Rare presentations of small bowel endometriosis.

Despite endometriosis being a relatively common chronic gynecological condition in women of childbearing age, small bowel endometriosis is rare. Presentations can vary from completely asymptomatic to reported symptoms of abdominal pain, bloating, and diarrhea. The following two cases depict very atypical manifestations of ileal endometriosis that presented as obscure intermittent gastrointestinal bleeding and bowel obstruction requiring surgical intervention. The first case describes a previously healthy 40-year-old woman with severe symptomatic iron deficiency anemia and intermittent melena. A small bowel enteroscopy diagnosed multiple ulcerated strictures in the distal small bowel as the likely culprit. Despite nonsteroidal anti-inflammatory drug-induced enteropathy being initially considered as the likely etiology, histopathological examination of the resected distal ileal segment revealed evidence of endometriosis. The second case describes a 66-year-old with a presumptive diagnosis of Crohn's disease who reported a 10-year history of intermittent perimenstrual abdominal pain, diarrhea, and nausea with vomiting. Following two subsequent episodes of acute bowel obstruction and surgical resection of the patient's stricturing terminal ileal disease, histopathological examination demonstrated active chronic inflammation with endometriosis. Small bowel endometriosis should be considered as an unusual differential diagnosis in women who may present with obscure gastrointestinal bleeding from the small bowel or recurrent bowel obstruction.

"The Green Peace" How ICG can prevent complications in endometriosis surgery?

This literature review summarises the investigation into using Indocyanine Green (ICG) in the surgical management of endometriosis, focusing mainly on its application in Deep Endometriosis (DE). The study reviews the development, fluorescence characteristics, and clinical usage of ICG in enhancing the precision of identifying endometrial lesions during surgery. Emphasizing the technology's contribution to improved lesion visualisation, the paper discusses how ICG facilitates increased diagnostic accuracy, potentially reducing recurrence rates and the necessity for subsequent interventions. Additionally, it explores ICG's role in minimizing the risk of iatrogenic injuries, especially in ureteral endometriosis, and its utility in surgical decision-making for rectosigmoid endometriosis by evaluating bowel perfusion. Conclusively, while acknowledging the clear benefits of ICG integration in endometriosis surgical procedures, the abstract calls for more extensive research to validate its efficacy and cost-efficiency in the broader context of endometriosis treatment.

Nerve-sparing surgery in deep endometriosis: Has its time come?

Nerve-sparing (NS) surgery was first introduced for the treatment of deep endometriosis (DE) 20 years ago, drawing on established neuroanatomy and success from oncological applications. It aims to identify and preserve autonomic nerve fibres, reduce iatrogenic nerve injury, and minimize postoperative visceral dysfunction, without compromising the therapeutic effectiveness against endometriosis. The evolution of NS surgical techniques over the past two decades has been supported by an expanding body of literature on anatomical details, dissection techniques, and functional outcomes. Recent evidence suggests that NS surgery results in reduced postoperative voiding dysfunction (POVD). Transient POVD may be influenced by preoperative dysfunction, with parametrial infiltration being a strong predictive factor for POVD. While the benefits in bowel and sexual functions are less pronounced and consistent, NS surgery potentially prevents de novo dysfunctions in these areas. Furthermore, perioperative complication rates, effectiveness in pain relief, and fertility outcomes are reportedly on par with conventional surgery.

Diagnostic Value and Molecular Function of MicroRNAs in Endometrial Diseases: A Systematic Review.

The human endometrium experiences significant cyclic morphological and biochemical changes throughout the menstrual cycle to prepare for embryo implantation. These processes are meticulously regulated by ovarian steroids and various locally expressed genes, encompassing inflammatory reactions, apoptosis, cell proliferation, angiogenesis, differentiation (tissue formation), and tissue remodeling. MicroRNAs (miRNAs) have been recognized as crucial regulators of gene expression, with their altered expression being linked to the onset and progression of various disorders, including cancer. This review examines the expression of miRNAs in the endometrium and their potential regulatory roles under pathological conditions such as endometriosis, recurrent implantation failure and endometrial cancer. Given miRNAs' critical role in maintaining gene expression stability, understanding the regulatory mechanisms of endometrial miRNAs and identifying their specific target genes could pave the way for developing preventive and therapeutic strategies targeting specific genes associated with these reproductive disorders.

Inflammatory Changes after Medical Suppression of Suspected Endometriosis for Implantation Failure: Preliminary Results.

Unexplained euploid embryo transfer failure (UEETF) is a frustrating and unanswered conundrum accounting for 30 to 50% of failures in in vitro fertilization using preimplantation genetic testing for aneuploidy (PGT-A). Endometriosis is thought by many to account for most of such losses and menstrual suppression or surgery prior to the next transfer has been reported to be beneficial. In this study, we performed endometrial biopsy in a subset of women with UEETF, testing for the oncogene BCL6 and the histone deacetylase SIRT1. We compared 205 PGT-A cycles outcomes and provide those results following treatment with GnRH agonist versus controls (no treatment). Based on these and previous promising results, we next performed a pilot randomized controlled trial comparing the orally active GnRH antagonist, elagolix, to oral contraceptive pill (OCP) suppression for 2 months before the next euploid embryo transfer, and monitored inflammation and miRNA expression in blood, before and after treatment. These studies support a role for endometriosis in UEETF and suggest that medical suppression of suspected disease with GnRH antagonist prior to the next transfer could improve success rates and address underlying inflammatory and epigenetic changes associated with UEETF.

The impact of surgical treatment for deep endometriosis: metabolic profile, quality of life and psychological aspects.

Objective: To evaluate the effects of surgical treatment of deep endometriosis on the metabolic profile, quality of life and psychological aspects. Methods: Prospective observational study, carried out with women of reproductive age diagnosed with deep endometriosis, treated in a specialized outpatient clinic, from October/2020 to September/2022, at a University Hospital in Fortaleza - Brazil. Standardized questionnaires were applied to collect data on quality of life and mental health, in addition to laboratory tests to evaluate dyslipidemia and dysglycemia, at two moments, preoperatively and six months after surgery. The results were presented using tables, averages and percentages. Results: Thirty women with an average age of 38.5 years were evaluated. Seven quality of life domains showed improved scores: pain, control and impotence, well-being, social support, self-image, work life and sexual relations after surgery (ES ≥ 0.80). There was an improvement in mental health status with a significant reduction in anxiety and depression postoperatively. With the metabolic profile, all average levels were lower after surgery: total cholesterol 8.2% lower, LDL 12.8% lower, triglycerides 10.9% lower, and fasting blood glucose 7.3% lower (p < 0.001). Conclusion: Surgical treatment of deep endometriosis improved the quality of life and psychological aspects of patients. The lipid profile of patients after laparoscopy was favorable when compared to the preoperative lipid profile.

The impact of metronidazole on pain persistence after fertility-sparing endometriosis surgery: METROFERT randomized study.

BACKGROUND: Recent studies have shown that a disrupted microbiome is associated with endometriosis. Despite endometriosis affecting 1 in 10 reproductive-aged women, there is a lack of innovative and nonhormonal long-term effective treatments. Studies have reported an approximately 20-37.5% persistence of pain after fertility-sparing endometriosis surgery. Metronidazole has been shown to decrease inflammatory markers and the size of endometriosis lesions in animal studies. OBJECTIVE: To determine if modulating the microbiome with oral metronidazole for 14 days after fertility-sparing endometriosis surgery decreases pain persistence postoperatively. STUDY DESIGN: This was a randomized, multicenter, placebo-controlled, double-blind trial. Individuals 18-50 years old were prospectively randomized to placebo versus oral metronidazole for 14 days immediately after endometriosis fertility-sparing excision surgery. The primary outcome was binary, subjective pain persistence at six weeks postoperatively. Secondary outcomes of quality of life, sexual function, and endometriosis-associated pain scores according to the Endometriosis Health Profile-5, Female Sexual Function Index, and a visual analog scale. RESULTS: 152 participants were approached from October 2020 to October 2023 to enroll in the study. 64 participants were excluded either because they did not meet inclusion or exclusion criteria or because they declined to participate. 88 participants were randomized in a 1:1 ratio to receive either the oral placebo or metronidazole after endometriosis excision surgery. 18.2% of participants were lost to follow-up or discontinued treatment and this was not significantly different between the two arms, yielding a final cohort of 72 participants. Baseline demographics of the two study groups were similar. There was no statistically significant improvement in the primary outcome of binary subjective pain persistence between the metronidazole group compared to placebo (84% vs 88%, p=0.74) at 6 weeks postoperatively. Further, no significant differences between treatments were detected in the secondary outcomes. CONCLUSION: A postoperative 14-day regimen of oral metronidazole immediately after fertility-sparing endometriosis surgery was not associated with any significant differences between treatment groups in the in the persistence of endometriosis-related pain symptoms compared to placebo at 6 weeks.

Case report: A rare cause of intestinal perforation in a third-trimester pregnant woman.

Background: An acute abdomen is a medical emergency that requires early diagnosis and treatment. In pregnancy, this process is significantly more challenging, and radiological findings are sometimes unclear due to the enlarged uterus displacing other structures. Moreover, endometriosis-related complications are rare, and the disease is often undiagnosed. Case presentation: We report a case of acute perforation of the cecum and appendix during pregnancy (35 weeks of gestation) caused by a previously unknown, deep infiltrating endometriosis with focal ulceration of the affected bowel wall, which sonographically seemed to be acute appendicitis. Conclusion: Despite the relatively low risk, clinicians should be aware of possible endometriosis-associated complications in pregnancy with potentially life-threatening events, even in previously unknown endometriosis. Further studies should evaluate intestinal complications during pregnancy in relation to previous treatment of intestinal endometriosis (conservative vs. surgical).

Prevalence of neuropathic pain in patients with symptomatic endometriosis: Assessment using the DN4 score.

The mechanisms underlying pain in cases of endometriosis or chronic pelvic pain are complex, often involving various types of pain; mainly nociceptive pain, central sensitization, and neuropathic pain. Our main objective was to examine the prevalence of neuropathic pain in women with symptomatic endometriosis, and secondary, to explore the factors associated with this type of pain and to assess the prevalence of a positive PPSC score and a history of sexual violence within this population. This study is a retrospective, comparative, single-center cohort study conducted from September 2019 to January 2023. The presence of neuropathic pain was confirmed by a positive DN4 score, defined as greater than or equal to 4. The association with the following variables was studied: age, BMI, marital status, smoking, alcohol and drugs consumption, age at menarche, gestity, parity, duration of exposure to endometriosis, MRI locations, laparoscopy for endometriosis and post-laparoscopy r-ASRM classification, hormone treatment, associated symptoms, VAS, associated pathologies, infertility consultation, Pain Center consultation, EPH-5 score, positive PPSC score (≥5), and history of sexual violence. The prevalence of neuropathic pain was 44.1%. Younger age, being in a relationship, having a high EPH-5 score and undergoing laparoscopy for endometriosis are associated with neuropathic pain independently of other variables. Our study underscores the persistent high prevalence of neuropathic pain in endometriosis cases, emphasizing the importance of actively screening for it. Identifying neuropathic pain could prompt referrals to pain specialists, integrating it into a comprehensive multidisciplinary approach.

Nerve-sparing deep endometriosis surgery with rectal discoid resection using da Vinci SP.

OBJECTIVE: To demonstrate the anatomical and technical highlights of nerve-sparing deep endometriosis (DE) surgery with rectal discoid resection using a newer single-port robotic system. DESIGN: Step-by-step demonstration of this method with narrated video footage. SETTING: An urban general hospital. Single-port laparoscopic surgery is a useful surgical approach in gynecology because of the excellent cosmetic results, but shows challenges including reduced intracorporeal triangulation and conflict with non-articulating instruments. The range of indications has thus been limited. PATIENT: A 46-year-old woman was referred with severe pelvic pain, dysmenorrhea and pain on defecation. Magnetic resonance imaging revealed uterine adenomyosis, bilateral ovarian endometriomas, and 3 cm of rectal endometriosis. CT colonography confirmed 38% stenosis of the rectum. INTERVENTION: A newer single-port robotic system. MAIN OUTCOME MEASURES: The technical safety and feasibility of intrapelvic complex DE surgery using a newer single-port robotic platform. RESULTS: The procedure was performed using 9 steps with a da Vinci SP surgical system (Intuitive Surgical, Sunnyvale, California). Importantly, the surgical steps were completely identical to conventional multiport laparoscopic or robotic surgery. This suggests that conventional laparoscopic or robotic skills are highly transferrable to the newer system: Step 1, adhesiolysis and adnexal surgery; Step 2, separation of the nerve plane; Step 3, dissection of the ureter; Step 4, reopening of the pouch of Douglas; Step 5, complete removal of DE lesions while avoiding injury to the nerve plane; Step 6, hysterectomy (if the patient desires non-fertility-sparing surgery); Step 7, rectal discoid resection with circular stapler; Step 8, checking for rectal injury using an air leakage test and tissue perfusion; and Step 9, application of barrier agents for adhesion prevention. The newer single-port system offered several advantages, including high-resolution three-dimensional visualization, articulating instruments (intracorporeal instrument triangulation), and improved dexterity and range of motion. These advantages allow precise dissection even in difficult situations such as deep endometriosis. CONCLUSIONS: This appears to be the first reported use of the da Vinci SP for nerve-sparing DE surgery or rectal discoid resection. The newer single-port robotic system can provide the same quality of surgery as conventional multi-port laparoscopic and robotic platforms with cosmetic advantages for the treatment of complex pelvic pathologies.

Endometriotic tissue fragments are viable after cryopreservation in an ex vivo tissue model recapitulating the fibrotic microenvironment.

STUDY QUESTION: Is it possible to establish an ex vivo endometriosis model using cryopreserved endometriotic tissue fragments? SUMMARY ANSWER: Cryopreserved endometriotic tissue fragments remain viable after thawing and during at least 3 days of culture and can therefore be used to establish an ex vivo endometriosis model to efficiently test potential therapeutic agents. WHAT IS KNOWN ALREADY: Endometriosis is the most prevalent benign gynecologic disease with an enormous societal burden; however, curative therapies are still lacking. To efficiently test potential new therapies, an ex vivo model based on previously cryopreserved endometriotic tissue that recapitulates the different endometriosis subtypes and their microenvironment is highly desirable. STUDY DESIGN, SIZE, DURATION: Endometriotic tissue fragments of three different subtypes were obtained from 28 patients by surgical resection. After cryopreservation and thawing, viability and metabolic activity of these tissue fragments were assessed. Viability was compared with fresh fragments from 11 patients directly after surgical removal. Experimental intervention studies were performed in cryopreserved and thawed tissue fragments from two patients to confirm the usability of these tissues for ex vivo intervention studies. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometriotic tissue fragments (n = 45) were cryopreserved according to three different protocols. After thawing, fragments were cultured for 24 h. A resazurin-based assay was performed to assess the metabolic activity of the tissue fragments. In addition, cell type-specific viability was analyzed by VivaFix, Hoechst 33342, and α-smooth muscle actin immunofluorescence staining and confocal microscopy. The presence of endometriosis was histologically confirmed based on hematoxylin-eosin staining. Cryopreserved and thawed tissue fragments were treated for 72 h with pirfenidone or metformin and COL1A1 and CEMIP gene expressions were assessed using RT-PCR and RT-qPCR, either in the whole tissue fragments or in myofibroblasts isolated by laser capture microdissection. MAIN RESULTS AND THE ROLE OF CHANCE: Metabolic activity of endometriotic tissue fragments obtained from peritoneal (PER), ovarian (OMA), and deep (DE) endometriotic lesions was well preserved after cryopreservation in a dimethyl sulfoxide-based medium and was comparable with fresh tissue fragments. Relative metabolic activity compared to fresh tissue was 70% (CI: 92-47%) in PER, 43% (CI: 53-15%) in OMA and 94% (CI: 186-3%) in DE lesions. In fragments from PE lesions 92% (CI: 87-96%), from OMA lesions 95% (CI: 91-98%), and from DE lesions 88% (CI: 78-98%) of cells were viable after cryopreservation and thawing followed by a 24-h culture period. Differences in gene expression of fibrotic markers COL1A1 and CEMIP after 72-h treatment with pirfenidone or metformin could be detected in whole tissue fragments and in isolated myofibroblasts, indicating that cryopreserved and thawed endometriotic tissue fragments are suitable for testing anti-fibrotic interventions. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Viability and metabolic activity of the endometriotic tissue fragments may have been partially compromised by damage sustained during the surgical procedure, contributing to inter-sample variance. WIDER IMPLICATIONS OF THE FINDINGS: The storage of viable endometriotic tissue fragments for later usage in an ex vivo model creates the possibility to efficiently test potential new therapeutic strategies and facilitates the exchange of viable endometriotic tissue between different research laboratories. STUDY FUNDING/COMPETING INTEREST(S): This study was not financially supported by external funding. The authors declare no competing interest. TRIAL REGISTRATION NUMBER: N/A.

Musculoskeletal evaluation of the lower pelvic complex in women with endometriosis: A case-control study.

OBJECTIVE: Use clinical pain measurement tools to investigate and compare the prevalence of pelvic loin disoders in women with and without endometriosis. STUDY DESIGN: Chronic pelvic pain (CPP) associated with endometriosis has diverse origins, including musculoskeletal factors. Musculoskeletal dysfunction in the pelvic region is theorized to result from sustained muscular contraction, triggered by altered visceral stimuli and adoption of antalgic postures, causing secondary damage to muscles, ligaments, and joints. CPP significantly impacts quality of life, relationships, sexuality, and mental health. However, limited data exists on musculoskeletal impacts of endometriosis and CPP. It was made a case-control study at Maternidade Escola Assis Chateaubriand from August 2017 to January 2021. Evaluated 71 women: 41 in endometriosis group (EG) and 30 in control group (CG). Data collection included sociodemographic questionnaires, musculoskeletal physiotherapeutic evaluations, pain mapping, pressure pain thresholds, kinesiophobia, and disability measurements. Statistical analysis was performed using Spearman's Rho test to determine correlations. RESULTS: Mean age of participants was 31 years. EG exhibited lower pain threshold variations in lumbopelvic trigger points than CG (P < .05). Significant muscle flexibility differences between groups were observed; EG had reduced flexibility (P < .05). Most common pain areas were hypogastrium in EG (48.78 %) and left lumbar in CG (30 %). EG had higher kinesiophobia values (P = .009). There was a weak association between kinesiophobia-pressure threshold association observed in CG's lumbar pelvic region. CONCLUSION: Women with Endometriosis and CPP exhibit higher prevalence of musculoskeletal disorder, lower pain thresholds, decreased lumbopelvic muscle range of motion, higher kinesiophobia scores, and increased disability indices with low back pain compared to healthy women.

Common Beverage Consumption and Benign Gynecological Conditions.

The purpose of this article is to review the effects of four commonly consumed beverage types-sugar-sweetened beverages (SSBs), caffeinated beverages, green tea, and alcohol-on five common benign gynecological conditions: uterine fibroids, endometriosis, polycystic ovary syndrome (PCOS), anovulatory infertility, and primary dysmenorrhea (PD). Here we outline a plethora of research, highlighting studies that demonstrate possible associations between beverage intake and increased risk of certain gynecological conditions-such as SSBs and dysmenorrhea-as well as studies that demonstrate a possible protective effect of beverage against risk of gynecological condition-such as green tea and uterine fibroids. This review aims to help inform the diet choices of those with the aforementioned conditions and give those with uteruses autonomy over their lifestyle decisions.

Hypoxia-induced Semaphorin 3A promotes the development of endometriosis through regulating macrophage polarization.

BACKGROUND: Semaphorin 3A (Sema3A) is a member of neural guidance factor family well-known for inducing the collapse of nerve cell growth cone and regulating nerve redistribution. It also has been characterized as an immunoregulatory and tumor promoting factor. Our previous study showed that Sema3A was involved in the regulation of sympathetic innervation and neuropathic pain of endometriosis. Nevertheless, the role of Sema3A in the development of endometriosis and its potential upstreaming factor are still not clear. METHODS: Histology experiments were carried to detect the expression of Sema3A, hypoxia -inducible factor 1α (HIF-1α) and the distribution of macrophages. Cell experiments were used to explore the effect of Sema3A on the proliferation and migration of endometrial stromal cells (ESCs) and to confirm the regulatory action of HIF-1α on Sema3A. In vivo experiments were carried out to explore the role of Sema3A on the development of endometriosis. RESULTS: Sema3A was highly expressed in endometriotic lesions and could enhanced the proliferation and migration abilities of ESCs. Aberrant macrophage distribution was found in endometriotic lesions. Sema3A also promoted the differentiation of monocytes into anti-inflammatory macrophages, so indirectly mediating the proliferation and migration of ESCs. Hypoxic microenvironment induced Sema3A mRNA and protein expression in ESCs via HIF-1α. Administration of Sema3A promoted the development of endometriosis in a mouse model. CONCLUSIONS: Sema3A, which is regulated by HIF-1α, is a promoting factor for the development of endometriosis. Targeting Sema3A may be a potential treatment strategy to control endometriotic lesions.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The co-primary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy versus placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was < 1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Diagnostic MRI for deep pelvic endometriosis: towards a standardized protocol?

OBJECTIVES: To assess the diagnostic efficacy of an MRI protocol and patient preparation in detecting deep pelvic endometriosis (DPE). MATERIAL AND METHODS: The cohort is from the ENDOVALIRM database, a multicentric national retrospective study involving women who underwent MRI followed by pelvic surgery for endometriosis (reference standard). Two senior radiologists independently analyzed MRI findings using the deep pelvic endometriosis index (dPEI) to determine lesion locations. The study evaluated the impact of bowel preparation, vaginal and rectal opacification, MRI unit type (1.5-T or 3-T), additional sequences (thin slice T2W or 3DT2W), and gadolinium injection on reader performance for diagnosing DPE locations. Fisher's exact test assessed differences in diagnostic accuracy based on patient preparation and MRI parameters. RESULTS: The final cohort comprised 571 women with a mean age of 33.3 years (± 6.6 SD). MRI with bowel preparation outperformed MRI without bowel preparation in identifying torus/uterosacral ligament (USL) locations (p < 0.0001) and rectosigmoid nodules (p = 0.01). MRI without vaginal opacification diagnosed 94.1% (301/320) of torus/USL locations, surpassing MR with vaginal opacification, which diagnosed 85% (221/260) (p < 0.001). No significant differences related to bowel preparation or vaginal opacification were observed for other DPE locations. Rectal opacification did not affect diagnostic accuracy in the overall population, except in patients without bowel preparation, where performance improved (p = 0.04). There were no differences in diagnostic accuracy regarding MRI unit type (1.5-T/3-T), presence of additional sequences, or gadolinium injection for any endometriotic locations. CONCLUSION: Bowel preparation prior to MRI examination is preferable to rectal or vaginal opacification for diagnosing deep endometriosis pelvic lesions. CLINICAL RELEVANCE STATEMENT: Accurate diagnosis and staging of DPE are essential for effective treatment planning. Bowel preparation should be prioritized over rectal or vaginal opacification in MRI protocols. Optimizing MRI protocols for diagnostic performance with appropriate opacification techniques will help diagnose deep endometriosis more accurately. KEY POINTS: Evaluating deep endometriosis in collapsible organs such as the vagina and rectum is difficult. Bowel preparation and an absence of vaginal opacification were found to be diagnostically beneficial. Bowel preparation should be prioritized over rectal or vaginal opacification in MRI protocols.

Colorectal endometriosis - a challenging, often overlooked cause of colorectal pathology: a clinicopathological review of 114 cases.

The colon is the most common site for endometriosis outside the genital tract. It has a varied presentation and can mimic numerous other conditions, both clinically and pathologically. We investigated the clinicopathological features of a series of colorectal endometriosis with a particular emphasis on the features seen in cases with colonic mucosal involvement. A total of 114 consecutive cases of colorectal endometriosis were reviewed. Forty-eight percent did not have a prior diagnosis of endometriosis and in 34 patients (30%) the endometriosis was determined as the cause for the presentation. Mucosal involvement was present in 31 specimens. Features of chronic colitis were seen in the adjacent mucosa in 90% of cases whilst there were glandular changes mimicking adenocarcinoma in two cases (1.8%). Fifty percent of cases with mucosal involvement also showed glands with a hybrid intestinal-endometrial phenotype by morphology and/or by immunohistochemistry. Endometriosis is an important mimic of other conditions.

MCP-1 exerts the inflammatory response via ILK activation during endometriosis pathogenesis.

AIMS: MCP-1 has been shown to be elevated in endometriosis. ILK functions in several cellular events and interacts with MCP-1-signaling. In the current study, we evaluated the role of MCP-1-ILK signaling in human endometriotic cell's (Hs832(C).TCs) potential for colonization, invasion, adhesion, etc. and differentiation of macrophage along with inflammation in an endometriosis mouse model. MATERIALS AND METHODS: A mouse model of endometriosis with elevated levels of MCP-1 was developed by injecting MCP-1. We examined the migration, adhesion, colonization and invasion of Hs832(C).TCs in response to MCP-1-ILK signaling. We also examined the differentiation of THP-1 cells to macrophage in response to MCP-1-ILK signaling. KEY FINDINGS: We observed that MCP-1 increased Ser246 phosphorylation of ILK in Hs832(C).TCs and enhanced the migration, adhesion, colonization, and invasion of Hs832(C).TCs. In the mouse model of endometriosis, we found elevated chemokines (CCL-11, CCL-22 and CXCL13) levels. An increased level of MCP-1 mediated ILK activation, leading to increased inflammatory reaction and infiltration of residential and circulatory macrophages, and monocyte differentiation, but suppressed the anti-inflammatory reaction. The inhibitor (CPD22) of ILK reversed the MCP-1-mediated action by restoring Hs832(C).TCs and THP-1 phenotype. ILK inhibition in a mouse model of endometriosis reduced the effects of MCP-1 mediated pro-inflammatory cytokines, but increased anti-inflammatory response along with T-regulatory and T-helper cell restoration. SIGNIFICANCE: Targeting ILK restores MCP-1 milieu in the peritoneal cavity and endometrial tissues, reduces the inflammatory response, improves the T-regulatory and T-helper cells in the endometriosis mouse model and decreases the migration, adhesion, colonization and invasion of endometriotic cells.

Identifying novel potential drug targets for endometriosis via plasma proteome screening.

Background: Endometriosis (EM) is a chronic painful condition that predominantly affects women of reproductive age. Currently, surgery or medication can only provide limited symptom relief. This study used a comprehensive genetic analytical approach to explore potential drug targets for EM in the plasma proteome. Methods: In this study, 2,923 plasma proteins were selected as exposure and EM as outcome for two-sample Mendelian randomization (MR) analyses. The plasma proteomic data were derived from the UK Biobank Pharmaceutical Proteomics Project (UKB-PPP), while the EM dataset from the FinnGen consortium R10 release data. Several sensitivity analyses were performed, including summary-data-based MR (SMR) analyses, heterogeneity in dependent instruments (HEIDI) test, reverse MR analyses, steiger detection test, and bayesian co-localization analyses. Furthermore, proteome-wide association study (PWAS) and single-cell transcriptomic analyses were also conducted to validate the findings. Results: Six significant (p < 3.06 × 10-5) plasma protein-EM pairs were identified by MR analyses. These included EPHB4 (OR = 1.40, 95% CI: 1.20 - 1.63), FSHB (OR = 3.91, 95% CI: 3.13 - 4.87), RSPO3 (OR = 1.60, 95% CI: 1.38 - 1.86), SEZ6L2 (OR = 1.44, 95% CI: 1.23 - 1.68) and WASHC3 (OR = 2.00, 95% CI: 1.54 - 2.59) were identified as risk factors, whereas KDR (OR = 0.80, 95% CI: 0.75 - 0.90) was found to be a protective factor. All six plasma proteins passed the SMR test (P < 8.33 × 10-3), but only four plasma proteins passed the HEIDI heterogeneity test (PHEIDI > 0.05), namely FSHB, RSPO3, SEZ6L2 and EPHB4. These four proteins showed strong evidence of co-localization (PPH4 > 0.7). In particular, RSPO3 and EPHB4 were replicated in the validated PWAS. Single-cell analyses revealed high expression of SEZ6L2 and EPHB4 in stromal and epithelial cells within EM lesions, while RSPO3 exhibited elevated expression in stromal cells and fibroblasts. Conclusion: Our study identified FSHB, RSPO3, SEZ6L2, and EPHB4 as potential drug targets for EM and highlighted the critical role of stromal and epithelial cells in disease development. These findings provide new insights into the diagnosis and treatment of EM.

Vilaprisan for the treatment of symptomatic endometriosis: results from a terminated phase 2b randomized controlled trial.

Objective: To evaluate the efficacy and safety of 2 doses of vilaprisan vs. placebo in participants with symptomatic endometriosis. Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2b trial (NCT03573336). The initially planned sample size was 315 patients. Recruitment was paused to assess long-term toxicity findings in rodents; although the findings were assessed as likely to be of limited clinical relevance in humans, the study was closed by the sponsor. During the pause, enrolled patients completed 3 or 6 months of treatment per their assigned regimen. Setting: University hospitals, a regional hospital, and a private clinic. Patients: Premenopausal adults with confirmed endometriosis and moderate-to-severe pelvic pain (≥4/10 on a numerical rating scale) were enrolled. Inclusion required protocol adherence, including ≥24 diary entries, and an average pain score of ≥3.5. Intervention: Participants were randomly assigned 1:1:1 to receive vilaprisan (2 mg), vilaprisan (4 mg), or placebo. Main Outcome Measures: The primary outcome was a change in the 7-day mean "worst pain" (per the endometriosis symptom diary item 1) from baseline to month 3. All analyses were descriptive only. Results: Eight participants were randomly assigned to treatment before the study pause: 6 received vilaprisan (4 mg, n = 4 and 2 mg, n = 2), and 2 received placebo. The 6 vilaprisan recipients experienced an improvement in endometriosis-associated pelvic pain, whereas the 2 placebo recipients experienced no change or increased pain; all 8 participants had decreased use of pain medication. Bleeding intensity decreased from baseline in the vilaprisan group. Conclusion: The study findings suggest that vilaprisan may improve outcomes in patients with endometriosis. Further studies in larger populations would be needed to accurately assess treatment effects. Clinical Trial Registration Number: NCT03573336.