Treatment Of Endometriosis Research Articles

P-308 Relugolix combination therapy vs relugolix monotherapy with transition to relugolix combination therapy for the treatment of endometriosis-associated pain: implications for cumulative benefit/risk profile

Abstract Study question How does the benefit/risk profile compare in women with endometriosis-associated pain who initiated relugolix combination therapy (Relugolix-CT) vs relugolix monotherapy with transition to Relugolix-CT? Summary answer Initiation with Relugolix-CT showed a more favourable benefit/risk profile than relugolix monotherapy: similar efficacy, lower rate of vasomotor symptoms and clinically significant bone loss. What is known already Treatment of endometriosis with a gonadotropin-releasing hormone antagonist monotherapy may be associated with vasomotor symptoms (e.g. hot flushes) and bone mineral density (BMD) loss. Relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg) was developed to minimise these hypoestrogenic adverse effects. In the pivotal SPIRIT 1 and 2 studies and long-term extension (LTE), once-daily Relugolix-CT demonstrated improved dysmenorrhoea early in treatment that was sustained for the duration of therapy over 104 weeks, with BMD loss <1%. This analysis evaluates the benefit of initiation with Relugolix-CT vs relugolix monotherapy and transition to Relugolix-CT on the 104-week benefit/risk profile. Study design, size, duration In the 24-week SPIRIT 1 and 2 studies, premenopausal women with endometriosis and moderate-to-severe pain at baseline were randomised 1:1:1 to placebo, Relugolix-CT, or delayed Relugolix-CT (relugolix 40 mg monotherapy then Relugolix-CT; 12 weeks each). Study completers were eligible to enrol in the open-label, 80-week LTE study where all women received once-daily Relugolix-CT. Efficacy and safety data over 104 weeks from the SPIRIT studies were assessed in this ad hoc analysis. Participants/materials, setting, methods Efficacy and safety were analysed as cumulative proportions, evaluating time to benefit and time to harm. Time to benefit was defined as median time to minimal-to-no dysmenorrhoea (Numerical Rating Scale score ≤1), time to harm as time to first vasomotor symptoms (hyperhidrosis, feeling hot, hot flush, night sweats and flushing), and time to lumbar spine BMD loss from baseline to > 3% among those meeting protocol-specified BMD criteria. Median time was not estimable for safety. Main results and the role of chance In total, 1251 women were treated in the SPIRIT 1 and 2 studies. Of 418 and 417 women in the Relugolix-CT and delayed Relugolix-CT groups, time to minimal-to-no dysmenorrhoea was 8 weeks in 56.3% and 75.7% of women, respectively, increasing to 82.5% and 86.4% at Week 24, 94.5% and 95.9% at Week 52, and 95.3% and 95.9% at Week 104. In both groups, median time to minimal/no dysmenorrhea-associated pain occurred within two menstrual cycles. Cumulative proportion of patients with first vasomotor symptoms in the Relugolix-CT and delayed Relugolix-CT groups was 4.1% and 16.8%, respectively, at Week 4, 13.5% and 35.3% at Week 24, 16.4% and 38.3% at Week 52, and 16.8% and 38.8% at Week 104. Cumulative proportion of patients with first BMD loss >3% in the Relugolix-CT and delayed Relugolix-CT groups was 1.1% and 5.9%, respectively, at Week 12, 10.2% and 23.5% at Week 24, 15.5% and 29.4% at Week 52, and 21.5% and 32.1% at Week 104. Given similar time to pain improvement with higher risk of vasomotor symptoms or clinically significant BMD loss with delayed Relugolix-CT treatment, these findings support the benefit of initiation of Relugolix-CT to mitigate hypoestrogenic adverse events. Limitations, reasons for caution The 80-week, open-label SPIRIT LTE did not have a control group. This evaluation was an ad hoc investigation of SPIRIT data and was not part of the prespecified statistical analysis plan. Comparisons between groups were qualitative, and no statistical inferences were generated. Wider implications of the findings Although Relugolix-CT and relugolix monotherapy showed similar efficacy benefit, monotherapy was associated with a higher risk of vasomotor symptoms and clinically significant BMD loss. The more favourable Relugolix-CT benefit/risk profile vs monotherapy helps fulfil an unmet need for long-term, effective, and well-tolerated hormonal treatment of symptoms of endometriosis. Trial registration number SPIRIT 1 (ClinicalTrials.gov: NCT03204318; EudraCT: 2017–001588–19); SPIRIT 2 (NCT03204331; 2017–001632–19); SPIRIT LTE (NCT03654274; 2017-004066-10)

O-267 Extracellular vesicles as biomarkers of endometriosis

Abstract Study question Can extracellular vesicles serve as biomarkers of endometriosis, particularly for stages I and II, which are difficult to detect by ultrasound? Summary answer Our findings suggest the feasibility of defining a protein signature of endometriosis based on EV cargoes. What is known already Endometriosis is characterised by intraperitoneal lesions of endometrial tissue. Although ultrasound detection of severe endometriosis is possible, the diagnosis of peritoneal lesions currently relies on invasive laparoscopy, which leads to a delay of 8-10 years. We have previously shown that peritoneal fluid (PF) of women with endometriosis contains endometriosis specific EVs. Traced in peripheral blood (PB), EVs could serve as biomarkers of endometriosis, particularly for stages I and II, which are difficult to detect by ultrasound. Study design, size, duration Women 18-45 years of age undergoing laparoscopic surgery for endometriosis or unrelated conditions were invited to participate in our study (HREC 20-159A/HREC 20-882A). Following informed consent, we collected PF and PB samples from n = 101 participants (n = 47 controls, n = 54 cases). Exclusion criteria were pregnancy, malignancy, and menopause. Participants/materials, setting, methods We processed PF and PB samples by differential ultracentrifugation and validated the presence of EVs by nanoparticle tracking analysis (NTA), Western blotting and transmission electron microscopy (TEM). EVs were analysed by untargeted, label-based quantitative proteomics using Tandem Mass Tags (TMT). Data analysis was performed using Proteome Discoverer v2.4 (Thermo Fisher) followed by statistical analysis using R. Candidate biomarker proteins were tested by traditional and automated Western blotting (WES, ProteinSimple). Main results and the role of chance We ascertained the identity of EVs by TEM and NTA (mode size 121.8 ± 18.0 nm (blood, n = 5) and 155.9 ± 37.2 (PF, n = 6)), and signals for syntenin and ALIX in immunoblots as well as expression of CD9, CD63 and CD81 in capture bead-flow cytometry. Proteomic analysis identified 9145 protein groups across all sample groups, with 602 significantly regulated between comparisons (adjusted P-value <0.05). In PF, 533 proteins changed significantly in abundance (245 up/288 down), while in blood, only four proteins changed in abundance. We tested the presence/absence of two of these as candidate markers on PB EV protein preparations from n = 32 samples to date; our best marker showed a sensitivity of 67% and a specificity of 90%; upon exclusion of severe endometriosis cases, sensitivity improved to 80%. Limitations, reasons for caution Because of the changes in vesicle composition and amounts with the menstrual cycle, we have to group the samples by menstrual cycle phase and disease severity. This leaves relatively small numbers per group per condition. Another limitation concerns the relatively small amount of sample liquid and thus, EVs available for analysis. Wider implications of the findings Our findings suggest the feasibility of defining a protein signature of endometriosis based on EV cargoes. A non-invasive clinical test would allow for earlier diagnosis and thus treatment of endometriosis. It would also allow patients to initiate fertility treatment early. Trial registration number not applicable

P-275 Advanced hemostasis assessment in endometriosis: strengthening confidence in the safety of hormonal treatments

Abstract Study question Are women with endometriosis in a state of systemic imbalance between pro- and anti-coagulants? Summary answer Women with endometriosis do not seem to exhibit a coagulation imbalance, at least at a systemic level. What is known already A state of platelet hyperactivation potentially leading to a hypercoagulation status has been described in women with endometriosis. This phenomenon could induce an altered local environment, promoting platelet-mediated paracrine changes in endometrial tissue and also increasing cardiovascular risk, which could be worsened by the use of estrogen dependent hormonal treatments. However, despite a slight difference in some coagulation parameters has been observed between women affected and controls, their levels remain, generally, within the normal reference range. Study design, size, duration This prospective case-control study including 101 women seeking infertility consultation at the Infertility Unit of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano between January and July 2023 aimed to assess hemostasis function beyond traditional coagulation parameters. Participants/materials, setting, methods Blood of women with endometriosis (n = 51) or tubal or male factor infertility (controls; n = 50) was obtained before any ART treatment, and a complete panel of coagulation tests were performed, including basic parameters (aPTT, PT, FVIII, FII, PC, AT, FIV-C, DD, vWF, ADMT) as well as more sophisticated ones, such as Thrombin Generation Assay and Thromboelastometry, providing data on endogenous thrombin potential (ETP), clot formation time (CFT) and maximal clot firmness (MCF). Main results and the role of chance There were no significant differences between cases and controls in terms of age (37 [34-39] vs 36 [33-39]; p = 0.53, respectively) and smoking habits (14% vs 28%; p = 0.14, respectively). Women affected had a lower BMI compared to controls (22.7 [20.9-24.9] vs 21.4 [19.6-23.8]; p = 0.03), as it is usually expected. Results from TGA were expressed as ETP ratio (with-/without- thrombomodulin), and high ones were indicative of thrombomodulin resistance, taken as indexes of procoagulant imbalance; however, it was not different between women with and without the disease (0.75 [0.65-0.82] vs 0.75 [0.66-0.82]; p = 0.82, respectively). Other markers of procoagulant imbalance evaluated by thromboelastometry were also similar between cases and controls, including CFT (66 sec [58-78] vs 65 sec [59-79]; p = 0.69, respectively) and MCF (65 mm [62-68] vs 66mm [63-68]; p = 0.95, respectively). Considering the vWF/ADAMTS13 ratio, recently proposed to be altered in endometriosis, no difference was seen between affected and no-affected women (0.95 [0.76-1.14] vs 0.91 [0.68-1.15]; p = 0.41, respectively). Finally, all the basic coagulation parameters were also similar between groups. Limitations, reasons for caution Our sample size does not allow us to perform sub-analyses regarding the type of endometriosis, although we cannot exclude differences according to the various manifestations of the disease. Also, not having a systemic haemostasis imbalance does not exclude the possibility of local coagulation imbalances. Wider implications of the findings An altered systemic haemostasis could be worsened by the use of hormonal treatments. Our result indicating that there is no coagulation imbalance at a systemic level reassures about the absence of further contraindications to hormonal drugs as a treatment for endometriosis. Trial registration number not applicable

Current Status of the Diagnosis and Treatment of Adenomyosis

Adenomyosis refers to the endometrial glands and mesenchyme that invade the myometrium through the basal layer, and under the action of hormones, repeated bleeding, myofibrous connective tissue hyperplasia formed by diffuse or limited lesions. It is a common disease in women of childbearing age and is more common in women over 40 years of age with menstruation. In recent years, the age of onset of the disease tends to be younger, which may be related to the various uterine surgical operations in clinical work, such as abortion, childbirth, curettage, chronic endometritis, and so on. The mechanism of the disease is currently thought to be due to the invasion of the basal endometrium into the myometrium for growth, but the ectopic endometrium is immature, has reactive changes to estrogen, and is insensitive to progesterone. Its main symptoms are increased menstrual flow, dysmenorrhea, and low fertility, which seriously affect the quality of life of patients. Among them, the incidence of excessive menstrual flow is 40%–50% and the incidence of dysmenorrhea is 15%–30%. There are numerous treatments available for adenomyosis aimed at reducing menstrual flow, relieving dysmenorrhea, and improving fertility. A brief review of the various treatments available for adenomyosis in the clinic is as follows.

P-281 Surgery and IVF for diagnosed ovarian endometriosis and deep infiltrative endometriosis

Abstract Study question To evaluate the effectiveness of surgical treatment of endometrioid cysts and deep infiltrative endometriosis before an IVF program Summary answer Laparoscopic excision of deep infiltrative endometriosis has a positive effect on the reproductive function of women What is known already One of the most severe and aggressive manifestations of endometriosis is deep infiltrative endometriosis. Endometriosis is a socially significant disease that reduces a woman’s quality of life and affects reproductive health. Women with endometriosis often experience severe menstrual and non-menstrual pain affecting the lower abdomen, pelvis or lumbosacral region, profound dyspareunia, dyschezia and dysuria (Uimari et al., 2021) and infertility in 30–50% of cases (Prescott et al.., 2016). Patients with endometriosis suffer from chronic fatigue (Ramin-Wright et al., 2018) and have a higher risk of mental health problems (56.4%) than patients without endometriosis (43.6%) (Pope et al., 2015) Study design, size, duration The our institute is conducting a controlled, non-randomized, retro- and prospective study on genital endometriosis. The study period is from 2012 to the present. Participants/materials, setting, methods The study included 450 women with deep infiltrating endometriosis in combination with infertility All patients were divided into 4 groups Group 1 – 128 patients with deep infiltrative endometriosis, sent for IVF without surgery Group 2 – 297 patients with deep infiltrative endometriosis, initially referred for surgery Group 2a – 156 patients with ovarian cysts, sent for preliminary collection of eggs before surgery Group 2c – 141 patients with ovarian cysts, referred for surgery without prior egg retrieval Main results and the role of chance In group 1, the number of pregnancies occurred was 65.6% (84 women), in group 2a - 71.7% (112 women), in group 2 - 53.9% (76 women). Pregnancy occurred spontaneously in 18 (4.2%) women from group 2 after surgery. In group 2, four women, after three unsuccessful attempts at in vitro fertilization, became pregnant after using donor eggs - the results were excluded from the final pregnancy calculations. In terms of pregnancy, IVF with preliminary surgery (Me: 2.10; Q1-Q-3:0) had a statistically significant advantage compared to IVF without surgery (Me: 5.00; Q1-Q-3:0), and IVF with surgery without egg retrieval (Me:3.0; Q1-Q-3:0). The lowest statistically significant pregnancy rate was recorded during laparoscopic surgery without prior egg retrieval (Me: 6.95; Q1-Q-3:1). When performing a post-hoc analysis, a statistically significant shorter pregnancy time was also found when performing IVF with preliminary laparoscopy and egg freezing: group 1 (M: 126.25; SD111.1), group 2a (M: 79.97; SD: 19.785 ), group 2c (M: 130.50; SD: 82.149) (p = 0.000). During the period of observation of women for twelve years after surgery, 93% of patients noted an improvement in the quality of life and 63.7% of women on average achieved reproductive function after the IVF program for endometriosis. Limitations, reasons for caution no restrictions Wider implications of the findings The results of the IVF program for deep infiltrative endometriosis are statistically higher after surgery, but with preliminary cryopreservation of oocytes. The question of radical resection of the rectum in comparison with shaving when planning an IVF program remains open, which forms the planning of further research in this area. Trial registration number not applicable

O-234 Indication for fertility preservation in patients with endometriosis

Abstract Endometriosis is a complex gynecological condition that not only causes debilitating symptoms but also significantly impacts fertility. As the disease affects approximately 10% of women of reproductive age, addressing fertility preservation strategies becomes paramount. The conventional treatments for endometriosis, such as medical therapy and surgery, often fail to fully address its adverse effects on ovarian reserve and reproductive potential. Consequently, there is a growing interest in exploring fertility preservation options, particularly oocyte cryopreservation (OOC), for endometriosis patients. Despite the prevalence and impact of endometriosis on fertility, comprehensive data and guidelines specifically tailored to fertility preservation in this population remain scarce. The available evidence suggests that endometriosis, particularly when it involves ovarian endometriomas, is associated with a significant reduction in ovarian reserve, as indicated by lower levels of anti-Müllerian hormone (AMH). Surgical interventions, often necessary for managing endometriosis-related complications, can further compromise ovarian function and diminish fertility prospects. However, recent studies have shed light on the potential benefits of OOC in preserving fertility for endometriosis patients. OOC offers a minimally invasive approach with no impact on ovarian reserve compared to other fertility preservation techniques. Despite the lack of randomized controlled trials, our retrospective data have demonstrated promising outcomes, with a notable number needed to treat (NNT) of 16 for one successful pregnancy. This underscores the significance of discussing and considering OOC as part of the treatment plan for endometriosis patients, especially those at risk of ovarian compromise due to the disease or its management. The decision to pursue fertility preservation through OOC should be made on a case-by-case basis, taking into account various factors such as disease severity, patient age, ovarian reserve, and treatment history. French guidelines recommend considering OOC for endometriosis patients with bilateral ovarian endometriomas larger than 3 cm or those with endometriomas on a single ovary. Initiating fertility preservation discussions early, preferably before surgical intervention, allows patients to make informed decisions regarding their reproductive future. It is crucial to acknowledge the challenges and uncertainties associated with fertility preservation in endometriosis patients. Socio-economic factors, patient preferences, and the lack of clear criteria for selecting candidates for OOC pose significant hurdles. Furthermore, the effectiveness and cost-effectiveness of OOC in this population warrant further investigation. In addition to OOC, alternative fertility preservation options, such as ovarian tissue preservation, could be considered, particularly in cases where ovarian stimulation is not feasible or declined by the patient. However, data on the efficacy and safety of ovarian tissue preservation specifically in endometriosis patients are limited, highlighting the need for further research in this area. In conclusion, fertility preservation, particularly through OOC, holds promise for mitigating the adverse effects of endometriosis on ovarian function and fertility. While uncertainties persist, integrating fertility preservation discussions into the comprehensive management of endometriosis is essential. This ensures that patients are empowered to make informed decisions about their reproductive health and maximizes their chances of achieving desired fertility outcomes despite the challenges posed by endometriosis.

O-021 Magnetic Resonance Imaging (MRI) evaluation of Quinagolide Vaginal Ring (QVR) treatment on endometrioma, Deep Infiltrating Endometriosis (DIE), and adenomyosis lesion characteristics: QLARITY trial results

Abstract Study question Can MRI provide a useful assessment of changes to endometrioma, DIE, and adenomyosis lesion burden resulting from QVR treatment? Summary answer MRI successfully measured changes in the number, size, diffusion, and perfusion biomarkers of endometriotic and adenomyotic lesions enabling evaluation of QVR treatment efficacy. What is known already Endometriosis and adenomyosis are associated with chronic pelvic pain, painful menses, and infertility. Determining treatment efficacy is reliant on patient reported outcomes (PRO) which are sensitive to response style effects and may lag changes in underlying pathology. Availability of biomarkers measuring lesion burden could accelerate the development of therapies treating disease rather than managing symptoms. MRI is routinely used in oncology to provide non-invasive biomarkers of treatment effect, a paradigm adapted in this trial. Quinagolide is a dopamine D2 receptor agonist formulated in an extended-release vaginal ring in development for treatment of endometriosis based on presumed inhibition of lesion angiogenesis. Study design, size, duration QLARITY was a randomized, placebo-controlled phase 2 trial investigating the mechanism of action of QVR (1080 µg) administered for four menstrual cycles. Randomization was 1:1 QVR (n = 35) to placebo vaginal ring (n = 32). Primary endpoint was change in the sum of lesion sizes by type from baseline to end of cycle 4 as measured by MRI. Secondary endpoints included changes in lesion volume, PROs and adverse events. MRI-derived imaging biomarkers were analyzed as exploratory endpoints. Participants/materials, setting, methods Women, 18-45 years old with at least one type of lesion (endometrioma, adenomyosis, and/or DIE) visualized by MRI, were enrolled. The analyses were performed by treatment for each of the three lesion types individually and for all types combined. Change in lesion size was analyzed using ANCOVA adjusted for baseline. Number of subjects with lesion regression was analyzed using a Chi-Square test. MRI-derived diffusion and perfusion imaging biomarkers were analyzed as exploratory endpoints. Main results and the role of chance Demographics and baseline characteristics were comparable between treatment groups. Patients had a mean age of 36.1 years and had been diagnosed for 5.25 years on average. Most patients (n = 42, 62.7%) had 2-4 lesions. No statistically significant changes in the sum of lesion sizes or PROs (Numerical Rating Scale, Biberoglu and Behrman Scale, and Endometriosis Health Profile-30) after treatment were noted, when compared to placebo. However, across all lesion types, a statistically significantly higher proportion of QVR patients than placebo patients demonstrated lesion regression of ≥ 65.0% volume (61.3% vs 35.5%, p = 0.042). In the DIE group, lesion regression occurred in more patients treated with QVR than those on placebo (36.8% vs 7.7%, p = 0.016). For diffusion imaging biomarkers, a significant difference in the diffusion coefficient standard deviation of DIE lesions (p = 0.039) was found in the QVR group compared to placebo. For perfusion imaging biomarkers, a statistically significant relationship with the treatment was identified in the endometrioma group for the 25th percentile of difference in fractional volume of extravascular extracellular space (mean difference −1.69, p = 0.009) from baseline. Incidence and severity of adverse events were similar between QVR and placebo. Limitations, reasons for caution MRI cannot currently detect superficial, highly vascularized endometriosis, which may be more responsive to QVR treatment than the more advanced stage of endometriosis (indicated by relatively large endometrioma and DIE) imaged in QLARITY. Moreover, 4 cycles may not be of sufficient duration for optimal treatment of these lesions. Wider implications of the findings QLARITY provides support for the use of MRI to diagnose and characterize changes in endometriotic/adenomyotic lesions. It is also the first MRI characterization of the placebo response in this population. Imaging biomarkers show promise in generating insights. QVR is safe and well tolerated; further studies of its efficacy are warranted. Trial registration number NCT03749109

O-110 Adenomyosis : the challenge of classification and diagnosis

Abstract Study question What does the collaborative document on adenomyosis terminology, classification, and diagnosis by ESGE, ESHRE, and WES provides? Summary answer This good practice recommendations paper offers guidance on the technical aspects, terminology, classification, and diagnosis of adenomyosis in women of reproductive age. What is known already The existing literature on adenomyosis terminology is heterogeneous and confusing. Various classification systems based on ultrasound and MRI have been proposed, yet none have gained international acceptance or clinical validation. The contradictory data on the diagnostic accuracy of these modalities further complicate adenomyosis diagnosis in reproductive-age women. Study design, size, duration A working group from ESGE, ESHRE, and WES has collaborated to write recommendations concerning the terminology, classification, and diagnosis of adenomyosis. Participants/materials, setting, methods Focusing on terminology, classification, and diagnosis, this good practice paper paves the way for further recommendations on the management and surgical treatment of adenomyosis in reproductive-age women. Main results and the role of chance The document overviews adenomyosis terminology and reviews proposed classification systems based on histology, ultrasound, and MRI, concluding with diagnostic recommendations. Limitations, reason for caution Owing the scarcity of evidence, these recommendations predominantly rely on clinical expertise. Wider implications of the findings The recommendations aim to enhance existing adenomyosis guidelines. Study funding/Competing interests All costs were covered by ESHRE funds, with no external funding for the development process or manuscript production.

Surgical Treatment of Patients with Endometriosis in the Certified Endometriosis Centers of the DACH Region - A Subanalysis of the Quality Assurance Study QS ENDO pilot.

Introduction After puberty, at least 10% of all women and girls suffer from endometriosis. Surgery is useful for both the diagnosis and therapy. To date, quality indicators for the surgical treatment of endometriosis are lacking. QS ENDO aims to record the quality of care provided in the DACH region and to introduce quality indicators for the diagnosis and treatment of endometriosis. In the first phase of the study, QS ENDO real, the reality of care was recorded using a questionnaire. The second phase, QS ENDO pilot, investigated the treatment of patients who underwent surgery in certified endometriosis centers in a defined time-period. Material and Methods The surgical data of 10 patients from each of the 44 endometriosis centers in the DACH region was recorded using an online tool. Collected data included the approach used, the endometriosis phenotype, a description of the surgical site, resection status, histological confirmation, the use of a classification, and any complications. All operations were carried out in October 2016 as the defined time-period. The surgical approaches used were compared with the recommendations in the current guidelines. Results The data of 435 patients with a median age of 34years were evaluated. 315 (72.4%) were nulliparous. 120patients had given birth to at least one child and 42.5% (51) of them had delivered their child by caesarean section. About 50% of all patients also had deep infiltrating endometriosis in addition to ovarian endometriosis, and the median NAS score was 7.5. With regards to the surgical treatment, endometriomas were completely resected in 81% (94) of patients. 87.3% of patients underwent resection of peritoneal endometriosis. Forty-one patients had a hysterectomy, with a total hysterectomy carried out in 26 (63.4%) and a supracervical hysterectomy in 15 (36.6%) patients. Of the 59 patients with bowel endometriosis, half had segmental resection and half had shaving of the anterior rectal wall. Complications requiring revision occurred in 0.9% of cases. Conclusion The surgical procedures carried out in the certified endometriosis centers of the DACH region are largely in line with the recommendations for appropriate surgical approaches in the current standard guidelines.

Unveiling the fibrotic puzzle of endometriosis: An overlooked concern calling for prompt action

Endometriosis is a benign, estrogen-dependent, persistent chronic inflammatory heterogeneous condition that features adhesions caused by estrogen-dependent periodic bleeding. It is characterised by a widely spread fibrotic interstitium that comprising of fibroblasts, myofibroblasts, collagen fibres, extracellular proteins, inflammatory cells, and active angiogenesis found outside the uterus. Thus, fibrosis is recognized as a critical component because of which current treatments, such as hormonal therapy and surgical excision of lesions are largely ineffective with severe side effects, high recurrence rates, and significant morbidity. The symptoms include dysmenorrhea (cyclic or non-cyclic), dyspareunia, abdominal discomfort, and infertility. The significant lack of knowledge regarding the underlying root cause, etiology, and complex pathogenesis of this debilitating condition, makes it challenging to diagnose early and to implement therapeutic approaches with minimal side effects presenting substantial hurdles in endometriosis management. Research on understanding the pathogenesis of endometriosis is still ongoing to find biomarkers and develop non-hormonal therapeutic approaches. Current clinical research indicates a close relationship between endometriosis and fibrosis, which is thought to be tightly linked to pain, a major factor for the decline in the patient’s quality of life but little is known about the underlying pathophysiological cellular and molecular signaling pathways that lead to endometriosis-related fibrosis. The available experimental disease models have tremendous challenges in reproducing the human characteristics of the disease to assess treatment effectiveness. Future translational research on the topic has been hindered by the lack of an adequate fibrotic model of endometriosis emphasizing the necessity of etiological exploration. This review article’s goal is to examine recent developments in the field and pinpoint knowledge gaps that exist with a focus on the development of novel fibrotic mouse models for the early diagnosis and treatment of endometriosis and how this knowledge aids in the development of novel anti-fibrotic treatments which opens fresh avenues for a thorough investigation and extended research in the field of endometriosis.

Minimally-invasive multidisciplinary treatment of deep endometriosis: 103 cases

Minimally-invasive multidisciplinary treatment of deep endometriosis: 103 cases

Mapping Single-Cell Transcriptomes of Endometrium Reveals Potential Biomarkers in Endometrial Cancer.

The heterogeneity and dynamic changes of endometrial cells have a significant impact on health as they determine the normal function of the endometrium during the menstrual cycle. Dysfunction of the endometrium can lead to the occurrence of various gynecological diseases. Therefore, deconvolution of immune microenvironment that drives transcriptional programs throughout the menstrual cycle is key to understand regulatory biology of endometrium. Herein, we comprehensively analyzed single-cell transcriptome of 59,397 cells across ten human endometrium samples and revealed the dynamic cellular heterogeneity throughout the menstrual cycle. We identified two perivascular cell subtypes, four epithelial subtypes and four fibroblast cell types in endometrium. Moreover, we inferred the cell type-specific transcription factor (TF) activities and linked critical TFs to transcriptional output of diverse immune cell types, highlighting the importance of transcriptional regulation in endometrium. Dynamic interactions between various types of cells in endometrium contribute to a range of biological pathways regulating differentiation of secretory. Integration of the molecular biomarkers identified in endometrium and bulk transcriptome of 535 endometrial cancers (EC), we revealed five RNA-based molecular subtypes of EC with highly intratumoral heterogeneity and different clinical manifestations. Mechanism analysis uncovered clinically relevant pathways for pathogenesis of EC. In summary, our results revealed the dynamic immune microenvironment of endometrium and provided novel insights into future development of RNA-based treatments for endometriosis and endometrial carcinoma.

Effect of GNRH Agonist and LNG-IUS for Treatment of Adenomyosis

Effect of GNRH Agonist and LNG-IUS for Treatment of Adenomyosis

Efficacy and safety of the combination of estetrol 15 mg/drospirenone 3 mg in a cyclic regimen for the treatment of endometriosis-associated pain and objective gynecological findings: a multicenter, placebo-controlled, double-blind, randomized study

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. A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. A total of 162 Japanese women diagnosed with endometriosis. 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 one-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. Changes in visual analog scale 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. E4/DRSP showed changes in average visual analog scale scores for the most severe pelvic pain (-33.2 mm) from baseline to the end of the six-cycle treatment. The between-group difference was significant (-8.5 mm, two-sided 95% confidence interval: -16.1 to -0.9 mm), showing superiority to placebo (p=0.028). Responder rates, ≥30% and ≥50% reduction in visual analog scale scores from baseline, were larger in the E4/DRSP group than in the placebo group: 53.2% versus 29.6% (p=0.004) and 36.4% versus 12.3% (p<0.001). Objective gynecological findings (induration of the cul-de-sac, pelvic tenderness, 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. E4/DRSP reduced the size of endometriomas and improved quality of life, based on 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. E4/DRSP effectively treats endometriosis-associated pain and improves gynecological findings. E4/DRSP may be a safe, new option for endometriosis treatment with a potentially reduced risk of thromboembolic events.

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

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

Evaluating the safety of high-intensity focused ultrasound treatment for rectal endometriosis: results from a French prospective multicentre study including 60 patients.

Is increasing the intensity of high-intensity focused ultrasound (HIFU) by 30% in the treatment of rectal endometriosis a safe procedure? This study demonstrates the safety of a 30% increase in the intensity of HIFU in the treatment of rectal endometriosis, with no Clavien-Dindo Grade III complications overall, and namely no rectovaginal fistulae. A feasibility study including 20 patients with rectal endometriosis demonstrated, with no severe complications, a significant improvement in digestive disorders, dysmenorrhoea, dyspareunia, and health status, although the volume of the endometriosis nodule did not appear to be reduced. A prospective multicentre cohort study was conducted between 2020 and 2022 with 60 patients with symptomatic rectal endometriosis. Following the failure of medical treatment, HIFU treatment was offered as an alternative to surgery. As the main objective of this study was to examine safety, all adverse events observed during the 6 months of follow-up were analysed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and Clavien-Dindo classifications. Secondary objectives included evaluating the evolution of symptoms using validated questionnaires: gynaecological and digestive pain symptoms with a visual analogue scale, health status with the Medical Outcomes Study 36-item Short Form (SF-36) questionnaire, average post-operative daily pain level, and analgesic medication required in the 10 days following treatment. MRI was also performed at Day 1 to detect early complications. Finally, we performed a blinded MRI review of the evolution of the nodule at 6 months post-treatment. The procedure was performed under spinal anaesthesia for 30% of the patients. The median duration of treatment was 32 min. Fifty-five patients left the hospital on Day 1. MRI scans performed on Day 1 did not highlight any early-onset post-operative complication. Using the Clavien-Dindo classification, we listed 56.7% Grade I events, 3.4% Grade II events, and no events Grade III or higher. At 1, 3, and 6 months, all gynaecologic, digestive and general symptoms, as well as health status, had significantly improved. The evolution of the nodule was also significant (P < 0.001) with a 28% decrease in volume. The main objective was safety and not effectiveness. The study was not randomized and there was no control group. HIFU treatment for rectal endometriosis results in an improvement of symptoms with low morbidity; as such, for selected patients, it could be a valuable alternative to surgical approaches following the failure of medical treatment. The study was funded by the company EDAP TMS. Professors Dubernard and Rousset are consultants for EDAP TMS. Dubernard received travel support from EDAP-TMS. Dr F. Chavrier received industrial grants from EDAP-TMS. He has developed a device for generating focused ultrasonic waves with reduced treatment time. This device has been patented by EDAP-TMS. Dr Lafon received industrial grants from EDAP-TMS; he declares that EDAP-TMS provided funding directly to INSERM to support a young researcher chair in therapeutic ultrasound, which is unrelated to the current study. ClinicalTrials.gov identifier NCT04494568.

Endometriosis: Molecular Pathophysiology and Recent Treatment Strategies-Comprehensive Literature Review.

Endometriosis is an enigmatic disease, with no specific cause or trigger yet discovered. Major factors that may contribute to endometriosis in the pelvic region include environmental, epigenetic, and inflammatory factors. Most experts believe that the primary mechanism behind the formation of endometrial lesions is associated with Sampson's theory of "retrograde menstruation". This theory suggests that endometrial cells flow backward into the peritoneal cavity, leading to the development of endometrial lesions. Since this specific mechanism is also observed in healthy women, additional factors may be associated with the formation of endometrial lesions. Current treatment options primarily consist of medical or surgical therapies. To date, none of the available medical therapies have proven effective in curing the disorder, and symptoms tend to recur once medications are discontinued. Therefore, there is a need to explore and develop novel biomedical targets aimed at the cellular and molecular mechanisms responsible for endometriosis growth. This article discusses a recent molecular pathophysiology associated with the formation and progression of endometriosis. Furthermore, the article summarizes the most current medications and surgical strategies currently under investigation for the treatment of endometriosis.

Surgical and/ or conservative treatment improves quality of life (EHP-30) in patients with endometriosis.

To investigate the quality of life of women with endometriosis before treatment and 3 months after the start of surgical and/or conservative treatment. The sample comprised of 38 patients, of whom 26 underwent surgical treatment, 6 had pharmacological treatment, and 6 had both surgical and pharmacological treatment. The Endometriosis Health Profile (EHP-30) questionnaire in the Czech version and the Numeric Rating Scale (NRS) were used to assess quality of life. The questionnaires were completed before treatment and 3 months into the treatment. When comparing quality of life with the EHP-30 questionnaire, 3 months after the start of treatment, significantly better quality of life scores were found in all domains except the domain "Infertility." Statistically significant improvement was observed in the domains of "Control and powerlessness," "Emotional well-being," and "Pain" (P &lt; 0.0001). Pain assessment using NRS showed subjective improvement in pain during menstruation, outside menstruation, during intercourse, micturition, and defecation. Statistically significant improvement was reported in pain during menstruation and outside menstruation (P &lt; 0.0001). Treatment of endometriosis improves the quality of life and also leads to a subjective reduction of pain intensity as one of the main symptoms of the disease.

The PD-1/PD-L1 Gateway: Peripheral Immune Regulation in the Pathogenesis of Endometriosis.

Endometriosis is a chronic inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, causing pain and infertility. Despite the rather unclear etiopathogenesis, recent studies suggest the involvement of the immune system in the development and progression of endometriosis. The role of the PD-1/PD-L1 axis in the modulation of the immune response in this disease seems to be particularly interesting. This preliminary study aimed to investigate the expression of PD-1 and PD-L1 on T and B lymphocytes in peripheral blood in patients with endometriosis to assess their potential impact on disease progression. Our study involved peripheral blood samples from 80 patients diagnosed with endometriosis and 20 healthy women as a control group were analyzed. Flow cytometry was used to assess the expression of PD-1 and PD-L1 on T and B lymphocytes, and enzyme-linked immunosorbent assays were used to assess their soluble forms in serum and peritoneal fluid.in our research we observe significantly higher expression of PD-1 and PD-L1 on T and B lymphocytes was found in patients with endometriosis compared to the control group. Higher expression of both tested molecules correlated with the stage of endometriosis. The results of our preliminary studies indicate a potential role of the PD-1/PD-L1 axis in the modulation of the immune response in endometriosis. Modified expression of these proteins may contribute to immune evasion by ectopic tissues, supporting their survival and proliferation. These findings suggest that targeting PD-1/PD-L1 could be explored as a therapeutic option for the treatment of endometriosis, though further research with larger sample sizes is necessary to confirm these results and clarify the role of PD-1/PD-L1 in the pathogenesis of the disease.

The Need to Look at Transgender and Gender Diverse People's Health: A Preliminary Descriptive Report on Pain, Sexual Distress, and Health Profile of Five Transmasculine People and One Non-Binary Person with Endometriosis.

The sexual health of transgender and gender diverse (TGD) people with endometriosis has been overlooked, and important emotional experiences, such as sexual distress and its correlates, have been ignored. This has prevented a more comprehensive look at the health experiences of TGD individuals. This descriptive online survey study preliminarily explored the experiences of pain symptoms, sexual distress, and mental health of N = 6 TGD individuals diagnosed with endometriosis. Descriptive results showed a mean delay of 10 years from the onset of symptoms to the diagnosis. Endometriosis-related pain was a common symptom, although with low to moderate intensity. Results also showed higher mean levels of pain impact, powerlessness and lack of control, somatization, depression, anxiety, and sexual distress, and lower mean levels of emotional well-being, social support, and worse self-image compared to reports on cisgender women with endometriosis in the literature. These results suggested that sexual and mental health in the context of TGD people with endometriosis has specificities and may be associated with factors that need to be accounted for to provide comprehensive and socially just healthcare, such as the recognition of the impact of endometriosis treatment on symptoms of gender dysphoria. To achieve sexual health equity for TGD people, continuous and updated professional training and inclusive research with multiple informants are necessary.