Neurotrophins and Their Receptors, Novel Therapeutic Targets for Pelvic Pain in Endometriosis, Are Coordinately Regulated by IL-1ß via the JNK Signaling Pathway.

Pelvic pain in women with endometriosis is attributed to neuroinflammation and afferent nociceptor nerves in ectopic and eutopic endometrium. The hypothesis that uterine nociception is activated by IL-1ß, a prominent cytokine in endometriosis, was tested herein. Immunofluorescence histochemistry confirmed the presence of neurons in human endometrial tissue. Expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and their receptors in endometrial tissue and cells was validated by immunohistochemistry and Western blotting. Isolated endometrial stromal cells (ESCs) were subjected to dose-response and time-course experiments with IL-1ß and kinase inhibitors to characterize in vitro biomarkers. Neural biomarkers were co-localized in endometrial nerve fibers. NGF, BDNF, and their receptors tropomyosin receptor kinase (Trk) A, TrkB, and p75 neurotrophin receptor were all expressed in primary ESCs. IL-1ß stimulated higher TrkA/B expression in ESCs derived from endometriosis cases (2.8- ± 0.2-fold) than cells from controls (1.5- ± 0.3-fold, t-test, P < 0.01), effects that were mediated via the c-Jun N-terminal kinase (JNK) pathway. BDNF concentrations trended higher in peritoneal fluid of endometriosis cases but were not statistically different from controls (P = 0.16). The results support the hypothesis that NGF and BDNF and their corresponding receptors orchestrate innervation of the endometrium, which is augmented by IL-1ß. We postulate that JNK inhibitors, such as SP600125, have the potential to reduce neuroinflammation in women with endometriosis.

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.

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.

The Burden of Pelvic Pain Associated with Endometriosis among Women in Selected European Countries and the United States: A Restricted Systematic Review.

OBJECTIVE: To evaluate the burden of endometriosis-associated pelvic pain (EAPP) on health-related quality of life (HRQoL) among women living in similar socio-economic conditions. DATA SOURCES: Searches were performed in PubMed and Embase on September 26, 2022. The review was performed in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocol (PRISMA-P) and was registered on PROSPERO (ID: CRD42023370363). METHODS OF STUDY SELECTION: Due to the high volume of eligible publications following initial review, inclusion criteria were restricted to studies undertaken in France, Germany, Italy, Spain, the United Kingdom, and the United States. This restriction was applied before screening as these countries have broad social and economic similarities, and previous studies in the literature suggest pain reporting and experience are influenced by numerous socio-cultural factors. Eligible studies were those published between 2013 and 2022 and include a sample size of ≥50 participants. The search strategy identified all relevant publications relating to the burden of illness due to EAPP. A variety of terms are used in the literature to describe pain associated with endometriosis, and this was considered in the design of the search strategy and screening procedure. TABULATION, INTEGRATION, AND RESULTS: The database searches resulted in a total of 6139 records. After removal of duplicates, 3855 records were assessed further. A total of 27 publications were identified as eligible. Fourteen (52%) were from Italy, 5 (19%) were multinational studies, 4 (15%) were from the United States, 3 (11%) were from Spain, and 1 (4%) was from Germany. Most studies were cross-sectional (n = 15; 56%); 7 (26%) were case-control studies; 3 (11%) were cohort studies; and 2 (7%) were longitudinal studies. These publications collectively highlighted an association between EAPP and reduced HRQoL. Several studies showed that EAPP was associated with lower HRQoL when compared with endometriosis without pain and potentially with chronic pelvic pain caused by other conditions, although the evidence is limited in this case. Moreover, the studies reported detrimental effects on general HRQoL, mental health functioning, and sexual functioning, culminating in reduced work productivity and difficulties in performing everyday activities. The associations were generally similar across study populations, including adolescents, as well as younger and older women. Results were consistent across the range of different patient-reported outcome tools used to assess HRQoL. CONCLUSION: The existing literature suggests that, among women in selected European countries and the United States, EAPP is associated with reduced HRQoL, including impaired mental and sexual functioning, as well as reduced work performance and productivity; each of which may contribute to the societal burden of endometriosis.

Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2).

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.

Psychosocial predictors of change in sexual activity and sexual function after hysterectomy in women with pelvic pain.

BACKGROUND: Potential impact on sexual function is an often-cited concern for many patients considering hysterectomy. The existing literature indicates that sexual function remains stable to slightly improved for most patients who undergo hysterectomy, but most studies demonstrate a small subset of patients in whom sexual function declines after surgery. Unfortunately, there is a lack of clarity as to surgical, clinical, and psychosocial factors that may influence the likelihood of sexual activity after surgery or the magnitude and direction of change in sexual function. Although psychosocial factors are strongly associated with overall female sexual function, there is minimal data exploring the potential impact of these factors on the change in sexual function after hysterectomy. OBJECTIVE: This study aimed to evaluate the relationship between baseline psychosocial factors and both sexual activity and sexual function at 6 months after hysterectomy. STUDY DESIGN: Patients undergoing hysterectomy for benign, non-obstetric indications were prospectively recruited as part of an observational cohort study evaluating presurgical predictors of posthysterectomy outcomes on pain, quality of life, and sexual function. The Female Sexual Function Index was administered before hysterectomy and 6 months after surgery. Presurgical psychosocial assessments included validated self-reported measures of depression, resilience, relationship satisfaction, emotional support, and social participation. RESULTS: Complete data was available for 193 patients, of whom 149 (77.2%) reported sexual activity at 6 months after hysterectomy. In the binary logistic regression model examining sexual activity at 6 months, older age was associated with a lower likelihood of sexual activity (odds ratio, 0.91; 95% confidence interval, 0.85-0.96; P=.002). Higher relationship satisfaction before surgery was associated with a greater likelihood of sexual activity at 6 months (odds ratio, 1.09; 95% confidence interval, 1.02-1.16; P=.008). As expected, preoperative sexual activity was associated with a greater likelihood of postoperative sexual activity (odds ratio, 9.78; 95% confidence interval, 3.95-24.19, P<.001). Analyses using Female Sexual Function Index scores were limited to patients who were sexually active at both time points (n=132 [68.4%]). The total Female Sexual Function Index score did not change significantly from baseline to 6 months, but there were statistically significant changes in several individual domains of sexual function. Patients reported significant improvement in desire (P=.012), arousal (P=.023), and pain (P<.001) domains. However, significant decreases were reported in orgasm (P<.001) and satisfaction (P<.001) domains. The proportion of patients who met the criteria for sexual dysfunction was quite high (>60%) at both time points, but there was not a statistically significant change in the proportion from baseline to 6 months. In the multivariate linear regression model, there was no relationship between change in sexual function score and any of the variables examined, including age, endometriosis history, pelvic pain severity, or psychosocial measures. CONCLUSION: In this cohort of patients with pelvic pain undergoing hysterectomy for benign indications, both sexual activity and sexual function remained fairly stable after hysterectomy. Higher relationship satisfaction, younger age, and preoperative sexual activity were associated with a greater probability of sexual activity at 6 months after surgery. Psychosocial factors, such as depression, relationship satisfaction, and emotional support, and history of endometriosis were not related to change in sexual function among patients who were sexually active both before hysterectomy and at 6 months after surgery.

Development of the Bleeding and Pelvic Discomfort Scale for Use in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids.

OBJECTIVES: This study aimed to define a cardinal symptom burden measure based on items from the Uterine Fibroid Symptom and Quality of Life questionnaire for use as a clinical trial endpoint. METHODS: Exploratory factor analysis was computed to assess the Uterine Fibroid Symptom and Quality of Life symptom severity scale factor structure, using phase 2 data. Pooled blinded data from phase 3 studies were used for the confirmatory factor analysis and the psychometric evaluation of the new measure. Exit interviews in 30 patients from phase 3 studies provided additional qualitative evidence. A meaningful change threshold was determined using anchor-based analyses supported by patient feedback in the exit interviews. RESULTS: Three factors emerged from the exploratory factor analysis. Factor 1, called the bleeding and pelvic discomfort (BPD) scale, consists of cardinal symptoms, measuring menstrual distress owing to heavy bleeding, passing blood clots, and feeling tightness or pressure in pelvic area. Patients generally understood the items in the scale and the recall period as intended. The BPD scale had good item performance and internal consistency reliability, strong item-to-total correlations, good item discrimination, known-groups validity, and ability to detect change. A 20-point change on the BPD scale was determined as the clinically meaningful change threshold. CONCLUSIONS: The BPD scale assesses symptom burden owing to bleeding, passing blood clots, and pelvic pressure. The subscale is based on a subset of items selected to measure the cardinal symptoms of uterine fibroids in a clinical trial setting. The responder threshold evaluates whether patients experience a meaningful treatment benefit over the on-treatment period.

Progression of Peritoneal Mesothelioma In Situ to Invasive Mesothelioma Arising in the Setting of Endometriosis With Germline BAP1 Mutation: A Case Report.

Mesothelioma in situ has been proposed as a precursor to malignant mesothelioma arising in the pleura or peritoneum. We report a case of malignant peritoneal mesothelioma which progressed from mesothelioma in situ over a 10-mo period in a 24-yr-old woman with stage IV endometriosis. Initial surgery showed deeply infiltrative endometriosis with progestin effect. Postoperatively the patient had intractable pelvic pain and vaginal discharge. Imaging studies were negative. Repeat laparoscopy 10 mo later revealed vesicular lesions on the omentum and pinpoint white lesions studding the small bowel, appendix, and pelvic peritoneum. A diagnosis of epithelioid mesothelioma was established on biopsy of the omentum and confirmed by immunohistochemistry showing complete loss of BRCA1-associated protein-1 (BAP1) nuclear staining. Retrospectively, BAP1 loss was identified in the cytologically bland, single-layer surface mesothelium of the prior resection specimen, consistent with mesothelioma in situ . The patient underwent genetic testing and was found to have a pathogenic germline mutation in BAP1 .

Effects of Pharmacologic Venous Thromboembolism Prophylaxis in Benign Hysterectomy.

STUDY OBJECTIVE: To evaluate whether the addition of pharmacologic prophylaxis to mechanical prophylaxis for venous thromboembolism (VTE) is associated with changes in perioperative outcomes in hysterectomy for benign indications. DESIGN: Retrospective cohort study. SETTING: Michigan Surgical Quality Collaborative database. PATIENTS: Patients who underwent hysterectomy between July 2012 and June 2015 when VTE prophylaxis data were collected. INTERVENTIONS: Patients who received mechanical prophylaxis alone were compared with those receiving dual prophylaxis (mechanical and pharmacologic). Minimally invasive surgeries (MIS) included laparoscopic, vaginal, robotic-assisted, and laparoscopic-assisted vaginal hysterectomies and were analyzed separately from abdominal (ABD) hysterectomy. MEASUREMENTS AND MAIN RESULTS: Propensity score matching was used to minimize confounding because of the differences in demographic and perioperative characteristics. The primary outcome was estimated blood loss (EBL). The secondary outcomes were operative time, postoperative blood transfusion, VTE, surgical site infection, reoperation, readmission, and death. There were 1803 matched pairs in the MIS analysis. In the ABD hysterectomy analysis, 2:1 matching was used with a total of 1168 patients receiving mechanical prophylaxis alone matched to 616 patients receiving dual prophylaxis. EBL was higher by 54.5 mL (95% confidence interval [CI], 16.9-92.1) in those receiving dual prophylaxis in the ABD hysterectomy analysis but did not differ between groups in the MIS analysis. Operative time was significantly longer with dual prophylaxis in both MIS (18.3 minutes; 95% CI, 13.8-22.8) and ABD (15.3 minutes; 95% CI, 9.0-21.6) surgical approaches. There was no difference in other secondary outcomes. CONCLUSION: The addition of pharmacologic prophylaxis to mechanical prophylaxis in benign hysterectomy was associated with longer operative time, regardless of surgical approach and increased EBL in ABD hysterectomy. Given very low rates of VTE, no difference in other perioperative outcomes, and possible harm, it seems reasonable to encourage individualized rather than routine use of pharmacologic prophylaxis in patients undergoing benign hysterectomy receiving mechanical prophylaxis.

Sexual function after hysterectomy according to surgical indication: a prospective cohort study.

BACKGROUND: Our aims were to describe characteristics of sexual function prior to and 6months following benign hysterectomy in patients with three common surgical indications, and to identify preoperative factors that influence the magnitude and direction of change in sexual function after the procedure. METHODS: This prospective observational cohort study enrolled women (n =80) undergoing hysterectomy for benign indications. Patients were categorised into three groups according to surgical indication: (1) pelvic pain (PP), (2) abnormal uterine bleeding (AUB), and (3) pelvic organ prolapse (POP). Primary outcome was Female Sexual Function Index (FSFI), which patients completed preoperatively and 6months postoperatively. RESULTS: The study included 80 patients, of whom 25.0% (n =20) had surgical indication of PP, 46.3% (n =37) of AUB, and 28.7% (n =23) of POP. PP patients experienced a significant improvement in overall sexual function, as well as orgasm and pain domains following hysterectomy. Significant improvements were not found in AUB and POP patients. In multivariate analysis, lower baseline sexual function (P <0.001), younger age (P =0.013), and pelvic pain<6months (P =0.020) were each independently associated with improvement in sexual function, but surgical indication was not significant. CONCLUSION: Individual patient factors including younger age, lower baseline sexual function, and short duration of pelvic pain are associated with a higher likelihood of improvement in sexual function after hysterectomy. Surgical indication does not appear to be predictive of postoperative sexual function once accounting for other factors.

Patient Factors Associated With Opioid Consumption in the Month Following Major Surgery.

OBJECTIVE: The aim of this study was to determine preoperative patient characteristics associated with postoperative outpatient opioid use and assess the frequency of postoperative opioid overprescribing. SUMMARY BACKGROUND DATA: Although characteristics associated with inpatient opioid use have been described, data regarding patient factors associated with opioid use after discharge are lacking. This hampers the development of individualized approaches to postoperative prescribing. METHODS: We included opioid-naïve patients undergoing hysterectomy, thoracic surgery, and total knee and hip arthroplasty in a single-center prospective observational cohort study. Preoperative phenotyping included self-report measures to assess pain severity, fibromyalgia survey criteria score, pain catastrophizing, depression, anxiety, functional status, fatigue, and sleep disturbance. Our primary outcome measure was self-reported total opioid use in oral morphine equivalents. We constructed multivariable linear-regression models predicting opioids consumed in the first month following surgery. RESULTS: We enrolled 1181 patients; 1001 had complete primary outcome data and 913 had complete phenotype data. Younger age, non-white race, lack of a college degree, higher anxiety, greater sleep disturbance, heavy alcohol use, current tobacco use, and larger initial opioid prescription size were significantly associated with increased opioid consumption. Median total oral morphine equivalents prescribed was 600 mg (equivalent to one hundred twenty 5-mg hydrocodone pills), whereas median opioid consumption was 188 mg (38 pills). CONCLUSIONS: In this prospective cohort of opioid-naïve patients undergoing major surgery, we found a number of characteristics associated with greater opioid use in the first month after surgery. Future studies should address the use of non-opioid medications and behavioral therapies in the perioperative period for these higher risk patients.

Incidence and predictors of persistent pelvic pain following hysterectomy in women with chronic pelvic pain.

BACKGROUND: Chronic pelvic pain is a debilitating problem that afflicts 15% to 20% of women in the United States. Although more than 200,000 hysterectomies are performed annually for the treatment of chronic pelvic pain, previous studies indicate that 1 in 4 women undergo the discomfort and morbidity of hysterectomy without the relief of pain. The factors that predict treatment failure remain poorly characterized. OBJECTIVE: To describe the incidence of persistent pelvic pain 6 months following hysterectomy in women with chronic pelvic pain and determine whether a simple, self-reported measure of central sensitization is associated with a greater risk of persistent pelvic pain following hysterectomy. STUDY DESIGN: We conducted a prospective, observational cohort study of women undergoing hysterectomy at an academic tertiary care center for a benign indication. Patients with preoperative chronic pelvic pain, defined as average pelvic pain ≥3 on a 0 to 10 numeric rating scale for >3 months before hysterectomy, were included in this analysis. The patients completed validated assessments of pain, anxiety, depression, and centralized pain (using the 2011 Fibromyalgia Survey Criteria, 0-31 points) preoperatively and 6 months after hysterectomy. The demographic information, surgical history, intraoperative findings, and surgical pathology were abstracted from the electronic medical records. Multivariate logistic regression was used to identify the independent predictors of persistent pelvic pain 6 months following hysterectomy, defined as <50% improvement in pelvic pain severity. RESULTS: Among 176 participants with pelvic pain before hysterectomy, 126 (71.6%) were retained at 6 months, and 15 (11.9%) reported persistent pelvic pain. There was no difference in age (P=.46), race (P=.55), average pain severity during menses (P=.68), average overall pelvic pain (P=.10), or pain duration (P=.80) in those with and without persistent pelvic pain. Whereas intraoperative findings of endometriosis (P=.05) and uterine fibroids (P=.03) were associated with a higher incidence of persistent pain on univariate analysis, the surgical route (P=.46), pelvic adhesions (0.51), uterine weight (P=.66), and adenomyosis on histopathology (P=.27) were not related to the risk of persistent pain. Higher preoperative centralized pain scores (P=.01) but not depression (P=.64) or anxiety (P=.45) were more common in women with persistent pelvic pain. Multivariate logistic regression adjusting for age, preoperative pain severity, anxiety, depression, and operative findings of endometriosis and fibroids indicated that every 1-point increase in centralized pain before hysterectomy was associated with a 27% increase in the odds of persistent pelvic pain (odds ratio, 1.27; 95% confidence interval, 1.03-1.57) 6 months after surgery. CONCLUSION: Although the majority of women with chronic pelvic pain report considerable improvement in pain following hysterectomy, higher degrees of centralized pain before hysterectomy is a robust predictor of persistent pelvic pain.

Surgical interventions for the management of chronic pelvic pain in women.

BACKGROUND: Chronic pelvic pain (CPP) is a common gynaecological condition accounting for 20% of all gynaecological referrals. There are wide ranges of causes with overlapping symptomatology, therefore the management of the condition is a formidable challenge for clinicians. The aetiology of CPP is heterogeneous and in many cases, no clear diagnosis can be reached. It is in this scenario that the label of chronic pelvic pain syndrome (CPPS) can be applied. We defined women with CPPS as having a minimum duration of pain of at least 6 months, including with a diagnosis of pelvic congestion syndrome, but excluding pain caused by a condition such as endometriosis. Many surgical interventions have been tried in isolation or in conjunction with non-surgical interventions in the management with variable results. Surgical interventions are invasive and carry operative risks. Surgical interventions must be evaluated for their effectiveness prior to their prevalent use in the management of women with CPPS. OBJECTIVES: To review the effectiveness and safety of surgical interventions in the management of women with CPPS. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO, on 23 April 2021 for any randomised controlled trials (RCT) for surgical interventions in women with CPPS. We also searched the citation lists of relevant publications, two trial registries, relevant journals, abstracts, conference proceedings and several key grey literature sources. SELECTION CRITERIA: RCTs with women who had CPPS. The review authors were prepared to consider studies of any surgical intervention used for the management of CPPS. Outcome measures were pain rating scales, adverse events, psychological outcomes, quality of life (QoL) measures and requirement for analgesia. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated studies for inclusion and extracted data using the forms designed according to Cochrane guidelines. For each included trial, we collected information regarding the method of randomisation, allocation concealment, blinding, data reporting and analyses. We reported pooled results as mean difference (MDs) or odds ratios (OR) and 95% confidence interval (CI) by the Mantel-Haenszel method. If similar outcomes were reported on different scales, we calculated the standardised mean difference (SMD). We applied GRADE criteria to judge the overall certainty of the evidence. MAIN RESULTS: Four studies met our inclusion criteria involving 216 women with CPP and no identifiable cause. Adhesiolysis compared to no surgery or diagnostic laparoscopy We are uncertain of the effect of adhesiolysis on pelvic pain scores postoperatively at three months (MD -7.3, 95% CI -29.9 to 15.3; 1 study, 43 participants; low-certainty evidence), six months (MD -14.3, 95% CI -35.9 to 7.3; 1 study, 43 participants; low-certainty evidence) and 12 months postsurgery (MD 0.00, 95% CI -4.60; 1 study, 43 participants; very low-certainty evidence). Adhesiolysis may improve both the emotional wellbeing (MD 24.90, 95% CI 7.92 to 41.88; 1 study, 43 participants; low-certainty evidence) and social support (MD 23.90, 95% CI -1.77 to 49.57; 1 study, 43 participants; low-certainty evidence) components of the Endometriosis Health Profile-30, and both the emotional component (MD 32.30, 95% CI 13.16 to 51.44; 1 study, 43 participants; low-certainty evidence) and the physical component of the 12-item Short Form (MD 22.90, 95% CI 10.97 to 34.83; 1 study, 43 participants; low-certainty evidence) when compared to diagnostic laparoscopy. We are uncertain of the safety of adhesiolysis compared to comparator groups due to low-certainty evidence and lack of structured adverse event reporting. No studies reported on psychological outcomes or requirements for analgesia. Laparoscopic uterosacral ligament ablation or resection compared to diagnostic laparoscopy/other treatment We are uncertain of the effect of laparoscopic uterosacral ligament/nerve ablation (LUNA) or resection compared to other treatments postoperatively at three months (OR 1.26, 95% CI 0.40 to 3.93; 1 study, 51 participants; low-certainty evidence) and six months (MD -2.10, 95% CI -4.38 to 0.18; 1 study, 74 participants; very low-certainty evidence). At 12 months post-surgery, we are uncertain of the effect of LUNA on the rate of successful treatment compared to diagnostic laparoscopy. One study of 56 participants found no difference in the effect of LUNA on non-cyclical pain (P = 0.854) or dyspareunia (P = 0.41); however, there was a difference favouring LUNA on dysmenorrhea (P = 0.045) and dyschezia (P = 0.05). We are also uncertain of the effect of LUNA compared to vaginal uterosacral ligament resection on pelvic pain at 12 months (MD 2.00, 95% CI 0.47 to 3.53; 1 study, 74 participants; very low-certainty evidence). We are uncertain of the safety of LUNA or resection compared to comparator groups due to the lack of structured adverse event reporting. Women undergoing LUNA may require more analgesia postoperatively than those undergoing other treatments (P < 0.001; 1 study, 74 participants). No studies reported psychological outcomes or QoL. AUTHORS' CONCLUSIONS: We are uncertain about the benefit of adhesiolysis or LUNA in management of pain in women with CPPS based on the current literature. There may be a QoL benefit to adhesiolysis in improving both emotional wellbeing and social support, as measured by the validated QoL tools. It was not possible to synthesis evidence on adverse events as these were only reported narratively in some studies, in which none were observed. With the inadequate objective assessment of adverse events, especially long-term adverse events, associated with adhesiolysis or LUNA for CPPS, there is currently little to support these interventions for CPPS.

Short-acting and Long-acting Opioids Utilization among Women Diagnosed with Endometriosis in the United States: A Population-based Claims Study.

STUDY OBJECTIVE: To determine the prevalence and pattern of opioid use in endometriosis and the characteristics of patients prescribed an opioid using medical insurance claims data. DESIGN: We performed a retrospective cohort analysis of data from the Truven MarketScan Commercial database for the period of January 1, 2011 to December 31, 2016. SETTING: The Truven database includes inpatient, outpatient, and prescription claims covering more than 115 million unique individuals and over 36 million inpatient hospital discharges across multiple payer types and all 50 states. PATIENTS: Women with endometriosis were defined as those with 1 inpatient or 2 outpatient codes for endometriosis. INTERVENTIONS: No interventions were assigned. Women who filled an opioid prescription within 12 months of diagnosis were placed in the opioid cohort and women who did not fill an opioid prescription were placed in the nonopioid cohort. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics were evaluated 12 months preindex (date of the first diagnosis) and opioid use was assessed for 12 months after the index date. The dataset included 58 472 women with endometriosis. Of these, 61.7% filled an opioid prescription during the study period. More than 95% filled prescriptions for short-acting opioids (SAOs) only, 4.1% filled prescriptions for both SAOs and extended-release/long-acting opioids (LAOs), and 0.6% filled prescriptions for LAOs only. Patients who filled an opioid prescription had higher baseline comorbidities (especially gynecologic and chronic pain comorbidities) and endometriosis-related medication use compared with patients who did not fill an opioid prescription during the study period. Patients who filled both LAO and SAO prescriptions had the highest total days' supply of opioids, the proportion of days covered by prescriptions, and morphine equivalent daily dose. These patients also had the highest proportions of opioid switching and dose augmentation. Statistical trends in data were not substantially altered when analyses excluded patients with chronic pain comorbidities or surgical opioid prescriptions. CONCLUSION: Although opioids are not a recommended treatment for endometriosis, more than half of our cohort filled an opioid prescription within 1 year after a first recorded diagnosis of endometriosis. Patients who filled an opioid prescription tended to use more endometriosis-related medications and have a higher comorbidity burden. Additional research is necessary to better understand the reasons and outcomes associated with opioid utilization in endometriosis and to determine if there is a more effective pain management treatment plan for patients taking opioids.

To Robot or Not To Robot: The Use of Robotics in Benign Gynecologic Surgery.

The use of robotic-assisted laparoscopic surgery has continued to grow since the Food and Drug Administration approval for robotic-assisted gynecologic surgery in 2005. However, despite this growth in utilization, the data supporting its use in benign gynecologic surgery has not strongly supported its advantages over conventional laparoscopy. Controversy exists between supporters of robotic-assisted laparoscopic surgery and conventional laparoscopy. This article discusses the current literature regarding the use of robotic-assisted surgery in benign gynecologic surgery.

Assessing research gaps and unmet needs in endometriosis.

Endometriosis, a systemic disease that is often painful and chronic, affects ∼10% of reproductive-age women. The disease can have a negative impact on a patient's physical and emotional well-being, quality of life, and productivity. Endometriosis also places significant economic and social burden on patients, their families, and society as a whole. Despite its high prevalence and cost, endometriosis remains underfunded and underresearched, greatly limiting our understanding of the disease and slowing much-needed innovation in diagnostic and treatment options. Due in part to the societal normalization of women's pain and stigma around menstrual issues, there is also a lack of disease awareness among patients, health care providers, and the public. The Society for Women's Health Research convened an interdisciplinary group of expert researchers, clinicians, and patients for a roundtable meeting to review the current state of the science on endometriosis and identify areas of need to improve a woman's diagnosis, treatment, and access to quality care. Comprehensive and interdisciplinary approaches to disease management and increased education and disease awareness for patients, health care providers, and the public are needed to remove stigma, increase timely and accurate diagnosis and treatment, and allow for new advancements.

Psychology of Chronic Pelvic Pain: Prevalence, Neurobiological Vulnerabilities, and Treatment.

Patients with pelvic pain suffer from psychological conditions at a disproportionately high rate compared with their peers. We review environmental, genetic, inflammatory, and neurobiological factors that increase vulnerability to developing both of these conditions. We review treatment strategies for chronic pelvic pain in patients who have comorbid psychological conditions, including both nonpharmacologic and pharmacologic options.

Descriptors of Vulvodynia: A Multisocietal Definition Consensus (International Society for the Study of Vulvovaginal Disease, the International Society for the Study of Women Sexual Health, and the International Pelvic Pain Society).

OBJECTIVES: Three scientific societies, the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS) developed the "2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia" (referred to as the "2015 consensus terminology").The terminology included 11 descriptors of vulvodynia. However, the definitions of the descriptors were not included in the 2015 consensus terminology publications. The objective of this article was to provide these definitions. MATERIALS AND METHODS: The ISSVD led a discussion on the definitions for the 11 vulvodynia descriptors, with participation from the ISSWSH and IPPS. The definitions were created through a consensus process. RESULTS: The definitions are described and the rationale for their choice is elucidated. CONCLUSIONS: The definitions of vulvodynia descriptors were determined by a multistaged process of discussion among health care providers with expertise in the pathophysiology, evaluation, and treatment of vulvodynia. The definitions were approved by the ISSVD, ISSWSH, and IPPS. It is recommended that these definitions of vulvodynia descriptors as well as the 2015 consensus terminology be used for the classification of vulvodynia.

Definition development and prevalence of new persistent opioid use following hysterectomy.

BACKGROUND: Opioids used for postoperative pain control after surgery have been associated with an increased risk of chronic opioid use. Hysterectomy is the most common major gynecological procedure in the United States; however, we lack a data-driven definition of new persistent opioid use specific to hysterectomy. OBJECTIVE: The objectives of the study were as follows: (1) determine a data-driven definition of new persistent opioid use among opioid naïve women undergoing hysterectomy and (2) determine the prevalence of and risk factors for new persistent opioid use. STUDY DESIGN: We used data from Optum Clinformatics that include both medical and pharmacy data from a single national private health insurer. Hysterectomies performed from Jan. 1, 2011, to Dec. 31, 2014, were identified using current procedural terminology and International Classification of Diseases, ninth revision, codes. Inclusion criteria included the following: age ≤63 years at hysterectomy, no opioid fills for 8 months preceding (excluding the 30 days immediately prior), and no additional surgical procedures within 6 months after hysterectomy. The perioperative period was defined as 30 days prior to 14 days after hysterectomy. Number of opioid prescription fills, days supplied, and total oral morphine equivalents were analyzed to determine the distribution of opioid use in the perioperative and postoperative periods. We obtained demographics including age, race, educational level, and division of the country according to the US Census Bureau and used International Classification of Diseases, ninth revision, diagnosis codes to identify hysterectomy indications, surgical route, chronic pain disorders, depression/anxiety, and substance abuse. Bivariate analyses were used to compare persistent with nonpersistent opioid users. A hierarchical logistic regression model controlling for regional variation was used to determine factors associated with new persistent opioid use following hysterectomy. RESULTS: A total of 24,331 women were included in the analysis. New persistent opioid use was defined as follows: ≥2 opioid fills within 6 months of hysterectomy with ≥1 fill every 3 months and either total oral morphine equivalent ≥1150 or days supplied ≥39. Based on this definition, the prevalence of new persistent opioid use was 0.5% (n = 122). Median perioperative oral morphine equivalents prescribed to those who became new persistent users was 437.5 mg (interquartile range, 200-750) compared with 225 mg (interquartile range, 150-300) for nonpersistent users (P < .0001). Factors independently associated with new persistent opioid use included the following: increasing age (adjusted odds ratio, 1.04, 95% confidence interval, 1.01-1.06, P = .006), African-American race (reference: white, adjusted odds ratio, 1.61 95% confidence interval, 1.02-2.55, P = .04), gynecological malignancy (adjusted odds ratio, 7.61, 95% confidence interval, 3.35-17.27, P < .0001), abdominal route (adjusted odds ratio, 3.61, 95% confidence interval, 2.03-6.43, P < .0001), depression/anxiety (adjusted odds ratio, 2.62, 95% confidence interval, 1.71-4.02, P < .0001), and preoperative opioid fill (adjusted odds ratio, 2.76, 95% confidence interval, 1.87-4.07, P < .0001). The C-statistic for this model is 0.74. CONCLUSION: Based on our definition, the prevalence of new persistent opioid use among opioid-naïve women undergoing hysterectomy is low; however, 2 potentially modifiable risk factors are preoperative opioid prescription and abdominal route of surgery.

The Use of Opportunistic Salpingectomy at the Time of Benign Hysterectomy.

STUDY OBJECTIVE: To delineate the use of opportunistic salpingectomy over the study period, to examine factors associated with its use, and to evaluate whether salpingectomy was associated with perioperative complications. DESIGN: A retrospective cross-sectional study (Canadian Task Force classification II-2). SETTING: The Michigan Surgical Quality Collaborative. PATIENTS: Women undergoing ovarian-conserving hysterectomy for benign indications from January 2013 through April 2015. INTERVENTIONS: The primary outcome was the performance of opportunistic salpingectomy with ovarian preservation during benign hysterectomy. The change in the rate of salpingectomy was examined at 4-month intervals to assess a period effect over the study period. Multivariate logistic regression was performed to evaluate independent effects of patient, operative, and period factors. Perioperative outcomes were compared using propensity score matching. MEASUREMENTS AND MAIN RESULTS: There were 10 676 (55.9%) ovarian-conserving hysterectomies among 19 090 benign hysterectomies in the Michigan Surgical Quality Collaborative in the study period. The rate of opportunistic salpingectomy was 45.8% (n = 4890). Rates of opportunistic salpingectomy increased over the study period from 27.5% to 61.6% (p < .001), demonstrating a strong period effect in the consecutive 4-month period analysis. Salpingectomy was more likely with the laparoscopic approach (odds ratio = 3.48; 95% confidence interval, 3.15-3.85) and among women younger than 60 years of age (odds ratio = 1.60; 95% CI, 1.34-1.92). There was substantial variation in salpingectomy across hospital sites, ranging from 3.6% to 79.9%. Salpingectomy was associated with a 12-minute increase in operative time (p < .001), but there were no differences in the estimated blood loss or perioperative complications. CONCLUSION: The rates of salpingectomy increased significantly over the study period. The laparoscopic approach and younger age are associated with an increased probability of salpingectomy. Salpingectomy is not associated with increased blood loss or perioperative complications.