Symptom flares in women with chronic pelvic pain: Questionnaire study within a cohort study (translational research in pelvic pain (TRiPP)).

OBJECTIVE: To quantify the variation, triggers and impact on quality of life of symptom flares in women with chronic pelvic pain (CPP). DESIGN: Cross-sectional questionnaire within the Translational Research in Pelvic Pain clinical cohort study. SETTING: Women with CPP, with subgroups of women with endometriosis (EAP), interstitial cystitis/bladder pain syndrome (BPS), comorbid endometriosis and interstitial cystitis/bladder pain syndrome (EABP), and those with pelvic pain without endometriosis or interstitial cystitis/bladder pain syndrome (PP). POPULATION OR SAMPLE: A total of 100 participants. METHODS: Descriptive and comparative analysis from flares questionnaire. MAIN OUTCOME MEASURES: The prevalence, characteristics and triggers of short, medium and long symptom flares in CPP. RESULTS: We received 100 responses of 104 questionnaires sent. Seventy-six per cent of women with CPP have ever experienced symptom flares of at least one length (short, medium and/or long). Flares are associated with painful and non-painful symptoms. There is large variation for the frequency, duration, symptoms and triggers for flares. Over 60% of participants reported flares as stopping them from doing things they would usually do, >80% reported thinking about symptoms of flares and >80% reported flares being bothersome. CONCLUSIONS: Flares are prevalent and clinically very important in CPP. More research is needed to elucidate the mechanisms and characteristics underlying flares. Clinical practice should include an enquiry into flares with the aim of finding strategies to lessen their burden.

Fertility preservation service for children and young adults at high risk of infertility; the hub and spoke model.

PURPOSE: To evaluate the evolution of fertility preservation surgery in children and young adults at high risk of infertility from a single centre to a networked 'Hub and Spoke' service. METHODS: A case note review of patients referred for ovarian or testicular cryopreservation between Jan 2013 and Dec 2023. Demographic data, procurement numbers, and site of procurement were collected. Specialist feedback was obtained to identify the challenges faced. RESULTS: Over time, the number of referrals increased from 4 to 349 patients per year with the number of Spoke centres rising to 36 ovarian and 16 testicular. In 2013-2014; 100% of procurement was ovarian as compared to 2023; 51% ovarian, 49% testicular. Of the 395 referrals in 2021, 81% (n = 319) went on to have procurement and storage of tissue. Between 2013 and 2016, 96% of cases were performed at the Hub. In 2023, 53/349 (15%) cases were performed at the Hub with the remaining 296 (85%) procured at Spoke sites. Surgical issues such as access to theatre, variation and availability of surgical equipment, thermal injury to ovarian tissue and variation in the size of the testicular specimen were identified. CONCLUSION: The Hub and Spoke model successfully delivers treatment to patients close to home as safely possible within their local treatment centre.

Impact of relugolix combination therapy on functioning and quality of life in women with endometriosis-associated pain.

OBJECTIVE: To evaluate the effect of relugolix combination therapy (relugolix CT; 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethisterone acetate) for up to 2 years in the SPIRIT long-term extension study on functioning and health-related quality of life (QoL), using the Endometriosis Health Profile (EHP)-30 questionnaire, and assess how changes in QoL domains correlated with improvements in dysmenorrhea as well as nonmenstrual pelvic pain (NMPP). DESIGN: Long-term extension study of the SPIRIT phase 3 trials. SETTING: Clinics and University Hospitals. PATIENT(S): Premenopausal women with moderate-to-severe endometriosis pain who previously completed the randomized SPIRIT trials were eligible to enroll in an 80-week long-term extension where all women received relugolix CT. INTERVENTION(S): Relugolix CT (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg). MAIN OUTCOME MEASURE(S): Least squares (LS) mean changes in the EHP-30 domain and total scores from baseline (pivotal) were analyzed using a mixed-effects model. Results up to 104 weeks are reported by a pivotal trial treatment group with a focus on the relugolix CT group (i.e., relugolix CT or placebo for 24 weeks, or delayed relugolix CT [relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT for 12 weeks]). In addition, the relationships between changes in dysmenorrhea and NMPP as well as changes in EHP-30 scores were assessed. RESULT(S): In the 277 women treated with relugolix CT, LS mean EHP-30 pain domain scores improved by 57.8% (LS mean change: -32.8; 95% CI: -35.5, -30.1), 66.4% (LS mean change: -37.7; 95% CI: -40.3, -35.0), and 72.2% (LS mean change: -41.3; 95% CI: -43.9, -38.7) at weeks 24, 52, and 104, respectively. The proportions of women with clinically meaningful improvement in the EHP-30 pain domain were 75.9%, 83.6%, and 88.6% at weeks 24, 52, and 104, respectively. Non-pain EHP-30 domain and total scores likewise improved. A positive correlation between changes in dysmenorrhea/NMPP and all EHP-30 domain scores was observed. Results were similar for the delayed relugolix CT and placebo → relugolix CT groups. CONCLUSION(S): Sustained reduction of endometriosis-associated pain with relugolix CT observed up to 104 weeks was accompanied by improvements in functioning and health-related QoL. These findings complement the results of the pivotal SPIRIT trials, which showed that relugolix combination therapy significantly reduced dysmenorrhea, NMPP, and dyspareunia vs. placebo in premenopausal women with endometriosis-associated pain. CLINICAL TRIAL REGISTRATION NUMBER: Registration/clinicaltrials.gov identifier: SPIRIT Extension Study (NCT03654274).

Non-Invasive Imaging Techniques for Diagnosis of Pelvic Deep Endometriosis and Endometriosis Classification Systems: An International Consensus Statement.

The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and International Deep Endometriosis Analysis (IDEA) group, the European Endometriosis League (EEL), the European Society for Gynaecological Endoscopy (ESGE), the European Society of Human Reproduction and Embryology (ESHRE), the International Society for Gynecologic Endoscopy (ISGE), the American Association of Gynecologic Laparoscopists (AAGL) and the European Society of Urogenital Radiology (ESUR) elected an international, multidisciplinary panel of gynecological surgeons, sonographers and radiologists, including a steering committee, which searched the literature for relevant articles in order to review the literature and provide evidence-based and clinically relevant statements on the use of imaging techniques for non-invasive diagnosis and classification of pelvic deep endometriosis. Preliminary statements were drafted based on review of the relevant literature. Following two rounds of revisions and voting orchestrated by chairs of the participating societies, consensus statements were finalized. A final version of the document was then resubmitted to the society chairs for approval. Twenty statements were drafted, of which 14 reached strong and three moderate agreement after the first voting round. The remaining three statements were discussed by all members of the steering committee and society chairs and rephrased, followed by an additional round of voting. At the conclusion of the process, 14 statements had strong and five statements moderate agreement, with one statement left in equipoise. This consensus work aims to guide clinicians involved in treating women with suspected endometriosis during patient assessment, counseling and planning of surgical treatment strategies.

FEMaLe: The use of machine learning for early diagnosis of endometriosis based on patient self-reported data-Study protocol of a multicenter trial.

INTRODUCTION: Endometriosis is a chronic disease that affects up to 190 million women and those assigned female at birth and remains unresolved mainly in terms of etiology and optimal therapy. It is defined by the presence of endometrium-like tissue outside the uterine cavity and is commonly associated with chronic pelvic pain, infertility, and decreased quality of life. Despite the availability of various screening methods (e.g., biomarkers, genomic analysis, imaging techniques) intended to replace the need for invasive surgery, the time to diagnosis remains in the range of 4 to 11 years. AIMS: This study aims to create a large prospective data bank using the Lucy mobile health application (Lucy app) and analyze patient profiles and structured clinical data. In addition, we will investigate the association of removed or restricted dietary components with quality of life, pain, and central pain sensitization. METHODS: A baseline and a longitudinal questionnaire in the Lucy app collects real-world, self-reported information on symptoms of endometriosis, socio-demographics, mental and physical health, economic factors, nutritional, and other lifestyle factors. 5,000 women with confirmed endometriosis and 5,000 women without diagnosed endometriosis in a control group will be enrolled and followed up for one year. With this information, any connections between recorded symptoms and endometriosis will be analyzed using machine learning. CONCLUSIONS: We aim to develop a phenotypic description of women with endometriosis by linking the collected data with existing registry-based information on endometriosis diagnosis, healthcare utilization, and big data approach. This may help to achieve earlier detection of endometriosis with pelvic pain and significantly reduce the current diagnostic delay. Additionally, we may identify dietary components that worsen the quality of life and pain in women with endometriosis, upon which we can create real-world data-based nutritional recommendations.

Ovarian Tissue Collection for Fertility Preservation in Children: The Need for Standardised Surgical Practice Guidance.

BACKGROUND: Chemotherapy, pelvic radiotherapy (including total body irradiation) and novel compounds used to treat children and teenagers with benign or malignant diseases can lead to impaired fertility. For prepubertal female patients at high risk of treatment-related infertility, upfront storage of ovarian tissue is increasingly being recognised as standard of care. No surgical guidelines exist to ensure best practice technique. We reviewed current UK practice to assess surgical management. METHODS: A ten-item, anonymous multiple-choice survey was distributed to the lead surgeons in all paediatric centres in England/Wales undertaking ovarian procurement for cryopreservation. RESULTS: There are currently 18 centres in England and Wales that provide ovarian procurement for cryopreservation. Responses were received from 100% of the invited paediatric surgical oncology centres in England and Wales. 39.3% of participants stated that in their centre <10 cases of ovarian harvest are performed annually. In 32.1% of centres >20 cases are undertaken per year. In 64% of centres surgery is performed by a paediatric surgeon with interest in oncology or fertility preservation. The majority of cases were performed by a Consultant or Senior Registrar (89%). Regarding the surgical technique, 82% of respondents stated they gain access to the abdominal cavity using standard 3-port laparoscopy, 7% use single-port laparoscopy. Most frequently used energy devices for ovary/ovarian tissue resection were Ligasure™ (44%) and Harmonic Scalpel™ (18.5%). 96% of respondents perform a total oophorectomy, 1 respondent stated they perform a hemi-oophorectomy. 53% stated they place the ovary into a retrieval bag only if the ovary was too big for easy removal via the camera port, 28.5% always place it in a retrieval bag. Most surgeons use the umbilical port site for retrieval (82%). CONCLUSION: This national survey shows significant heterogeneity in the surgical management of ovarian procurement for cryopreservation. To ensure best outcomes, research into the various surgical methods is necessary to provide data for a standardised best practice approach. LEVEL OF EVIDENCE: This is a level II evidence study. In itself, it is a national survey of specialists, which was undertaken in a prospective manner.

Crimson clues: advancing endometriosis detection and management with novel blood biomarkers.

Endometriosis is an inflammatory condition affecting approximately 10% of the female-born population. Despite its prevalence, the lack of noninvasive biomarkers has contributed to an established global diagnostic delay. The intricate pathophysiology of this enigmatic disease may leave signatures in the blood, which, when detected, can be used as noninvasive biomarkers. This review provides an update on how investigators are utilizing the established disease pathways and innovative methodologies, including genome-wide association studies, next-generation sequencing, and machine learning, to unravel the clues left in the blood to develop blood biomarkers. Many blood biomarkers show promise in the discovery phase, but because of a lack of standardized and robust methodologies, they rarely progress to the development stages. However, we are now seeing biomarkers being validated with high diagnostic accuracy and improvements in standardization protocols, providing promise for the future of endometriosis blood biomarkers.

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.

Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis.

BACKGROUND: Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. OBJECTIVES: To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP. SEARCH STRATEGY: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023. SELECTION CRITERIA: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications. DATA COLLECTION AND ANALYSIS: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. MAIN RESULTS: The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I2 = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I2 = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I2 = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I2 = 0%; low-certainty evidence). CONCLUSIONS: Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.

Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: results from an Eastern Mediterranean population.

BACKGROUND: There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an under-represented region in Europe. METHODS: Cyprus Women's Health Research Initiative, a cross-sectional study recruited 7646 women aged 18-55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n = 2922) and without (n = 4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. RESULTS: Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9-5.9%, n = 410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P < 0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P = 0.027) and asymptomatic (0.3%, P < 0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03-2.38) higher than the symptomatic and 1.95 (95% CI: 1.30-2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P = 0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811-$10 917) including healthcare, costs relating to absence and loss of productivity at work. CONCLUSION: Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain.

Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study.

OBJECTIVE: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018). METHODS: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values). RESULTS: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004). CONCLUSION: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty.

A Plain Language Summary to learn about relugolix combination therapy for the treatment of pain associated with endometriosis.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called SPIRIT 1 and SPIRIT 2. The SPIRIT 1 and SPIRIT 2 studies compared how well a medicine called relugolix combination therapy worked in relieving pain in women with moderate to severe endometriosis compared to a placebo, a pill with no active medication. Endometriosis occurs when tissue similar to what normally lines the uterus grows in other places, such as the ovaries, fallopian tubes, and bowels. WHAT WERE THE RESULTS?: Researchers looked at 1261 adult women with moderate to severe endometriosis. Randomly, 420 (33%) of these women were assigned to relugolix combination therapy, 420 (33%) were assigned to delayed relugolix combination therapy (relugolix alone first and then relugolix combination therapy for the remainder of the study), and 421 (33%) were assigned to placebo. The SPIRIT 1 and SPIRIT 2 studies showed that more women taking relugolix combination therapy (75% from SPIRIT 1 and 75% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain during menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (27% from SPIRIT 1 and 30% from SPIRIT 2). The SPIRIT 1 and SPIRIT 2 studies also showed that more women taking relugolix combination therapy (59% from SPIRIT 1 and 66% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain between menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (40% from SPIRIT 1 and 43% from SPIRIT 2). Women taking relugolix combination therapy had less pelvic or groin pain during and between menstrual periods within 4 weeks of starting the medicine. The most common side effects were headaches, the common cold, and hot flushes or feeling hot among women taking relugolix combination therapy, delayed relugolix combination therapy, and placebo. Relugolix combination therapy was considered safe for those with no major medical problems. Women taking relugolix combination therapy had little to no loss of bone mineral density (a way of knowing how strong bones are) after 24 weeks of treatment. WHAT DO THE RESULTS OF THESE STUDIES TELL US?: Women with moderate to severe endometriosis taking relugolix combination therapy had much less pain from endometriosis than women taking placebo. Clinical Trial Registration: NCT03204318 (SPIRIT-1); NCT03204331 (SPIRIT-2) (ClinicalTrials.gov).

The role of small extracellular vesicle-miRNAs in endometriosis.

Endometriosis is defined by the presence of extrauterine endometrial-like tissue, which can cause pain and infertility in 10% of reproductive-age women. To date, the pathogenesis is poorly understood resulting in significant diagnostic delays and poor therapeutic outcomes in many women. Small extracellular vesicles (sEVs) (<200 nm) are cell-derived vesicles containing molecules that can influence gene expression and behaviour in target cells. One such cargo are microRNAs (miRNAs), which are short, non-coding RNAs mostly 19-25 nucleotides in length that regulate post-transcriptional gene expression. This mini-review focuses on the role of sEV-miRNAs, which are conceivably better biomarkers for endometriosis than free miRNAs, which reflect the true pathophysiological state in the body, as sEV-encapsulated miRNAs are protected from degradation compared to free miRNA and provide direct cell-to-cell communication via sEV surface proteins. sEV-miRNAs have been implicated in the immunomodulation of macrophages, the proliferation, migration and invasion of endometrial cells, and angiogenesis, all hallmarks of endometriosis. The diagnostic potential of sEV-miRNA was investigated in one study that reported the sensitivity and specificity of two sEV-miRNAs (hsa-miR-22-3p and hsa-miR-320a-3p) in distinguishing endometriosis from non-endometriosis cases. Only three studies have explored the therapeutic potential of sEV-miRNAs in vivo in mice-two looked into the role of sEV-hsa-miR-214-3p in decreasing fibrosis, and one investigated sEV-hsa-miR-30c-5p in suppressing the invasive and migratory potential of endometriotic lesions. While early results are encouraging, studies need to further address the potential influence of factors such as the menstrual cycle as well as the location and extent of endometriotic lesions on miRNA expression in sEVs. Given these findings, and extrapolating from other conditions such as cancer, diabetes, and pre-eclampsia, sEV-miRNAs could present an attractive and urgently needed future diagnostic and therapeutic target for millions of women suffering from endometriosis. However, research in this area is hampered by lack of adherence to the International Society for Extracellular Vesicles 2018 guideline in separating and characterising sEVs, as well as the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project protocols.

Timed intercourse for couples trying to conceive.

BACKGROUND: Many factors influence fertility, one being the timing of intercourse. The 'fertile window' describes a stage in the cycle when conception can occur and is approximately five days before to several hours after ovulation. 'Timed intercourse' is the practice of prospectively identifying ovulation and, thus, the fertile window to increase the likelihood of conception. Methods of predicting ovulation include urinary hormone measurement (luteinising hormone (LH) and oestrogen), fertility awareness-based methods (FABM) (including tracking basal body temperatures, cervical mucus monitoring, calendar charting/tracking apps), and ultrasonography. However, there are potentially negative aspects associated with ovulation prediction, including stress, time consumption, and cost implications of purchasing ovulation kits and app subscriptions. This review considered the evidence from randomised controlled trials (RCTs) evaluating the use of timed intercourse (using ovulation prediction) on pregnancy outcomes. OBJECTIVES: To evaluate the benefits and risks of ovulation prediction methods for timing intercourse on conception in couples trying to conceive. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group Specialised Register, CENTRAL, MEDLINE, and Embase in January 2023. We also checked the reference lists of relevant studies and searched trial registries for any additional trials. SELECTION CRITERIA: We included RCTs that compared methods of timed intercourse using ovulation prediction to other forms of ovulation prediction or intercourse without ovulation prediction in couples trying to conceive. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane to select and analyse studies in this review. The primary review outcomes were live birth and adverse events (such as depression and stress). Secondary outcomes were clinical pregnancy, pregnancy (clinical or positive urinary pregnancy test not yet confirmed by ultrasound), time to pregnancy, and quality of life. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. MAIN RESULTS: This review update included seven RCTs involving 2464 women or couples. Four of the five studies from the previous review were included in this update, and three new studies were added. We assessed the quality of the evidence as moderate to very low, the main limitations being imprecision, indirectness, and risk of bias. Urinary ovulation tests versus intercourse without ovulation prediction Compared to intercourse without ovulation prediction, urinary ovulation detection probably increases the chance of live birth in couples trying to conceive (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.02 to 1.81, 1 RCT, n = 844, moderate-quality evidence). This suggests that if the chance of a live birth without urine ovulation prediction is 16%, the chance of a live birth with urine ovulation prediction is 16% to 28%. However, we are uncertain whether timed intercourse using urinary ovulation detection resulted in a difference in stress (mean difference (MD) 1.98, 95% CI -0.87 to 4.83, I² = 0%, P = 0.17, 1 RCT, n = 77, very low-quality evidence) or clinical pregnancy (RR 1.09, 95% CI 0.51 to 2.31, I² = 0%, 1 RCT, n = 148, low-quality evidence). Similar to the live birth result, timed intercourse using urinary ovulation detection probably increases the chances of clinical pregnancy or positive urine pregnancy test (RR 1.28, 95% CI 1.09 to 1.50, I² = 0, 4 RCTs, n = 2202, moderate-quality evidence). This suggests that if the chance of a clinical pregnancy or positive urine pregnancy test without ovulation prediction is assumed to be 18%, the chance following timed intercourse with urinary ovulation detection would be 20% to 28%. Evidence was insufficient to determine the effect of urine ovulation tests on time to pregnancy or quality of life. Fertility awareness-based methods (FABM) versus intercourse without ovulation prediction Due to insufficient evidence, we are uncertain whether timed intercourse using FABM resulted in a difference in live birth rate compared to intercourse without ovulation prediction (RR 0.95, 95% CI 0.76 to 1.20, I² = 0%, 2 RCTs, n = 157, low-quality evidence). We are also uncertain whether FABM affects stress (MD -1.10, 95% CI -3.88 to 1.68, 1 RCT, n = 183, very low-quality evidence). Similarly, we are uncertain of the effect of timed intercourse using FABM on anxiety (MD 0.5, 95% CI -0.52 to 1.52, P = 0.33, 1 RCT, n = 183, very low-quality evidence); depression (MD 0.4, 95% CI -0.28 to 1.08, P = 0.25, 1 RCT, n = 183, very low-quality evidence); or erectile dysfunction (MD 1.2, 95% CI -0.38 to 2.78, P = 0.14, 1 RCT, n = 183, very low-quality evidence). Evidence was insufficient to detect a benefit of timed intercourse using FABM on clinical pregnancy (RR 1.13, 95% CI 0.31 to 4.07, 1 RCT, n = 17, very low-quality evidence) or clinical or positive pregnancy test rates (RR 1.08, 95% CI 0.89 to 1.30, 3 RCTs, n = 262, very low-quality evidence). Finally, we are uncertain whether timed intercourse using FABM affects the time to pregnancy (hazard ratio 0.86, 95% CI 0.53 to 1.38, 1 RCT, n = 140, low-quality evidence) or quality of life. No studies assessed the use of timed intercourse with pelvic ultrasonography. AUTHORS' CONCLUSIONS: The new evidence presented in this review update shows that timed intercourse using urine ovulation tests probably improves live birth and pregnancy rates (clinical or positive urine pregnancy tests but not yet confirmed by ultrasound) in women under 40, trying to conceive for less than 12 months, compared to intercourse without ovulation prediction. However, there are insufficient data to determine the effects of urine ovulation tests on adverse events, clinical pregnancy, time to pregnancy, and quality of life. Similarly, due to limited data, we are uncertain of the effect of FABM on pregnancy outcomes, adverse effects, and quality of life. Further research is therefore required to fully understand the safety and effectiveness of timed intercourse for couples trying to conceive. This research should include studies reporting clinically relevant outcomes such as live birth and adverse effects in fertile and infertile couples and utilise various methods to determine ovulation. Only with a comprehensive understanding of the risks and benefits of timed intercourse can recommendations be made for all couples trying to conceive.

The role of CD8+ T cells in endometriosis: a systematic review.

Background: Endometriosis is a chronic disease affecting 6-10% of women of reproductive age. It is an important cause of infertility and chronic pelvic pain with poorly understood aetiology. CD8+ T (CD8 T) cells were shown to be linked to infertility and chronic pain and play a significant role in lesion clearance in other pathologies, yet their function in endometriosis is unknown. We systematically evaluated the literature on the CD8 T in peripheral blood and endometriosis-associated tissues to determine the current understanding of their pathophysiological and clinical relevance in the disease and associated conditions (e.g. infertility and pelvic pain). Methods: Four databases were searched (MEDLINE, EMBASE, Web of Science, CINAHL), from database inception until September 2022, for papers written in the English language with database-specific relevant terms/free-text terms from two categories: CD8 T cells and endometriosis. We included peer-reviewed papers investigating CD8 T cells in peripheral blood and endometriosis-associated tissues of patients with surgically confirmed endometriosis between menarche and menopause, and animal models with oestrous cycles. Studies enrolling participants with other gynaecological pathologies (except uterine fibroids and tubal factor infertility used as controls), cancer, immune diseases, or taking immune or hormonal therapy were excluded. Results: 28 published case-control studies and gene set analyses investigating CD8 T cells in endometriosis were included. Data consistently indicate that CD8 T cells are enriched in endometriotic lesions in comparison to eutopic endometrium, with no differences in peripheral blood CD8 T populations between patients and healthy controls. Evidence on CD8 T cells in peritoneal fluid and eutopic endometrium is conflicting. CD8 T cell cytotoxicity was increased in the menstrual effluent of patients, and genomic analyses have shown a clear trend of enriched CD8 T effector memory cells in the eutopic endometrium of patients. Conclusion: Literature on CD8 T cells in endometriosis-associated tissues is inconsistent. Increased CD8 T levels are found in endometriotic lesions, however, their activation potential is understudied in all relevant tissues. Future research should focus on identifying clinically relevant phenotypes to support the development of non-invasive diagnostic and treatment strategies. Systematic Review Registration: PROSPERO identifier CRD42021233304.

Predictors and trends of Caesarean section and breastfeeding in the Eastern Mediterranean region: Data from the cross-sectional Cyprus Women's Health Research (COHERE) Initiative.

INTRODUCTION: Caesarean section (C-section) is a life-saving procedure when medically indicated but unmet need and overuse can add to avoidable morbidity and mortality. It is not clear whether C-section has a negative impact on breastfeeding and there is limited data available on rates of C-section or breastfeeding from Northern Cyprus, an emerging region in Europe. This study aimed to investigate prevalence, trends and associations of C-section and breastfeeding in this population. METHODS: Using self-reported data from the representative Cyprus Women's Health Research (COHERE) Initiative, we used 2,836 first pregnancies to describe trends in C-section and breastfeeding between 1981 and 2017. Using modified Poisson regression, we examined the relationship between year of pregnancy and C-section and breastfeeding, as well as the association between C-section and breastfeeding prevalence and duration. RESULTS: C-section prevalence in first pregnancies increased from 11.1% in 1981 to 72.5% in 2017 with a relative risk of 2.60 (95%CI; 2.14-2.15) of babies being delivered by C-section after 2005 compared to before 1995, after full adjustment for demographic and maternal medical and pregnancy related factors. Prevalence of ever breastfeeding remained steady throughout the years at 88.7% and there was no significant association between breastfeeding initiation and the year of pregnancy, or demographic and maternal medical and pregnancy related variables. After full adjustment, women who gave birth after 2005 were 1.24 (95%CI; 1.06-1.45) times more likely to breastfeed for >12 weeks compared to women who gave birth before 1995. There was no association between C-section and breastfeeding prevalence or length. CONCLUSION: Prevalence of C-section in this population is much higher than WHO recommendations. Public awareness campaigns surrounding choice during pregnancy and change in legal framework to allow for midwife-led continuity models of birthing care should be implemented. Further research is required to understand the reasons and drivers behind this high rate.

Clinical profiling of specific diagnostic subgroups of women with chronic pelvic pain.

Introduction: Chronic pelvic pain (CPP) is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. Its clinical presentation is varied and there are frequently comorbid conditions both within and outside the pelvis. We aim to explore whether specific subgroups of women with CPP report different clinical symptoms and differing impact of pain on their quality of life (QoL). Methods: The study is part of the Translational Research in Pelvic Pain (TRiPP) project which is a cross-sectional observational cohort study. The study includes 769 female participants of reproductive age who completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this population we defined a control group (reporting no pelvic pain, no bladder pain syndrome, and no endometriosis diagnosis, N = 230) and four pain groups: endometriosis-associated pain (EAP, N = 237), interstitial cystitis/bladder pain syndrome (BPS, N = 72), comorbid endometriosis-associated pain and BPS (EABP, N = 120), and pelvic pain only (PP, N = 127). Results: Clinical profiles of women with CPP (13-50 years old) show variability of clinical symptoms. The EAP and EABP groups scored higher than the PP group (p < 0.001) on the pain intensity scales for non-cyclical pelvic pain and higher than both the BPS and PP groups (p < 0.001) on the dysmenorrhoea scale. The EABP group also had significantly higher scores for dyspareunia (p < 0.001), even though more than 50% of sexually active participants in each pain group reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Scores for the QoL questionnaire (SF-36) reveal that CPP patients had significantly lower QoL across all SF-36 subscales (p < 0.001). Significant effects were also observed between the pain groups for pain interference with their work (p < 0.001) and daily lives (p < 0.001), with the EABP suffering more compared to the EAP and PP groups (p < 0.001). Discussion: Our results demonstrate the negative impact that chronic pain has on CPP patients' QoL and reveal an increased negative impact of pain on the comorbid EABP group. Furthermore, it demonstrates the importance of dyspareunia in women with CPP. Overall, our results demonstrate the need for further exploration of interventions targeting QoL more broadly and suggest that novel approaches to classifying women with CPP are needed.

Effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women (ESPriT2): protocol for a multi-centre randomised controlled trial.

BACKGROUND: Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. METHODS: We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons' preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants' preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. DISCUSSION: This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. TRIAL REGISTRATION: ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

Comprehensive quantitative sensory testing shows altered sensory function in women with chronic pelvic pain: results from the Translational Research in Pelvic Pain (TRiPP) Study.

ABSTRACT: Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in <7% of CPP participants. Specific QST measures correlated with sensory symptoms assessed by the painDETECT questionnaire (pressure-evoked pain [painDETECT] and PPT [QST] [ r = 0.47, P < 0.001]; mechanical hyperalgesia (painDETECT) and mechanical pain sensitivity [MPS from QST] [ r = 0.38, P = 0.009]). The data suggest that participants with CPP are sensitive to both deep tissue and cutaneous inputs, suggesting that central mechanisms may be important in this cohort. We also see phenotypes such as thermal hyperalgesia, which may be the result of peripheral mechanisms, such as irritable nociceptors. This highlights the importance of stratifying patients into clinically meaningful phenotypes, which may have implications for the development of better therapeutic strategies for CPP.

Macrophages and small extracellular vesicle mediated-intracellular communication in the peritoneal microenvironment: Impact on endometriosis development.

Endometriosis is an inflammatory disease that is defined as the growth of endometrium-like tissue outside the uterus, commonly on the lining of the pelvic cavity, visceral organs and in the ovaries. It affects around 190 million women of reproductive age worldwide and is associated with chronic pelvic pain and infertility, which greatly impairs health-related life quality. The symptoms of the disease are variable, this combined with a lack of diagnostic biomarkers and necessity of surgical visualisation to confirm disease, the prognosis can take an average timespan of 6-8 years. Accurate non-invasive diagnostic tests and the identification of effective therapeutic targets are essential for disease management. To achieve this, one of the priorities is to define the underlying pathophysiological mechanisms that contribute to endometriosis. Recently, immune dysregulation in the peritoneal cavity has been linked to endometriosis progression. Macrophages account for over 50% of immune cells in the peritoneal fluid and are critical for lesion growth, angiogenesis, innervation and immune regulation. Apart from the secretion of soluble factors like cytokines and chemokines, macrophages can communicate with other cells and prime disease microenvironments, such as the tumour microenvironment, via the secretion of small extracellular vesicles (sEVs). The sEV-mediated intracellular communication pathways between macrophages and other cells within the peritoneal microenvironment in endometriosis remain unclear. Here, we give an overview of peritoneal macrophage (pMΦ) phenotypes in endometriosis and discuss the role of sEVs in the intracellular communication within disease microenvironments and the impact they may have on endometriosis progression.