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STUDY QUESTION What are the attitudes and perceptions towards endocrine endometriosis therapy? SUMMARY ANSWER Among the study population, endocrine endometriosis therapies are associated with negative mental images and emotions and there seems to be a pre-therapeutic information deficit on the part of physicians. WHAT IS KNOWN ALREADY Endocrine therapies, as the current standard of conservative endometriosis treatment, have good efficacy and improve symptoms and quality of life in most patients. Nevertheless, clinical practice repeatedly shows rejection on the part of patients, which may result in reduced compliance and discontinuation of therapy. STUDY DESIGN, SIZE, DURATION Cross-sectional study among endometriosis patients using a multilingual questionnaire distributed via the most popular social media channels between November 2020 and February 2021. A total of 3348 women participated in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on a pilot phase, an international, multilingual online survey was conducted among women affected by endometriosis. The questionnaire included free-word associations and questions about personal medical history, source of information, and demographic data. Mental representations were detected based on modules of the co-occurrence network of associations. MAIN RESULTS AND THE ROLE OF CHANCE Six modules with different dominant emotional labels emerged from the confluence of associations to endocrine endometriosis therapy mentioned by participants. Five modules reflected negative mental associations, with the most frequently mentioned words being 'side effects', 'pain', 'ineffective', 'depression', and 'uncertainty'. Of the 12 most frequently selected emotions, only 'optimistic' was positive. Side effects affecting mental health are the most important reason for deciding against endocrine therapy in our survey population. Twenty-seven percent of respondents reported knowing little about endocrine therapies for endometriosis. Social media are the most frequently used sources of information and were rated as the most useful. LIMITATIONS, REASONS FOR CAUTION By translating the questionnaire, questions might have been understood differently depending on the language. By using social media channels for distribution, digitally literate patients were targeted. The survey population might not be representative as patients who are critical/unhappy with therapy are more likely to seek advice from peer groups. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study replicate the findings of a recent survey in three European countries. Given the prevalence of endometriosis and the few emerging pharmaceutical alternatives, these data point to a growing need for further research and development of non-hormonal drugs for treating endometriosis. Most endometriosis patients are young and digitally literate, and much information is obtained from alternative sources, such as social media. Careful education before starting therapy should be taken seriously, and patients' concerns should be addressed individually by health care providers. This could help reduce misunderstanding and misinformation and improve treatment adherence and satisfaction. STUDY FUNDING/COMPETING INTEREST(S) There is no funding or conflict of interest to declare. TRIAL REGISTRATION NUMBER The trial is not registered at any trial registry. [ABSTRACT FROM AUTHOR]

Endometriosis, characterized by the presence of endometrial-like tissue outside the uterus, is a condition associated with pain and infertility. In this issue of the JCI, Lv et al. illuminate the critical pathophysiological role of the ten-eleven translocation 3 (TET3) in endometriosis. TET3 expression levels were higher in macrophages of endometriotic lesions compared with control endometrial tissue, implicating TET3 as a contributing factor in the chronic inflammation that occurs in endometriosis. TGF-β1 and MCP1 are present in the peritoneal cavity of women with endometriosis, and macrophage exposure to these factors resulted in upregulation of TET3, thereby promoting their survival. Notably, Bobcat339, a selective TET inhibitor, induced apoptosis in these macrophages. Further, myeloid-specific TET3 loss reduced endometriosis in mice. RNA-Seq analysis following TET3 knockdown revealed alterations in cytokine signaling and cell-death pathways, underscoring the therapeutic potential of targeting TET3 in macrophages as a strategy for managing endometriosis.

Problem: What is the effect of SR-16234 (SR), a selective estrogen receptor (ER) modulator, on human endometriotic stromal cells (ESCs)?, Method of Study: Endometriotic tissues were obtained from 21 patients undergoing laparoscopic surgery for ovarian endometriomas (OEs). Normal eutopic endometrium during the luteal phase was obtained from 18 patients without endometriosis. ESCs isolated from OEs and normal eutopic endometrial stromal cells (NESCs) were cultured with SR and subsequently exposed to tumor necrosis factor (TNF)-α. After 48 h of incubation, the effect of SR on cell proliferation was evaluated by the WST-8 assay. The gene expressions of inflammatory and pain-related factors, including interleukin (IL)-6, IL-8, cyclooxygenase (COX)-2, transient receptor potential vanilloid (TRPV)1, ESR1, and ESR2, were evaluated by real-time RT-PCR. The phosphorylation of Inhibitor κBα (IκBα), extracellular signal-regulated kinase (ERK)1/2, and Protein Kinase B (AKT) were evaluated by western blot analysis. ILs, prostaglandin (PG) E2, and intranuclear p65 syntheses were assessed by ELISA., Results: SR treatment repressed TNF-α-induced proliferation by 20% in ESCs but not　NESCs. SR also reduced IL-6, IL-8, COX-2, TRPV1, ESR1, and ESR2 mRNA expressions and ILs protein, and PGE2 synthesis in ESCs, whereas in NESCs, only TRPV1 mRNA expression was decreased. SR suppressed TNF-α-induced phosphorylated IκBα levels by approximately 50%, and intranuclear p65 protein was reduced by 30% compared to addition of only TNF-α in ESCs. However, SR did not affect the phosphorylation of AKT and ERK1/2., Conclusions: SR appears to be a potential therapeutic agent for endometriosis by suppressing inflammatory and pain-related factor expressions by inhibiting the nuclear factor-kappa B pathway., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The author describes the results of a study to examine the effect of three treatment regimens on pain associated with endometriosis., Competing Interests: Conflict of Interest The author reports no conflicts of interest or relevant financial relationships., (Copyright © 2024 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.)

Endometriosis seriously affects 6-10 % of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. STATEMENT OF SIGNIFICANCE: Macrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues outside of the uterine cavity. Currently available drugs are efficacious in treating endometriosis-related pain, however it's not a targeted treatment. The aim of this work is to evaluate the effects of R-954, a bradykinin B1 receptor antagonist, in a murine model of endometriosis. The model was induced in animals through autologous transplantation of part of the uterine horn. After 51 days, it was observed that implants developed into endometriotic lesions. The administration of R-954 or progesterone, for 15 consecutive days, prevented the progression of cyst development, reduced the size and weight of the cysts. Both treatments also reduced cellular infiltrate and production of inflammatory mediators (interleukin-1β, interleukin-6, tumor necrosis factor). However, only R-954 decreased angiogenic factors (VEGF and VEGF receptor). In addition, treatment with the antagonist did not interfere in the females' estrous cycle, as well as prevented gestational losses (reduction in the number of intermediate resorptions in pregnant females with endometriosis). Data suggested that R-954 has anti-inflammatory and anti-angiogenic effects; does not influence the estrous cycle; and prevents the number of gestational losses suggesting it as a good candidate for endometriosis treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Patricia Dias Fernandes reports financial support was provided by Federal University of Rio de Janeiro. Patricia Dias Fernandes reports a relationship with Carlos Chagas Filho Foundation for Research Support of Rio de Janeiro State that includes: funding grants. Patricia Dias Fernandes reports a relationship with National Council for Scientific and Technological Development that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Elagolix, an approved non-peptide GnRH antagonist, shows promise in relieving endometriosis-related pain, but its short- and mid-term efficacy and potential side effects are still under investigation., Objective: The aim is to provide data for therapeutic applications by methodically evaluating elagolix's safety and effectiveness in treating endometriosis-related pain., Methods: Databases such as PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and others were thoroughly searched. The search time was from the establishment date to September 2023. The study included randomized controlled trials (RCTs) that compared the efficacy of elagolix versus placebo in treating endometriosis-associated pain. After data extraction and literature scanning, quality assessment was carried out using Quality evaluation was carried out using the bias risk assessment tool suggested by the Cochrane Reviewers' Handbook 5.1.0 after literature screening and data extraction. Stata 15.0 was used to do the meta-analysis., Results: In total, five RCTs involving 2056 patients were included in the analysis. The meta-analysis demonstrated a significant superiority of elagolix over placebo in the management of endometriosis-related pain, specifically in endometriosis pain [WMD=-0.77, 95% CI (-1.00, -0.53), P<0.001], as well as in non-menstrual pelvic pain, daily assessment of dysmenorrhea (DYS), and dyspareunia (DYSP), all of which are associated with endometriosis. Regarding safety, no discernible variation was observed in the incidence of serious adverse responses between the elagolix and placebo groups [RR=0.90, 95% CI (0.58, 1.40), P=0.643]. Conversely, the elagolix group exhibited a significantly higher incidence rate of general adverse responses [RR = 1.34, 95% CI (1.18, 1.52), P<0.001] compared to the control group., Conclusions: The efficacy of elagolix in reducing pain in premenopausal women with endometriosis has been demonstrated over the short- to mid-term. However, careful monitoring for potential adverse effects is essential throughout the treatment duration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: To evaluate the effect of dienogest on urinary symptoms and sexual functioning within a 6-month follow-up period., Methods: We recruited 22 women with symptoms with dysmenorrhea, deep dyspareunia, and dyschezia accompanied with irritative urinary symptoms including frequency and urgency at Kaohsiung Medical University Chung-Ho Memorial Hospital from 2017 Jan 1 to 2019 Jan 1. The diagnosis of endometriosis mainly focused on vaginal examination and transvaginal ultrasound was performed in each patient. The participating patients took a daily dose of 2 mg Dienogest and underwent outpatient visits at the beginning, 1, 2, 3, and 6 months following treatment., Results: Our data showed a significant improvement in the visual Analog Scale (VAS) score from the first month till the sixth month after DNG treatment. The Overactive Bladder Symptom Score (OABSS), Urogenital Distress Inventory (UDI-6), and Incontinence Impact Questionnaire (IIQ-7) were significantly improved after the DNG treatment. Besides, serum estradiol was also decreased. Our data also showed that DNG treatment for 6 months did not affect Female Sexual Function Index (FSFI) score. Some patients with heavy menstruation also improved; however, some patients with regular periods missed or skipped a period after DNG treatment, while other adverse effects were also observed., Conclusion: Our study demonstrated that DNG could not only alleviate endometriosis pelvic pain but reduce urinary symptoms within the 6-month follow-up as well. DNG did not affect sexual function as measured by the FSFI score, although some adverse effects were recorded., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Purpose: Endometriosis is a chronic inflammatory disease that can cause various pain symptoms. Current therapy options do not always provide sufficient pain relief and often cause unpleasant side effects. Recent studies have shown that the endocannabinoid system is involved in the endometriosis pathophysiology, and using Cannabinoids may be a potential therapeutic option. We aimed to determine for the first time, the Cannabis use prevalence, self-rated effectiveness, and the possible reduction in medication in German-speaking countries., Methods: A cross-sectional online survey was distributed through endometriosis support and advocacy groups on social media. German-speaking endometriosis patients aged ≤ 18, residing in Germany, Austria, and Switzerland were eligible to participate., Results: Out of 912 participants who provided valid answers, 114 reported using cannabis for self-management. Cannabis was rated as the most effective self-management strategy to reduce symptom intensity (self-rated efficacy 7.6 out of 10). Additionally, ~ 90% of the participants were able to decrease their pain medication intake. The greatest improvement was observed in sleep (91%), menstrual pain (90%), and non-cyclic pain (80%). Apart from increased fatigue (17%), side effects were infrequent (≤ 5%)., Conclusion: At the time of the study, Cannabis consumption was still illegal in Germany, Austria, and Switzerland, with medical cannabis being rarely prescribed due to complex requirements. Results suggest that Cannabis has become a popular self-management method for treating endometriosis-related symptoms, leading to substantial symptom improvement. Further studies are needed to investigate the best administration methods, dosage, THC/CBD ratio, potential side effects, and long-term effects to provide official recommendations to patients and healthcare providers., (© 2024. The Author(s).)

Objective: To evaluate the efficacy and safety of 24-week cyclic administration of estetrol (E4) (15 mg)/drospirenone (DRSP) (3 mg) in Japanese patients with endometriosis., Design: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study., Setting: Twenty-five study centers in Japan., Patient(s): A total of 162 Japanese women diagnosed with endometriosis., Intervention(s): Participants were randomly allocated to the E4/DRSP group or the placebo group. In the E4/DRSP group, participants were orally administered one tablet containing E4 (15 mg) and DRSP (3 mg) daily for 24 days, followed by one placebo tablet for 4 days for a hormone-free interval, constituting a 1-cycle regimen. One placebo tablet was administered once daily for 28 days to participants in the placebo group. The treatments were continued for six cycles (24 weeks) throughout the confirmatory period., Main Outcome Measure(s): Changes in visual analogue scale (VAS) scores for the most severe pelvic pain (lower abdominal and back pain) from baseline to six treatment cycles at the end of the confirmatory study period., Result(s): Estetrol/drospirenone showed changes in the mean VAS scores for the most severe pelvic pain (-33.2 mm) from baseline to the end of the 6-cycle treatment. The between-group difference was significant (-8.5 mm; 2-sided 95% confidence interval, -16.1 to -0.9 mm), showing superiority to placebo. The responder rates, ≥30% and ≥50% reductions in the VAS scores from baseline, were higher in the E4/DRSP group than in the placebo group: 53.2% vs. 29.6% and 36.4% vs. 12.3%. Objective gynecological findings (induration of the cul-de-sac, pelvic tenderness, and limited uterine mobility) were significantly improved by E4/DRSP treatment, and the proportions of stable and worsened participants were significantly lower than in the placebo group. Estetrol/drospirenone decreased the size of endometriomas and improved quality of life, on the basis of quality of life-related questionnaires and global impression scores. No safety concerns were observed with E4/DRSP treatment. Few differences were observed in the proportion of participants with hemostasis parameters outside the reference range between the E4/DRSP and placebo groups., Conclusion(s): Estetrol/drospirenone effectively treats endometriosis-associated pain and improves gynecological findings. Estetrol/drospirenone may be a safe, new option for endometriosis treatment with a potentially decreased risk of thromboembolic events., Clinical Trial Registration Number: jRCT2011210027., Competing Interests: Declaration of Interests T.H. reports a medical writing and clinical trial advisory fee payment on the basis of the medical expert contract from Fuji Pharma Co., Ltd., and case study meeting fee payment on the basis of the medical expert contracts and medical writing fees for other clinical trials other than this manuscript in accordance with the medical expert contract from Fuji Pharma Co., Ltd. T.K. reports a medical writing and clinical trial advisory fee payment on the basis of the medical expert contract from Fuji Pharma Co., Ltd. A.H. reports a medical writing and clinical trial advisory fee payment on the basis of clinical biostatistics expert contract from Fuji Pharma Co., Ltd., and clinical biostatistics educational seminar fee payment on the basis of clinical biostatistics expert contract from Fuji Pharma Co., Ltd. T.T. reports salary and article processing charges from Fuji Pharma Co., Ltd. M.N. reports salary and article processing charges from Fuji Pharma Co., Ltd.; and patent filed with regard to the improvement of cul-de-sac induration, pelvic tenderness, and uterine mobility in subjects with endometriosis complicated by adenomyosis (Fuji Pharma Co., Ltd., and Mithra Pharmaceuticals). T.M. reports salary and article processing charges from Fuji Pharma Co., Ltd. M.H. reports salary and article processing charges from Fuji Pharma Co., Ltd.; and patent filed with regard to the improvement of cul-de-sac induration, pelvic tenderness, and uterine mobility in subjects with endometriosis complicated by adenomyosis (Fuji Pharma Co., Ltd., and Mithra Pharmaceuticals). J.-M.F. is a member of the Board at Mithra Pharmaceuticals and received financial support for the supervision of this study and consulting fees. Y.O. reports a medical writing and clinical trial advisory fee payment on the basis of the medical expert contract from Fuji Pharma Co., Ltd., and case study meeting fee payment on the basis of the medical expert contracts from Fuji Pharma Co., Ltd., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Endometriosis (EM) is an inflammatory condition in which the endometrium is observed to develop outside the uterine cavity. Endometrium has conventionally been recognized as a rich source of endometrial mesenchymal stem cells (E-MSCs). The influence of dienogest, a medication frequently prescribed for EM, on E-MSCs has not been extensively investigated., Aims: To explore effects of dienogest on the E-MSCs derived from healthy (E-MSCs-control) and diseased (E-MSCs-endometriosis) endometrial tissue samples in vitro., Study Design: In vitro study., Methods: We collected samples from healthy and diseased endometrial tissues. E-MSCs were derived from both healthy and EM tissues. The effect of dienogest (VISANNE) on E-MSCs was assessed by examining cell proliferation, telomerase activity, cell migration, and estrogen secretion levels after the isolation and characterization of E-MSCs., Results: We discovered that cellular proliferation rate was higher in the E-MSCs derived from EM tissues compared to those derived from healthy tissue. The proliferation rate and telomerase activity were both suppressed by dienogest treatment, particularly in E-MSCs-endometriosis. The drug treatment also resulted in a decrease in the migration capacity of E-MSCs-endometriosis, from 60.4% to 59.2%. The expression of CXCL12, Ki67, and beta-catenin was analyzed in both E-MSCs-endometriosis and E-MSCs-control. The CXCL12 and Ki67 expressions were quite elevated in the E-MSCs-endometriosis without drug treatment compared to the E-MSCs-control. Following the treatment, these levels declined drastically to the levels close to E-MSCs-control. Similarly, this decrease in gene expression was accompanied by a decrease in estrogen secretion into the medium., Conclusion: This research demonstrates that dienogest exerts a substantial impact on both stromal and stem cells, as it effectively controls the disease by reversing EM markers, despite the absence of progesterone receptors on endometrial stem cells., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Background: Inflammation and immune cell dysfunction are critical facilitators of endometriosis pathophysiology. Macrophages are renowned for stimulating lesion growth, vascularization, innervation, and pain generation. By combining macrophages and endometriotic cells, we determined if resveratrol and its natural analogs can target the immune dysregulation and oxidative imbalance in endometriosis. Methods: After treatment with compounds (5, 10, 25 µM), we evaluated the expression of key inflammatory and oxidative stress markers, cytokines release, and ROS production by applying q-PCR, ELISA, Cytometric Beads Array, and multiplexed fluorogenic staining and flow cytometry analysis with bioimaging. Results: The results showed that endometriosis-related macrophages treated with stilbenes have impaired expression of pro-inflammatory markers ( IL6 , IL8 , IL1B , TNF , CCL2 , CXCL10 , PTGS2 ). The effect of resveratrol, pterostilbene, and piceatannol was observed, especially in reducing IL1B , CCL2 , and CXCL10 genes up to 3.5-, 5-, and 7.7-fold at 25 µM, respectively. Also, with piceatannol or polydatin exposure, the IL-6 decrease was noticeable. This study reported an antioxidant effect by reducing ROS-positive cells from 96% to 48% by pterostilbene. Results from flow cytometry correlated with the transcript activation of detoxification enzymes ( SOD , GPX ). Conclusions: Prospects for potential therapy based on regulating the immune microenvironment and reducing the accumulation of free radicals with stilbenes application were described in the article.

Examining the impact of Sanjie Zhentong capsules on hormone levels and serum expression of folate receptor 1 (FOLR1) and Mesothelin (MSLN) in endometriosis patients. A cohort of 150 endometriosis patients admitted between June 2019 and June 2023 was divided into 2 groups based on Sanjie Zhentong intake, comprising 75 cases each. Comparative analyses encompassed uterine artery hemodynamic parameters, ultrasound (B-mode) findings, Visual Analog Scale scores, traditional Chinese medicine symptom scores, Endometriosis Health Profile-30 scores, and serum levels of FOLR1, MSLN, and sex hormones before and after treatment. Post-treatment, both groups exhibited increased peak systolic velocity compared to pretreatment, with the Sanjie Zhentong group showing a significantly higher increase (P < .05). Moreover, resistance index decreased in both groups post-treatment, with the Sanjie Zhentong group displaying a greater reduction (P < .05). Adnexal mass diameters, endometrial thickness, and uterine volume decreased post-treatment in both groups, with the Sanjie Zhentong group experiencing a more pronounced decrease (P < .05). Serum FOLR1, MSLN, and sex hormone levels also decreased post-treatment in both groups, with the Sanjie Zhentong group exhibiting a more significant decrease (P < .05). Additionally, pain scores, traditional Chinese medicine symptoms, and Endometriosis Health Profile-30 scores decreased post-treatment in both groups, with the Sanjie Zhentong group demonstrating a greater reduction (P < .05). Sanjie Zhentong capsules demonstrate efficacy in regulating sex hormones, reducing serum FOLR1 and MSLN expression, alleviating pain, shrinking adnexal masses, decreasing uterine size, and improving uterine artery blood flow in endometriosis patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The aim of the study was to determine the expression pattern of long pentraxin 3 (PTX3) mRNA in cumulus cells (CCs) isolated from metaphase II oocytes of women with unilateral endometrioma undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone antagonist (GnRHa) protocol., Patients and Methods: A total of 60 CC samples, 30 from the affected ovary and 30 from the contralateral ovary, were collected from 12 patients with unilateral endometrioma who underwent flexible GnRHa protocol with recombinant human chorionic gonadotropin (rhCG) trigger. Thirty CC samples collected from the left ovary of 12 women with male factor infertility were used as external controls. Long PTX3 mRNA expression in each group was analyzed by real-time polymerase chain reaction (RT-PCR). Relative gene expression (fold-change) was calculated according to the 2-ΔΔCt equation. Fertilization rates after intracytoplasmic sperm injection (ICSI) were recorded for each group., Results: CC-PTX3 mRNA expression in the unilateral endometrioma group was significantly lower than the mRNA expression of the disease-free ovary (0.90±0.01 vs. 0.25±0.02, p<0.01). CC-PTX3 mRNA expression of MII oocytes of the disease-free ovary was found to be similar to the control group (1.02±0.03 vs. 0.90±0.01, p=0.107). A significant 3.6-fold downregulation was observed in the CC-PTX3 mRNA expression of the endometrioma group compared to the CC-PTX3 mRNA expression in the contralateral ovary. CC-PTX3 mRNA expression in the endometrioma group was downregulated 4.08-fold compared to the CC-PTX3 mRNA expression of the control group (1.02±0.03 vs. 0.25±0.02, p<0.001). The cumulus morphologies of the endometrioma group with low CC-PTX3 expression and the groups with normal CC-PTX3 levels were similar. Fertilization rates of the endometrioma group were similar to the contralateral ovary and control groups., Conclusions: Unilateral endometrioma reduces CC-PTX3 expression but does not affect disease-free ovaries. The GnRHa protocol improved the fertilization rates, suggesting that failed CC-PTX3 expression is an in vivo pathology.

Objective: To investigate the effects and mechanisms of the Jiawei Pentongling formula (, JWPTL) in treating endometriosis-related pain using network pharmacology study and experimental validation., Methods: Active ingredients and relevant targets of JWPTL, as well as genes for endometriosis-related pain, were collected from public databases. Prediction of core targets and pathways of JWPTL against pain associated with endometriosis by protein-protein interaction (PPI) network work, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis. The Sprague-Dawley rat endo-metriosis model was constructed using the autologous endosomal transplantation method, and the successfully modeled rats were randomly divided into the model group and the JWPTL group, with 8 rats in each group. Another 8 rats were set up in the sham group. Rats in the JWPTL group used the rectal delivery method with the addition of JWPTL (7.77 g·kg -1 ·d -1 ) once a day for 28 d. Rats in the model and sham-operated groups were given equal amounts of saline using the same administration method. The 50% paw withdrawal threshold (PWT) of the rats was measured at different time points. After the intervention, the expression of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) proteins and mRNA in endometriotic tissues was detected by immune-ohistochemistry and reverse transcription-polymerase chain reaction., Results: From GeneCards, Online Mendelian Inheritance in Man and other databases, a total of 964 endometriosis (EMs) -related pain targets were screened, 142 active ingredients of JWPTL, 605 targets, and 221 potential targets were obtained by intersection of Venn diagram; 44 core targets were identified by constructing PPI network. KEGG enrichment analysis showed that JWPTL mainly involves the PI3K-Akt signaling pathway, estrogen signaling pathway, hypoxia inducible factor-1 signaling pathway, tumour necrotizing factor signaling pathway, and other signaling pathways in the treatment of EMs-related pain. Animal experiments showed that JWPTL could up-regulate the mechanical pain threshold and reduce the expression of PI3K and Akt proteins and mRNA in ectopic endometrial tissues of model rats., Conclusions: The present study preliminarily analyzed the pharmacological mechanism of the formula, and molecular docking and animal experiments showed the feasibility of this study, suggesting that the formula may inhibit the release of inflammatory factors and reverse the pain associated with EMs by downregulating the PI3K/Akt signaling pathway.

Gonadotrophin-releasing hormone (GnRH) antagonists have been demonstrated to reduce endometriosis-associated pain. Because of the hypo-oestrogenic state they induce, however, higher dosages of GnRH antagonists are not recommended for used long term. This unwanted effect may be eliminated by so-called add-back therapy (ABT). This review was conducted to assess the safety and efficacy of GnRH antagonists, with or without add-back hormonal replacement therapy. Out of the 345 studies selected through the initial search, seven randomized controlled trials were included, comparing different oral GnRH antagonists at varying dosages, from a minimum of 50 mg to a maximum of 200 mg once or twice daily. Women treated with the lowest dose of GnRH antagonists had significantly greater mean pain score reductions from baseline throughout treatment compared with those treated with placebo (odds ratio [OR] -13.12, 95% CI -17.35 to -8.89 and OR -3.08, 95% CI -4.39 to -1.76 for dysmenorrhoea and non-menstrual pelvic pain, respectively). Compatible with the dose-response effect, a positive correlation was found between response rates and adverse event rates. While GnRH antagonists offer an advantage in terms of pain reduction for endometriosis, the more recent literature suggests using GnRH antagonists with ABT, which, while mitigating the hypo-oestrogenic effects of GnRH antagonists, maintain their efficacy, while allowing their long-term use., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Endometriosis is a female hormone-dependent gynecological disorder characterized by chronic inflammation. Therefore, the development of novel treatment strategies that can diminish the side effects of the long-term use of hormone-based drugs has been emphasized. S-Allyl-L-cysteine (SAC) is the major constituent of aged garlic extracts. Although the therapeutic effects resulting from the antioxidant properties of SAC have been extensively studied in inflammatory diseases, the therapeutic efficacy of SAC in endometriosis has not been described. In this study, we investigated the therapeutic potential of SAC for endometriosis using a mouse model., Methods: An endometriosis mouse model was surgically induced, and oral treatment with 30 mg/kg SAC was administered daily for 28 days. The development of endometriotic lesions was assessed by histological analysis, and the expression profiles of adhesion-, apoptosis-, and inflammation-related genes were evaluated by PCR. Flow cytometric analysis of mouse spleen was conducted to assess changes in lymphocyte subpopulations., Results: SAC treatment significantly inhibited endometriotic lesion growth. Transcriptional expression analysis revealed the antiadhesion and apoptosis-promoting effects of SAC. In particular, SAC showed an effective immune modulatory response by altering splenic CD4 + and CD8 + T cell subsets and inflammatory cytokine production in the spleen and endometriotic lesions., Conclusion: This study newly elucidates the inhibitory effects of SAC on the growth of endometriosis in a mouse model and describes its immunomodulatory effects., (© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Purpose of Review: While laparoscopic surgery plays a key role in the management of endometriosis, symptoms commonly recur, and repeat surgery comes with increased risk. Medical management, including hormonal and nonhormonal treatment, is vital in managing painful symptoms. This review summarizes recent evidence regarding various medical management options available to treat pelvic pain associated with endometriosis., Recent Findings: Efficacy of dienogest vs. combined oral contraceptive on pain associated with endometriosis: randomized clinical trial.Once daily oral relugolix combination therapy vs. placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2).A randomized, double-blind, placebo-controlled pilot study of the comparative effects of dienogest and the combined oral contraceptive pill in women with endometriosis.Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study., Summary: All symptomatic women with suspected endometriosis who are not desiring immediate fertility can be offered suppressive treatment to control symptoms and slow the progression of disease. First-line treatments include the combined oral contraceptive pill and progestogens. Second-line treatments include gonadotropin-releasing hormone agonists and antagonists but current guidelines recommend that these should be reserved for people whose symptoms fail to be controlled by first-line agents. The use of complementary and alternative medicines is also increasing in both volume and number of agents used., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate the effect of relugolix combination therapy (relugolix CT; 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethisterone acetate) for up to 2 years in the SPIRIT long-term extension study on functioning and health-related quality of life (QoL), using the Endometriosis Health Profile (EHP)-30 questionnaire, and assess how changes in QoL domains correlated with improvements in dysmenorrhea as well as nonmenstrual pelvic pain (NMPP)., Design: Long-term extension study of the SPIRIT phase 3 trials., Setting: Clinics and University Hospitals., Patient(s): Premenopausal women with moderate-to-severe endometriosis pain who previously completed the randomized SPIRIT trials were eligible to enroll in an 80-week long-term extension where all women received relugolix CT., Intervention(s): Relugolix CT (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg)., Main Outcome Measure(s): Least squares (LS) mean changes in the EHP-30 domain and total scores from baseline (pivotal) were analyzed using a mixed-effects model. Results up to 104 weeks are reported by a pivotal trial treatment group with a focus on the relugolix CT group (i.e., relugolix CT or placebo for 24 weeks, or delayed relugolix CT [relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT for 12 weeks]). In addition, the relationships between changes in dysmenorrhea and NMPP as well as changes in EHP-30 scores were assessed., Result(s): In the 277 women treated with relugolix CT, LS mean EHP-30 pain domain scores improved by 57.8% (LS mean change: -32.8; 95% CI: -35.5, -30.1), 66.4% (LS mean change: -37.7; 95% CI: -40.3, -35.0), and 72.2% (LS mean change: -41.3; 95% CI: -43.9, -38.7) at weeks 24, 52, and 104, respectively. The proportions of women with clinically meaningful improvement in the EHP-30 pain domain were 75.9%, 83.6%, and 88.6% at weeks 24, 52, and 104, respectively. Non-pain EHP-30 domain and total scores likewise improved. A positive correlation between changes in dysmenorrhea/NMPP and all EHP-30 domain scores was observed. Results were similar for the delayed relugolix CT and placebo → relugolix CT groups., Conclusion(s): Sustained reduction of endometriosis-associated pain with relugolix CT observed up to 104 weeks was accompanied by improvements in functioning and health-related QoL. These findings complement the results of the pivotal SPIRIT trials, which showed that relugolix combination therapy significantly reduced dysmenorrhea, NMPP, and dyspareunia vs. placebo in premenopausal women with endometriosis-associated pain., Clinical Trial Registration Number: Registration/clinicaltrials.gov identifier: SPIRIT Extension Study (NCT03654274)., Competing Interests: Declaration of Interests S.A. reports personal fees from Myovant Sciences, Bayer, Organon, and UpToDate. M.S.A has nothing to disclose. G.R. has nothing to disclose. K.W. has nothing to disclose. Y.Z. is an employee of Sumitomo Pharma. J.P. is an employee of Sumitomo Pharma. E.H. is an employee of Sumitomo Pharma. G.S. is an employee of Sumitomo Pharma. C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva all of which went to the University of Oxford, and Chair of ESHRE Endometriosis Guideline Group. The authors did not receive compensation for manuscript writing, review, and revision., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To observe the effects and safety of dienogest on the volume and symptoms of ovarian endometrioma (OMA). Methods: The clinical data of 75 patients with OMA who underwent treatment with dienogest (2 mg/day) at the First Affiliated Hospital of Nanjing Medical University from July 1st 2020 to March 31st 2024 were retrospectively analysed, mainly comparing the changes in the volume of OMA and the visual analogue scale (VAS) scores of endometriosis-related pain before and after the treatment, as well as observing the changes in the blood biological indicators, liver and kidney function, coagulation function and changes in breast. Results: The median cyst volumes of the OMA patients at 3, 6 and 12 months of dienogest treatment were 13.21 cm 3 (volume reduction rate: 36.00%), 8.33 cm 3 (volume reduction rate: 56.00%) and 4.10 cm 3 (volume reduction rate: 77.62%), respectively, which were all significantly decreased from the pre-treatment period (all P <0.05). The VAS scores of pain of the OMA patients at 3, 6 and 12 months of dienogest treatment all were 0 mm. Blood cancer antigen 125 (CA 125 ) and cancer antigen 19-9 (CA 19-9 ) levels decreased progressively during treatment (all P <0.05). There were no statistical differences in the coagulation indexes, liver and kidney function indexes of the patients during dienogest treatment compared with those before treatment (all P >0.05). During the follow-up period, there were a few patients with changes in the growth sites or lesion category of the breast nodules, but there were no occurrence of breast cancer or precancerous lesions. Conclusion: Dienogest is effective in reducing OMA volume and alleviating endometriosis-related pain with few adverse effects.

To investigate the effects of pretreatment with long-acting gonadotropin-releasing hormone agonist (GnRH-a) before frozen-thawed embryo transfer (FET) on pregnancy outcomes in patients after minimal-mild (stages I-II) peritoneal endometriosis surgery. A retrospective cohort study was performed from March 2018 to May 2019. Overall, 274 patients met inclusion criteria of undergoing FET after minimal/mild peritoneal endometriosis surgery. For the FET protocol, patients were divided into 2 groups: GnRH-a plus hormone replacement therapy (HRT) (group A, n = 154) and HRT-only (group B, n = 120), with the former divided into 2 subgroups receiving 1 (group A1, n = 80) or 2 doses (group A2, n = 74) of GnRH-a. Basic characteristics and pregnancy outcomes of groups A and B and groups A1 and A2 were compared. Clinical pregnancy rate (CPR) and live birth rate (LBR) were the primary outcomes and logistic regression was used to analyze independent correlation factors. The CPR and LBR in group A were 58.4% and 50.0%, respectively, and were not significantly higher than in group B (49.2% and 40.0%; respectively, χ2 = 2.339, P = .126 and χ2 = 2.719, P = .099, respectively). CPR and LBR in group A1 were not significantly lower than those in group A2 (52.5% and 45.0% vs 64.9% and 55.4%, respectively; χ2 = 2.420, P = .120 and χ2 = 1.665, P = .197, respectively). However, group A2's CPR and LBR were significantly higher than group B's (64.9% and 55.4% vs 49.2% and 40.0%, respectively; χ2 = 4.560, P = .023 and χ2 = 4.375, P = .026, respectively). Logistic regression analysis showed that GnRH-a pretreatment (1 or 2 doses) had no significant effect on CPR and LBR compared with the HRT-only group. Patients with minimal-mild (stages I-II) peritoneal endometriosis surgery may not require GnRH-a pretreatment before FET., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option., Objectives: To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life., Design: A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women's lived experience of endometriosis and a pretrial economic model., Setting: Thirty-four United Kingdom hospitals., Participants: Women of reproductive age undergoing conservative surgery for endometriosis., Interventions: Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel)., Main Outcome Measures: The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained., Results: Four hundred and five women were randomised to receive either long-acting reversible contraceptive ( N  = 205) or combined oral contraceptive pill ( N  = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: -0.8, 95% confidence interval -5.7 to 4.2; p  = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval -0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman., Limitations: Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment., Conclusions: At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women., Future Work: Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence., Trial Registration: This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment ; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word 'woman' is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary.

Objective: This study investigates the therapeutic effects of colchicine and melatonin on endometriotic implants in an experimentally created endometriosis model in rats., Study Design: Forty-four adult female Wistar albino rats weighing between 260 and 300 g, 8 weeks old, were selected for the study. The unilateral uterine horn of rats with a bicornuate uterus was excised for 1 cm, washed with sterile saline, incised longitudinally, and the endometrium was exposed. A 0.5*0.5 cm endometrial tissue sample taken with a scalpel was implanted with suturing (4/0 Vicryl) to the abdominal wall. Forty-four rats were divided into four groups. Group 1 was randomized as the endometriosis group (control), Group 2 as endometriosis + colchicine treatment, Group 3 as endometriosis + melatonin treatment, and Group 4 as the endometriosis + melatonin + colchicine treatment group. The colchicine (Sigma Chemical Co., St Louis, Missouri) group was administered orally at a dose of 0.1 mg/kg, and the Melatonin group orally at a dose of melatonin (20 mg/kg per day). Treatment continued daily for 30 days., Results: In the post-treatment focal diameter measurements, the endometrial focal diameter in the colchicine and colchicine + melatonin group was significantly lower than the control group (p=0.026). Bcl-2 levels of the colchicine group were lower than the control group and the melatonin group (p=0.021)., Conclusion: Colchicine and melatonin reduce adhesion to the peritoneal surface in ectopic endometrial cells. It also acts by increasing apoptosis and decreasing cell survival., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Neoangiogenesis is necessary for adhesion and invasiveness of endometriotic lesions in women affected by endometriosis. Vascular endothelial growth factor (VEGF) is one of the main components of angiogenesis and is part of the major pathway tissue factor (TF)-protease activated receptor-2 (PAR-2)-VEGF that leads to neoangiogenesis. Specificity protein 1 (SP1) is a transcriptional factor that has recently been studied for its crucial role in angiogenesis via a specific pathway. We hypothesize that by blocking angiogenetic pathways we can suppress endometriotic lesions. Gonadotrophin-releasing hormone-agonists (GnRH-a) are routinely used, especially preoperatively, in endometriosis. It would be of great interest to clarify which angiogenetic pathways are affected and, thereby, pave the way for further research into antiangiogenetic effects on endometriosis., Methods: We used quantitative real-time polymerase chain reaction (qRT-PCR) to study mRNA expression levels of TF, PAR-2, VEGF, and SP1 in endometriotic tissues of women who underwent surgery for endometriosis and received GnRH-a (leuprolide acetate) preoperatively., Results: VEGF, TF, and PAR-2 expression is significantly lower in patients who received treatment (p < 0,001) compared to those who did not, whereas SP1 expression is not altered (p = 0.779)., Conclusions: GnRH-a administration does affect some pathways of angiogenesis in endometriotic lesions, but not all of them. Therefore, supplementary treatments that affect the SP1 pathway of angiogenesis should be developed to enhance the antiangiogenetic effect of GnRH-a in patients with endometriosis., Trial Registration: Clinicaltrial.gov ID: NCT06106932., (© 2024. The Author(s).)

Introduction: Endometriosis, a common and distressing gynecological condition, affects fertility and causes pain, is often managed with medications such as Elagolix. The present study aimed to construct a physiologically based pharmacokinetic (PBPK) model for elagolix to predict its pharmacokinetics in different populations, including those with special conditions, to enhance treatment strategies for endometriosis., Methods: The PBPK model was optimized using observational data based on the oral administration of elagolix in a healthy Chinese population under fasting conditions. Model accuracy was further verified by comparing the predicted postprandial elagolix concentration data for healthy Chinese individuals with observed data and by comparing these values with the predicted values in a US population model with renal injury or following multiple-dose administration., Results: Elagolix pharmacokinetic (PK) profiles in the Chinese and American populations exhibited no differences that were attributable to ethnicity. The model predicted in vivo PK in adolescents aged 14-18 years, revealing no clinically significant differences in the effects of elagolix between adolescents and adults. In addition, no predicted PK differences in individuals with overweight were observed. However, notable variations emerged in those classified as obesity class 2 and above compared to healthy individuals., Conclusion: Our study presents a novel PBPK model for elagolix in healthy Chinese women, addressing a clinical data gap for its use in adolescents and obese patients. By validating the model with real-world factors, including diet and renal impairment, we provide initial pharmacokinetic predictions for these populations, contributing to a more informed clinical approach., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

According to this study., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Peritoneal infiltrating and fibrotic endometriosis, also known as deep endometriosis, is the most severe manifestation of the disease that can cause severe complications including bowel and ureteral stenosis. The natural history of these lesions and the possible effect of hormonal treatments on their progression are undefined. Therefore, we conducted a systematic review and meta-analysis to investigate whether and how frequently deep endometriosis progresses over time without or with ovarian suppression. This could inform management decisions in asymptomatic and mildly symptomatic patients., Material and Methods: For this pre-registered systematic review (CRD42023463518), the PubMed and Embase databases were screened, and studies published between 2000 and 2023 that serially evaluated the size of deep endometriotic lesions without or with hormonal treatment were selected. Data on the progression, stability, or regression of deep endometriotic lesions were recorded as absolute frequencies or mean volume variations. Estimates of the overall percentage of progression and corresponding 95% confidence intervals were calculated using a random-effect model. When studies reported lesion progression as pre- and post-treatment volume means, the delta of the two-volume means was calculated and analyzed using the inverse variance method., Results: A total of 29 studies were identified, of which 19 studies with 285 untreated and 730 treated patients were ultimately selected for meta-analysis. The overall estimate of the percentage of lesion progression in untreated individuals was 21.4% (95% CI, 6.8-40.8%; I 2  = 90.5%), whereas it was 12.4% during various hormonal treatments (95% CI, 9.0-16.1%; I 2  = 0%). Based on the overall meta-analysis estimates, the odds ratio of progression in treated vs untreated patients was 0.52 (95% CI, 0.41-0.66). During hormonal suppression, the mean volume of deep endometriotic lesions decreased significantly by 0.87 cm 3 (95% CI, 0.19-1.56 cm 3 ; I 2  = 0%), representing -28.5% of the baseline volume., Conclusions: Untreated deep endometriotic lesions progressed in about one in five patients. Medical therapy reduced but did not eliminate this risk. Given the organ function failure potentially caused by these lesions, the decision whether to use hormonal treatments in asymptomatic or mildly symptomatic women should always be shared, carefully weighing the potential benefits and harms of the two alternatives after extensive counseling., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: To assess the efficacy and safety of Sanjie Analgesic Capsule (SAC) in Chinese patients with endometriosis-associated pain., Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial conducted at 15 centers between November 2013 and July 2017 in China. Eligible 323 patients with endometriosis were randomized at a 3:1 ratio to the SAC group (241 cases) and placebo group (82 cases) by stratified block randomization. Patients in the SAC or placebo groups were given SAC or placebo 1.6 g 3 times per day, orally, respectively since the first day of menstruation for 3 consecutive menstrual cycles. The primary endpoint was clinical response to dysmenorrhea evaluated using a 10-point Visual Analogue Scale at 3 and 6 months. The secondary endpoint was the pain score evaluated by VAS (chronic pelvic pain, defecation pain, and dyspareunia) at 3 and 6 months, and the pain recurrence rate at 6 months. Adverse events (AEs) were recorded during the study., Results: A total of 241 women were included in the SAC group, and 82 were in the placebo group. Among these women, 217 (90.0%) and 71 (86.6%) completed the intervention, respectively. At 3 months, overall response rate (ORR) was significantly higher in women administered SAC (80.1%) compared with those who received a placebo (30.5%, P<0.01). Six months after treatment, the ORR for dysmenorrhea was 62.7% in the SAC group and 31.7% in the placebo group (P<0.01). Chronic pelvic pain and defecation pain were significantly improved by SAC compared with placebo (both P<0.05). The incidence rates of total AEs events in the SAC and placebo groups were 6.6% and 9.8%, respectively, and no significant difference was shown between the two groups (P=0.339)., Conclusion: SAC is well-tolerated and may improve dysmenorrhea in women with endometriosis-associated pain. (Trial registration: ClinicalTrials.gov, No. NCT02031523)., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Ethnopharmacological Relevance: Wenshen Xiaozheng Tang (WXT), a traditional Chinese medicine (TCM) decoction, is effective for treating endometriosis. However, the effect of WXT on endometrium-derived mesenchymal stem cells (eMSCs) which play a key role in the fibrogenesis of endometriosis requires further elucidation., Aims of the Study: The aim of this study was to clarify the potential mechanism of WXT in improving fibrosis in endometriosis by investigating the regulation of WXT on differentiation and paracrine of eMSCs., Materials and Methods: The nude mice with endometriosis were randomly divided into model group, WXT group and mifepristone group. After 21 days of treatment, the lesion volume was calculated. Fibrosis in the lesions was evaluated by Masson staining and expression of fibrotic proteins. The differentiation of eMSCs in vivo was explored using a fate-tracking experiment. To further clarify the regulation of WXT on eMSCs, primary eMSCs from the ectopic lesions of endometriosis patients were isolated and characterized. The effect of WXT on the proliferation and differentiation of ectopic eMSCs was examined. To evaluate the role of WXT on the paracrine activity of ectopic eMSCs, the conditioned medium (CM) from ectopic eMSCs pretreated with WXT was collected and applied to treat ectopic endometrial stromal cells (ESCs), after which the expression of fibrotic proteins in ectopic ESCs was assessed. In addition, transcriptome sequencing was used to investigate the regulatory mechanism of WXT on ectopic eMSCs, and western blot and ELISA were employed to determine the key mediator., Results: WXT impeded the growth of ectopic lesions in nude mice with endometriosis and reduced collagen deposition and the expression of fibrotic proteins fibronectin, collagen I, α-SMA and CTGF in the endometriotic lesions. The fate-tracking experiment showed that WXT prevented human eMSCs from differentiating into myofibroblasts in the nude mice. We successfully isolated eMSCs from the lesions of patients with endometriosis and demonstrated that WXT suppressed proliferation and myofibroblast differentiation of ectopic eMSCs. Moreover, the expression of α-SMA, collagen I, fibronectin and CTGF in ectopic ESCs was significantly down-regulated by the CM of ectopic MSCs pretreated with WXT. Combining the results of RNA sequencing, western blot and ELISA, we found that WXT not only reduced thrombospondin 4 expression in ectopic eMSCs, but also decreased thrombospondin 4 secretion from ectopic eMSCs. Thrombospondin 4 concentration-dependently upregulated the expression of collagen I, fibronectin, α-SMA and CTGF in ectopic ESCs, indicating that thrombospondin 4 was a key mediator of WXT in inhibiting the fibrotic process in endometriosis., Conclusion: WXT improved fibrosis in endometriosis by regulating differentiation and paracrine signaling of eMSCs. Thrombospondin 4, whose release from ectopic eMSCs is inhibited by WXT, may be a potential target for the treatment of endometriosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Endometriosis (EMS) is a common gynecological disease that causes dysmenorrhea, chronic pelvic pain and infertility. Luoshi Neiyi Prescription (LSNYP), a traditional Chinese medicine (TCM) formula, is used to relieve EMS in the clinic., Aims: This study aimed to examine the active components of LSNYP and the possible mechanism involved in its treatment of EMS., Materials and Methods: Ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to identify the chemical components of LSNYP. Human primary ectopic endometrial stromal cells (ecESCs) and eutopic endometrial stromal cells (euESCs) were isolated, and the expression levels of hypoxia inducible factor 1A (HIF1A), enhancer of zeste homolog 2 (EZH2) and steroidogenic factor 1 (SF-1) were detected by immunofluorescence and qPCR. Cobalt chloride (CoCl 2 ) was utilized to construct an in vitro hypoxic environment, and lentiviruses were engineered to downregulate HIF1A and EZH2 and upregulate EZH2. Subsequently, the expression levels of HIF1A, EZH2, and SF-1 were measured using qPCR or western blotting. The binding of EZH2 to the SF-1 locus in ESCs was examined via ChIP. Furthermore, the effects of LSNYP on the HIF1A/EZH2/SF-1 pathway were evaluated both in vitro and in vivo., Results: A total of 185 components were identified in LSNYP. The protein and gene expression levels of HIF1A and SF-1 were increased, whereas those of EZH2 were decreased in ecESCs. After treating euESCs with 50 μmol L -1 CoCl 2 for 24 h, cell viability and estradiol (E 2 ) production were enhanced. Hypoxia decreased EZH2 protein expression, while si-HIF1A increased it. SF-1 was increased when EZH2 was downregulated in normal and hypoxic environments, whereas the overexpression of EZH2 led to a decrease in SF-1 expression. ChIP revealed that hypoxia reduced EZH2 binding to the SF-1 locus in euESCs. In vitro, LSNYP-containing serum decreased E 2 and prostaglandin E 2 (PGE 2 ) production, inhibited cell proliferation and invasion, and reduced the expression of HIF1A, SF-1, steroidogenic acute regulatory protein (StAR), and aromatase cytochrome P450 (P450arom). In vivo, LSNYP suppressed inflammation and adhesion and inhibited the HIF1A/EZH2/SF-1 pathway in endometriotic tissues., Conclusions: LSNYP may exert pharmacological effects on EMS by inhibiting E 2 synthesis and inflammation through regulation of the HIF1A/EZH2/SF-1 pathway. These results suggest that LSNYP may be a promising candidate for the treatment of EMS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endometriosis is a chronic gynecological disorder characterized by significant chronic pelvic pain (CPP) and infertility, adversely affecting the quality of life for many women worldwide. This review aims to synthesize recent findings on natural bioactive compounds derived from various plant sources that exhibit beneficial effects in the management of endometriosis and related CPP. A thorough search of databases, including PubMed, Scopus, and Google Scholar, was conducted to identify studies evaluating the efficacy of natural compounds on endometriosis and related CPP. In alphabetical order, curcumins, ginsenosides, polyphenols and other secondary metabolites showed promising effects on oxidative stress, inflammation, and pain modulation associated with endometriosis acting on multiple pathways. Most of the selected articles were in vitro and in vivo studies in animal models, with a limited number of clinical trials. The reported natural compounds according to the highlighted multiple bioactivities, might be valuable complementary alternatives as supplements, nutraceuticals, or in advanced personalized nutrition. Further clinical investigations are needed to comprehensively evaluate their therapeutic potential, safety, efficacy and to establish effective treatment protocols., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endometriosis is a common disease, affecting approximately 5-10% of reproductively aged women. Symptoms, such as painful periods, negatively impact an individual's quality of life; however, these symptoms are often normalized, leading to delays in diagnosis and treatment, and worsening of the disease. In this podcast, a reproductive endocrinologist (Dr Sanjay K Agarwal) and patient advocate (Tara Mangum) provide their perspectives on the diagnosis and management of endometriosis. They also discuss Relugolix combination therapy as a treatment option for patients with endometriosis.Podcast available for this article., (© 2024. The Author(s).)

Objective: This prospective observational study aims to demonstrate the clinical efficacy of dienogest in treating endometriomas with a maximum diameter of ≥4 cm., Methods: Patients ( n  = 81) with endometriomas (diameter of ≥4 cm) were enrolled and administered orally with dienogest (2 mg daily) and followed up for a year [Ethical approval code: 2020 Research 343]. Further, the efficacy was determined by recording the largest diameter and volume of the endometriomas, uterine volume, endometrial thickness, and the largest diameter of uterine fibroids in the patients during 0, 6, and 12 months. The pain symptoms were assessed using the Numerical Rating Scale (NRS), and the side effects of medication were monitored. With the consent, some patients underwent routine blood tests, and serum hormone, as well as Anti-Müllerian Hormone (AMH) levels were measured., Results: The dienogest treatment resulted in a significant reduction of the maximum diameter of these cysts from 50.5 mm to 41 mm in 6 months and 34 mm in 12 months. In addition, the volume of the cysts significantly decreased from 37.8 ml from baseline to 18.5 ml in 6 months and 11.8 ml in 12 months. Among 26 subjects with ultrasonic signs of endometrial polyps, 92.3% of cases displayed no polyps after 12 months. No significant changes were observed in the size of uterine fibroids and AMH levels. The NRS score showed a decrease from an average of 6.6-1.2 in 12 months., Conclusion: Dienogest could effectively reduce the diameter and volume of endometriomas with a maximum diameter of ≥4 cm, improving anemia, as well as pain symptoms and preserving ovarian function.

Endometriosis is a gynecological disorder among reproductive-aged women. Recent epidemiological investigations suggest endometriosis increases the risk of endometrial cancer. However, the molecular entity leading to endometriosis-to-endometrial cancer is largely unknown. This study aimed to combine a variety of computational approaches to identify the key therapeutic target promoting endometriosis-to-endometrial cancer and screen potential inhibitors against target to prevent cancer development. Our systematic investigations, includes transcriptomic profiling, protein network, pharmacophore modeling, docking, binding free energy calculation, dynamics simulation, and quantum mechanics. The gene expression analysis on endometriosis and endometrial cancer was performed and showed 108 shared upregulated genes in both conditions. Further construction of interaction network with 108 genes showed intercellular adhesion molecule 1 (ICAM1) to be a crucial molecule with a high degree of connectivity that influences vital mechanisms related to cancer pathways. We then generated ligand-based pharmacophore models using established ICAM1 inhibitors. Among the models, the ADRRR&#95;8 pharmacophore exhibited a robust area under curve (AUC = 0.83), was employed to screen 1739 anti-cancer drugs. On screening, 421 anti-cancer drugs displayed ICAM1-inhibiting pharmacophore features. Further, the docking of 421 drugs with ICAM1 showed lanreotide (-7.80 kcal/mol) with better affinity than the reference ICAM1 inhibitor (-3.59 kcal/mol). Further validation though binding free energy and dynamics simulation of the lanreotide-ICAM1 complex showed a high binding affinity of -55.90 kcal/mol and contributed stable confirmation. According to quantum chemical calculations, lanreotide's electronic properties favour ICAM1 binding with highest occupied molecular orbital was -6.91 eV and lowest unoccupied molecular orbital was -3.93 eV. Our study supports using lanreotide to treat endometriosis, which could delay or prevent endometrial cancer. These predictions need to be confirmed and examined to determine the use of lanreotide in endometriosis treatment., Competing Interests: Compliance with Ethical Standards Conflict of interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Dienogest (DNG) improves endometriosis-associated pain (EAP) and patients' quality of life; however, the modern cornerstone of the management of endometriosis is the long-term adherence of the patient to medical treatment., Objective: To evaluate DNG as a long-term treatment of endometriosis, focusing on patients' compliance and side effects, also correlating with different phenotypes of endometriosis., Methods: This was a cohort study on a group of patients with endometriosis ( n  = 114) undergoing long-term treatment with DNG. During the follow up visits (12, 24, and 36 months) patients were interviewed: an assessment of EAP was performed by using a visual analogue scale (VAS) and side effects were evaluated by using a specific questionnaire of 15 items., Results: At 12 months, 81% were continuing the DNG treatment, with a significant reduction of dysmenorrhea, dyspareunia, dyschezia, dysuria and chronic pelvic pain. Of the 19% that discontinued the treatment: 62% was due to spotting, reduced sexual drive, vaginal dryness, and mood disorders. The improvement of EAP was significant for all endometriosis phenotypes, especially in patients with the deep infiltrating type. At 36 months, 73% of patients were continuing the treatment, showing a significant reduction of EAP through the follow up, along with an increase of amenorrhea (from 77% at 12 months to 93% at 36 months). In a subgroup of 18 patients with gastrointestinal disorders, DNG was administered vaginally at the same dosage, showing similar results in terms of efficacy and tolerability., Conclusions: DNG was an effective long-term treatment for all endometriosis phenotypes, with few side effects that caused the discontinuation of the treatment mainly during the first year. Thus, the course of 1-year treatment is a predictive indicator for long-term treatment adherence.

Introduction: Endometriosis is delineated as a benign yet steroid-dependent disorder characterized by the ectopic presence of endometrial glandular and stromal cells outside the uterine cavity, affecting estimated 10%-15% of women of reproductive age, 20%-50% of all women with infertility and costing a great economic burden per-patient. Endometriosis exerts pervasive influence on multiple facets of female reproductive physiology. Given its characterization as a chronic inflammatory disorder, escalated levels of pro-inflammatory cytokines were unequivocally recognized as well-established characteristics of endometriosis, which might attribute to mechanisms like retrograde menstruation, progesterone receptor resistance, and immune dysregulation. Therapeutic utilization of non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, analgesic agent for reducing pain, inflammation, and fever, could be holding promise in augmenting reproductive outcomes of endometriosis women. Therefore, the objective of this comprehensive review is to elucidate the intricate interplay between endometriosis and aspirin, both within the context of infertility and beyond. We meticulously explore potential pharmacological agents targeting endometriosis, which may concurrently optimize the efficacy of reproductive interventions, while also delving into the underlying mechanistic pathways linking endometriosis with inflammatory processes., Methods: We conducted a comprehensive search in the data available in PubMed and the Web of Science using the terms 'endometriosis' and 'aspirin'. Then analyzed the identified articles based on established inclusion and exclusion criteria independently by three reviewers., Results: The survey of the chosen terms revealed 72 articles, only 10 of which were considered for review., Discussion: Based on the research available currently, it is not substantial enough to address the conclusion that aspirin shall be an effective therapeutic choice for endometriosis, further studies are needed to elucidate the efficacy, safety profile, and optimal dosing regimens of aspirin in the context of endometriosis treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Lai, Li and Zhang.)

Endometriosis (EMS) is defined as the appearance, growth, infiltration, and repeated bleeding of endometrioid tissue (glands and stroma) outside the uterus cavity, which can form nodules and masses. Endometriosis is a chronic inflammatory estrogen-dependent disease and occurs in women of reproductive age. This disorder may significantly affect the quality of life of patients. The pathogenic processes involved in the development and maintenance of endometriosis remain unclear. Current treatment options for endometriosis mainly include drug therapy and surgery. Drug therapy mainly ties to the use of non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal drugs. However, these drugs may produce adverse effects when used for long-term treatment of endometriosis, such as nausea, vomiting gastrointestinal reactions, abnormal liver and kidney function, gastric ulcers, and thrombosis. Although endometriosis lesions can be surgically removed, the disease has a high recurrence rate after surgical resection, with a recurrence rate of 21.5% within 2 years and 40% to 50% within 5 years. Thus, there is an urgent need to develop alternative or additional therapies for the treatment of endometriosis. In this review, we give a systematic summary of therapeutic multiple component prescriptions (including traditional Chinese medicine and so on), bioactive crude extracts of plants/herbs and purified compounds and their newly found mechanisms reported in literature in recent years against endometriosis., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Gu et al.)

Background: Patients with endometriosis suffer with chronic pelvic pain and infertility, and from the lack of pharmacologic therapies that consistently halt disease progression. Differences in the endometrium of patients with endometriosis vs. unaffected controls are well-documented. Specifically, shed endometrial tissues (delivered to the pelvic cavity via retrograde menstruation) reveal that a subset of stromal cells exhibiting pro-inflammatory, pro-fibrotic, and pro-senescence-like phenotypes is enhanced in endometriosis patients compared to controls. Additionally, cultured biopsy-derived endometrial stromal cells from endometriosis patients exhibit impaired decidualization, a defined differentiation process required for human embryo implantation and pregnancy. Quercetin, a senolytic agent, shows therapeutic potential for pulmonary fibrosis, a disorder attributed to senescent pulmonary fibroblasts. In rodent models of endometriosis, quercetin shows promise, and quercetin improves decidualization in vitro. However, the exact mechanisms are not completely understood. Therefore, we investigated the effects of quercetin on menstrual effluent-derived endometrial stromal cells from endometriosis patients and unaffected controls to define the signaling pathways underlying quercetin's effects on endometrial stromal cells., Methods: Menstrual effluent-derived endometrial stromal cells were collected and cultured from unaffected controls and endometriosis patients and then, low passage cells were treated with quercetin (25 µM) under basal or standard decidualization conditions. Decidualization responses were analyzed by measuring the production of IGFBP1 and PRL. Also, the effects of quercetin on intracellular cAMP levels and cellular oxidative stress responses were measured. Phosphokinase arrays, western blotting, and flow cytometry methods were performed to define the effects of quercetin on various signaling pathways and the potential mechanistic roles of quercetin., Results: Quercetin significantly promotes decidualization of control- and endometriosis-endometrial stromal cells. Quercetin substantially reduces the phosphorylation of multiple signaling molecules in the AKT and ERK1/2 pathways, while enhancing the phosphorylation of p53 and total p53 levels. Furthermore, p53 inhibition blocks decidualization while p53 activation promotes decidualization. Finally, we provide evidence that quercetin increases apoptosis of endometrial stromal cells with a senescent-like phenotype., Conclusions: These data provide insight into the mechanisms of action of quercetin on endometrial stromal cells and warrant future clinical trials to test quercetin and other senolytics for treating endometriosis., (© 2024. The Author(s).)

Background: Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it., Objective: This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways., Findings: Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL-β), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor β1 (TGF-β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1β, IL-6, TNF-α, VEGF, TGFβ, and MMPs in different animal models of diseases., Conclusion: It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Study Objective: To evaluate the efficacy and tolerability of a progestin-only pill containing 4 mg drospirenone (DRSP) as a hormonal therapy for the management of endometriosis-associated symptoms in adolescents and young adults., Design: Retrospective cohort study., Methods: A retrospective chart review was performed of all adolescents who were prescribed DRSP continuously (without placebo) for treatment of endometriosis at a single pediatric tertiary care center between 2019 and 2022. Electronic medical records were reviewed to obtain demographics and clinical characteristics of the patients. Measured outcomes included symptom resolution and medication discontinuation. The study was deemed IRB exempt., Results: A total of 61 patients with endometriosis were prescribed DRSP during the study period, with a median age of 18.9 years (SD 2.3). The majority (97%) were laparoscopically confirmed to have endometriosis, and 85% had stage I disease. Before DRSP use, the most common medications trialed were norethindrone (57%) and norethindrone acetate (68%), and 56% had at least one medical contraindication to receiving estrogen-containing therapy. Of those with follow-up, 52% established an absence of bleeding/spotting, and 67% reported less pain at follow-up. One in 4 patients discontinued DRSP during the study period, most commonly due to breakthrough bleeding., Conclusion: DRSP is a well-tolerated and effective option for the treatment of endometriosis-associated symptoms in adolescents and young adults., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: To evaluate the effect of injecting vasopressin during laparoscopic excision of ovarian endometriomas on ovarian reserve., Evidence Acquisition: Four different databases (PubMed, Cochrane Library, Scopus, and ISI Web of Science) were searched to identify relevant studies in March 2023. We selected randomized controlled trials (RCTs) that compared vasopressin injection in the intervention group versus no injection of vasopressin in the control group among women undergoing laparoscopic cystectomy of ovarian endometriomas. The main outcomes were the amount of bleeding, number of coagulation events, and levels of serum anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH). The available data were extracted and analyzed in a meta-analysis model using RevMan software., Evidence Synthesis: Seven RCTs, involving a total number of 478 patients, were included in our study. The vasopressin group had significantly reduced blood loss amount and number of coagulation events compared to the control group (P=0.004 and P=0.005). There was a significant improvement in the AMH levels within 6 months after surgery in the vasopressin group (MD=0.52, 95% CI: 0.11, 0.93, P=0.01). In addition, the FSH levels within 6 months after laparoscopic cystectomy were significantly reduced with vasopressin injection., Conclusions: Vasopressin injection during laparoscopic cystectomy of ovarian endometriomas is effective in reducing blood loss amount and frequency of coagulation, as well as protecting the ovarian reserve. More trials are encouraged to confirm our findings.

Background and Objective: Endometriosis and adenomyosis are two common diseases that impair women's health, and dienogest is one of the pharmacologic treatments which is the first-line therapeutic option for patients with pelvic pain and individuals who have no desire for immediate pregnancy. The goal of this study was to summarize the current evidence of adverse events associated with dienogest as well as the prevalence of these adverse events during treatment with dienogest., Methods: Several databases (PubMed, Embase, Cochrane Central and Clinicaltrials.gov, etc.) and the US FDA Adverse Event Reporting System (FAERS) Public Dashboard were searched on May 31, 2023, using the topic words alongside free words of dienogest and "adverse reaction". Studies were incorporated into this research if they reported or assessed safety issues or adverse reactions of dienogest during the period of endometriosis treatment or adenomyosis therapy. The extracted information comprised trial design, dienogest and control group demographics, as well as reported side effects., Results: This systematic review comprehended 39 publications in total. The mean age of patients in the included studies was 34.43 years. The follow-up duration varied from 3 to 60 months. Most adverse reactions were common and not serious, and the most common adverse reactions during dienogest medication were abnormal uterine bleeding (55%, 95% CI 37-73%), amenorrhea (17%, 95% CI 2-42%) and swelling (13%, 95% CI 3-28%). Uncommon adverse reactions included dysmenorrhea (0.2%, n = 1), dyspepsia (0.4%, n = 1), and (lower) abdominal pain (1%, 95% CI 0-3%), urticaria (1%, 95% CI 0-3%) and peritonitis (1%, n = 1). Serious adverse reactions including decreased lumbar spine Bone Mineral Density (BMD), depression, peritonitis and so on have been reported. Heterogeneity assessment revealed that patient number and study design are influencing factors to adverse reaction prevalence. Moreover, abdominal pain, diarrhea, nausea and vomiting, back pain and anemia are side effects reported both in the FAERS database and in the systematic review., Conclusions: Dienogest's most frequent side effects were not severe. Dienogest is generally safe for treating endometriosis and adenomyosis. Nevertheless, people should be aware of serious adverse reactions, such as decreased lumbar spine BMD and hemorrhagic shock., (© 2024. The Author(s).)

People with endometriosis use cannabis to manage their symptoms. This study aimed to identify costs, modes of administration, product composition, and self-reported effectiveness for those accessing medicinal cannabis in Australia. There were 192 survey responses analysed. Most (63.5%) used a 'cannabis clinic' doctor, incurring an initial consultation cost of $100-$200+ (10.2% Medicare bulk-billed) and median cannabinoid medicine costs of $300AUD per month. Cost was a major barrier to access, necessitating reducing dosage (76.1%) and/or consuming illicit cannabis (42.9%), despite a prescription. Most (77%) medical consumers used two or more cannabis products, with delta-9-tetrahydrocannabinol predominant oil and flower products most frequently prescribed., (© 2024 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Women with deep infiltrating endometriosis (DIE) can benefit from the use of progestins. Our aim is to explore if levonorgestrel-releasing intrauterine system (LNG-IUS) non inferior to dienogest (DNG) in improving deep endometriosis women's quality of life (QoL). This randomized open-label clinical trial included forty women with DIE assessed using clinical history and physical examination, transvaginal ultrasonography and magnetic resonance of the pelvis without any previous surgical treatment, with two treatments arms. The two groups underwent a 3-month washout of hormonal treatments, and then received either DNG or LNG-IUS for 6 months. QoL was assessed prior to and 6 months after the intervention, using the SF36 and the EHP30. DNG and LNG-IUS showed an increase on all domains of the SF36 ( p  < .001). There was no difference between treatments on the improvement observed ( p  > .05 for all domains). DNG and LNG-IUS, also, showed improvement on all domains of EHP30 ( p  < .001), except "relationship with children" and "feelings about pregnancy." However, there was no statistical difference between treatments for all sections scores ( p  > .05). The treatment of deep endometriosis symptoms using either DNG or LNG-IUS in women with no prior surgical treatment is associated with improvement in QoL. Trial Registration Number : This trial is registered on "The Brazilian Registry of Clinical Trials (ReBECID: RBR-8fjx2jp)," that is part of Primary Registries in the WHO Registry Network, under the title: "Dienogest versus Levonorgestrel IUS on deep endometriosis patient´s QoL without surgery" on June 14, 2021; https://ensaiosclinicos.gov.br/rg/RBR-8fjx2jp.

Background: Baicalein is a flavonoid extracted from the roots of Scutellaria baicalensis G. that has anti-inflammatory and antitumor effects. However, therapeutic mechanisms of baicalein in patients with endometriosis in vivo have yet to be elucidated. As a chronic inflammatory gynecological disease, endometriosis causes pain and infertility, and has no complete treatment to date. Current treatment strategies cause several side effects and have high recurrence rates., Purpose: This study aimed to identify the in vivo therapeutic effects of baicalein on endometriosis and verify the action mechanisms of baicalein, focusing on regulating inflammation., Methods: In this study, an autologous transplant mouse model and patient-derived immortalized human ovarian endometriotic stromal cells (ihOESCs) were used to investigate the therapeutic activities of baicalein. The mouse model was administered with 40 mg/kg baicalein by oral gavage for 4 weeks, and the treatment outcomes of baicalein-treated mice were compared with vehicle- and dienogest-treated groups. ihOESCs were treated with 0-5 μg/ml baicalein for in vitro studies., Results: Baicalein significantly alleviated the progression of endometriosis in mouse models. Baicalein reduced the expression of proinflammatory cytokines in endometriotic lesions and ihOESCs, and cytokine expression and T cell proportions in mouse spleen. in vitro results showed that baicalein increased mitochondrial calcium flux and induced mitochondrial depolarization and ROS generation in ihOESCs. Ultimately, baicalein inactivated the MAPK/PI3K signaling and induced cell death in ihOESCs., Conclusion: In conclusion, baicalein effectively attenuated the progression of endometriosis through its anti-inflammatory activities. Baicalein can be an alternative or supplemental treatment for endometriosis to ameliorate the side effects of hormonal therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Ethnopharmacological Relevance: Guizhi Fuling Wan (GFW), is a traditional Chinese herbal formula that consists of Cinnamomi Ramulus (Guizhi), Poria Cocos(Schw.) Wolf. (Fuling), Persicae Semen (Taoren), Radix Paeoniae Rubra (Chishao), and Cortex Moutan (Mudanpi). This formula has been used in traditional Chinese medicine for more than 1800 years to treat disorders caused by stagnation of circulation and qi (air)., Aim of the Study: Based on pre-clinical and clinical studies, this review aimed to reveal the potential mechanisms of GFW in inhibiting endometriosis. The enhancement of therapeutic effects of western medications on endometriosis by GFW was also shown., Materials and Methods: A bibliographic assessment of publications on "Guizhi Fuling Wan" and "endometriosis" indexed in PubMed, Science Direct, and China National Knowledge Infrastructure (CNKI) was conducted. Five pre-clinical studies and 13 clinical studies were selected for this review. Moreover, the targeted molecules of each herb were first extracted from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform followed by obtaining the endometriosis-related genes from DisGeNET. Subsequently, pathway and gene ontology analyses using David Bioinformatics Resources explored the potential mechanisms of therapeutic effects of GFW in treating endometriosis., Results: Pre-clinical and clinical studies showed that GFW might inhibit the growth of endometriotic lesion through the modulation of immunity, apoptosis-regulating molecules, and angiogenesis-associated factors, while enhancing the therapeutic effects of western medications in treating endometriosis. Furthermore, pathway and gene ontology analyses demonstrated that GFW might attenuate the disease primarily by affecting AGE-RAGE signaling pathway in diabetic complications (hsa04933) as well as pathways involved in Kaposi sarcoma-associated herpesvirus infection (hsa05167), human cytomegalovirus infection (has05163), and fluid shear stress and atherosclerosis (hsa05418). These pathways were all involved in the regulation of inflammation, angiogenesis, and apoptosis and commonly affected by all herbs., Conclusions: The current review revealed that endometriosis is highly associated with aberrant inflammatory, angiogenic, and apoptotic activities. The therapeutic effects of GFW on endometriosis are likely to act through regulating these activities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background : Immunological imbalances characteristic of endometriosis may develop as early as the primary manifestations of the disease in adolescence. Objective : To evaluate subpopulation dynamics of monocytes and lymphocytes in peripheral blood and peritoneal fluid of adolescents with peritoneal endometriosis at diagnosis and after 1-year progestogen therapy. Methods : This study included 70 girls, 13-17 years old, diagnosed laparoscopically with peritoneal endometriosis ( n = 50, main group) or paramesonephric cysts ( n = 20, comparison group). Phenotypes of monocytes and lymphocytes of the blood and macrophages of the peritoneal fluid were analyzed by flow cytometry at diagnosis and during progestogen therapy. Results : Differential blood counts of CD16 + ( p < 0.001) and CD86 + ( p = 0.017) monocytes were identified as independent risk factors for peritoneal endometriosis in adolescents. During the treatment, cytotoxic lymphocytes CD56dimCD16bright ( p = 0.049) and CD206+ monocytes ( p < 0.001) significantly increased while CD163+ monocytes decreased in number ( p = 0.017). The CD56dimCD16bright blood counts before ( p < 0.001) and during progestogen therapy ( p = 0.006), as well as CD206 + blood counts during the treatment ( p = 0.038), were associated with the efficacy of pain relief after 1-year progestogen therapy. Conclusions : Adolescents with peritoneal endometriosis have altered counts of pro- and anti-inflammatory monocytes and lymphocytes both before and after 1-year progestogen therapy, correlating with treatment efficacy and justifying long-term hormonal therapy.