quality of life in women with endometriosis. This retrospective study included 1129 patients who underwent surgical treatment for endometriosis. Dysmenorrhea, acyclic pelvic pain, deep dyspareunia, dyschezia, and dysuria were assessed using a 0-10 cm VAS. The Short Form-36 (SF-36) questionnaire was employed to evaluate the quality of life 6 months prior to surgery. Dysmenorrhea was the most prevalent symptom reported in 93.6% of cases, with a mean VAS of 7.6 cm. The quality of life reported was reduced in most patients, with domain scores ranging from 49.4 to 80.1. The mean SF-36 scores in all domains were significantly lower in patients with severe pain (VAS score ≥ 7 cm) compared to those with mild to moderate pain (VAS < 7 cm). This trend was observed across all evaluated pain symptoms. Our research demonstrates that the prevalent VAS cut-off point for establishing severe pain symptoms in endometriosis (VAS ≥ 7 cm) accurately represents the negative impact of the disease on women's quality of life, as assessed via the SF-36 questionnaire.

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Abstract Endometriosis's pathophysiology remains incompletely understood, with evidence pointing towards a dysregulated immune response. Regulatory T (Treg) cells, pivotal in maintaining self-tolerance, may facilitate the survival of ectopic endometrial cells within the abdominal cavity, thereby contributing to endometriosis development. This study aimed to assess the prevalence of CD39+CD73+ suppressor Treg cell subsets in the peripheral blood of endometriosis patients. This research focuses on the pivotal role of regulatory T-cells (Tregs), which are essential for maintaining immune tolerance and preventing autoimmune diseases. A case-control study was conducted, including 32 women diagnosed with endometriosis and 22 control subjects. The frequency of peripheral blood CD39+CD73+ suppressor Treg cells was quantified using flow cytometry. No significant differences were observed in the frequency of CD3+CD4+CD25High cells (Median [M]: 10.1; Interquartile Range [IQR]: 6.32‒18.3 vs. M: 9.72; IQR: 6.22-19.8) or CD3+CD4+CD25HighCD39+Foxp3+ cells (M: 31.1; IQR: 19.7-44.0 vs. M: 30.55; IQR: 18.5-45.5) between controls and patients. However, a significantly lower frequency of CD3+CD4+CD25HighCD39+CD73+ cells was observed in the endometriosis group compared to controls (M: 1.98; IQR: 0.0377-3.17 vs. M: 2.25; IQR: 0.50-4.08; p = 0.0483), suggesting a reduction in systemic immune tolerance among these patients. This finding highlights the potential role of CD39 and CD73 expression on Treg cells as biomarkers for assessing disease severity and progression. Furthermore, elucidating the mechanisms driving these alterations may unveil new therapeutic strategies to restore immune equilibrium and mitigate endometriosis symptoms.

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STUDY OBJECTIVE: To compare the accuracy of preoperative ultrasound (US) in predicting the laparoscopically defined 2021 American Association of Gynecologic Laparoscopists (AAGL) Endometriosis Staging. DESIGN: Retrospective multicenter study of patients treated at 3 specialized endometriosis centers. SETTING: Three specialized endometriosis surgical centers in São Paulo (Brazil), Barcelona (Spain), and Avellino (Italy) participated. PATIENTS: A total of 878 patients aged 15 to 45 years with no history of pelvic malignancy underwent laparoscopic (LPS) treatment for suspected endometriosis. INTERVENTIONS: Retrospective review of preoperative transvaginal and transabdominal US (index test) assessed for endometriosis at all sites used in the 2021 AAGL Endometriosis Classification and classified patients into AAGL-US stages 1 to 4. Results were compared with reference-standard LPS (AAGL-LPS) staging. MEASUREMENTS AND MAIN RESULTS: The AAGL-US and AAGL-LPS stage were concordant in 586 cases (66.7%) (weighted kappa [WK] 0.759; intraclass correlation = 0.906), with the highest agreement observed in patients with no endometriosis (n = 70, 75.3% concordance), AAGL-LPS stage 1 (104, 50.7%) and stage 4 disease (358, 88.2%). Endometriosis was most accurately diagnosed in the rectum/sigmoid colon (WK 0.862), bladder (WK 0.911), and ovaries (WK 0.835/0.795 for right/left, respectively) and least accurately diagnosed at superficial peritoneal (WK 0.442), tubal (WK 0.391/0.363 for right/left, respectively), and retrocervical/uterosacral ligament (WK 0.656) sites. CONCLUSION: Sonographic estimation of the 2021 AAGL Endometriosis Staging is greatest in AAGL-LPS stages 1 and 4 and among patients with no endometriosis. US best identifies endometriosis of the ovaries, bladder, and bowel but is more limited for the tubes and superficial peritoneum.

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Endometriosis can be classified into three phenotypes: superficial, ovarian, and deep. Deep endometriosis (DE) has been associated with more severe pain symptoms, although no large-scale studies have evaluated the association between pain intensity and infertility and the different compartments of the pelvis affected by superficial and DE. This retrospective study included 1116 women who underwent laparoscopy for endometriosis treatment at two referral centers between 2009 and 2019. For the evaluation of each symptom, patients were divided according to their visual analog scale score (< 7 and ≥ 7) and fertility status. On multiple logistic regression, severe dysmenorrhea and dyschezia were correlated with DE of the posterior compartment alone (odds ratio (OR) = 1.6, confidence interval (CI) 1.09-2.34, and p = 0.02 and OR = 2.09, CI 1.36-3.23, and p < 0.01, respectively) and in combination with other compartments. DE of the posterior and lateral compartments had the most consistent statistical power (OR = 3.55 for dysmenorrhea and OR = 4.4 for dyschezia). Infertility was associated with DE of the posterior compartment alone (OR = 1.6, CI 1.06-2.54, p = 0.04) and in combination with the anterior compartment (OR = 2.62, CI 1.29-5.29, p < 0.01), with the combination of posterior and anterior compartment having the highest OR value. Severe dyschezia and infertility were also correlated with the presence of multiple localizations of DE (p = 0.04 and p < 0.01). This study confirms the association between DE and severe pain symptoms as well as the influence of the number of DE compartments on the severity of symptoms and the chance of infertility.

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OBJECTIVE: To evaluate the expression of Ezrin and Phosphorylated Ezrin (Phospho-Ezrin) in endometriosis lesions and its relation to the menstrual cycle phase, stage of endometriosis, histological classification, and clinical symptoms. MATERIAL AND METHODS: The authors conducted a retrospective study, with endometriotic lesions collected from women with endometriosis (n = 57) who underwent laparoscopy from 2017 to 2018. The expression of Ezrin and Phosphorylated Ezrin proteins was analyzed by immunohistochemistry. RESULTS: All the endometriotic lesions contained immunostaining for Ezrin in the glands. Phosphorylated Ezrin was expressed in the stroma of all endometriotic lesions. There was no difference in the Ezrin and Phosphorylated Ezrin's expression in the retrocervical, ovarian, superficial, and intestinal lesions in the same patient. Dysmenorrhea, dyspareunia, acyclic pain, infertility, and dysuria were similar in the three groups of Ezrin staining. There was an inversely proportional relationship between severe dyschezia and Ezrin's intensity, being 66.7% of Ezrin 1 (weak intensity), 36.7 Ezrin 2 (moderate intensity), and 10.0% of Ezrin 3 (p = 0.013). Regarding Phospho-Ezrin there wasn't a significant difference between all the analyzed variables. Histological classification and menstrual cycle phase had also no significant difference between Ezrin and Phospho-Ezrin immunostaining. CONCLUSION: Ezrin protein and Phospho-Ezrin can be considered important markers to elucidate the mechanisms related to migration and attachment of endometriotic lesions. It is still unclear if Ezrin and Phospho-Ezrin are a cause or consequence of endometriosis. Further studies comparing different types of lesions and eutopic endometrium are necessary to elucidate the role of these proteins in the pathogenesis of endometriosis.

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OBJECTIVE: To evaluate the frequencies of iNKT cells and their subsets in patients with deep endometriosis. METHODS: A case-control study was conducted between 2013 and 2015, with 73 patients distributed into two groups: 47 women with a histological diagnosis of endometriosis and 26 controls. Peripheral blood, endometriosis lesions, and healthy peritoneal samples were collected on the day of surgery to determine the frequencies of iNKT cells and subtypes via flow cytometry analysis. RESULTS: The authors observed a lower number of iNKT (p = 0.01) and Double-Negative (DN) iNKT cells (p = 0.02) in the blood of patients with endometriosis than in the control group. The number of DN iNKT IL-17+ cells in the secretory phase was lower in the endometriosis group (p = 0.049). There was an increase in the secretion of IL-17 by CD4+ iNKT cells in the blood of patients with endometriosis and severe dysmenorrhea (p = 0.038), and severe acyclic pelvic pain (p = 0.048). Patients with severe dysmenorrhea also had a decreased number of CD4+ CCR7+ cells (p = 0.022). CONCLUSION: The decreased number of total iNKT and DN iNKT cells in patients with endometriosis suggests that iNKT cells play a role in the pathogenesis of endometriosis and can be used to develop new diagnostic and therapeutic agents.

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INTRODUCTION: Endometriosis is a chronic inflammatory disease that affects approximately 10%-15% of women of childbearing age. Laparoscopic surgery is the preferred surgical approach. Recently, robotic surgery has been used for benign gynecologic surgery, but its role in the treatment of endometriosis is still unknown. AREAS COVERED: We included studies that evaluated the outcomes of robotic surgery for endometriosis. Using the keywords 'endometriosis' and 'robotics', a comprehensive literature search on PubMed, Embase, and the Cochrane Library was performed in July 2021. EXPERT OPINION: Robotic surgery for endometriosis has similar outcomes as conventional laparoscopy, with no evidence of increased complication rates. Despite the non-inferiority of the surgical route, the associated costs of robotic surgery limit its availability. Rapid development of robot-assisted surgery necessitates long-term prospective randomized controlled trials. However, the limitations of robotic surgery should not be overlooked. If robotic surgery can facilitate the spread of minimally invasive surgery, it will be necessary to evaluate the cost, availability, complexity of the lesions, and most importantly, the results of patient satisfaction and values of value-based medicine.

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