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

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

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.

Magnetic Resonance Imaging-Based Classification Systems for Informing Better Outcomes of Adenomyosis After Ultrasound-Guided High-Intensity Focused Ultrasound Ablating Surgery.

BACKGROUND: A referenced MRI-based classification associated with focused ultrasound ablation surgery (FUAS) outcomes is lacking in adenomyosis. PURPOSE: To identify an MRI-based classification system for informing the FUAS outcomes. STUDY TYPE: Retrospective. POPULATION: Patients with FUAS for adenomyosis, were divided into a training set (N = 643; 355 with post-FUAS gonadotropin-releasing hormone/levonorgestrel, 288 without post-FUAS therapy) and an external validation set (N = 135; all without post-FUAS therapy). FIELD STRENGTH/SEQUENCE: 1.5 T, turbo spin-echo T2-weighted imaging and single-shot echo-planar diffusion-weighted imaging sequences. ASSESSMENT: Five MRI-based adenomyosis classifications: classification 1 (C1) (diffuse, focal, and mild), C2 (intrinsic, extrinsic, intramural, and indeterminate), C3 (internal, adenomyomas, and external), C4 (six subtypes on areas [internal or external] and volumes [<1/3 or ≥2/3]), and C5 (internal [asymmetric or symmetric], external, intramural, full thickness [asymmetric or symmetric]) for FUAS outcomes (symptom relief and recurrence). STATISTICAL TESTS: The optimal classification was significantly associated with the most subtypes of FUAS outcomes. Relating to the timing of recurrence was measured using Cox regression analysis and median recurrence time was estimated by a Kaplan-Meier curve. A P value <0.05 was considered statistically significant. RESULTS: Dysmenorrhea relief and recurrence were only associated with C2 in training patients undergoing FUAS alone. Compared with other subtypes, the extrinsic subtype of C2 was significantly associated with dysmenorrhea recurrence in the FUAS group. Besides, the median dysmenorrhea recurrence time of extrinsic subtype was significantly shorter than that of other subtypes (42.0 months vs. 50.3 months). In the validation cohort, C2 was confirmed as the optimal system and its extrinsic subtype was confirmed to have a significantly shorter dysmenorrhea recurrence time than other subtypes. DATA CONCLUSION: Classification 2 can inform dysmenorrhea relief and recurrence in patients with adenomyosis undergoing FAUS only. Itsextrinsic subtype was associated with an earlier onset of dysmenorrhea recurrence after treatment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.

The impact of metronidazole on pain persistence after fertility-sparing endometriosis surgery: METROFERT randomized study.

BACKGROUND: Recent studies have shown that a disrupted microbiome is associated with endometriosis. Despite endometriosis affecting 1 in 10 reproductive-aged women, there is a lack of innovative and nonhormonal long-term effective treatments. Studies have reported an approximately 20-37.5% persistence of pain after fertility-sparing endometriosis surgery. Metronidazole has been shown to decrease inflammatory markers and the size of endometriosis lesions in animal studies. OBJECTIVE: To determine if modulating the microbiome with oral metronidazole for 14 days after fertility-sparing endometriosis surgery decreases pain persistence postoperatively. STUDY DESIGN: This was a randomized, multicenter, placebo-controlled, double-blind trial. Individuals 18-50 years old were prospectively randomized to placebo versus oral metronidazole for 14 days immediately after endometriosis fertility-sparing excision surgery. The primary outcome was binary, subjective pain persistence at six weeks postoperatively. Secondary outcomes of quality of life, sexual function, and endometriosis-associated pain scores according to the Endometriosis Health Profile-5, Female Sexual Function Index, and a visual analog scale. RESULTS: 152 participants were approached from October 2020 to October 2023 to enroll in the study. 64 participants were excluded either because they did not meet inclusion or exclusion criteria or because they declined to participate. 88 participants were randomized in a 1:1 ratio to receive either the oral placebo or metronidazole after endometriosis excision surgery. 18.2% of participants were lost to follow-up or discontinued treatment and this was not significantly different between the two arms, yielding a final cohort of 72 participants. Baseline demographics of the two study groups were similar. There was no statistically significant improvement in the primary outcome of binary subjective pain persistence between the metronidazole group compared to placebo (84% vs 88%, p=0.74) at 6 weeks postoperatively. Further, no significant differences between treatments were detected in the secondary outcomes. CONCLUSION: A postoperative 14-day regimen of oral metronidazole immediately after fertility-sparing endometriosis surgery was not associated with any significant differences between treatment groups in the in the persistence of endometriosis-related pain symptoms compared to placebo at 6 weeks.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The co-primary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy versus placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was < 1% and was attenuated compared with bone loss observed with elagolix monotherapy.

A multidimensional appraisal of early menstrual pain experience.

BACKGROUND: Symptomatic dysmenorrhea is a global problem, affecting more than 40% of menstruating persons. Cross-sectional studies have implicated psychosocial, biological, and sensory factors in dysmenorrhea but the mechanisms are not fully understood. Only a few prospective longitudinal studies have evaluated such factors in relation to the emergence and course of dysmenorrhea at menarche. OBJECTIVE: This study aimed to describe the initial menstruation experience and to evaluate the association of premenarchal psychosocial and sensory factors with the intensity of dysmenorrhea during the period in the fourth month. STUDY DESIGN: This was a prospective cohort study of adolescents who completed premenarchal assessments and postmenarchal daily menstrual diaries for their first (n=149) and fourth month periods (n=114). They were recruited shortly before menarche and completed baseline assessments, including psychosocial questionnaires and experimental pain sensitivity (pressure testing, bladder provocation), and their parents completed related pain questionnaires. The relation between the hypothesized premenarchal factors and month 4 dysmenorrhea intensity was evaluated using Kruskal-Wallis and chi-square tests for low (<3 on a 0-10 scale) vs higher (≥3) menstrual pain groups based on maximal pain ratings recorded in a daily diary. RESULTS: Low levels of dysmenorrhea characterized the first (median, 1; interquartile range, 0-2) and fourth month periods (1; 0-3). Maximal pain ratings increased from the first to the fourth period (3; 1-5 vs 4; 1-6; P=.007). The distribution of dysmenorrhea was multimodal at month 4 with 31.6% of the participants having low levels of maximal pain (1; 0-1) and 68.4% having higher levels (5; 4-6; Hartigan's dip test P<.001). The baseline demographic, psychosocial, and parental pain characteristics were not associated with the development of worse dysmenorrhea. The baseline experimental pain sensitivity, based on pressure pain thresholds, did not differ between the low (15.7 N; 12.5-22.3) and higher (15.0 N; 10.9-21.4]) level dysmenorrhea groups. Baseline bladder pain at first urge also did not differ (low, 6; 0-20 vs higher, 7; 0-19). CONCLUSION: By their fourth month period, two-thirds of adolescents fell into the higher group for maximal dysmenorrhea, half reported some related impairments in physical activity, and one-seventh reported some related school absence. Premenarchal factors (experimental pain sensitivity, psychosocial profile, parental pain experience) linked to chronic pain emergence in the adult literature did not predict dysmenorrhea intensity, suggesting the dominant factor at menarche may be peripheral afferent activation. Further research is needed to understand the evolution of psychosocial and sensory mechanisms in the development and course of dysmenorrhea.

Ultrasound and magnetic resonance imaging-based investigation of the role of perfusion and oxygen availability in menstrual pain.

BACKGROUND: The mechanisms responsible for menstrual pain are poorly understood. However, dynamic, noninvasive pelvic imaging of menstrual pain sufferers could aid in identifying therapeutic targets and testing novel treatments. OBJECTIVE: To study the mechanisms responsible for menstrual pain, we analyzed ultrasonographic and complementary functional magnetic resonance imaging parameters in dysmenorrhea sufferers and pain-free controls under multiple conditions. STUDY DESIGN: We performed functional magnetic resonance imaging on participants with and those without dysmenorrhea during menses and outside menses. To clarify whether regional changes in oxygen availability and perfusion occur, functional magnetic resonance imaging R2∗ measurements of the endometrium and myometrium were obtained. R2∗ measurements are calculated nuclear magnetic resonance relaxation rates sensitive to the paramagnetic properties of oxygenated and deoxygenated hemoglobin. We also compared parameters before and after an analgesic dose of naproxen sodium. In addition, we performed similar measurements with Doppler ultrasonography to identify if changes in uterine arterial velocity occurred during menstrual cramping in real time. Mixed model statistics were performed to account for within-subject effects across conditions. Corrections for multiple comparisons were made with a false discovery rate adjustment. RESULTS: During menstruation, a notable increase in R2∗ values, indicative of tissue ischemia, was observed in both the myometrium (beta ± standard error of the mean, 15.74±2.29 s-1; P=.001; q=.002) and the endometrium (26.37±9.33 s-1; P=.005; q=.008) of participants who experienced dysmenorrhea. A similar increase was noted in the myometrium (28.89±2.85 s-1; P=.001; q=.002) and endometrium (75.50±2.57 s-1; P=.001; q=.003) of pain-free controls. Post hoc analyses revealed that the R2∗ values during menstruation were significantly higher among the pain-free controls (myometrium, P=.008; endometrium, P=.043). Although naproxen sodium increased the endometrial R2∗ values among participants with dysmenorrhea (48.29±15.78 s-1; P=.005; q=.008), it decreased myometrial R2∗ values among pain-free controls. The Doppler findings were consistent with the functional magnetic resonance imaging (-8.62±3.25 s-1; P=.008; q=.011). The pulsatility index (-0.42±0.14; P=.004; q=.004) and resistance index (-0.042±0.012; P=.001; q=.001) decreased during menses when compared with the measurements outside of menses, and the effects were significantly reversed by naproxen sodium. Naproxen sodium had the opposite effect in pain-free controls. There were no significant real-time changes in the pulsatility index, resistance index, peak systolic velocity, or minimum diastolic velocity during episodes of symptomatic menstrual cramping. CONCLUSION: Functional magnetic resonance imaging and Doppler metrics suggest that participants with dysmenorrhea have better perfusion and oxygen availability than pain-free controls. Naproxen sodium's therapeutic mechanism is associated with relative reductions in uterine perfusion and oxygen availability. An opposite pharmacologic effect was observed in pain-free controls. During menstrual cramping, there is insufficient evidence of episodic impaired uterine perfusion. Thus, prostaglandins may have protective vasoconstrictive effects in pain-free controls and opposite effects in participants with dysmenorrhea.

Endometriosis risk and hormonal contraceptive usage: A nationwide cohort study.

OBJECTIVE: To investigate whether an early need of hormonal contraceptive (HC), or a failure to find a suitable method, are warning signs for endometriosis. DESIGN: A retrospective cohort study. SETTING: Sweden. POPULATION: The cohort consisted of 720 805 women aged 12-27 years during the period 2005-2017. All women, regardless of whether they received a diagnosis of endometriosis or not (reference group), were included. METHODS: We used data from Swedish national registers. Risks are expressed as crude and adjusted hazard ratios (HRs and aHRs, respectively) with 95% confidence intervals (95% CIs), adjusted for age, education level, civil status, parity, country of birth, and diagnoses of infertility, dysmenorrhea or depression. MAIN OUTCOME MEASURES: A diagnosis of endometriosis between 12 and 27 years of age. RESULTS: During this period, 3268 women were diagnosed with endometriosis (0.45%). Women who started HC at the ages of 12-14 years had a higher risk of receiving the diagnosis (aHR 2.53, 95% CI 2.21-2.90) than those who began at age 17 years or older. Having tried more types of HCs was associated with a twofold increased risk of endometriosis (more that three types of HC, aHR 2.31, 95% CI 1.71-3.12). Using HC for more than 1 year was associated with a decreased risk of endometriosis (>1 year, aHR 0.53, 95% CI 0.48-0.59). Women with endometriosis more commonly had dysmenorrhea, depression or infertility. CONCLUSIONS: The use of HCs at an early age and a failure to find a suitable HC were identified as warning signs of later receiving an endometriosis diagnosis. A longer duration of HC usage reduced the risk of receiving the diagnosis.

Quality of patient-reported outcome measures for primary dysmenorrhea: a systematic review.

PURPOSE: To conduct a systematic review of the quality of patient-reported outcome measures (PROMs) for primary dysmenorrhea (PDys) using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology, and to derive recommendations for use of the PROMs. METHODS: We searched PubMed and Web of Science for studies reporting on the development and/or validation of any PROMs for women with PDys. Applying the COSMIN Risk of Bias Checklist, we assessed the methodological quality of each included study. We further evaluated the quality of measurement properties per PROM and study according to the criteria for good measurement properties, and graded the evidence. Based on the overall evidence, we derived recommendations for the use of the included PROMs. RESULTS: Data from seven studies reporting on four PROMs addressing different outcomes were included. Among those, the Adolescent Dysmenorrhic Self-Care Scale (ADSCS) and the on-menses version of the Dysmenorrhea Symptom Interference Scale (DSI) can be recommended for use. The Exercise of Self-Care Agency Scale (ESCAS) and the Dysmenorrhea Daily Diary (DysDD) have the potential to be recommended for use, but require further validation. The off-menses version of the DSI cannot be recommended for use. CONCLUSIONS: The ADSCS can be recommended for the assessment of self-care behavior in PDys. Regarding measures of impact, the on-menses version of the DSI is a suitable tool. Covering the broadest spectrum of outcomes, the DysDD is promising for use in medical care and research, encouraging further investigations. Further validation studies are indicated for all included PROMs.

Evaluating the development of endometriosis and adenomyosis lesions over time: An ultrasound study of symptomatic women.

INTRODUCTION: There is a gap in knowledge regarding development of endometriosis and adenomyosis lesions visible at transvaginal ultrasound. The objectives were to evaluate if women with symptoms suggestive of endometriosis or adenomyosis but normal ultrasound examination develop endometriosis or adenomyosis lesions visible at ultrasound over time and if alterations of symptoms over time are associated with ultrasound findings at follow-up. MATERIAL AND METHODS: This was a prospective cohort study of 100 symptomatic women with normal initial ultrasound examination during 2014-2017 who underwent follow-up ultrasound examination in 2022. Symptoms suggestive of endometriosis were assessed using visual analog scale at both examinations and minimal clinically important difference of 10 mm was considered as a significant alteration. An examiner with expertise in advanced ultrasound examination of endometriosis performed transvaginal ultrasound examinations in accordance with the consensus protocol by the International Deep Endometriosis Analysis group. RESULTS: At follow-up ultrasound examination of 100 women, 13 (13% [95% CI 7.1-21.2]) had visible endometriosis or adenomyosis lesions, 8 (8% [95% CI 3.5-15.2]) had endometriosis lesions, and 6 (6% [95% CI 2.2-12.6]) had adenomyosis. At follow-up, women with endometriosis or adenomyosis lesions reported lower intensity of dysmenorrhea and chronic pelvic pain compared to women without lesions (48 mm [IQR 16-79] vs. 73 mm [IQR 46-85] and 45 mm [IQR 26-57] vs. 57 mm [IQR 36-75], p = 0.087 and p = 0.026, respectively). None of the women with endometriosis or adenomyosis lesions reported increased intensity of dysmenorrhea at follow-up, compared to 32/86 women (37%) without lesions (p = 0.008). Increased intensity of chronic pelvic pain tended to be less common in women with lesions compared to those without (3/13 [23%] vs. 35/86 [41%], p = 0.223). CONCLUSIONS: Our findings suggest that in symptomatic women, endometriosis and adenomyosis lesions visible at ultrasound may develop over time. However, majority of women remain having normal ultrasound examinations despite symptoms. Exacerbation of dysmenorrhea or chronic pelvic pain during follow-up was not associated with the development of endometriosis or adenomyosis lesions visible at ultrasound, suggesting that even women with less severe symptoms might benefit from a follow-up ultrasound when indicated.

Lesion size and location in deep infiltrating bowel endometriosis: Correlation with gastrointestinal dysfunction and pain.

INTRODUCTION: Presence of deep infiltrating bowel endometriosis (DE) is associated with occurrence of dyschezia and gastrointestinal symptoms. The degree of the disease, the lesion length, and the location, that is, lesion-to-anal-verge distance (LAVD) of DE, as well as the severity of the symptoms appear to be correlated. Nevertheless, it is not yet known to what extent the size and LAVD of bowel DE influence the severity of gastrointestinal symptoms. The present study aims to evaluate a possible correlation of lesion location (LAVD) and size (according to the #Enzian classification) with preoperative symptoms. MATERIAL AND METHODS: In this prospective study, premenopausal patients with histologically confirmed DE undergoing modified limited nerve-vessel sparing rectal segmental bowel resection or full-thickness discoid resection were evaluated. Extent of endometriosis was defined according to the #Enzian classification during surgery. The primary outcome measure was the correlation between lesion size and location with the GI function impairment reflected by presurgical lower anterior resection syndrome (LARS) scores; the secondary outcome was differences in presurgical numeric rating scale pain scores of dyschezia, dyspareunia, and dysmenorrhea as well as the impact of concomitant DE of other locations on symptom intensity. RESULTS: Of 162 consecutive patients, 151 were included in the final analysis. No significant correlation was observed between lesion size (#Enzian compartments C1/C2/C3) or LAVD and GI dysfunction reflected by LARS-like symptoms (p = 0.314 and p = 0.185, respectively) or pain symptoms (dyschezia, p = 0.440; dyspareunia, p = 0.136; and dysmenorrhea p = 0.221). Furthermore, no significant correlation was observed between lesion size and GI dysfunction when merging two severity grades (#Enzian compartments C1 plus C2 vs. C3; p = 0.611). In addition, LAVD did not affect the degree of dyschezia (p = 0.892), dyspareunia (p = 0.395), or dysmenorrhea (p = 0.705). Finally, the presence of concomitant DE lesions infiltrating the vagina/rectovaginal space (#Enzian compartment A) and/or sacrouterine ligaments/parametrium (#Enzian compartment B) did not alter the severity of preoperative dyschezia (p = 0.493) or dysmenorrhea (p = 0.128) but showed a trend toward affecting gastrointestinal function (p = 0.078) and was significantly associated with dyspareunia (p = 0.035). CONCLUSIONS: In present study, we could not find a correlation between colorectal DE lesion size and location (LAVD) and gastrointestinal function impairment or intensity of dyschezia and dysmenorrhea. Additional involvement of vagina/rectovaginal space (#Enzian compartment A) and/or sacrouterine ligaments/parametrium (#Enzian compartment B) exerts a significant impact on the degree of dyspareunia in women with colorectal DE.

The relationship between dietary habits and menstruation problems in women: a cross-sectional study.

BACKGROUND: Nutrition is important to the management and relief of the symptoms in menstrual disorders. This study aims to investigate the relationship between menstrual disorders and specific foods and nutrient intake in women. METHODS: Five-hundred-nine menstruating women participated in the study. The questionnaire form was created by the researchers via Google Forms and distributed in online applications (WhatsApp, Instagram etc.). The questionnaire consists of 5 sections, including demographic data, declared anthropometric measurements (height (m or cm), weight (g or kg)), questions about eating habits, menstruation status, and 24-hour food consumption. Statistical analysis was made with SPSS 23; nutrient analysis of food consumption was made using BeBiS 9.0. RESULTS: It was found that the body mass index (BMI) of healthy participants was higher than women with menstrual disorders. Women with menstrual disorders have lower intake of protein, vitamin K, vitamin B3, vitamin B5 and sodium compared with healthy women. All participants have a higher intake of vitamin B3, sodium, phosphorus, and manganese, and have a lower intake of other nutrients compared with the national adequate intake. CONCLUSION: Our findings showed that women with menstrual disorders consume more high-sugar food/beverages and have inadequate nutrients intake.

The impact of COVID-19 on menstrual cycle's alterations, in relation to depression and sleep disturbances: a prospective observational study in a population of medical students.

BACKGROUND: The sars-Cov-2 pandemic has determined psychological stress, particularly in the young population of medical students. We studied the impact of the pandemic on menstrual cycle alteration in relation to psychological stress, presence of depression, sleep disturbances and post-traumatic stress, on a population of medical students. METHODS: 293 female students at the Faculty of Medicine and Psychology of the Sapienza University of Rome (23.08 years old ± 3.8) were enrolled. In March 2021, one year after quarantine, a personal data sheet on menstrual cycle, examining the quality of the menstrual cycle during the pandemic, compared to the previous period. Concomitantly, the Beck Depression Inventory and the Impact of Event Scale have been administered. A Pearson chi-square test was assessed to evaluate the difference between the characteristics of the menstrual cycle and the scores obtained with the questionnaires. RESULTS: A statistically significant association between menstrual alterations and stress during pandemic had been found. The onset of depressive symptoms and sleep disturbances was observed in 57.1% and in 58.1% of young women with cycle's alterations, respectively. Amenorrhea was three times more common in female students with depressive symptoms, premenstrual syndrome had a significant correlation with both depression and sleep disturbances. The pandemic has been related to menstrual alterations, with depressive symptoms and sleep disorders. Amenorrhea is connected to depression, as observed on the functional hypothalamic amenorrhea. CONCLUSIONS: The pandemic affected the menstrual cycle as well as the depressive symptoms and sleep. Practical implications of the study lead to the development of strategies for psychological intervention during the pandemic experience, in order to help medical trainees, with specific attention to women's needs. Future studies should analyze the impact of other types of social stress events, on sleep, depression and the menstrual cycle beside the pandemic.

Dysmenorrhea pattern in adolescences informing adult endometriosis.

BACKGROUND: Endometriosis (EMs) is a chronic and progressive disease that, if diagnosed late, can lead to infertility and deep infiltrating endometriosis (DIE). Dysmenorrhea is the most prominent symptom of EMs. However, limited research exists on the specific correlation between dysmenorrhea patterns and EMs. Early prevention of EMs is essential to effectively manage the progression of the disease, and is best detected during adolescence. Our objective was to associate the development of EMs with dysmenorrhea patterns during adolescence and quantify the risk of adult EMs for adolescent girls, with the aim of supporting primary intervention strategy planning. METHODS: This case-control study examined predictors for adult EMs based on dysmenorrhea patterns in adolescents. We collected 1,287 cases of 641 EMs and 646 healthy females regarding their basic demographic information, adolescent menstrual characteristics, adolescent dysmenorrheal patterns, and adolescent lifestyles. Age-matching (1-to-1) was employed to control for the confounding effect of age between the groups. Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression models were utilized to identify predictors for adult EMs. The predictive value of the model was evaluated using the area under the receiver operating characteristic curve (AUC) and the C-index, while Hosmer-Lemeshow Test assessed the goodness of fit of the model. Data from one additional cohort in Shenzhen hospitalized with EMs were used to external validation were analyzed. RESULTS: Individuals who always experienced dysmenorrhea had a risk of adult endometriosis 18.874 (OR = 18.874; 95%CI = 10.309-34.555) times higher than those occasional dysmenorrhea, The risk of developing EMs was 5.257 times higher in those who experienced dysmenorrhea more than 12 months after menarche than in those who experienced dysmenorrhea less than 6 months after menarche (OR = 5.257, 95% CI = 3.343-8.266), AUC in the external validation cohort was 0.794(95%CI: 0.741-0.847). We further found that high-intensity physical activity and sun-sensitive skin of burning were influential factors in high-frequency dysmenorrhea. The AUC value for the internal evaluation of the model was 0.812 and the AUC value for the external validation was 0.794. CONCLUSION: Our findings revealed that the frequency of dysmenorrhea during adolescence contributed to the development of adult endometriosis. The frequency and onset of dysmenorrhea in adolescence were promising predictors for adult EMs. Both internal and external validation proved the model's good predictive ability. TRIAL REGISTRATION: http://www.chictr.org.cn/ , TRN: ChicTR2200060429, date of registration: 2022/06/01, retrospectively registered.

The hidden burden of dysmenorrhea among adolescent girls in Palestine refugee camps: a focus on well-being and academic performance.

BACKGROUND: Dysmenorrhea (painful menstruation) is a condition that may have a profound effect on adolescent girls' health status and well-being. It can impede their engagement in daily activities and hamper their regular school attendance. This study aims to explore the relationship between dysmenorrhea, well-being, and academic performance among adolescent girls living in Palestine refugee camps in the West Bank and Jordan. METHODS: We conducted a household survey between June and September 2019, with a total sample of 2737 adolescent girls 15 to 18 years old. Dysmenorrhea severity was assessed using the Working Ability, Location, Intensity, Duration of pain Dysmenorrhea scale (WaLIDD). The WHO-5 scale was used to evaluate the girls' overall well-being. Menstrual academic disruption (MAD) was measured using a self-reported scale. Multiple linear regression models were employed to evaluate the association between dysmenorrhea, well-being, and academic performance. Directed Acyclic Graphs (DAGs) were employed to identify variables for control in regression models. RESULTS: The mean dysmenorrhea score was 6.6 ± 2.6, with 37.9% and 41.2% expressing moderate and severe symptoms, respectively. The mean WHO-5 score was 58.7 ± 25.1, and 34.9% reported a low well-being status. The mean MAD score was 3.1 ± 3.3. 26% reported missing school due to dysmenorrhea, 36% said dysmenorrhea impacted their ability to concentrate, and 39% were unable to study for tests, and complete homework. The first regression analysis showed a reduction of 1.45 units in WHO-5 score for each unit increase in dysmenorrhea. The second regression analysis showed a non-linear increase in MAD score for increasing dysmenorrhea. For each dysmenorrhea score less than 4 (mild) there was a modest increase in MAD scores (coefficient 0.08, p-value = 0.006), and for each dysmenorrhea score above 4 there was a stronger increase in MAD scores (coefficient 0.95, p < 0.001). CONCLUSION: Dysmenorrhea poses significant challenges to the well-being and academic performance of adolescent girls living in Palestine refugee camps. Collaborative efforts and multifaceted approaches are crucial to address dysmenorrhea effectively. This involves research, targeted interventions, culturally sensitive strategies, and fostering a supportive environment that empowers girls to thrive academically and beyond.

Carvacrol-Loaded Nanoemulsion Promotes Tocolytic and Anti-Dysmenorrhea Effects in Rodents.

INTRODUCTION: Carvacrol is a phenolic constituent of essential oils that has antinociceptive, anti-inflammatory, and antioxidant activities. METHOD: This study aimed to evaluate the in vitro spasmolytic and in vivo anti-dysmenorrhea potential of a nanoemulsion-containing carvacrol (nanoCARV). RESULTS: In isolated rat uterus, nanoCARV reduced spontaneous contractions (pEC50 = 3.91 ± 0.25) and relaxed preparations pre-contracted with oxytocin (pEC50 = 3.78 ± 0.2), carbachol (pEC50 = 4.15 ± 0.4), prostaglandin F2α (pEC50 = 3.00 ± 0.36), and KCl (pEC50 = 3.98 ± 0.32). The investigation of the mechanism of action revealed significant differences (p < 0.05) between the pEC50 values of nanoCARV in the absence or presence of aminophylline or tetraethylammonium. In a primary dysmenorrhea model, treatment with nanoCARV reduced the number of oxytocin-induced abdominal writhes. CONCLUSIONS: These data indicate that the anti-dysmenorrhea effect of nanoCARV may be related to the relaxation of uterine smooth muscle, with participation of the cAMP signaling pathway and potassium channels.

Virtual Mindfulness-Based Therapy for the Management of Endometriosis Chronic Pelvic Pain: A Novel Delivery Platform to Increase Access to Care.

OBJECTIVES: This study assessed the effectiveness of a virtual mindfulness-based stress reduction (MBSR) program to improve quality of life and pain in people with endometriosis. METHODS: This was a multiple-method, before and after study design. Fifteen patients with a clinical or surgical diagnosis of endometriosis were recruited from a Canadian outpatient gynaecology clinic. Participants completed the Endometriosis Health Profile, a validated survey tool, and a pain medication use questionnaire before and after a virtual 8-week MBSR program run by an experienced social worker. A focus group was held upon completion of the program to assess participants' experiences using mindfulness for management of endometriosis symptoms. Quantitative data was analyzed with paired-samples t tests. Qualitative data was thematically analyzed. RESULTS: A total of 67% of people enrolled completed the MBSR course (10/15). Following the MBSR program, participants had a statistically significant decrease in 4 components of the Endometriosis Health Profile: control and powerlessness (P = 0.012), emotional well-being (P = 0.048), social support (P = 0.030), and self-image (P = 0.014). There was no change in pain scores or medication use. Participants felt the program's benefits came from a sense of community, education about their condition, and application of mindfulness tools when approaching pain. Participants felt more comfortable with the virtual format over in-person sessions. CONCLUSIONS: A virtual MBSR course can improve quality of life domains in people with endometriosis. The virtual format was effective and preferred by participants. Virtual MBSR programs may increase access to this type of care.

Association of the Verbal Rating Scale-Measured Dysmenorrhea with Nausea and Vomiting in Pregnancy: A Retrospective Cohort Study.

OBJECTIVES: Nausea and vomiting in pregnancy (NVP) is a common condition that reduces the quality of life by negatively affecting work and family life, physical and mental health, and economic well-being. However, its risk factors remain unclear. This study aimed to explore the association between NVP and verbal rating scale (VRS)-measured dysmenorrhea and to explore potential protective factors. METHODS: This retrospective cohort study was conducted from June 2018 to December 2020 at Tongji Hospital in Wuhan. Information on baseline characteristics, pregnancy-related history, periconceptional micronutrient supplementation, and obstetric outcomes were collected. The severity of dysmenorrhea was assessed using VRS. RESULTS: A total of 443 pregnant women were recruited and divided into the NVP group (n = 76) and the control group (n = 367). A significant association was observed between NVP and VRS-measured dysmenorrhea (c2=10.038, P = 0.007). After adjusting for covariates, the association between moderate/severe dysmenorrhea and NVP remained significant (OR 2.384; 95% CI 1.104-5.148, P = 0.004). First-trimester docosahexaenoic acid supplement (OR 0.443; 95% CI 0.205-0.960, P = 0.039) may be beneficial in reducing the risk of NVP. CONCLUSIONS: Women with moderate to severe dysmenorrhea have a higher risk of experiencing NVP during the first trimester. Periconceptional docosahexaenoic acid supplementation may play a protective role.

Decidual cast: a rare cause of genital tract obstruction.

Decidual cast is a little-known entity characterized by sloughing of the endometrium in several large pieces or in one cylindrical or membranous piece retaining the shape of the uterine cavity. Accounts of the diagnosis are sporadic and have not previously appeared in the pediatric imaging literature. We describe a case of a post-menarchal adolescent girl presenting with abnormal uterine bleeding, severe dysmenorrhea, and imaging features of genital tract obstruction, the cause of which was found to be a large decidual cast during examination under anesthesia. While rare, awareness of this phenomenon should be useful to pediatric imagers as the combination of bleeding and obstructive symptoms produces a confusing picture that may lead to a protracted clinical and imaging course.

Influence of menstrual pain and symptoms on activities of daily living and work absenteeism: a cross-sectional study.

OBJECTIVE: To examine the prevalence of menstrual pain among women of reproductive age and its impact on their daily lives and professional responsibilities. METHODS: A cross-sectional and descriptive study was conducted in July and August 2022. Phone interviews were carried out using a random system to select women aged between 15 and 49 years old. The questionnaire included sociodemographic variables, contraception method used, characteristics of the menstrual pattern (pain and bleeding amount), its influence on their working life, and if they would need to resort to sick leaves due to the impairments arising from the menstrual symptoms. RESULTS: A total of 1800 women representative of the Spanish population took part in this study. 72.6% of them report menstrual pain, with 45.9% requiring medication. 35.9% identify their menstrual bleeding as intense or very intense. 38.8% assert that menstrual discomforts affect their everyday life. 34.3% would have required not attending their work activities or having requested sick leave due to the discomforts, although only 17.3% of the women finally requested so, mainly because 58.4% considered that it might imply consequences in their professional environment, especially those with Higher Education. The women who report more discomfort are the youngest ones and those who resort to condoms as a contraceptive method (p < 0.001). CONCLUSIONS: Menstrual pain is a prevalent problem among women of reproductive age and can affect their everyday life and professional environment, requiring work leaves on some occasions.

This study is a starting point to know the prevalence of menstrual discomforts among Spanish women of reproductive age and their effect on the professional environment, to enable an assessment of the possible impact of the menstrual leave legislation recently implemented in Spain.