Endometriosis: Etiology, pathobiology, and therapeutic prospects.

Endometriosis is a common condition associated with infertility that causes chronic pain in many, but not all, women. It is defined by the presence of endometrial-like tissue outside the uterus. Although the cause and natural history of the disorder remain uncertain, hormonal, neurological, and immunological factors are all implicated in the mechanisms contributing to development of symptoms. Because definitive diagnosis requires surgery, there is often a long diagnostic delay after onset of symptoms. Current interventions for endometriosis have limited efficacy and unacceptable side effects/risks and are associated with high rates of symptom recurrence. Here, we review recent advances in our understanding of the etiology of endometriosis, discuss current diagnostic and treatment strategies, highlight current clinical trials, and consider how recent results offer new avenues for the identification of endometriosis biomarkers and the development of effective non-surgical therapies that are fertility-sparing.

4-Octyl itaconate alleviates experimental autoimmune prostatitis by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway.

BACKGROUND: Chronic prostatitis demonstrates a prevalence rate of nearly 5%-10% among young and middle-aged individuals, significantly affecting their daily lives. Researchers have obtained significant outcomes investigating the anti-inflammatory properties of itaconic acid (IA) and its derivative, 4-Octyl itaconate (4-OI), against diverse chronic inflammatory disorders, such as osteoarthritis and airway inflammation. Nevertheless, whether IA can also exert anti-inflammatory effects in chronic prostatitis requires extensive research and validation. METHODS: Human prostate tissues obtained through transurethral prostate resection (TURP) from individuals were divided into three groups based on different levels of inflammation using hematoxylin and eosin staining (H&E). Subsequently, immunohistochemistry (IHC) was employed to detect the expression of immune-responsive gene 1 (IRG-1) in these different groups. The animal experiment of this study induced experimental autoimmune prostatitis (EAP) in nonobese diabetic mice through intradermal prostate antigen injection and complete Freund's adjuvant. Then, the experimental group received intraperitoneal injections of different doses of 4-OI, while the control group received injections of saline. Western blot (WB), H&E staining, and TUNEL staining helped analyze the prostate tissues, while enzyme-linked immunosorbent assay (ELISA) helped evaluate serum inflammatory factors. Reactive oxygen species, superoxide dismutase (SOD), and malondialdehyde (MDA) were assessed for oxidative stress across experimental groups. RESULTS: IHC analysis of human prostate tissue depicts that IRG-1 expression enhances as prostate inflammation worsens, highlighting the critical role of IA in human prostatitis. The application of 4-OI increased Nrf2/HO-1 expression while inhibited NLRP3 expression following the WB results, and its application resulted in a decrease in cell pyroptosis in prostate tissue, demonstrated by the results of TUNEL staining. Administering a Nrf2 inhibitor ML385 1 h before intraperitoneal injection of 50 mg/kg 4-OI reversed the previous conclusion, further confirming the above conclusion from another perspective. Meanwhile, the ELISA results of serum inflammatory factors (IL-1ß, IL-6, and TNF-α), as well as the measurements of oxidative stress markers MDA and SOD, further confirmed the specific anti-inflammatory effects of 4-OI in EAP. CONCLUSIONS: The present study indicates that 4-OI can alleviates EAP by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway, which may facilitate a novel approach toward prostatitis treatment.

Sodium butyrate alleviates experimental autoimmune prostatitis by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway.

BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) leads to severe discomfort in males and loss of sperm quality. Current therapeutic options have failed to achieve satisfactory results. Sodium butyrate (NaB) plays a beneficial role in reducing inflammation, increasing antioxidant capacities, and improving organ dysfunction; additionally NaB has good safety prospects and great potential for clinical application. The purpose of the current research was to study the effect of NaB on CP/CPPS and the underlying mechanisms using a mouse model of experimental autoimmune prostatitis (EAP) mice. METHODS: The EAP mouse model was successfully established by subcutaneously injecting a mixture of prostate antigen and complete Freund's adjuvant. Then, EAP mice received daily intraperitoneal injections of NaB (100, 200, or 400 mg/kg/day) for 16 days, from Days 26 to 42. We then explored anti-inflammatory potential mechanisms of NaB by studying the effects of Nrf2 inhibitor ML385 and HO-1 inhibitor zinc protoporphyrin on prostate inflammation and pelvic pain using this model. On Day 42, hematoxylin-eosin staining and dihydroethidium staining were used to evaluate the histological changes and oxidative stress levels of prostate tissues. Chronic pelvic pain was assessed by applying Von Frey filaments to the lower abdomen. The levels of inflammation-related cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor were detected by enzyme-linked immunosorbent assay. The regulation of Nrf2/HO-1 signaling pathway and the expression of NLRP3 inflammasome-related protein in EAP mice were detected by western blot analysis assay. RESULTS: Compared with the EAP group, chronic pain development, histological manifestations, and cytokine levels showed that NaB reduced the severity of EAP. NaB treatment could inhibit NLRP3 inflammasome activation. Mechanism studies showed that NaB intervention could alleviate oxidative stress in EAP mice through Nrf2/HO-1 signal pathway. Nrf2/HO-1 pathway inhibitors can inhibit NaB -mediated oxidative stress. The inhibitory effect of NaB on the activation of NLRP3 inflammasome and anti-inflammatory effect can also be blocked by Nrf2/HO-1 pathway. CONCLUSIONS: NaB treatment can alleviates prostatic inflammation and pelvic pain associated with EAP by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway. NaB has the potential as an effective agent in the treatment of EAP.

The role of gut microbiota involved in prostate microenvironment and symptoms improvement in chronic prostatitis/chronic pelvic pain syndrome patients treated with low-intensity extracorporeal shock wave.

BACKGROUND: Low-intensity extracorporeal shockwave therapy (Li-ESWT) is emerging as a promising and safe treatment for Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). In this study, we aimed to investigate the role of the gut microbiota involved in the prostate microenvironment and symptom improvement during the Li-ESWT for CP/CPPS patients. METHODS: CP/CPPS patients not taking antibiotics or other treatments were included. NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IIEF-5) were used to evaluate the effectiveness of Li-ESWT at the end of treatment. Visual analogue scale/score was used to evaluate the pain during procedure. Stool and semen samples were collected before and after Li-ESWT. Shotgun metagenomics analyzed gut microbiota, while ELISA and other diagnostic kits detected biochemical changes in seminal plasma. RESULT: Of the 60 enrolled patients, 52 completed treatment. Li-ESWT response rate was 78.8% (41/52) at end of treatment. Among responders, the subitems of the NIH-CPSI; IPSS; and IIEF-5 scores improved significantly, and the seminal plasma analysis showed decreased TNF-a and MDA levels and increased SOD and Zn2+ levels posttreatment. Gut microbiome analysis indicated that posttreatment, both α and ß diversity increased, and the abundance of certain specific species significantly increased. Fifty-eight pathways significantly enriched posttreatment, notably in branched-chain amino acid synthesis and butyrate synthesis. The abundance of several specific species was found to be significantly higher in non-responders than responders. Among responders, at the species level, some bacteria associated with NIH-CPSI and its subscales, IPSS, IIEF-5, and prostate microenvironment markers (TNF-a, MDA, Zn2+, and SOD) were identified. CONCLUSIONS: Our study demonstrates for the first time that Li-ESWT improves the prostate microenvironment and gut microbiota in CP/CPPS patients. Treatment nonresponse may be associated with a high abundance of specific pathogens before treatment. The gut microbiota could have a significant impact on Li-ESWT response and the prostate microenvironment.

Vaginal and rectal microbiome contribute to genital inflammation in chronic pelvic pain.

BACKGROUND: Chronic pelvic pain (CPP) is a multifactorial syndrome that can substantially affect a patient's quality of life. Endometriosis is one cause of CPP, and alterations of the immune and microbiome profiles have been observed in patients with endometriosis. The objective of this pilot study was to investigate differences in the vaginal and gastrointestinal microbiomes and cervicovaginal immune microenvironment in patients with CPP and endometriosis diagnosis compared to those with CPP without endometriosis and no CPP. METHODS: Vaginal swabs, rectal swabs, and cervicovaginal lavages (CVL) were collected among individuals undergoing gynecologic laparoscopy. Participants were grouped based on patients seeking care for chronic pain and/or pathology results: CPP and endometriosis (CPP-Endo) (n = 35), CPP without endometriosis (n = 23), or patients without CPP or endometriosis (controls) (n = 15). Sensitivity analyses were performed on CPP with endometriosis location, stage, and co-occurring gynecologic conditions (abnormal uterine bleeding, fibroids). 16S rRNA sequencing was performed to profile the microbiome, and a panel of soluble immune mediators was quantified using a multiplex assay. Statistical analysis was conducted with SAS, R, MicrobiomeAnalyst, MetaboAnalyst, and QIIME 2. RESULTS: Significant differences were observed between participants with CPP alone, CPP-Endo, and surgical controls for body mass index, ethnicity, diagnosis of ovarian cysts, and diagnosis of fibroids. In rectal microbiome analysis, both CPP alone and CPP-Endo exhibited lower alpha diversity than controls, and both CPP groups revealed enrichment of irritable bowel syndrome-associated bacteria. CPP-Endo exhibited an increased abundance of vaginal Streptococcus anginosus and rectal Ruminococcus. Patients with CPP and endometrioma (s) demonstrated increased vaginal Streptococcus, Lactobacillus, and Prevotella compared to other endometriosis sites. Further, abnormal uterine bleeding was associated with an increased abundance of bacterial vaginosis-associated bacteria. Immunoproteomic profiles were distinctly clustered by CPP alone and CPP-Endo compared to controls. CPP-Endo was enriched in TNF⍺, MDC, and IL-1⍺. CONCLUSIONS: Vaginal and rectal microbiomes were observed to differ between patients with CPP alone and CPP with endometriosis, which may be useful in personalized treatment for individuals with CPP and endometriosis from those with other causes of CPP. Further investigation is warranted in patients with additional co-occurring conditions, such as AUB/fibroids, which add additional complexity to these conditions and reveal the enrichment of distinct pathogenic bacteria in both mucosal sites. This study provides foundational microbiome-immunoproteomic knowledge related to chronic pelvic pain, endometriosis, and co-occurring gynecologic conditions that can help improve the treatment of patients seeking care for pain.

Urologic Chronic Pelvic Pain Syndrome Flares: A Comprehensive, Systematic Review and Meta-Analysis of the Peer-Reviewed Flare Literature.

PURPOSE: We sought to systematically review and summarize the peer-reviewed literature on urologic chronic pelvic pain syndrome flares, including their terminology, manifestation, perceived triggers, management and prevention strategies, impact on quality of life, and insights into pathophysiologic mechanisms, as a foundation for future empirical research. MATERIALS AND METHODS: We searched 6 medical databases for articles related to any aspect of symptom exacerbations for interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. A total of 1486 abstracts and 398 full-text articles were reviewed, and data were extracted by at least 2 individuals. RESULTS: Overall, we identified 59 articles, including 36 qualitative, cross-sectional, or case-control; 15 cohort-based; and 8 experimental articles. The majority of studies described North American patients with confirmed diagnoses. "Flare" was a commonly used term, but additional terminology (eg, exacerbation) was also used. Most flares involved significant increases in pain intensity, but less data were available on flare frequency and duration. Painful, frequent, long-lasting, and unpredictable flares were highly impactful, even over and above participants' nonflare symptoms. A large number of perceived triggers (eg, diet, stress) and management/prevention strategies (eg, analgesics, thermal therapy, rest) were proposed by participants, but few had empirical support. In addition, few studies explored underlying biologic mechanisms. CONCLUSIONS: Overall, we found that flares are painful and impactful, but otherwise poorly understood in terms of manifestation (frequency and duration), triggers, treatment, prevention, and pathophysiology. These summary findings provide a foundation for future flare-related research and highlight gaps that warrant additional empirical studies.

Psychological characteristics and structural brain changes in women with endometriosis and endometriosis-independent chronic pelvic pain.

STUDY QUESTION: Are there neurobiological changes induced by endometriosis? SUMMARY ANSWER: Women with endometriosis demonstrate specific neurobiological changes distinct from those in patients with chronic pelvic pain (CPP) in the absence of endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is a chronic disease affecting women of reproductive age that presents with pain and infertility often accompanied by comorbid mental disorders. Only one study with a number of limitations has investigated changes in gray matter volumes and functional connectivity in a small group of patients with endometriosis. STUDY DESIGN, SIZE, DURATION: This prospective study recruited 53 women undergoing a laparoscopy due to suspicion of symptomatic endometriosis and 25 healthy, pain-free women. Clinical and psychological characteristics, thermal pain perception, and voxel- and surface-based morphology were assessed in all study participants. Thereafter, the patients underwent a laparoscopy, where endometriosis was either histologically confirmed and removed, or ruled out. Correspondingly, patients were assigned into the group with endometriosis (n = 27) or with endometriosis-independent CPP (n = 26) and compared to the pain-free controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study groups were generally representative for the population of women with endometriosis. Sociodemographic, medical, clinical, and psychological characteristics were collected using various questionnaires and a structured clinical interview. Thermal pain perception and voxel- and surface-based morphometry were assessed using thermode and MRI, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Despite comparable pain intensity and burden of mental disorders, both patient groups demonstrated distinct neurobiological patterns. Women with endometriosis exhibited increased gray matter volume (GMV) in the left cerebellum, lingual gyrus and calcarine gyrus, compared to those with endometriosis-independent CPP. Patients with CPP had decreased GMV in the right cerebellum as compared to controls. Dysmenorrhoea severity correlated positively with GMV in the left inferior parietal lobule, whereas depressive symptoms were associated with decreased GMV in the right superior medial gyrus across patient groups. Dyspareunia correlated negatively with cortical thickness in the left inferior temporal gyrus and left middle temporal gyrus. LIMITATIONS, REASONS FOR CAUTION: The study groups differed in a few baseline-characteristics, including educational levels, smoking and BMI. While measuring pain perception thresholds, we did not attempt to mimic CPP by placement of the thermode on the abdominal wall. WIDER IMPLICATIONS OF THE FINDINGS: Changes in gray matter volume associated with endometriosis differ from those observed in women with endometriosis-independent CPP. Our results underline an involvement of the cerebellum in pain perception and the pathogenesis of pain associated with endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the START Program of the Faculty of Medicine, RWTH Aachen, Germany, and supported by the International Research Training Group (IRTG 2150) of the German Research Foundation (DFG)-269953372/GRK2150, Germany. S.T. was supported by postdoctoral fellowship of the Faculty of Medicine, RWTH Aachen, Germany. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: DRKS00021236.

Proposal for targeted, neo-evolutionary-oriented secondary prevention of early-onset endometriosis and adenomyosis. Part II: medical interventions.

According to consistent epidemiological data, the slope of the incidence curve of endometriosis rises rapidly and sharply around the age of 25 years. The delay in diagnosis is generally reported to be between 5 and 8 years in adult women, but it appears to be over 10 years in adolescents. If this is true, the actual onset of endometriosis in many young women would be chronologically placed in the early postmenarchal years. Ovulation and menstruation are inflammatory events that, when occurring repeatedly for years, may theoretically favour the early development of endometriosis and adenomyosis. Moreover, repeated acute dysmenorrhoea episodes after menarche may not only be an indicator of ensuing endometriosis or adenomyosis, but may also promote the transition from acute to chronic pelvic pain through central sensitization mechanisms, as well as the onset of chronic overlapping pain conditions. Therefore, secondary prevention aimed at reducing suffering, limiting lesion progression, and preserving future reproductive potential should be focused on the age group that could benefit most from the intervention, i.e. severely symptomatic adolescents. Early-onset endometriosis and adenomyosis should be promptly suspected even when physical and ultrasound findings are negative, and long-term ovulatory suppression may be established until conception seeking. As nowadays this could mean using hormonal therapies for several years, drug safety evaluation is crucial. In adolescents without recognized major contraindications to oestrogens, the use of very low-dose combined oral contraceptives is associated with a marginal increase in the individual absolute risk of thromboembolic events. Oral contraceptives containing oestradiol instead of ethinyl oestradiol may further limit such risk. Oral, subcutaneous, and intramuscular progestogens do not increase the thromboembolic risk, but may interfere with attainment of peak bone mass in young women. Levonorgestrel-releasing intra-uterine devices may be a safe alternative for adolescents, as amenorrhoea is frequently induced without suppression of the ovarian activity. With regard to oncological risk, the net effect of long-term oestrogen-progestogen combinations use is a small reduction in overall cancer risk. Whether surgery should be considered the first-line approach in young women with chronic pelvic pain symptoms seems questionable. Especially when large endometriomas or infiltrating lesions are not detected at pelvic imaging, laparoscopy should be reserved to adolescents who refuse hormonal treatments or in whom first-line medications are not effective, not tolerated, or contraindicated. Diagnostic and therapeutic algorithms, including self-reported outcome measures, for young individuals with a clinical suspicion of early-onset endometriosis or adenomyosis are proposed.

Towards comprehensive management of symptomatic endometriosis: beyond the dichotomy of medical versus surgical treatment.

Except when surgery is the only option because of organ damage, the presence of suspicious lesions, or the desire to conceive, women with endometriosis-associated pain often face a choice between medical and surgical treatment. In theory, the description of the potential benefits and potential harms of the two alternatives should be standardized, unbiased, and based on strong evidence, enabling the patient to make an informed decision. However, doctor's opinion, intellectual competing interests, local availability of specific services and (mis)information obtained from social media, and online support groups can influence the type of advice given and affect patients' choices. This is compounded by the paucity of robust data from randomized controlled trials, and the anxiety of distressed women who are eager to do anything to alleviate their disabling symptoms. Vulnerable patients are more likely to accept the suggestions of their healthcare provider, which can lead to unbalanced and physician-centred decisions, whether in favour of either medical or surgical treatment. In general, treatments should be symptom-orientated rather than lesion-orientated. Medical and surgical modalities appear to be similarly effective in reducing pain symptoms, with medications generally more successful for severe dysmenorrhoea and surgery more successful for severe deep dyspareunia caused by fibrotic lesions infiltrating the posterior compartment. Oestrogen-progestogen combinations and progestogen monotherapies are generally safe and well tolerated, provided there are no major contraindications. About three-quarters of patients with superficial peritoneal and ovarian endometriosis and two-thirds of those with infiltrating fibrotic lesions are ultimately satisfied with their medical treatment although the remainder may experience side effects, which may result in non-compliance. Surgery for superficial and ovarian endometriosis is usually safe. When fibrotic infiltrating lesions are present, morbidity varies greatly depending on the skill of the individual surgeon, the need for advanced procedures, such as bowel resection and ureteral reimplantation, and the availability of expert colorectal surgeons and urologists working together in a multidisciplinary approach. The generalizability of published results is adequate for medical treatment but very limited for surgery. Moreover, on the one hand, hormonal drugs induce disease remission but do not cure endometriosis, and symptom relapse is expected when the drugs are discontinued; on the other hand, the same drugs should be used after lesion excision, which also does not cure endometriosis, to prevent an overall cumulative symptom and lesion recurrence rate of 10% per postoperative year. Therefore, the real choice may not be between medical treatment and surgery, but between medical treatment alone and surgery plus postoperative medical treatment. The experience of pain in women with endometriosis is a complex phenomenon that is not exclusively based on nociception, although the role of peripheral and central sensitization is not fully understood. In addition, trauma, and especially sexual trauma, and pelvic floor disorders can cause or contribute to symptoms in many individuals with chronic pelvic pain, and healthcare providers should never take for granted that diagnosed or suspected endometriosis is always the real, or the sole, origin of the referred complaints. Alternative treatment modalities are available that can help address most of the additional causes contributing to symptoms. Pain management in women with endometriosis may be more than a choice between medical and surgical treatment and may require comprehensive care by a multidisciplinary team including psychologists, sexologists, physiotherapists, dieticians, and pain therapists. An often missing factor in successful treatment is empathy on the part of healthcare providers. Being heard and understood, receiving simple and clear explanations and honest communication about uncertainties, being invited to share medical decisions after receiving detailed and impartial information, and being reassured that a team member will be available should a major problem arise, can greatly increase trust in doctors and transform a lonely and frustrating experience into a guided and supported journey, during which coping with this chronic disease is gradually learned and eventually accepted. Within this broader scenario, patient-centred medicine is the priority, and whether or when to resort to surgery or choose the medical option remains the prerogative of each individual woman.

Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study.

STUDY QUESTION: What is the efficacy and safety of long-term treatment (up to 2 years) with relugolix combination therapy (CT) in women with moderate to severe endometriosis-associated pain? SUMMARY ANSWER: For up to 2 years, treatment with relugolix CT improved menstrual and non-menstrual pain, dyspareunia, and function in women with endometriosis; after an initial decline of <1%, the mean bone mineral density (BMD) remained stable with continued treatment. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition characterized by symptoms of dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia, which have a substantial impact on the lives of affected women, their partners, and families. SPIRIT 1 and 2 were phase 3, randomized, double-blind, placebo-controlled studies of once-daily relugolix CT (relugolix 40 mg, oestradiol 1 mg, norethisterone acetate 0.5 mg) in premenopausal women (age 18-50 years) with endometriosis and moderate-to-severe dysmenorrhea and NMPP. These trials demonstrated a significant improvement of dysmenorrhea, NMPP, and dyspareunia in women treated with relugolix CT, with minimal decline (<1%) in BMD versus placebo at 24 weeks. STUDY DESIGN, SIZE, DURATION: Patients participating in this open-label, single-arm, long-term extension (LTE) study of the 24-week SPIRIT pivotal studies (SPIRIT 1 and 2) received up to an additional 80 weeks of once-daily oral relugolix CT treatment between May 2018 and January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women with confirmed endometriosis and moderate to severe dysmenorrhea and NMPP who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials; Giudice et al., 2022) and who met all entry criteria were eligible to enrol. Two-year results were analysed by treatment group based on original randomization in pivotal studies: relugolix CT, delayed relugolix CT (relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT), or placebo→relugolix CT (placebo for 24 weeks followed by relugolix CT). The primary endpoints of the LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end-of-treatment (EOT). A responder was a participant who achieved a predefined, clinically meaningful reduction from baseline in Numerical Rating Scale (NRS) scores (0 = no pain, 10 = worst pain imaginable) for the specific pain type with no increase in analgesic use. The predefined clinically meaningful threshold for dysmenorrhea was 2.8 points and for NMPP was 2.1 points. Secondary efficacy endpoints included change from baseline in Endometriosis Health Profile-30 (EHP-30) pain domain scores, a measure of the effects of endometriosis-associated pain on daily activities (function), NRS scores for dysmenorrhea, NMPP, dyspareunia, and overall pelvic pain, and analgesic/opioid use. Safety endpoints included adverse events and changes in BMD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 1261 randomized patients, 1044 completed the pivotal studies, 802 enrolled in the LTE, 681 completed 52 weeks of treatment, and 501 completed 104 weeks of treatment. Demographics and baseline characteristics of the extension population were consistent with those of the original randomized population. Among patients randomized to relugolix CT at pivotal study baseline who continued in the LTE (N = 277), sustained improvements in endometriosis-associated pain were demonstrated through 104 weeks. The proportion of responders at Week 104/EOT for dysmenorrhea and NMPP was 84.8% and 75.8%, respectively. Decreases in dyspareunia and improvement in function assessed by EHP-30 pain domain were also sustained over 2 years. At Week 104/EOT, 91% of patients were opioid-free and 75% of patients were analgesic-free. Relugolix CT over 104 weeks was well tolerated with a safety profile consistent with that observed over the first 24 weeks. After initial least squares mean BMD loss <1% at Week 24, BMD plateaued at Week 36 and was sustained for the duration of 104 weeks of treatment. Efficacy and safety results were generally consistent in women in the placebo→relugolix CT and delayed relugolix CT groups. LIMITATIONS, REASONS FOR CAUTION: The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Of the 802 patients who were enrolled in this LTE study, 681 patients (84.9%) and 501 patients (62.5%) of patients completed 52 and 104 weeks of treatment, respectively. In addition, there currently are no comparative data to other hormonal medications. Finally, a third (37.4%) of the study population terminated participation early. WIDER IMPLICATIONS OF THE FINDINGS: In conclusion, relugolix CT offers an additional option to help address an important unmet clinical need for effective, safe, and well-tolerated medical treatments for endometriosis that can be used longer-term, reducing the need for opioids and improving quality of life. The findings from this study may help support the care of women with endometriosis seeking longer-term effective medical management of their symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Myovant Sciences GmbH (now Sumitomo Pharma Switzerland GmbH). C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva, and Chair of ESHRE Endometriosis Guideline Group (all funds went to the University of Oxford); N.P.J. reports personal fees from Myovant Sciences, during the conduct of the study, personal fees from Guerbet, personal fees from Organon, personal fees from Roche Diagnostics; S.A.-S. reports personal fees from Myovant Sciences, personal fees from Bayer, personal fees from Abbvie, personal fees from UpToDate; J.S.P., and R.B.W. are employees and shareholders of Myovant Sciences; J.C.A.F. and S.J.I. are shareholders of Myovant Sciences (but at time of publicaion are no longer employess of Myovant Sciences); M.S.A. and K.W. have no conflicts to declare; V.M. is a consultant to Myovant; L.C.G. reports personal fees from Myovant Sciences, Inc and Bayer. The authors did not receive compensation for manuscript writing, review, and revision. TRIAL REGISTRATION NUMBER: NCT03654274.

Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3).

STUDY QUESTION: Does linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone or 200 mg in combination with add-back therapy (ABT) (1.0 mg estradiol; 0.5 mg norethindrone acetate, also known as norethisterone acetate [NETA]) demonstrate better efficacy than placebo in the management of endometriosis-related dysmenorrhea and non-menstrual pelvic pain? SUMMARY ANSWER: Combining 200 mg linzagolix with ABT was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain at 3 months of therapy, while a daily dose of 75 mg linzagolix yielded a significant decrease only in dysmenorrhea at 3 months. WHAT IS KNOWN ALREADY?: A previously published Phase 2, dose-finding study reported that at a dose of 200 mg daily, linzagolix promotes full suppression of estradiol secretion to serum levels below 20 pg/ml and noted that the addition of ABT may be needed to manage hypoestrogenic side effects. At lower doses (75 mg and 100 mg/day), linzagolix maintains estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. STUDY DESIGN, SIZE, DURATION: EDELWEISS 3 was a multicenter, prospective, randomized, placebo-controlled, double-blind, double-dummy Phase 3 study to evaluate the safety and efficacy of linzagolix for the treatment of moderate-to-severe endometriosis-associated pain. Treatment was administered orally once daily for up to 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the EDELWEISS 3 trial, 486 subjects with moderate-to-severe endometriosis-associated pain were randomized at a 1:1:1 ratio to one of the three study groups: placebo, 75 mg linzagolix alone or 200 mg linzagolix in association with ABT. Pain was measured daily on a verbal rating scale and recorded in an electronic diary. MAIN RESULTS AND THE ROLE OF CHANCE: At 3 months, the daily 200 mg linzagolix dose with ABT met the primary efficacy objective, showing clinically meaningful and statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain, with stable or decreased use of analgesics. The proportion of responders for dysmenorrhea in the 200 mg linzagolix with ABT group was 72.9% compared with 23.5% in the placebo group (P < 0.001), while the rates of responders for non-menstrual pelvic pain were 47.3% and 30.9% (P = 0.007), respectively. The 75 mg linzagolix daily dose demonstrated a clinically meaningful and statistically significant reduction in dysmenorrhea versus placebo at 3 months. The proportion of responders for dysmenorrhea in the 75 mg linzagolix group was 44.0% compared with 23.5% in the placebo group (P < 0.001). Although the 75 mg dose showed a trend toward reduction in non-menstrual pelvic pain at 3 months relative to the placebo, it was not statistically significant (P = 0.279). Significant improvements in dyschezia and overall pelvic pain were observed in both linzagolix groups when compared to placebo. Small improvements in dyspareunia scores were observed in both linzagolix groups but they were not significant. In both groups, hypoestrogenic effects were mild, with low rates of hot flushes and bone density loss of <1%. A daily dose of 200 mg linzagolix with ABT or 75 mg linzagolix alone was found to significantly reduce dysmenorrhea and non-menstrual pelvic pain also at 6 months of therapy. LIMITATIONS, REASONS FOR CAUTION: Efficacy was compared between linzagolix groups and placebo; however, it would be useful to have results from comparative studies with estro-progestogens or progestogens. It will be important to ascertain whether gonadotropin-releasing hormone antagonists have significant benefits over traditional first-line medications. WIDER IMPLICATIONS OF THE FINDINGS: Linzagolix administered orally once daily at a dose of 200 mg in combination with add-back therapy (ABT) demonstrated better efficacy and safety than placebo in the management of moderate-to-severe endometriosis-associated pain. The quality of life was improved and the risks of bone loss and vasomotor symptoms were minimized due to the ABT. The 75 mg dose alone could be suitable for chronic treatment of endometriosis-associated pain without the need for concomitant hormonal ABT, but further research is needed to confirm this. If confirmed, it would offer a viable option for women who do not want to wish to have ABT or for whom it is contraindicated. STUDY FUNDING/COMPETING INTEREST(S): Funding for the EDELWEISS 3 study was provided by ObsEva (Geneva, Switzerland). Analysis of data and manuscript writing were partially supported by ObsEva (Geneva, Switzerland), Theramex (London, UK) and Kissei (Japan) and grant 5/4/150/5 was awarded to M.-M.D. by FNRS. J.D. was a member of the scientific advisory board of ObsEva until August 2022, a member of the scientific advisory board of PregLem, and received personal fees from Gedeon Richter, ObsEva and Theramex. J.D. received consulting fees, speakers' fees, and travel support from Gedeon Richter, Obseva and Theramex, which was paid to their institution. C.B. has received fees from Theramex, Gedeon Richter, and Myovant, and travel support from Gedeon Richter-all funds went to the University of Oxford. He was a member of the data monitoring board supervising the current study, and served at an advisory board for endometriosis studies of Myovant. H.T. has received grants from Abbvie and was past president of ASRM. F.C.H. has received fees from Gedeon Richter and Theramex. O.D. received fees for lectures from Gedeon Richter and ObsEva and research grants for clinical studies from Preglem and ObsEva independent from the current study. A.H. has received grants from NIHR, UKRI, CSO, Wellbeing of Women, and Roche Diagnostics; he has received fees from Theramex. A.H.'s institution has received honoraria for consultancy from Roche Diagnostics, Gesynta, and Joii. M.P. has nothing to declare. F.P. has received fees from Theramex. S.P.R. has been a member of the scientific advisory board of Gedeon Richter and received fees from Gedeon Richter. A.P. and M.B. are employees of Theramex. E.B. was an employee of ObsEva, sponsor chair of the data monitoring board supervising the current study, and has been working as a consultant for Theramex since December 2022; she owns stock options in ObsEva. M.-M.D. has received fees and travel support from Gedeon Richter and Theramex. TRIAL REGISTRATION NUMBER: NCT03992846. TRIAL REGISTRATION DATE: 20 June 2019. DATE OF FIRST PATIENT'S ENROLLMENT: 13 June 2019.

Adenomyosis diagnosis among adolescents and young women with dysmenorrhoea and heavy menstrual bleeding.

RESEARCH QUESTION: What is the prevalence of adenomyosis at ultrasonography among adolescents and young women reporting dysmenorrhoea and/or heavy menstrual bleeding (HMB)? DESIGN: This observational cohort study involved adolescents and young women referred for dysmenorrhoea and/or HMB to the Adolescent Medicine Unit at Careggi University Hospital, Italy. Patients with endometriosis and bleeding disorders were excluded. Transvaginal ultrasonography or transrectal sonography using a transvaginal probe was performed. The myometrium was described according to the Morphological Uterus Sonographic Assessment criteria. Details of baseline characteristics, clinical data and symptoms were collected. The presence of sonographic features of adenomyosis and the association between imaging findings and clinical symptoms were evaluated. RESULTS: The cohort included 95 patients aged between 13 and 25 years, referred for dysmenorrhoea (88.4%), HMB (23.2%) or both (13.7%). According to the MUSA criteria the sonographic diagnosis of adenomyosis was made in 27.4% of patients, with the diffuse type the most prevalent. Uterine wall asymmetry, hyperechoic intramyometrial islands, translesional vascularity and an interrupted junctional zone were the most common features. Patients with imaging findings of adenomyosis had significantly higher rates of HMB than those with a normal myometrial appearance (38.5% versus 17.4%, P = 0.030). In addition, the coexistence of dysmenorrhoea and HMB was significantly associated with adenomyosis (odds ratio 5.68, 95% confidence interval 1.65-19.5). CONCLUSIONS: Adenomyosis may be diagnosed among teenagers and young women referred with dysmenorrhoea and/or HMB. The clinical presentation is relevant for the diagnosis, with HMB alone and HMB plus dysmenorrhoea significantly associated with the sonographic identification of adenomyosis.

Screening women in young adulthood for disabling dysmenorrhoea: a nationwide cross-sectional study from the CONSTANCES cohort.

RESEARCH QUESTION: How do different warning indicators help to identify disabling dysmenorrhoea among women in young adulthood? DESIGN: A nationwide cross-sectional study of women aged 18-25 years from the CONSTANCES cohort was constructed. Disability was assessed with the Global Activity Limitation Indicator question 'For the past 6 months, have you been limited in routine activities?Yes, severely limited/Yes, limited/ No, not limited'. Dysmenorrhoea pain intensity and other chronic pelvic pain symptoms (dyspareunia and non-menstrual pain) were evaluated according to questions from a specific questionnaire. Probability of disability was estimated using a logistic prediction model according to dysmenorrhoea intensity, other indicators of pelvic pain symptoms and other obvious covariates. The results of the predictive model of disabling dysmenorrhoea were presented on a nomogram. RESULTS: Among 6377 women, the rate of disability was estimated at 7.5%. Increased intensity of dysmenorrhoea (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.04-1.13), increased frequency of dyspareunia (from OR 1.69, 95% CI 1.33-2.14 up to OR 3.41, 95% CI 2.16-5.38) non-menstrual chronic pelvic pain (OR 1.75, 95% CI 1.40-2.19), body mass index over 25 kg/m2 (OR 1.45, 95% CI 1.17-1.80) and non-use of the hormonal contraceptive pill (OR 1.29, 95% CI 1.05-1.59) were significantly associated with disability. According to the nomogram, a predicted probability of 15% or more could be chosen as a threshold. This represents almost 4.6% of young women in this sample being classified at risk of disabling dysmenorrhoea. CONCLUSIONS: Dysmenorrhoea pain intensity and associated pelvic pain symptoms are warning indicators that can be measured to help screen young women who may suffer from disabling dysmenorrhoea.

Obstetric outcomes of nulliparous women with pelvic pain undergoing fertility treatment.

RESEARCH QUESTION: Is there any association between pelvic pain and primary caesarean delivery for patients undergoing assisted reproductive technology (ART) treatment? DESIGN: Retrospective cohort study of nulliparous patients with singleton pregnancies who underwent ART treatment and achieved a live birth between 2012 and 2020. Cases included patients diagnosed with pelvic pain. A 3:1 ratio propensity-score-matched population of patients without a history of pelvic pain was included as the control group. Comparative statistics were performed using chi-squared test and Student's t-test. A multivariate regression analysis was conducted to evaluate the association between pelvic pain and mode of delivery. RESULTS: One hundred and seventy-four patients with pelvic pain were compared with 575 controls. Patients with pelvic pain reported a significantly longer duration of infertility compared with controls (18.98 ± 20.2 months versus 14.06 ± 14.06 months; P = 0.003). Patients with pelvic pain had a significantly higher rate of anxiety disorders (115 ± 21.9 versus 55 ± 31.6; P = 0.009) and use of anxiolytics at embryo transfer (17 ± 3.2 versus 12 ± 6.9; P = 0.03) compared with controls. In addition, patients with pelvic pain had a higher rate of primary caesarean delivery compared with controls (59.8% versus 49.0%; P = 0.01). After adjusting for multiple variables, a significant association was found between pelvic pain and increased odds of primary caesarean delivery (adjusted OR 1.48, 95% CI 1.02-2.1). CONCLUSION: Patients with pelvic pain have significantly higher odds of primary caesarean delivery compared with patients without a history of pelvic pain. The infertility outpatient setting may be uniquely positioned to identify patients at risk for undergoing primary caesarean delivery, and could facilitate earlier intervention for pelvic floor physical therapy during the preconception and antepartum periods.

Why do oestrogens matter: systematic review and meta-analysis assessing GnRH antagonists, considering add-back therapy, for endometriosis-associated pain.

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.

A prospective study of dietary patterns and the incidence of endometriosis diagnosis.

BACKGROUND: Although endometriosis is a common condition-affecting ∼10% of premenopausal individuals-its etiology is unknown. Diet receives a lot of attention from patients, but studies of the role of diet are limited. Examining dietary patterns is essential to provide new insight. OBJECTIVE: We sought to determine whether dietary patterns are associated with laparoscopically-confirmed endometriosis diagnosis. STUDY DESIGN: We conducted a prospective cohort study among 81,997 premenopausal participants of the Nurses' Health Study II, who were followed from 1991-2015. Diet was assessed with validated food frequency questionnaires every 4 years. We examined 6 dietary patterns: Western, Prudent, Alternative Healthy Eating Index, Dietary Approaches to Stop Hypertension, an estrogen-associated pattern, and a proinflammatory pattern. Cox proportional hazard ratios and 95% confidence intervals were used to quantify the association between each of these patterns and laparoscopically-confirmed endometriosis diagnosis. RESULTS: Three thousand eight hundred ten incident cases of endometriosis were diagnosed during 24 years of follow-up. Adherence to the Alternative Healthy Eating Index, reflecting a healthier dietary pattern, was associated with a 13% lower risk of endometriosis diagnosis (fifth vs first quintile 95% confidence interval, 0.78-0.96; Ptrend=.02). Participants in the highest quintile of the Western dietary pattern, characterized by high intake of red meat, processed meat, refined grains, and desserts, had a 27% higher risk of endometriosis diagnosis than those in the lowest quintile (95% confidence interval, 1.09-1.47; Ptrend=.004). The Prudent, Dietary Approaches to Stop Hypertension, and estrogen-associated dietary patterns did not demonstrate clear associations with endometriosis risk, and there was the suggestion of a higher risk of endometriosis diagnosis among those with a higher proinflammatory diet score (hazard ratio for fifth vs first quintile, 1.10 [95% confidence interval, 0.99-1.23]; Ptrend=.01). CONCLUSION: Our results suggest that consuming a dietary pattern that adheres to the Alternative Healthy Eating Index-2010 recommendations lowers the risk of endometriosis diagnosis, potentially through a beneficial impact on pelvic pain. In addition, consuming a less healthy diet high in red/processed meats and refined grains may have a detrimental impact on endometriosis symptoms.

Effectiveness of nonpharmacological conservative therapies for chronic pelvic pain in women: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of nonpharmacological conservative therapies for women with CPP. DATA SOURCES: A systematic search of electronic databases (Amed, CINAHL, PsycINFO, SportDiscuss, Medline, PubMed, Embase, and Cochrane Central Register of Controlled Trials) was performed in January 2023, and updated in December 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing a nonpharmacological conservative therapy to inert (eg, placebo, usual care) or nonconservative (eg, surgical, pharmacological) treatment were included. Conservative therapies of interest to this review were: multimodal physical therapy, predominantly psychological approaches, acupuncture, and other tissue-based monotherapies (eg, electrophysical agents, manual stretching). STUDY APPRAISAL AND SYNTHESIS METHODS: All study data were aggregated, and analyses of the included studies were performed. Effects on pain; sexual measures; psychological and physical function; health-related quality of life; symptom severity/bother; pelvic floor muscle function and morphometry; perceived improvement; and adverse events were analyzed. Meta-analyses (random effects model) were conducted using postintervention scores for data that included similar interventions and outcomes. Standardized mean differences were calculated. A narrative summary of findings that could not be included in the meta-analysis is provided. The quality of the evidence was assessed with the Physiotherapy Evidence Database scale and the certainty of evidence with Grading of Recommendations, Assessment, Development, and Evaluations criteria. RESULTS: Of 5776 retrieved studies, 38 randomized controlled trials including 2168 women (mean age 35.1±8.6) were included. Meta-analyses revealed that multimodal physical therapy resulted in lower pain intensity compared to inert or nonconservative treatments in both the short (standardized mean difference -1.69, 95% confidence interval -2.54, -0.85; high certainty) and intermediate-terms (standardized mean difference -1.82, 95% confidence interval -3.13, -0.52; moderate certainty), while predominantly psychological approaches resulted in no difference in pain intensity (standardized mean difference -0.18, 95% confidence interval -0.56, 0.20; moderate certainty) and a slight difference in sexual function (standardized mean difference -0.28, 95% confidence interval -0.52, -0.04; moderate certainty). The level of evidence regarding the meta-analysis of the effects of acupuncture on pain intensity (standardized mean difference 1.08, 95% confidence interval -1.38, 3.54, nonstatistically significant results in favor of control treatment) precluded any statement of certainty. A limited number of trials investigated individual tissue-based monotherapies, providing a restricted body of evidence. CONCLUSION: This systematic review with meta-analysis revealed that multimodal physical therapy is effective in women with chronic pelvic pain with a high certainty of evidence.

Topical lidocaine for pessary removal and reinsertion pain reduction: a randomized clinical trial.

BACKGROUND: Vaginal pessaries are an inexpensive nonsurgical treatment for pelvic organ prolapse and stress urinary incontinence. Pessary maintenance includes periodic removal, cleaning, and reinsertion, which can be painful. Lidocaine-prilocaine cream has been shown to significantly reduce pain during pessary maintenance exams. In some practices, lidocaine hydrochloride (HCl) 2% jelly may be more readily available and serve as an alternative to lidocaine-prilocaine cream. However, the effect of lidocaine HCl 2% jelly use during pessary maintenance exams has not been tested. OBJECTIVE: To estimate the effect of lidocaine HCl 2% jelly versus lubricating jelly on pain at the time of office pessary removal and reinsertion. STUDY DESIGN: This study is a single-blind randomized clinical trial among patients presenting to a urogynecology office at a tertiary care center. Participants were randomized to the application of 5 cc of lidocaine HCl 2% jelly or a water-based lubricating jelly 5 minutes before pessary removal. Visual analog scale pain scores were collected from the participants at baseline, at pessary removal, and at pessary reinsertion. The primary outcome was the visual analog scale pain score at the time of pessary removal. A sample size of 33 per group (n=66) was planned to estimate an absolute mean difference in visual analog pain scale of 2.05 cm at the time of pessary removal. RESULTS: Between September 2022 and June 2023, 192 women were screened, and 66 were enrolled. Thirty-three participants were randomized into the lubricating jelly group and 33 participants were randomized into the lidocaine hydrochloride (HCl) 2% jelly group. The 2 groups were similar in baseline characteristics. Most participants were postmenopausal, using vaginal estrogen, wearing a 70-mm ring pessary with support for pelvic organ prolapse and reported being very satisfied with the pessary. Other pessaries worn included ring without support, incontinence rings with and without support, Gellhorn, and donut. The pessary sizes ranged from 51 mm to 96 mm. There was no significant difference in pessary type and size between groups. Visual analog scale pain scores at pessary removal were low in both groups: 3.23±3.00 cm in the lubricating group and 2.66±2.77 cm in the lidocaine group. After adjusting for baseline pain, there was no significant difference in pain at pessary removal between the lidocaine jelly and the lubricating jelly groups (mean difference=-0.56 cm, 95% confidence interval: -1.97-0.85; P=.44). Despite no significant difference in visual analog scale pain scores, 71.2% of participants reported a desire for numbing jelly at future pessary examinations. CONCLUSION: Pain during pessary removal and reinsertion is low. Compared to lubricating jelly, lidocaine jelly did not further reduce pain during pessary examinations.

Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis.

BACKGROUND: Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. OBJECTIVE: To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. STUDY DESIGN: We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. RESULTS: The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). CONCLUSION: Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.

A feasible procedure for laparoscopic cesarean scar defect repair.

In 1995, Morris first described cesarean scar defect (CSD) as an "isthmocele" by macroscopy following hysterectomy in women with a prior cesarean delivery. CSD is associated with gynecological symptoms such as abnormal uterine bleeding (AUB), secondary infertility, pelvic pain, and obstetrical complications such as cesarean scar pregnancy, placenta accreta, and uterine rupture. Surgical treatment techniques include hysteroscopic resection, transabdominal repair (laparotomy, laparoscopic, and robotic), and vaginal repair. If the residual myometrial thickness is <3 mm and the patient is symptomatic, consideration is made for defect repair laparoscopically rather than hysteroscopic resection. The advantages of laparoscopic repair include anatomic restoration of myometrial thickness, correction of uterine retroflexion, exploration of other causes of infertility and pelvic pain, and pathological diagnosis of scar tissue with endometriosis. CSD often cannot be visualized from the abdominal cavity; therefore, it is difficult to identify the extent of the defect laparoscopically. Herein, we introduce laparoscopic CSD repair through a surgical video with narration (Video 1). This technique uses a uterine manipulator to distend and help delineate the defect, and a laparoscopic support suture within the defect as a "handle" to place the scar tissue on tension to ensure complete resection of the fibrotic tissue. Temporary uterine artery occlusion can be included to reduce bleeding in the surgical field to support visualization for complete fibrotic tissue removal and to achieve good apposition with a double-layer suture to promote proper anatomic wound healing. Symptom relief was achieved, and the patient became pregnant one year postoperatively. This video demonstrated a feasible, safe, effective procedure for laparoscopic CSD repair in the patient.