Macrophage polarization in adenomyosis: A review.

Adenomyosis (AM) is a common gynecological disorder characterized by the presence of endometrial glands and stroma within the uterine myometrium. It is associated with abnormal uterine bleeding (AUB), dysmenorrhea, and infertility. Although several mechanisms have been proposed to elucidate AM, the exact cause and development of the condition remain unclear. Recent studies have highlighted the significance of macrophage polarization in the microenvironment, which plays a crucial role in AM initiation and progression. However, a comprehensive review regarding the role and regulatory mechanism of macrophage polarization in AM is currently lacking. Therefore, this review aims to summarize the phenotype and function of macrophage polarization and the phenomenon of the polarization of adenomyosis-associated macrophages (AAMs). It also elaborates on the role and regulatory mechanism of AAM polarization in invasion/migration, fibrosis, angiogenesis, dysmenorrhea, and infertility. Furthermore, this review explores the underlying molecular mechanisms of AAM polarization and suggests future research directions. In conclusion, this review provides a new perspective on understanding the pathogenesis of AM and provides a theoretical foundation for developing targeted drugs through the regulation of AAM polarization.

Effects of menstrual disorders and dysmenorrhea on cardiovascular disease: a Mendelian randomization study.

Background: Observational studies have demonstrated associations between menstrual disorders, dysmenorrhea, and cardiovascular disease (CVD). However, it remains unclear whether these associations are causal. This study is to investigate whether menstrual disorders and dysmenorrhea causally affect the risk of CVD. Methods: The summary data for menstrual disorders (excessive menstruation and irregular menses) and dysmenorrhea were obtained from FinnGen study, summary data for CVD were obtained from UK Biobank and meta-analysis. The inverse-variance-weighted method was mainly used in the Mendelian randomization for causality analysis. Sensitivity analyses were performed by several methods under different model assumptions. Results: Genetic liability to excessive menstruation was associated with higher risk of atrial fibrillation (odds ratio (OR), 1.078 [95% confidence interval (CI), 1.015-1.145]; P=0.014), but a lower risk of hypertension (OR, 0.994 [95% CI: 0.989-0.999]; P=0.016). Irregular menses was associated with higher risk of atrial fibrillation (OR, 1.095 [95% CI: 1.015-1.182]; P=0.02), hypertension (OR, 1.007 [95% CI: 1.000-1.013]; P=0.047), myocardial infarction (OR, 1.172 [95% CI: 1.060-1.295]; P=0.02), ischemic heart disease, (OR, 1.005 [95% CI: 1.000-1.010]; P=0.037) and coronary heart disease (OR, 1.004 [95% CI: 1.001-1.008]; P=0.026). Dysmenorrhea was associated with higher risk of atrial fibrillation (OR, 1.052 [95% CI: 1.014-1.092]; P=0.008) and Ischemic stroke (cardioembolic) (OR, 1.122 [95% CI: 1.002-1.257]; P=0.046). After Benjamini-Hochberg correction, irregular menses was associated with higher risk of myocardial infarction. Conclusion: We confirmed a causal relationship of excessive menstruation, irregular menses and dysmenorrhea on cardiovascular outcomes independent of sex hormone levels, with an emphasis on the link between irregular menses and myocardial infarction. These clinical features can be utilized as markers to identify women at higher risk of developing CVD in the future, recommending early clinical intervention of menstrual diseases.

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.

Efficacy and safety of a novel pain management device, AT-04, for endometriosis-related pain: study protocol for a phase III randomized controlled trial.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

Endometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-related pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endometriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first randomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, that incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a multicenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone standard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains effective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 on reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects the strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole efficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual cycles may influence the assessment of pain and quality of life. However, the study findings regarding the effectiveness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain that is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproductive health within society.

Evaluation of long-term efficacy and safety of dienogest in patients with chronic cyclic pelvic pain associated with endometriosis.

PURPOSE: To evaluate the efficacy and long-term safety (up to 108 months) of treatment with Dienogest in patients with endometriosis. METHODS: Patients with chronic pelvic pain endometriosis-related were enrolled in this observational study from June 2012 to July 2021. The patients enrolled took Dienogest 2 mg as a single daily administration. Group B of long-term therapy patients (over 15 months) were compared with group A of short-term therapy patients (0-15 months). The effects of the drug on pain variation were assessed using the VAS scale and endometriomas dimensions through ultrasonographic evaluation. Furthermore, has been valuated the appearance of side effects and the effect of the drug on bone metabolism by performing MOC every 24 months in group B. RESULTS: 157 patients were enrolled. The mean size of the major endometrioma progressively decreased from 33.2 mm (29.4-36.9) at T0 to 7 mm (0-15.8) after 108 months of treatment. We found a significant improvement in dysmenorrhea, dyspareunia, dyschezia and non-cyclic pelvic pain. As for the side effects, both groups complained menstrual alterations present in 22.9%. In 27.6% of group B, osteopenia was found. Group B had a higher percentage statistically significant of side effects such as headaches, weight gain and libido reduction compared to group A. 2 CONCLUSION: Long-term therapy with Dienogest has proven effective in controlling the symptoms of the disease and reducing the size of endometriomas, with an increase in the positive effects related to the duration of the intake and in the absence of serious adverse events. Study approved by the "Palermo 2" Ethics Committee on July 2, 2012 No. 16.

Evaluation of the Characteristics of Ovarian Endometriomas in Patients with Endometriosis: Efficacy of a Low-Dose Estrogen/Progestogen Combination.

OBJECTIVES: Approximately 17-44% of women diagnosed with endometriosis have ovarian endometriomas (cysts). Although ovarian endometriomas may adversely affect quality of life and work performance, the associations among patient characteristics, cyst size, and pain in women with endometriosis have not yet been reported. Thus, the objective of this study was to assess the association among age, cyst size, and pain in women with ovarian endometriomas. DESIGN: This was a retrospective secondary analysis of pooled data from six randomized clinical trials on the use of low-dose estrogen/progestogen drugs for endometriosis. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Data on 491 patients enrolled in four randomized and two nonrandomized trials between 2003 and 2017 were pooled. None of the participants had undergone surgical treatment before trial participation. We examined differences in dysmenorrhea score, menstrual pain score, analgesic score, and pelvic pain, as measured using a visual analog scale (VAS), by age and endometrioma size. RESULTS: The mean dysmenorrhea, menstrual pain, and analgesic scores were 4.2, 2.2, and 2.0, respectively. The mean VAS for pelvic pain was 55, which decreased significantly with an increase in age. Age was not associated with endometrioma size, including volume and maximum diameter, or dysmenorrhea score. Additionally, endometrioma volume and maximum diameter were not associated with menstrual pain, analgesic score, or pelvic pain. LIMITATIONS: The details of past treatment history were not available; therefore, these could not be considered in the analysis. Additionally, the assessment of pain is heavily influenced by psychological factors, making it difficult to assess the true extent of pain. CONCLUSIONS: Endometrioma size was not associated with dysmenorrhea or pelvic pain measured using the VAS.

Pain Frequency and Health Care Utilization Patterns in Women with Sickle Cell Disease Experiencing Menstruation-Associated Pain Crises.

Background: Pain crises in sickle cell disease (SCD) lead to high rates of health care utilization. Historically, women have reported higher pain burdens than men, with recent studies showing a temporal association between pain crisis and menstruation. However, health care utilization patterns of SCD women with menstruation-associated pain crises have not been reported. We studied the frequency, severity, and health care utilization of menstruation-associated pain crises in SCD women. Materials and Methods: A multinational, cross-sectional cohort study of the SCD phenotype was executed using a validated questionnaire and medical chart review from the Consortium for the Advancement of Sickle Cell Research (CASiRe) cohort. Total number of pain crises, emergency room/day hospital visits, and hospitalizations were collected from a subcohort of 178 SCD women within the past 6 months and previous year. Results: Thirty-nine percent of women reported menstruation-associated pain crises in their lifetime. These women were significantly more likely to be hospitalized compared with those who did not (mean 1.70 vs. 0.67, p = 0.0005). Women reporting menstruation-associated pain crises in the past 6 months also experienced increased hospitalizations compared with those who did not (mean 1.71 vs. 0.75, p = 0.0016). Forty percent of women reported at least four menstruation-associated pain crises in the past 6 months. Conclusions: Nearly 40% of SCD women have menstruation-associated pain crises. Menstruation-associated pain crises are associated with high pain burden and increased rates of hospitalization. Strategies are needed to address health care disparities within gynecologic care in SCD.

Investigating influencing factors on premenstrual syndrome (PMS) among female college students.

BACKGROUND: Premenstrual syndrome (PMS) affects women's physical and mental health. Depression, stress, sleep disturbance, and eating attitude problems have been known to influence PMS. Furthermore, restrictions of daily life due to the COVID-19 pandemic have led to changes in sleep patterns and eating attitudes. Thus, it is necessary to closely examine how these factors affect PMS. This study aimed to examine the levels of PMS, stress, depression, sleep disturbance, and eating attitude problems among female college students who experience dysmenorrhea and determine the factors associated with PMS. METHODS: A cross-sectional online survey design was conducted using a convenience sample of 143 female college students in C City, South Korea. Data were collected from September 1 to 19, 2021 in South Korea using an online self-administered survey. Differences in participants' level of PMS according to physical health variables (e.g., smoking, water intake, menstrual pain intensity) and psychological issues (i.e., stress, depression, sleep disturbances, and eating attitude problems) were assessed with independent sample t-tests and one-way ANOVAs. Correlational analyses between these variables were also conducted. Additionally, multiple regression was performed to identify the factors influencing PMS. RESULTS: PMS severity was between normal (27.3%) and premenstrual dysphoric disorder (PMDD) (72.7%). PMS was associated positively with depression (r = .284, p = 001), stress (r = .274, p = .001), sleep disturbance (r = .440, p < .001), and eating attitude problems (r = .266, p = .001). Additionally, menstrual pain intensity (ß = 0.204), sleep disturbances (ß = 0.375), and eating attitude problems (ß = 0.202) were found to influence PMS. The regression model was significant (F = 16.553, p < .001) with an explanatory power of 24.7%. CONCLUSIONS: Considering the influencing factors of PMS identified in this study, interventions for participants experiencing PMS should be made. We propose that further study should be conducted to examine whether the severity of PMS changes according to menstrual pain, the pattern and degree of its change, and the paths through which sleep quality and eating attitude problems affect PMS.

Menstrual Status Is Associated with the Prevalence of Irritable Bowel Syndrome in a Japanese Young Population: A Cross-Sectional Study.

INTRODUCTION: There is evidence regarding the association between dysmenorrhea and irritable bowel syndrome (IBS), although it is lacking in the Asian population. Therefore, the purpose of this study was to investigate the association between menstrual status and IBS in a young Japanese. METHODS: Overall, 4,693 female college students were included in the analysis of this study. Information regarding lifestyle habits, menstrual status (irregularity, pain severity, and medication), and IBS (Rome III criteria) was obtained using a self-reported questionnaire. Age, body mass index, exercise habits, smoking, drinking habits, and anemia were analyzed as potential confounders. RESULTS: The prevalence of IBS was 6.1%. Moderate {adjusted odds ratio (OR): 1.89 (95% confidence interval [CI]: 1.27-2.91)} and heavy (adjusted OR: 2.14 [95% CI: 1.42-3.45]) menstrual pain were independently positively associated with IBS (p for trend = 0.001). Using medication sometimes (adjusted OR: 1.41 [95% CI: 1.09-1.84]) and often (adjusted OR: 1.60 [95% CI: 1.13-2.24]) was independently positively associated with IBS. There was no association between menstrual cycle and IBS. In subjects without functional dyspepsia, irregular menstrual cycle was independently positively associated with IBS. CONCLUSION: In the young Japanese population, menstrual pain and medications for menstrual pain may have a significant positive association with IBS.

Menstrual disturbances and its association with sleep disturbances: a systematic review.

BACKGROUND: Menstrual disturbances harm women's health, and general well-being. As growing evidence highlights the relationship between sleep and menstrual disturbances, it is imperative to comprehensively examine the association between sleep and menstrual disturbance considering the multiple dimensions of sleep. This systematic review aims to identify the association between sleep and menstrual disturbances by evaluating using Buysse's sleep health framework. METHODS: A comprehensive search of the literature was conducted in PubMed, EMBASE, psychINFO, and CINAHL to identify publications describing any types of menstrual disturbances, and their associations with sleep published between January 1, 1988 to June 2, 2022. Quality assessment was conducted using the Joanna Briggs Institute Critical Appraisal Checklist for Analytical Cross-Sectional Studies. The findings were iteratively evaluated menstrual disturbances and their association with sleep using Buysse's sleep health framework. This framework understands sleep as multidimensional concept and provides a holistic framing of sleep including Satisfaction, Alertness during waking hours, Timing of sleep, Efficiency, and Sleep duration. Menstrual disturbances were grouped into three categories: premenstrual syndrome, dysmenorrhea, and abnormal menstrual cycle/heavy bleeding during periods. RESULTS: Thirty-five studies were reviewed to examine the association between sleep and menstrual disturbances. Premenstrual syndrome and dysmenorrhea were associated with sleep disturbances in sleep health domains of Satisfaction (e.g., poor sleep quality), Alertness during waking hours (e.g., daytime sleepiness), Efficiency (e.g., difficulty initiating/maintaining sleep), and Duration (e.g., short sleep duration). Abnormal menstrual cycle and heavy bleeding during the period were related to Satisfaction, Efficiency, and Duration. There were no studies which investigated the timing of sleep. CONCLUSIONS/IMPLICATIONS: Sleep disturbances within most dimensions of the sleep health framework negatively impact on menstrual disturbances. Future research should longitudinally examine the effects of sleep disturbances in all dimensions of sleep health with the additional objective sleep measure on menstrual disturbances. This review gives insight in that it can be recommended to provide interventions for improving sleep disturbances in women with menstrual disturbance.

[Dysmenorrhea and pelvic pain secondary to an accessory and cavitated uterine mass]. / Dysménorrhée et douleurs pelviennes secondaires à une masse utérine cavitaire accessoire.

An accessory and cavitated uterine mass (ACUM) is a rare anomaly with an embryological origin of dysfunctionning female gubernaculum. It is an accessory mass internally lined with normal endometrium, separated from the uterine cavity and located near the insertion of the round ligament. ACUM's clinical manifestations are severe dysmenorrhea and/or chronic pelvic pain. It is a relatively unknown condition, which makes its diagnosis complicated and suggests a large differential diagnosis. We report the case of a 31-year-old female presenting with pelvic chronic pain and crippling dysmenorrhea. The initial work-up consists of a magnetic resonance imaging showing an interstitial lesion possibly corresponding to an ACUM. This supposition was then confirmed by histopathology.

La masse utérine cavitaire accessoire (MUCA) est une anomalie rare dont l'origine est embryologique et serait liée à un dysfonctionnement du gubernaculum féminin. Il s'agit d'une masse accessoire non communicante située à proximité de l'insertion du ligament rond, tapissée par un endomètre normal. La MUCA se manifeste par une dysménorrhée sévère et/ou des douleurs pelviennes chroniques. Il s'agit d'une pathologie relativement méconnue, ce qui rend son diagnostic difficile, et qui suggère un large diagnostic différentiel. Nous rapportons ici le cas d'une femme de 31 ans présentant des douleurs pelviennes chroniques et une dysménorrhée invalidante. La mise au point initiale par résonance magnétique pelvienne a montré la présence d'une lésion interstitielle pouvant correspondre à une MUCA, qui a ensuite été confirmée à l'examen histopathologique.

Transvaginal ultrasound- and laparoscopy-guided percutaneous microwave ablation for adenomyosis has short- and long-term benefits: a single-center study.

OBJECTIVES: Transvaginal ultrasound- and laparoscopy-guided percutaneous microwave ablation (TLPMA) is a minimally invasive alternative technique with low risk, fast recovery and few side effects. We aimed to evaluate the safety and long-term efficacy of TLPMA for treating adenomyosis. METHODS: We included 79 patients with symptomatic adenomyosis who underwent TLPMA and 44 patients with adenomyosis who received the levonorgestrel-releasing intrauterine system (LNG-IUS). We evaluated the role of laparoscopy in TLPMA as well as the short- and long-term effects of TLPMA. RESULTS: The mean age of the 79 patients who underwent TLPMA was 41.8 years. There was no difference in the mean age between the TLPMA and LNG-IUS groups. Laparoscopy could help to separate pelvic adhesions, provide a wide antenna path, and observe the uterine surface and bowel movement. No major complications were found in patients who underwent TLPMA. There was a significant post-treatment reduction in both the uterine and lesion volumes (p < 0.001). After a median follow-up duration of 36 months (range: 1-60 months), the uterine and lesion volumes remained stable. Additionally, most patients remained without dysmenorrhea, which confirms the long-term efficacy of TLPMA. CONCLUSIONS: TLPMA is a feasible, minimally invasive technique for the treatment of adenomyosis, which significantly decreases the uterine and lesion volumes and has a good long-term effect.

Dienogest alone or dienogest combined with estrogens in the treatment of ovarian endometriomas, that is the question. A retrospective cohort study.

PURPOSE: to compare the effects of Dienogest 2 mg (D) alone or combined with estrogens (D + ethinylestradiol 0.03 mg, D + EE; D + estradiol valerate 1-3 mg, D + EV) in terms of symptoms and endometriotic lesions variations. METHODS: This retrospective study included symptomatic patients in reproductive age with ultrasound diagnosis of ovarian endometriomas. Medical therapy for at least 12 months with D, D + EE or D + EV was required. Women were evaluated at baseline visit (V1) and after 6 (V2) and 12 months (V3) of therapy. RESULTS: 297 patients were enrolled (156 in the D group, 58 in the D + EE group, 83 in the D + EV group). Medical treatment leaded to a significant reduction in size of endometriomas after 12 months, with no differences between the three groups. When comparing D and D + EE/D + EV groups, a significant decrease of dysmenorrhea was detected in the D group than in D + EE/D + EV group. Conversely, the reduction of dysuria was more significative in the D + EE/D + EV groups rather than in the D group. Regarding tolerability, treatment associated side effects were reported by 16.2% patients. The most frequent one was uterine bleeding/spotting, significantly higher in the D + EV group. CONCLUSION: Dienogest alone or associated with estrogens (EE/EV) seems to be equally effective in reducing endometriotic lesions mean diameter. The reduction of dysmenorrhea was more significative when D was administered alone, while dysuria seems to improve more when D is associated with estrogens.

Comparison of pregnancy outcomes in infertile patients with different types of adenomyosis treated with high-intensity focused ultrasound.

OBJECTIVE: This study assessed the improvement of symptoms and pregnancy outcomes in infertile patients with various types of adenomyosis who were treated with high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: Between October 2017 and January 2022, 129 infertile patients with adenomyosis who wished to conceive were treated with HIFU. Based on the relationship between the adenomyotic lesion, the endometrium, and the subserosa of the uterus on magnetic resonance imaging, the adenomyotic lesions were divided into internal, external, intramural, and full-thickness types. Menstruation pain score, menstruation blood volume score, anti-Müllerian hormone (AMH) levels, reproductive results, pregnancy and delivery complications, and other clinical variables were compared among these four groups. RESULTS: Patients with external adenomyosis had the greatest menstrual distress, whereas patients with internal adenomyosis had the greatest menstrual blood volume. Dysmenorrhea and heavy menstruation were significantly improved after HIFU treatment in all groups. AMH levels were not significantly different before and six months after HIFU. Of the 129 patients, 50 (38.7%) became pregnant after HIFU, and patients with internal adenomyosis had the highest pregnancy rate. Patients with adenomyotic lesions located in the posterior wall of the uterus had a higher pregnancy rate than those with lesions located in the fundus of the uterus. CONCLUSIONS: The classification of adenomyosis is closely related to distinctions in clinical symptoms and pregnancy outcomes. Infertile patients with different types of adenomyosis could be effectively treated with HIFU. HIFU can be considered as an option for infertile patients with adenomyosis who want to maintain their fertility.

Adjuvant use of melatonin for pain management in endometriosis-associated pelvic pain-A randomized double-blinded, placebo-controlled trial.

Considering the pharmacological treatment options for endometriosis-associated pain are confined to hormonal therapy and analgesics, we studied the analgesic effect of 20 mg melatonin as an adjuvant therapy in women with endometriosis-associated pain. This randomized double-blinded, placebo-controlled trial was conducted at the Research Center for Womens' Health at Södersjukhuset, a university hospital in Stockholm, Sweden. Forty women from 18 to 50 years of age with endometriosis and severe dysmenorrhea with or without chronic pelvic pain were given 20 mg Melatonin or placebo orally daily for two consecutive menstrual cycles or months. The level of pain was recorded daily on the 11-point numeric rating scale, a difference of 1.3 units was considered clinically significant. Clincaltrials.gov nr NCT03782740. Sixteen participants completed the study in the placebo group and 18 in the melatonin group. The difference in endometriosis-associated pain between the groups showed to be non-significant statistically as well as clinically, 2.9 (SD 1.9) in the melatonin group and 3.3 (SD 2.0) in the placebo group, p = 0.45. This randomized, double-blinded, placebo-controlled trial could not show that 20 mg of melatonin given orally at bedtime had better analgesic effect on endometriosis-associated pain compared with placebo. No adverse effects were observed.

The Prevalence of Menstrual Cycle Disorders and Menstrual Cycle-Related Symptoms in Female Athletes: A Systematic Literature Review.

BACKGROUND: Menstrual cycle (MC) disorders and MC-related symptoms can have debilitating effects on the health and performance of female athletes. As the participation of women in sports continues to increase, understanding the prevalence of a range of MC disorders and MC-related symptoms may guide preventive strategies to protect the health and optimise the performance of female athletes. OBJECTIVE: To examine the prevalence of MC disorders and MC-related symptoms among female athletes who are not using hormonal contraceptives and evaluate the assessment methods used to identify MC disorders and MC-related symptoms. METHODS: This systematic review was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Six databases were searched until September 2022 for all original research that reported the prevalence of MC disorders and/or MC-related symptoms in athletes not using hormonal contraceptives, which included the definitions of the MC disorders examined, and the assessment methods used. MC disorders included amenorrhoea, anovulation, dysmenorrhoea, heavy menstrual bleeding (HMB), luteal phase deficiency (LPD), oligomenorrhoea, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). MC-related symptoms included any affective and physical symptoms related to the MC that do not cause significant personal, interpersonal or functional impairment. The prevalence data across eligible studies were combined, and all studies were qualitatively synthesised to evaluate the assessment methods and tools used to identify MC disorders and MC-related symptoms. The methodological quality of studies was assessed using a modified Downs and Black checklist. RESULTS: Sixty studies involving 6380 athletes were included. A wide range of prevalence was observed for all types of MC disorders, with a dearth of data on anovulation and LPD. Based on pooled data, dysmenorrhoea (32.3%; range 7.8-85.6%) was the most prevalent MC disorder. Studies reporting MC-related symptoms mostly examined the premenstrual and menstruation phases, where affective symptoms appeared more prevalent than physical symptoms. A larger proportion of athletes reported symptoms during the initial days of menstruation compared with the premenstrual phase. MC disorders and MC-related symptoms were retrospectively assessed using self-report methods in 90.0% of studies. Most studies (76.7%) in this review were graded as moderate quality. DISCUSSION: MC disorders and MC-related symptoms are commonplace among female athletes, warranting further research examining their impact on performance and preventive/management strategies to optimise athlete health. To increase the quality of future studies, researchers should adopt standardised definitions of MC disorders and assessment methods such as a combination of calendar counting, urinary ovulation tests and a mid-luteal phase serum progesterone measurement when assessing menstrual function. Similarly, standardised diagnostic criteria should be used when examining MC disorders such as HMB, PMS and PMDD. Practically, implementing prospective cycle monitoring that includes ovulation testing, mid-luteal blood sampling (where feasible) and symptom logging throughout the MC could support athletes and practitioners to promptly identify and manage MC disorders and/or MC-related symptoms. TRIAL REGISTRATION: This review has been registered in the PROSPERO database (CRD42021268757).

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood. We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence. Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional ß2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.

Comparison of high-intensity focused ultrasound for the treatment of internal and external adenomyosis based on magnetic resonance imaging classification.

OBJECTIVE: To compare the safety and efficacy of high-intensity focused ultrasound (HIFU) treatment for patients with internal or external adenomyosis based on magnetic resonance imaging (MRI) classification. MATERIALS AND METHODS: A total of 238 patients with internal adenomyosis and 167 patients with external adenomyosis who received HIFU treatment were enrolled. HIFU treatment results and adverse effects between patients with internal and external adenomyosis were compared. RESULTS: The treatment time and sonication time for patients with external adenomyosis were significantly longer than that for patients with internal adenomyosis. The total energy used and EEF for patients with external adenomyosis were higher than that for patients with internal adenomyosis (p < 0.05). The pre-HIFU median dysmenorrhea score in patients with internal or external adenomyosis was 5 or 8 points, the median score decreased to 1 or 3 points in these two groups at 18-month post-HIFU (p < 0.05). The relief rate of dysmenorrhea was 79.5% in patients with internal adenomyosis, and it was 80.8% in patients with external adenomyosis. The pre-HIFU median menorrhagia score in patients with internal or external adenomyosis was 4 or 3 points, the median score decreased to 1 point in both groups at 18-month post-HIFU with a relief rate of 86.2% and 77.1%, respectively (p = 0.030). No serious complication occurred in any of these patients. CONCLUSIONS: HIFU is a safe and effective treatment either for patients with internal adenomyosis or external adenomyosis. It seemed that internal adenomyosis is easier to be treated with HIFU and with a higher relief rate of menorrhagia than external adenomyosis.

Endometriosis and the diagnosis of different forms of migraine: an association with dysmenorrhoea.

RESEARCH QUESTION: Women with endometriosis are frequently affected by headache. How many of these have a clear diagnosis of migraine? Are the different forms of migraine related to the phenotypes and/or characteristics of endometriosis? DESIGN: This was a prospective nested case-control study. A consecutive series of 131 women with endometriosis who attended the endometriosis clinic were enrolled and examined for the presence of headache. A headache questionnaire was used to determine the characteristics of the headaches, and the diagnosis of migraine was confirmed by a specialist. The case group included women with endometriosis and a diagnosis of migraine, while the control group included women with only endometriosis. History, symptoms and other comorbidities were collected. A pelvic pain score and associated symptoms were assessed using a visual analogue scale. RESULTS: A diagnosis of migraine was made in 53.4% (70/131) of participants. Pure menstrual migraine was reported by 18.6% (13/70), menstrually related migraine by 45.7% (32/70) and non-menstrual migraine by 35.7% (25/70). Dysmenorrhoea and dysuria were significantly more frequent in patients with endometriosis and migraine than in those without migraine (P = 0.03 and P = 0.01). No difference was found for other variables, including age at diagnosis and duration of endometriosis, endometriosis phenotype, the presence of other autoimmune comorbidities or heavy menstrual bleeding. In most patients with migraine (85.7%) the headache symptoms had started years before the diagnosis of endometriosis. CONCLUSION: The occurrence of headache in many patients with endometriosis is associated with the presence of different forms of migraine, is related to pain symptoms and often precedes the diagnosis of endometriosis.

Facilitated Central Pain Mechanisms Across the Menstrual Cycle in Dysmenorrhea and Enlarged Pain Distribution in Women With Longer Pain History.

Dysmenorrhea (DYS), or recurrent menstrual pain, is a highly prevalent pain condition among otherwise healthy women. However, the progression of DYS over time and the influence of the menstrual cycle phases need to be better understood. While the location and distribution of pain have been used to assess pain mechanisms in other conditions, they are unexplored in DYS. Thirty otherwise healthy women with severe DYS and 30 healthy control women were recruited into 3 subgroups (n = 10) according to the length of their menstrual history (<5, 5-15, or>15 years since menarche). The intensity and distribution of menstrual pain were recorded. Pressure pain thresholds at abdominal, hip, and arm sites, pressure-induced pain distribution, temporal summation of pain, and pain intensity after pressure cessation over the gluteus medius were assessed at 3 menstrual cycle phases. Compared with the healthy control women, those with DYS showed lower pressure pain thresholds in every site and menstrual cycle phase (P < .05), enlarged pressure-induced pain areas during menstruations (P < .01), and increased temporal summation and pain intensity after pressure cessation in the overall menstrual cycle (P < .05). Additionally, these manifestations were enhanced during the menstrual and premenstrual phases compared to ovulation in women with DYS (P < .01). Women with long-term DYS demonstrated enlarged pressure-induced pain distribution, enlarged menstrual pain areas, and more days with severe menstrual pain compared to the short-term DYS subgroup (P < .01). Pressure-induced and menstrual pain distributions were strongly correlated (P < .001). These findings suggest that severe DYS is a progressive condition underscored by facilitated central pain mechanisms associated with pain recurrence and exacerbation. PERSPECTIVE: Enlarged pressure-induced pain areas occur in DYS, associated with the length of the condition and the distribution of menstrual pain. Generalized hyperalgesia is present throughout the entire menstrual cycle and intensifies during premenstrual and menstrual phases.