Association of Uterine Tissue Innervation and Peripheral Nerve Density with Adenomyosis Related Pain. A Systematic Review.

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.

Evaluation of HLA-DQ2 and HLA-DQ8 haplotypes in patients with endometriosis, A case-control study.

OBJECTIVE: To evaluate the relationship between genetic haplotypes associated with celiac disease (Human Leucocyte Antigen [HLA] DQ2 and DQ8) with the diagnosis, clinical presentation, and location of endometriosis in Brazilian women. METHOD: A retrospective cross-sectional study, was conducted in a Tertiary hospital. PATIENTS: Women aged 18-50 years who underwent HLA-DQ2 and HLA-DQ8 haplotype analysis. INTERVENTION: The patients were divided into endometriosis and control groups and evaluated for symptoms; endometriosis location, American Society for Reproductive Medicine (ASRM) stage, and the presence of anti-tissue transglutaminase IgA (anti-TgA), HLA-DQ2, and HLA-DQ8 markers. RESULTS: A total of 434 consecutive patients with (n = 315) and without (n = 119) endometriosis were included. Pain and infertility were more frequent in the endometriosis group than in the control group. The presence of HLA-DQ2, HLA-DQ8, and anti-TgA was similar between both groups. The presence of HLA-DQ2 and HLA-DQ8 markers did not differ based on age, pain symptoms, ASRM stage, or endometriosis location. CONCLUSION: Although there are similarities in inflammatory markers and pathophysiology between celiac disease and endometriosis, this study found no significant associations in the presence of HLA-DQ2 or HLA-DQ8 haplotypes and endometriosis.

Soluble MICA in endometriosis pathophysiology: Impairs NK cell degranulation and effector functions.

PROBLEM: Endometriosis exhibits several immune dysfunctions, including deficient natural killer (NK) cell cytotoxicity. MICA (MHC class I chain-related molecule A) is induced by biological stress and soluble MICA (sMICA) negatively modulates the expression of the activating receptor, NKG2D, reducing NK cells activities. We investigated the involvement of soluble MICA in NK cell-deficient activity in endometriosis. METHODS OF STUDY: sMICA levels (serum and peritoneal fluid-PF) were evaluated by ELISA. Circulating NK cell subsets quantification and its NKG2D receptor expression, NK cell cytotoxicity and CD107a, IFN-γ and IL-10 expressions by NK cells stimulated with K562 cells were determined by flow cytometry. RESULTS: We found higher sMICA levels (serum and PF) in endometriosis, especially in advanced and deep endometriosis. Endometriosis presented lower percentages of CD56dim CD16+ cytotoxic cells and impaired NK cell responses upon stimulation, resulting in lower CD107a and IFN-γ expressions, and deficient NK cell cytotoxicity. NK cell stimulation in the MICA-blocked condition (mimicking the effect of sMICA) showed decreased cytotoxicity in initial endometriosis stages and the emergence of a negative correlation between CD107a expression and sMICA levels. CONCLUSIONS: We suggest that soluble MICA is a potential player in endometriosis pathophysiology with involvement in disease progression and severity, contributing to NK cell impaired IFN-γ response and degranulation. NK cell compartment exhibits multiple perturbations, including quantitative deficiency and impaired cytotoxicity, contributing to inadequate elimination of ectopic endometrial tissue.

Visual Analogue Scale Cut-off Point of Seven Represents Poor Quality of Life in Patients with Endometriosis.

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.

Deep Endometriosis: the Involvement of Multiple Pelvic Compartments Is Associated with More Severe Pain Symptoms and Infertility.

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.

Expression of ezrin protein and phosphorylated ezrin in pelvic endometriotic lesions.

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.

Altered Endometrial Expression of α-Inhibin Subunit and Its Co-Receptor Betaglycan in Infertile Women with Endometriosis.

BACKGROUND: Inhibins and their co-receptor betaglycan are members of the transforming growth factor ß superfamily, a group of signaling molecules that control the differentiation of human endometrium in the secretory phase of the menstrual cycle. OBJECTIVE: Since endometriosis is associated with endometrial dysfunction and infertility, this study aimed at evaluating the expression of α-inhibin and betaglycan mRNA and proteins in endometrial samples of infertile women with and without endometriosis. DESIGN: This was a cross-sectional study. Participants/Materials: Endometrial samples of women with (n = 17) and without (n = 22) endometriosis were subdivided according to the menstrual cycle phase into proliferative and secretory. SETTING: University hospital. METHODS: We used real-time RT-PCR to quantify mRNA levels and immunohistochemistry to localize the proteins. RESULTS: α-inhibin mRNA levels were significantly increased in the secretory phase (p < 0.01 vs. proliferative phase) only among women with endometriosis. Conversely, betaglycan mRNA levels were downregulated in the secretory endometrium of controls (p < 0.01 vs. proliferative) but failed to change between cycle phases of patients with endometriosis. Both proteins were present in the glandular epithelium and stroma in the endometrium of women with and without endometriosis. Immunostaining analysis showed that while α-inhibin protein expression did not vary significantly, the intensity of betaglycan immunostaining decreased in the secretory phase in the control group (p = 0.038 vs. proliferative phase) but not in the endometriosis group. LIMITATIONS: We cannot determine whether endometriosis causes the abnormal expression of α-inhibin and betaglycan in the eutopic endometrium or if this alteration already existed before the establishment of endometriotic lesions. CONCLUSION: Our findings suggest an abnormally increased expression of α-inhibin mRNA (not protein) and betaglycan (mRNA and protein) in the secretory-phase endometrium of women with endometriosis.

The role of dendritic cells in endometriosis: A systematic review.

Endometriosis (EDT), a common estrogen-dependent inflammatory disorder, is characterized by endometrial-like tissue outside the uterus. While its pathogenesis is poorly understood, it is supposed that the immune system plays a role in its pathophysiology, and increased number of immune cells and changes in both cell-mediated and humoral immunity have been described. Dendritic cells (DCs) are antigen-presenting cells (APC) of the immune system that recognize, capture, and process complex antigens and present them to T cells, conferring them a unique ability as mediators between the innate and adaptive immune systems. This systematic review aims to enlighten possible disturbances (systemically and locally) of DCs in the development and progression of endometriosis. A search using the strategy: ("dendritic cells" AND "immunology" AND "endometriosis") in databases resulted in 490 citations; after applying inclusion and exclusion criteria, a total of 13 studies were assessed. The evaluated studies demonstrated that DCs are susceptible to pro-endometriotic changes which could inhibit immature DCs (imDCs) from their maturation and induce imDCs into a macrophage phenotype. In addition, the growth and vascularization of endometriosis requires the presence of endogenous DC, which infiltrate endometriotic lesions and enhance endothelial cell migration by secreting proangiogenic factors. Whereas DC maturation suppresses this response, imDC actively promote angiogenesis and growth, leading to a switch in their immunologic role from presenting antigens to support angiogenesis and EDT progression.

Expression of ezrin protein and phosphorylated ezrin in pelvic endometriotic lesions

Abstract 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. Dysmenor-rhea, 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. HIGHLIGHTS The implantation of endometrial cells in the pelvic cavity has been related to some factors such as a receptive environment that allows the implantation and proliferation of these cells. Several studies have shown the participation of the Ezrin protein in the process of invasion of malignant cells. The expression of Ezrin and its activated form was observed in endometriotic lesions providing great evidence that these proteins can play an important role in the migration and attachment of endometriotic lesions.

The microbiome and endometriosis

The objective of this study was to systematically review the literature on the human microbiome in association with endometriosis. PubMed/Medline, Cochrane, and Embase databases were searched for literature published from 1986 to August 2021. All human studies that assessed the microbiome using 16S rRNA sequencing or shotgun sequencing in women with endometriosis were included. Two reviewers independently abstracted data from the selected articles into tables. To assess the quality of included studies, the National Institutes of Health Study Quality Assessment Tools were utilized. This review included 12 case–control studies. Included studies compared the microbiome from various anatomical sources (fecal, vaginal, cervical, peritoneal, endometrial, and intra-lesional) between patients with endometriosis and a heterogeneous set of control patients. Study quality ranged from poor to good, with 8 of 12 studies rated fair. Multiple studies reported a different distribution of bacteria among women with endometriosis across anatomical sites, but the results were highly heterogeneous. Pseudomonas was overrepresented in peritoneal fluid among women with endometriosis across multiple studies but was also observed to be increased in vaginal, endometrial, and intra-lesional samples. Among bacteria noted across different anatomical samples, Gardnerella was found to be increased in cervical but decreased in endometrial, fecal, and vaginal samples of patients with endometriosis, while Atopium was found to be decreased in vaginal and cervical samples from patients with endometriosis. Sphingobium was found to be increased in vagina, endometrium, and peritoneal fluid from patients with endometriosis. Streptococcus was found to be increased in peritoneal, endometrial, and cervical samples from women with endometriosis. Microbiomal comparisons stratified by endometriosis stage or site of endometriosis involvement were limited and highly heterogeneous.

Association of 2D and 3D transvaginal ultrasound findings with adenomyosis in symptomatic women of reproductive age: a prospective study.

OBJECTIVE: To evaluate the association of two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasound (TVUS) findings with adenomyosis symptoms. METHODS: This prospective study conducted between January and December 2018 enrolled 78 women aged 18 to 40 years with abnormal uterine bleeding (AUB), infertility, and/or pelvic pain. All patients underwent 2D and 3D TVUS. Signs of adenomyosis on TVUS were identified according to the consensus of the Morphological Uterus Sonographic Assessment group. RESULTS: The prevalence of adenomyosis on TVUS was 55.12%. Patients with adenomyosis were older (p=0.002) and had more dysmenorrhea, AUB, and endometriosis than those without adenomyosis. When comparing the presence of symptoms with each adenomyosis feature, on 2D TVUS, severe dyspareunia was significantly associated with the presence of a poorly defined junctional zone (JZ) (p=0.023) and on 3D TVUS, patients with AUB had a more irregular (p=0.003), poorly defined (p=0.028), and interrupted JZ (p=0.011). After logistic regression analysis, signs of adenomyosis on TVUS remained significantly associated only with age over 30 years (OR: 1.2; 95% CI: 1.0-1.2) and AUB (OR: 7.65; 95% CI: 2-29). Patients with diffuse adenomyosis were older and presented with more infertility and AUB than patients with focal or no adenomyosis. CONCLUSION: The findings of adenomyosis by 2D and 3D TVUS showed association with age and AUB. 3D TVUS alterations in the JZ were associated with AUB and dyspareunia. Diffuse adenomyosis was associated with older age, a greater prevalence of infertility, and AUB.

Structured MRI reporting increases completeness of radiological reports and requesting physicians' satisfaction in the diagnostic workup for pelvic endometriosis.

PURPOSE: MRI plays an important role in the diagnosis and surgical planning of pelvic endometriosis (PE), and imaging reports should contain all relevant information (completeness). As structured reports are being increasingly utilized, we aimed to evaluate whether structured MRI reporting increases the quality of reports regarding completeness and, consequently, their perceived value by gynecologists, in comparison to free-text reports. We also aimed to compare the diagnostic performance of both formats. METHODS: We retrospectively included 28 consecutive women with histologically proven PE who underwent MRI within one month before surgery. Two abdominal radiologists (Rd1/Rd2, 3y/12y experience), blinded to clinical and surgical data, individually elaborated free-text reports and, four months later, structured reports. Completeness (defined as description of six key anatomical sites deemed essential for surgical planning in a consensus of four-blinded external experts) and diagnostic performance (sensitivity and specificity) by site (histology as reference) were compared between reports using the McNemar test. The satisfaction of gynecologists was compared using the marginal homogeneity test. RESULTS: Structured reporting increased completeness for both Rd1 (rectosigmoid, retrocervical/uterosacral ligament, vagina, and ureter) and Rd2 (vagina, ureter, and bladder) (p < 0.05), without compromising sensitivity or specificity at any of the evaluated sites. Gynecologists' satisfaction was superior with structured reports in most comparisons. CONCLUSION: Structured MRI reports perform better in fully documenting essential features of PE and are similar in terms of diagnostic performance, therefore having higher potential for surgical planning. Gynecologists found them easier to assess and were more satisfied with the information provided by structured reports.

Impact of Surgery for Deep Infiltrative Endometriosis before In Vitro Fertilization: A Systematic Review and Meta-analysis.

OBJECTIVE: The aims of this systematic review and meta-analysis were to compare reproductive outcomes in patients who underwent surgery for deep infiltrative endometriosis (DIE) before in vitro fertilization (IVF) with those in patients who underwent IVF without a previous surgery for DIE, to analyze data according to different types of surgery (complete or incomplete) or subgroups of patients (DIE with or without bowel involvement), and to assess surgical and IVF complications and data regarding safety concerns. DATA SOURCES: A systematic literature search from January 1980 to November 2019 with no language restriction was performed in PubMed, MEDLINE, Embase, and Web of Science. The search strategy used the following Medical Subject Headings terms: "in vitro," "fertilization," "IVF," "assisted reproduction," "colorectal," "endometriosis," "deep," "infiltrating," "deep infiltrative endometriosis," "intestinal," "bowel," "rectovaginal," "uterosacral," "vaginal," and "bladder." METHODS OF STUDY SELECTION: We included studies that compared reproductive outcomes in women with infertility with DIE who received IVF with or without a previous surgery for DIE lesions. Meta-analysis was performed using Review Manager (RevMan v.5.3; Cochrane Training, London, United Kingdom). The risk of bias of the included studies was assessed using the method recommended by Cochrane Collaboration. TABULATION, INTEGRATION, AND RESULTS: The systematic search retrieved 150 articles; 98 studies were potentially eligible, and their full texts were reviewed. Of these, 12 studies met our inclusion criteria, and 5 presented data suitable for inclusion in a meta-analysis; however, 2 of the studies provided overlapping data, and only the larger study was finally included. No randomized controlled trials (RCTs) were found. The pregnancy rate per patient was 1.84 (95% confidence interval [CI], 1.28-2.64), the pregnancy rate per cycle was 1.84 (95% CI, 1.26-2.70), and the live birth rate per patient was 2.22 (95% CI, 1.42-3.46) times more likely for operated patients than for nonoperated ones. The addition of data from the incomplete surgery groups also showed a higher pregnancy rate per patient for surgery before IVF (odds ratio [OR] 1.63; 95% CI, 1.16-2.28). The results favor previous surgery in DIE with digestive involvement (OR 2.43; 95% CI, 1.13-5.22) and also in DIE without digestive involvement (OR 1.55; 95% CI, 0.61-3.95). A qualitative analysis of the complications of surgery and IVF showed a partial or complete lack of information on these issues as well as high heterogeneity in the reported data. None of these studies is an RCT; therefore, all have a high risk of selection and allocation bias, except for 1 study that statistically controlled the latter risk by using propensity scores. Funnel plots showed no asymmetry. CONCLUSION: The results were very consistent for all the studied outcomes, showing a statistically significant benefit for surgery before IVF, although they should be confirmed with RCTs. In addition to the reproductive outcomes, safety data should also be reported to obtain a complete assessment of the risks and benefits.