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Violence against women remains a severe human rights violation and public health challenge across Asia and Oceania, with significant variations in prevalence and response capacity among countries. Despite global frameworks such as the Convention on the Elimination of All Forms of Discrimination Against Women and regional initiatives like the ASEAN Declaration on the Elimination of Violence Against Women and Violence Against Children, implementation gaps hinder effective protection. The Asia-Oceania Federation of Obstetrics and Gynaecology (AOFOG) Declaration on Violence Against Women: A Commitment to Action and Change reinforces key commitments across 10 action areas, including recognizing violence against women as a critical issue, advancing international agreements, strengthening regional cooperation, mobilizing stakeholders, empowering healthcare professionals, enhancing comprehensive services, promoting public education, improving healthcare training, supporting research and data collection, and preparing for crisis responses such as pandemics. Emphasizing evidence-based policymaking and regional collaboration, the Declaration establishes a roadmap for accountability through robust monitoring and evaluation. By uniting stakeholders across sectors, AOFOG aims to eliminate VAW and foster environments where women's rights, safety, and dignity are universally upheld. This Declaration was officially presented at the 28th AOFOG Congress held in Busan, Korea, on May 18, 2024.

DOI： 10.1111/jog.70004

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Since 2005, the Reproductive Endocrinology Committee of the Japan Society of Obstetrics and Gynecology has conducted research and provided recommendations for reproductive medicine and endocrinology. This report summarizes the activities of eight subcommittees over 2 years, from 2023 to 2024. These subcommittees addressed various topics, including the review of medical and social indications for oocyte cryopreservation, the current status and challenges of embryo cryopreservation and disposal, the investigation of ovulatory disorders through the HyPO-P classification and a nationwide survey of young women with suspected polycystic ovary syndrome, the revision of polycystic ovary syndrome diagnostic criteria and the development of updated treatment guidelines, the survey of adoption rates of in vitro fertilization add-on treatments following insurance coverage, the national survey on the diagnosis and management of diffuse uterine leiomyomatosis and hereditary leiomyomatosis and renal cell carcinoma, the establishment of a clinical registry system for adenomyomectomy cases, the management of subclinical hypothyroidism in patients with infertility, and the promotion of effective utilization of assisted reproductive technology registry data in Japan. Each subcommittee provides valuable insights into the current status of reproductive medicine in Japan, identifies key challenges, and proposes recommendations to support clinical practice and guideline development. This report will serve as a foundation for advancing reproductive medicine and ensuring high-quality patient care in Japan.

DOI： 10.1111/jog.70008

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BACKGROUND: The age-related decline of fertility is caused by a reduction of the ovarian reserve, which is represented by the number and quality of oocytes in the ovaries. Anti-Müllerian hormone (AMH) is considered one of the most useful markers of the quantity of the ovarian reserve; however, a more accurate prediction method is required. Furthermore, there is no clinically useful tool to assess the quality of the ovarian reserve and therefore a prediction tool is required. Our aim is to produce a model for prediction of the ovarian reserve that contributes to preconception care and precision medicine. METHODS: This study was a retrospective analysis of 442 patients undergoing assisted reproductive technology (ART) treatment in Japan from June 2021 to January 2023. Medical records and residual serum of patients undergoing oocyte retrieval were collected. Binary classification models predicting the ovarian reserve were created using machine learning methods developed with many collected feature values. The best-performing model among 15 examined models was selected based on its area under the receiver operating characteristic curve (AUC) and accuracy. To maximize performance, feature values used for model creation were narrowed down and extracted. RESULTS: The best-performing model to assess the quantity of the ovarian reserve was the random forest model with an AUC of 0.9101. Five features were selected to create the model and consisted of data from only medical records. The best-performing model to assess the quality of the ovarian reserve was the random forest model, which had an AUC of 0.7983 and was created with 14 features, data from medical records and residual serum analysis. CONCLUSION: Our models are more accurate than currently popular methods for predicting the ovarian reserve. Furthermore, they can assess the ovarian reserve using only information obtained from a medical interview and single blood sampling. Enabling easy measurement of the ovarian reserve with this model would allow a greater number of women to engage in preconception care and facilitate the delivery of personalized medical treatment for patients undergoing infertility therapy. CLINICAL TRIAL NUMBER: Not applicable.

DOI： 10.1186/s13048-025-01732-0

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OBJECTIVE: To estimate the incidence and associated risk factors of failed induction of labor (IOL). MATERIALS AND METHODS: A retrospective, case-control study was conducted on a cohort of women who underwent IOL from January 2020 to December 2023 and delivered after 34 weeks of gestation at our hospital (n = 1541). Failed IOL was defined as delivering with a cesarean section for any reason. The control group consisted of successful vaginal deliveries, including forceps and vacuum deliveries after IOL. Both primiparous and multiparous women were included in the study. We identified associated risk factors of failed IOL via multivariable logistic regression analysis. RESULTS: During the study period, 1541 of 4244 women (36.3 %) who delivered at our hospital underwent IOL. Among them, 326 women had a failed IOL, an estimated incidence of 21.2 % (95 % confidence interval [CI]: 19.1 %-23.3 %). The multivariable analysis revealed that older age (adjusted odds ratio [aOR] = 1.07 for each 1-year increase, 95 % CI: 1.04-1.11, P < 0.001), primiparity (aOR = 0.24 95 % CI: 0.16-0.35, P < 0.001), conception by using assisted reproductive technology (aOR = 1.45 95 % CI: 1.06-2.00, P = 0.021) larger birth weight (aOR = 1.05 for each 100 g increase, 95 % CI: 1.01-1.65, P = 0.023), hypertensive disorders of pregnancy (HDPs) (aOR = 2.53, 95 % CI: 1.80-3.56, P < 0.001), the lower simplified Bishop score before induction (aOR = 0.70 for each 1-point increase, 95 % CI: 0.61-0.80 P < 0.001), and the use of no epidural anesthesia (aOR = 0.42, 95 % CI: 0.31-0.57, P < 0.001) were independently associated with failed IOL. CONCLUSIONS: Age, primiparity, method of conception, birth weight, HDPs, and simplified Bishop score should be considered as the predictor of failed IOL.

DOI： 10.1016/j.tjog.2025.04.010

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Homologous recombination deficiency (HRD) tests, including MyChoice CDx, are companion diagnostics for poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 promoter hypermethylation, a major HRD cause, may correlate with poorer prognosis. This study aimed to develop a simple, accurate method for detecting BRCA1 promoter hypermethylation and elucidate the characteristics of such cases. BRCA1 promoter methylation was analyzed using bisulfite sequencing (BIS-seq) in high-grade serous ovarian carcinoma specimens. We developed a newly developed BRCA1 methylation assay, BRCA1-Fragment Analysis of Methylation (BRCA1-FAM), which combines restriction enzyme digestion with fragment analysis. The accuracy of this assay was compared to the results of BIS-seq. We evaluated the relationship between BRCA1 promoter hypermethylation and prognosis and examined its association with BRCA1 expression and loss of heterozygosity. BRCA1 mutations and promoter methylation were mutually exclusive in the analyzed cases, with methylation observed in 28.9% (22/76) of primary debulking surgery cases. The BRCA1-FAM showed high sensitivity (91.3%) and specificity (100%) for detecting BRCA1 promoter hypermethylation, comparable to BIS-seq. Cases with BRCA1 promoter hypermethylation had significantly poorer progression-free survival (log-rank test, p = 0.048). Among these cases, 86.4% displayed abnormal BRCA1 immunostaining, with lower frequencies of BRCA1 loss of heterozygosity compared to those of other groups. BRCA1 promoter hypermethylation is associated with poor prognosis, underscoring the importance of its identification for HRD stratification. BRCA1-FAM is a simple and highly accurate method for evaluating BRCA1 promoter methylation. This approach may potentially enhance the precision of personalized therapies for ovarian cancer.

DOI： 10.1111/cas.70078

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Adenomyosis often causes dysmenorrhea in women of reproductive age. Progestins such as levonorgestrel intrauterine system (LNG-IUS) are often used for treatment, but some patients experience progesterone resistance, showing poor treatment response. However, the clinical characteristics of progesterone-resistant and progesterone-sensitive patients with symptomatic adenomyosis remain unclear. We analyzed data of 69 patients with adenomyosis treated with LNG-IUS. Dysmenorrhea was quantified using linear visual analog scale (VAS) scoring, and progesterone resistance was interpreted as continued dysmenorrhea during LNG-IUS treatment. The rate of change in VAS scores of dysmenorrhea was calculated: patients with the bottom 25% improvement were defined as progesterone-resistant group, and those with the top 25% improvement as progesterone-sensitive group. The localization of adenomyosis lesions was evaluated by magnetic resonance imaging (MRI) and classified as advanced (localized in all layers of the myometrium), extrinsic (localized on the uterine serosa side), and intrinsic (localized on the endometrial side) subtypes. Progesterone-resistant group had a significantly lower incidence of intrinsic adenomyosis (7.7% vs. 69.2%, p = 0.004) and a tendency toward a higher incidence of advanced adenomyosis (61.5% vs. 23.1%, p = 0.111) compared with progesterone-sensitive group. Progesterone-sensitive group showed significant improvement of dysmenorrhea 1 month after starting LNG-IUS treatment (p < 0.001). These findings indicate that the responsiveness to LNG-IUS treatment can be determined 1 month after starting the treatment and that intrinsic adenomyosis is a favorable prognostic factor for progestin treatment with LNG-IUS, while advanced and extrinsic adenomyosis are predictors for progesterone resistance.

DOI： 10.1186/s12905-025-03817-w

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AIM: To examine the cumulative ongoing pregnancy/live birth rate per patient by encompassing all embryo transfer (ET) cycles associated with a single oocyte retrieval cycle among women with diminished ovarian reserve (DOR), and to investigate whether serum anti-Müllerian hormone (AMH) levels can predict a live birth success. METHODS: This multi-institutional retrospective cohort study included infertile women with DOR (AMH <1.1 ng/mL) who began their first cycle of in vitro fertilization and/or intracytoplasmic sperm injection between January and December 2021. Outcomes using the retrieved embryos were evaluated for up to four ET cycles. RESULTS: Of 606 patients, 113 did not undergo ET. A total of 605 ET cycles were analyzed. Clinical pregnancy and ongoing pregnancy/live birth rates per ET cycle were significantly dependent on age, not AMH levels. Ongoing pregnancy/live birth rates per patient increased significantly with higher AMH levels. A significant difference in the cumulative ongoing pregnancy/live birth rate was observed depending on whether cases with no remaining embryos were included among the censored cases. CONCLUSION: Assisted reproductive technology (ART) outcomes per ET cycle in women with DOR were similar to those reported in the Japanese ART registry without distinguishing DOR. The greater the number of good-quality embryos that can be frozen, the higher the expected cumulative live birth rate.

DOI： 10.1111/jog.16336

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INTRODUCTION: Treatment interruptions due to adverse drug reactions (ADRs) are common in iron deficiency anemia (IDA). We evaluated medication completion rates and quality of life (QoL) changes in patients with IDA after starting ferric citrate hydrate (FCH) treatment. METHODS: This multicenter, open-label, uncontrolled, single-arm comparative study included 30 Japanese female patients with IDA who experienced nausea and/or vomiting (N/V) with previous oral iron preparations. Patients received FCH 500 mg orally daily (< 1000 mg/day). Those with hemoglobin levels ≥ 11.0 g/dl completed the study at week 4; others continued until week 8. The primary endpoint was medication completion rate. Secondary endpoints included medication compliance rate, treatment satisfaction scores, and QoL scores and changes. RESULTS: Thirty patients initiated and completed treatment; 24 reached ≥ 11.0 g/dl hemoglobin at week 4 and ended treatment, while 6 continued until week 8. The medication compliance rate was 93.92% ± 8.11% (mean ± standard deviation [SD]), and the completion rate was 100.0% (95% confidence interval 88.4-100.0%). Questionnaire findings revealed that the most severe nausea score decreased from 5.7 ± 2.4 to 1.7 ± 2.1 (mean ± SD), N/V incidence decreased from 100.0 to 63.3%, and patients reporting that N/V did not interfere with daily life increased from 6.7 to 52.6% following the switch to FCH. Twenty-four patients (80.0%) reported a satisfactory experience with FCH versus their previous oral iron preparation. Scores for all eight subscales of the Short-Form 36-Item Health Survey v2 improved, with significant increases in six. Nine ADR events occurred in six patients (20.0%), including nausea in three (10.0%); none were serious or resulted in treatment discontinuation. CONCLUSION: FCH treatment exhibited a satisfactory medication completion rate in patients with IDA. Switching to FCH reduced N/V incidence and improved N/V and QoL severity compared with previous oral iron preparations. TRIAL REGISTRATION: jRCTs031210634. Registration date: March 01, 2022.

DOI： 10.1007/s12325-025-03123-9

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AIM: This study aims to investigate the association between placental insufficiency and complications in extremely preterm infants in the context of ischemic placental disease (IPD), including preeclampsia, small-for-gestational-age (SGA), and placental abruption. METHODS: Infants born between 22 and 28 weeks of gestation were classified into IPD and non-IPD groups, matched 1:1 by gestational age and sex. The incidence of neonatal complications was analyzed. RESULTS: Analysis included 48 infants in each group. The IPD group had a significantly lower birth weight (IPD vs. non-IPD: 679 g vs. 979 g, p < 0.001), whereas the non-IPD group was characterized by a higher prevalence of spontaneous preterm births (12% vs. 79%, p < 0.001) and a significantly higher incidence of histological chorioamnionitis (CAM) (15% vs. 50%, p < 0.001). The IPD group showed a significantly higher incidence of bronchopulmonary dysplasia (BPD) compared to the non-IPD group (85% vs. 48%, p < 0.001), with no significant differences in other complications such as intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis. Logistic regression identified IPD as a significant risk factor for BPD (odds ratio [OR] [95% confidence interval]: 9.4 [2.8-31.8], p < 0.001), along with preeclampsia (OR: 4.9 [1.3-18.3], p = 0.01) and SGA (OR: 31.9 [5.9-171], p < 0.001). CAM was not associated with BPD (OR: 0.6 [0.2-1.7], p = 0.45). CONCLUSIONS: Placental insufficiency, manifesting as IPD, is strongly associated with an increased risk of BPD in extremely preterm infants.

DOI： 10.1111/jog.16315

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Chronic endometritis (CE) and endometrial dysbiosis (ED) are major causes of recurrent implantation failure (RIF). CE is diagnosed via hysteroscopy or the endometrial CD138 test; ED is examined using endometrial microbiome testing with next-generation sequencing. ED is characterized by a reduction in Lactobacillus species. However, correlations between the results of the three tests and the efficacy of treatment against CE and ED in pregnancy outcomes remain unclear. We analyzed 73 patients with RIF who underwent all three tests (hysteroscopy, endometrial CD138 test, and endometrial microbiome test). Patients with CE received antibiotics, whereas those with ED received antibiotics and vaginal Lactobacillus probiotics. The incidences of CE diagnosed using hysteroscopy and the CD138 test were 56.2 and 49.3%, respectively, and the prevalence of ED was 53.4%. No correlations were observed among the test-positive individuals in these three tests. Among patients with ED, 88.9% had a post-treatment clinical pregnancy, a significantly higher rate than that in patients without ED (p = 0.021). Multivariate analysis demonstrated that ED was associated with clinical pregnancy (odds ratio (OR): 6.29, p = 0.031). In conclusion, the three tests detected different populations of patients with RIF. ED diagnosed using the endometrial microbiome test was associated with favorable pregnancy outcomes after testing.

DOI： 10.1038/s41598-025-92906-9

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Minimally invasive surgery (MIS) for gynecologic cancers, which includes laparoscopic and robotic approaches, has seen significant growth in Japan over the past decade. While offering numerous benefits, including reduced postoperative pain and shorter hospital stays, its rapid adoption has also highlighted several challenges, particularly in the management of severe surgical adverse events and disparities in training and access to technology. This article explores the current trends in MIS adoption in Japan, focusing on laparoscopy and robotic surgery, their benefits and limitations, the regulatory and certification frameworks established by the Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy, and future directions for ensuring safety and efficacy in gynecologic oncology surgery.

DOI： 10.1007/s10147-025-02735-z

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Adenomyomectomy, a therapeutic option for women with adenomyosis who wish to preserve their fertility, has been reported to pose a risk of developing placenta accreta spectrum (PAS) and uterine rupture in future pregnancies. However, the specific clinical factors contributing to these occurrences remain elusive. This study aimed to explore the association between hysteroscopic findings after adenomyomectomy and the incidence of PAS in subsequent pregnancies. We conducted a retrospective analysis of 10 patients (11 pregnancies) who had undergone hysteroscopy following adenomyomectomy and had later delivered at our hospital. In 6/10 patients, postoperative hysteroscopy revealed endometrial defects. However, subsequent evaluations confirmed endometrial restoration within 7-21 months, with five patients achieving pregnancy afterward. The only other patient conceived naturally without waiting for endometrial restoration, resulting in uterine rupture from the site of the placenta percreta. The incidence of clinically diagnosed PAS during cesarean section was 100% (1/1) in pregnancies with preconceptional endometrial defects, 20% (1/5) in those with endometrial restoration, and 0% (0/5) in pregnancies without endometrial defects. Similarly, the incidence of pathologically diagnosed PAS was 100% (1/1), 60% (3/5), and 20% (1/5) in these groups, respectively. Thus, endometrial defects were frequently detected after adenomyomectomy and recovered over time, whereas one patient without endometrial restoration developed uterine rupture complicated by PAS. This study demonstrates that while the presence of an endometrial defect identified by postoperative hysteroscopy may be a risk factor for the occurrence of PAS in subsequent pregnancies, allowing sufficient recovery time for the endometrium may help reduce the risk of uterine rupture.

DOI： 10.1007/s43032-024-01758-7

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Uterine adenomyosis is a common disease in women of reproductive age that causes dysmenorrhea, abnormal uterine bleeding, infertility, and obstetric complications. Rarely, adenomyosis can lead to abscess formation, which is refractory to antibiotics and occasionally requires surgical treatment, such as hysterectomy. However, hysterectomy should be avoided in patients who seek to preserve fertility. Herein, for the first time, we report two cases of uterine adenomyosis with abscess formation during assisted reproductive procedures that were successfully treated with adenomyomectomy, thereby preserving fertility. A history of repeated intrauterine procedures and infections was crucial in making an appropriate preoperative diagnosis. Adenomyomectomy can be an effective treatment for adenomyosis associated with abscess in patients who wish to preserve fertility.

DOI： 10.1111/jog.16185

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BACKGROUND: Women's health is significantly influenced by the appropriate and timely secretion of female sex steroid hormones. Consequently, awareness of hormonal fluctuations at various life stages is crucial. In 2016, the Japanese Ministry of Health, Labour, and Welfare launched the HealthCareLabo (https://w-health.jp/) interactive women's health information website. OBJECTIVES: This study aimed to investigate user behavior on the website from its inception in March 2016 to December 2022 to enhance its quality and effectiveness. DESIGN: Retrospective web research. METHODS: Data analysis used Google Analytics to examine website engagement metrics, the number of pages visited per session, feature utilization rates, use access methods, and geographic locations. RESULTS: Over the 6-year study period, HealthCareLabo attracted 21,575,636 unique users, 26,200,559 sessions, and 53,595,955 page views. Returning users accounted for 10.7%, with an average of 2.05 pages viewed per session and an average session duration of 48 s. "Bounce rate" refers to the proportion of visitors who leave a website after viewing a single page without engaging further. The bounce rate of 67.75% suggests users did not find the content relevant, comprehensible, and actionable. The most frequently accessed page was "Self-check for All Women's Diseases," accounting for 10.95% of total page views. Notably, 64.19% of users were aged 25-44. The bounce rate increased with age, while the average session duration and pages viewed per session decreased. Traffic via social media had the highest average time on pages, most page views, and the lowest bounce rate. Among the top 10 Google Search queries leading to the website, four were related to BMI, with "BMI female" ranking highest and achieving a click-through rate of 48.53%. The Self-check feature was widely utilized, particularly for premenstrual syndrome, with 66% of respondents aged 25-44. CONCLUSIONS: The findings suggest that women of reproductive age are particularly attentive to health-related concerns, including body image and premenstrual syndrome. HealthCareLabo serves as an effective platform for promoting health literacy, with its Self-check feature playing a pivotal role in user engagement.

DOI： 10.1177/17455057251347088

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PURPOSE: This study evaluated whether embryo cryopreservation before surgery (ECBS) improves clinical outcomes in in vitro fertilization (IVF) patients with endometrioma. METHODS: This retrospective study included patients aged 28-42 years with endometrioma who underwent oocyte retrieval at our hospital from 2019 to 2022. Seventeen patients who underwent ECBS and 43 patients who underwent embryo transfer (ET) without surgery were included. Patient characteristics, reproductive outcomes, and obstetric outcomes were compared between the groups. RESULTS: Maximum cyst size was significantly larger in the ECBS group than in the control group. The abortion rate per pregnancy was significantly lower (0% vs. 35.5%) in the ECBS group than in the control group. The ongoing pregnancy rate per case was significantly higher in the ECBS group than in the control group (88.2% vs. 58.1%), while the time to ongoing pregnancy was similar. Among patients in the ECBS group who experienced live births, 84.6% became pregnant following three or fewer ET attempts. Multivariate analysis revealed that ECBS was the only factor associated with ongoing pregnancy. The rates of perinatal complications are comparable between the groups. CONCLUSIONS: ECBS is an effective method to improve reproductive outcomes in IVF patients with endometrioma without prolonging the time to pregnancy.

DOI： 10.1002/rmb2.12654

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RESEARCH QUESTION: How significant is the impact of dysmenorrhea on work productivity and quality of life (QoL) among Japanese women?. METHODS: This large-scale cross-sectional study was conducted using a web-based self-report questionnaire administered via a smartphone application (LunaLuna). The Work Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH) and the SF-36v2 health survey were used to assess work productivity and health-related QoL, respectively. Work productivity and health-related QoL were compared between the severe and non-severe groups as defined by the dysmenorrhea score, which assesses the severity of menstrual pain, its impact on daily activities, and medication use. A multiple regression analysis was performed to estimate the magnitude of the effect of dysmenorrhea on work productivity and health-related QoL after adjusting for confounding factors. RESULTS: In total, 2,555 women were included in the analysis. Among them, 2064 women completed the dysmenorrhea score questionnaire, and 902 (43.7%) participants with a dysmenorrhea score of ≥3 were categorized as the severe group. The median overall work impairment was 16% higher in the severe dysmenorrhea group than in the non-severe dysmenorrhea group. In the multiple regression analysis, despite adjusting for confounding factors, the severity of dysmenorrhea remained a significant predictor of impaired absenteeism; presenteeism; overall work impairment; activity impairment; and reduced physical, mental, and social QoL. Additionally, low annual household income (<5,000,000 yen) was a significant predictor of reduced work productivity and lower mental and social QoL. CONCLUSIONS: The severity of dysmenorrhea significantly affects the work productivity and quality of life of Japanese women. A dysmenorrhea score of ≥3 as a threshold for treatment eligibility may be a useful and potentially valid criterion. The application of a dysmenorrhea score may facilitate the screening of dysmenorrhea in clinical practice.

DOI： 10.1371/journal.pone.0329154

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

Although ovarian endometrioid carcinoma (OEC), frequently associated with endometrial endometrioid carcinoma (EEC), is often diagnosed at an early stage, the prognosis remains poor. The development of new, effective drugs to target these cancers is highly desirable. The bromodomain and extra-terminal domain (BET) family proteins serve a role in regulating transcription by recognizing histone acetylation, which is implicated in several types of cancer. BET inhibitors have been reported as promising cancer drugs. The present study aimed to assess the role of JQ1, a BET inhibitor, in ovarian and endometrial cancers. The sensitivity of OEC and EEC cell lines to JQ1 was assessed using cell viability and colony formation assays. Additionally, western blotting and cell cycle assays were performed to evaluate changes in c-Myc expression and apoptosis markers. Cell proliferation and colony formation assays revealed significant tumor suppression in both OEC and EEC cell lines in response to JQ1 treatment. Furthermore, treatment with JQ1 induced a decrease in c-Myc expression and an increase in apoptosis markers, such as cleaved PARP and the cell population in the sub-G1 phase, in both OEC and EEC cell lines. The findings of the present study indicate that JQ1 may induce cell death through c-Myc inhibition and could be a potentially novel therapeutic agent in the treatment in OEC and EEC. However, the direct mechanism, has not been fully elucidated, warranting further investigation.

DOI： 10.3892/ol.2024.14852

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Embryo implantation is crucial for successful pregnancy, requiring appropriate uterine responses to implantation-competent blastocysts. Molecular communication at the maternal–fetal junction governs this process. Leukemia inhibitory factor (Lif) plays a pivotal role in implantation across species. Lif is abundantly expressed in the glandular epithelium during blastocyst-receptive phase and is induced in the stroma surrounding attached blastocysts. While diminished Lif expression leads to infertility, its influence on peri-implantation uteri remains unclear. Therefore, we investigated the role of Lif in uterine physiology using its uterine-specific knockout (uKO) and uterine epithelial-specific KO (eKO) in mice. Lif eKO and uKO mice displayed infertility owing to failed embryo attachment. Recombinant Lif supplementation rescued the reproductive phenotype of Lif eKO mice, but not Lif uKO mice; however, recombinant Lif injection rescued embryo attachment in Lif uKO mice. RNA-seq analysis indicated that Lif governs uterine epithelial genes, but not embryonic genes, to facilitate embryo attachment via activating nuclear Stat3. Concordantly, three-dimensional imaging of the uterine epithelium revealed that luminal closure and crypt formation are regulated by the uterine Lif–Stat3 axis as well as the presence of blastocysts. Collectively, our findings shed light on previously unknown mechanism on how Lif influences uterine functions molecularly and physiologically during early pregnancy.

DOI： 10.1038/s41420-024-02228-4

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Other Link： https://www.nature.com/articles/s41420-024-02228-4

Language：Japanese   Publisher：(一社)日本女性医学学会  

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AIM: To present evidence- and consensus-based recommendations for the diagnosis abnormal uterine bleeding. METHODS: A literature search for the diagnosis of abnormal uterine bleeding was systematically conducted in PubMed from its inception to May 2024 to identify meta-analyses, reviews, randomized controlled trials, and clinical trials, followed by an additional systematic search using keywords. Based on this evidence, an expert panel developed background, clinical, and future research questions. RESULTS: Based on a systematic search and the collected evidence, we developed five background questions, three clinical questions, and one future research question, with recommendations and/or statements. Evidence and recommendations are provided for clinical questions. Additionally, we developed a flowchart for diagnosis showing the steps of the examinations to be performed. CONCLUSION: The flowchart and nine recommendations/statements specify an efficient diagnostic procedure to differentiate abnormal causative diseases of uterine bleeding optimized for actual Japanese situations.

DOI： 10.1111/jog.16073

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OBJECTIVE: Patients with ovarian clear cell carcinoma (OCCC) often present with thrombosis. While cancer patients with concomitant thrombosis were generally reported to have worse prognoses than those without, the association between thrombosis and prognosis has not been elucidated in OCCC. This study aimed to determine how the co-occurrence of thrombosis affects OCCC prognoses. METHODS: We retrospectively examined 115 patients with OCCC who were diagnosed and treated at the University of Tokyo Hospital between 2009 and 2019. RESULTS: Of 115 patients with OCCC, thrombosis was present in 12.5% of 80 patients and in 42.8% of 35 patients who had OCCC stage I/II and stage III/IV, respectively. In stage I/II, the 5-year progression-free survival was 20.6% and 91.8% among patients with thrombosis and among those without, respectively, while the corresponding 5-year overall survival rates were 50.0% and 94.1%. Therefore, the outcomes were significantly poorer among patients with thrombosis (p < 0.0001 and p < 0.0001, respectively). In stage III/IV, the 5-year progression-free survival was 26.7% and 52.8% among patients with thrombosis and among those without, respectively, while the corresponding 5-year overall survival rates were 32.0% and 62.2%. Similarly, the outcomes were significantly poorer among patients with thrombosis (p = 0.0139 and p = 0.369, respectively). CONCLUSION: We determined that thrombosis is more likely to develop in advanced OCCC stages than in early stages, and its co-occurrence is associated with a poor prognosis, regardless of disease stage.

DOI： 10.1007/s10147-024-02561-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

Embryo implantation is crucial for ensuring a successful pregnancy outcome and subsequent child health. The intrauterine environment during the peri-implantation period shows drastic changes in gene expression and cellular metabolism in response to hormonal stimuli and reciprocal communication with embryos. Here, we performed spatial transcriptomic analysis to elucidate the mechanisms underlying embryo implantation. Transcriptome data revealed that lipid metabolism pathways, especially arachidonic acid-related (AA-related) ones, were enriched in the embryo-receptive luminal epithelia. Cyclooxygenases (COXs), rate-limiting enzymes involved in prostaglandin production by AA, were spatiotemporally regulated in the vicinity of embryos during implantation, but the role of each COX isozyme in the uterus for successful pregnancy was unclear. We established uterine-specific COX2-knockout (uKO) and COX1/uterine COX2-double-KO (COX1/COX2-DKO) mice. COX2 uKO caused deferred implantation with failed trophoblast invasion, resulting in subfertility with reduced pregnancy rates and litter sizes. COX1/COX2 DKO induced complete infertility, owing to abrogated embryo attachment. These results demonstrate that both isozymes have distinct roles during embryo implantation. Spatial transcriptome and lipidome analyses revealed unique profiles of prostaglandin synthesis by each COX isozyme and spatiotemporal expression patterns of downstream receptors throughout the endometrium. Our findings reveal previously unappreciated roles of COXs at the fetomaternal interface to establish early pregnancy.

DOI： 10.1172/jci.insight.181865

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Attainment of optimal bone mineral density (BMD) in female athletes is a very important aspect of ensuring their well-being throughout their lives, and monitoring of BMD is essential to avoid fractures and bone-related injuries. Several tools for assessing bone health already exist, but either lack the practicality required for continuous monitoring or are not suited for the young female athlete demographic. Because of this, this study has the main objective of developing a binary classifier to discriminate between normal and low bone mass individuals among younger female athletes using features extracted from a questionnaire. The dataset consisted of data from 213 female athletes. Five different models were compared: logistic regression, decision tree, random forest, multi-layer perceptron and XGBoost. Validation was performed via cross-validation and feature importance was assessed via permutation importance. XGBoost showed the most balanced results in terms of sensitivity and specificity, achieving values of 0.93 and 0.62 respectively. It also obtained an AUC of 0.73 and an accuracy of 0.68. It was observed that the duration of the current period of amenorrhea, as well as the impact of the sport, showed the highest relevance, which is consistent with previous literature. Other features such as thinness level, number of training days in a week and age at menarche also showed high importance. The models demonstrated promising results in identifying low bone mass subjects from normal ones, indicating that features based on questionnaires can be an important source for evaluating low BMD in female athletes.

DOI： 10.1109/EMBC53108.2024.10781821

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AIM: To clarify the diagnostic process of the causative disease of abnormal uterine bleeding (AUB) in Japan according to the International Federation of Gynecology and Obstetrics AUB diagnostic system. METHODS: Patients diagnosed with AUB were included in a nationwide survey of AUB conducted during any 2-week period between December 2019 and January 2020. The second survey included information on patient background, AUB symptoms, examinations for diagnosing AUB, the order in which they were performed, and the causative diseases of AUB. RESULTS: Correspondence analysis showed an association between hormonal testing, hysterosalpingography, and magnetic resonance imaging (MRI) in patients with amenorrhea, and heavy menstrual bleeding was strongly correlated with various examinations, such as coagulation tests, pelvic MRI, and endometrial cytology or biopsy. The results also indicated that each AUB causative disease can be diagnosed based on a specific examination profile. CONCLUSION: We clarified the process of diagnosing the causative disease of AUB in our country and determined that it was mainly diagnosed by imaging and pathological examination in cases of structural disease. The high rate of AUB-E and the low rate of AUB-C are possibly associated with specific examination trends in Japan. The results of this study will be useful for the development of a standard protocol for AUB diagnosis in our country.

DOI： 10.1111/jog.16014

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Language：Japanese   Publisher：金原出版(株)  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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BACKGROUND: Premenstrual syndrome (PMS) is prevalent among women of reproductive age, but most do not seek medical advice. We hypothesized that building PMS awareness could promote medical help-seeking for PMS and thus reduce menstrual symptoms and improve work productivity. METHODS: In January 2020, women aged between 25 and 44 years, having paid work, and not currently consulting with an obstetrics and gynecology doctor (n = 3090) responded to the Menstrual Distress Questionnaire (MDQ), the Premenstrual Symptoms screening tool, and the World Health Organisation Health and Work Performance Questionnaire. In addition, they received checklist-based online education for PMS. Of 3090 participants, 2487 (80.5%) participated in a follow-up survey in September 2020. We conducted multiple logistic regression analyses and text analyses to explore factors that encouraged and discouraged medical help-seeking. We also evaluated changes in menstrual symptoms and work productivity, using generalized estimating equations with interactions between the severity of PMS, help-seeking, and time. RESULTS: During the follow-up period, 4.9% of the participants (121/2487) sought medical help. Those having high annual income (adjusted odds ratio [aOR] = 2.07, 95% confidence interval [CI]: 1.21-3.53) and moderate-to-severe PMS (aOR = 2.27, 95% CI: 1.49-3.46) were more likely to have sought medical help. Those who did not seek medical help despite their moderate-to-severe PMS reported normalization of their symptoms (36%), time constraints (33%), and other reasons for not seeking medical help. Participants with moderate-to-severe PMS who had sought medical help showed a significant improvement of - 8.44 points (95% CI: - 14.73 to - 2.15 points) in intermenstrual MDQ scores during the follow-up period. However, there were no significant improvements in premenstrual and menstrual MDQ scores or absolute presenteeism. CONCLUSION: Medical help-seeking alleviated intermenstrual symptoms in women with moderate-to-severe PMS, but only a small proportion of them sought medical help after PMS education. Further research should be conducted to benefit the majority of women who are reluctant to seek medical help, including the provision of self-care information. TRIAL REGISTRATION: UMIN Clinical Trials Registry number: UMIN000038917.

DOI： 10.1186/s12905-024-03067-2

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Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated β-galactosidase (SA-β-gal); and the SASP-related factor interleukin (IL)-6; were significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.

DOI： 10.1093/molehr/gaae015

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Language：Japanese   Publisher：診断と治療社  

DOI： 10.34433/og.0000000604

CiNii Books

CiNii Research

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I033413889

Language：English   Publishing type：Research paper (scientific journal)  

AIM: The effectiveness of hysteroscopy in diagnosing endometrial lesions has been demonstrated, showing high diagnostic accuracy for malignant endometrial lesions. Although the characteristic appearances of atypical and malignant endometria have been reported, they are not definitive and sometimes complicated. This study aimed to identify a small number of characteristic features to detect endometrial abnormalities using a simple judgment system and analyze the diagnostic characteristics and their accuracy in endometrial malignancy diagnosis. METHODS: We performed a retrospective analysis of hysteroscopy video data of 250 patients, of which we selected for analysis based on pathology examination 152 cases with benign changes, 16 with atypical endometrium, and 18 with carcinoma in situ or endometrial cancer. Endometrial characteristics assessed included protrusion, desquamation, extended vessel, atypical vessel, and white/yellow lesion. RESULTS: Multivariable analysis revealed that desquamation (p = 0.001, odds ratio [OR] 5.28), atypical vessels (p < 0.001, OR 8.50), and white/yellow lesions (p = 0.011, OR 1.37) were significant predictors for endometrial malignancy. From their contribution status, scoring points of 4, 6, and 1 were settled according to the odds ratio proportions. When scores ≥5 (at least both desquamation and white/yellow lesions or only atypical vessels) were used to define endometrial malignancy, sensitivity and specificity were 100% and 92%, respectively. When detecting cancer, atypical, and benign cases, sensitivity and specificity were 88% and 90%, respectively. CONCLUSION: Our characteristics hysteroscopic findings showed a higher predictive ability in detecting endometrial malignancies. However, further examination with more cases would be needed to accurately diagnose endometrial malignancy by hysteroscopy.

DOI： 10.1111/jog.15879

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BACKGROUND: In recent years, the number of athletes who aim to return to competition after childbirth has increased. However, few international reports have investigated complications during pregnancy, and changes in physical function after childbirth in many athletes. OBJECTIVE: To conduct a retrospective investigation of medical problems during pregnancy, and postpartum, in female athletes who aim to return to competition after childbirth, and to identify the barriers and facilitators for their return. METHODS: A voluntary web-based survey was aimed at former female athletes who became pregnant with their first child and gave birth during their active sports career. The survey items included respondent background, their exercise activities during and after childbirth, perinatal complications, mode of delivery, symptoms and physical function after childbirth. The participants were divided into a vaginal delivery group and a cesarean section group. RESULTS: Three hundred and twenty-eight (29.1 ± 5.1 years old) former athletes were included in the analysis, and about half reported undertaking exercise during pregnancy. The most common perinatal complication was anemia (27.4%). The appearance of any symptoms after childbirth, including low back pain (44.2%) and urinary incontinence (39.9%), was reported by 80.5%. The rate of urinary incontinence may be higher in the vaginal delivery than in the cesarean section group (p = 0.05). The most common physical decline after childbirth was in muscular strength, followed by speed and endurance. CONCLUSION: Addressing pregnancy-associated anemia and managing low back pain is critical for athletes aiming to return to competition after childbirth. Additionally, interventions to reduce the risk for and treat urinary incontinence are important. In addition, in order to return to competition after childbirth, it is important to strengthen muscles, especially the lower limbs and trunk, as well as to create a training program that takes into account the sport/events.

DOI： 10.1080/00913847.2023.2188395

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Ulipristal (UPA), a selective progesterone receptor modulator, has both agonistic and antagonistic effects on progesterone receptors. UPA suppresses ovulation by inhibiting the luteinizing hormone (LH) surge from the pituitary gland; however, the direct effect of UPA on ovarian tissue remains poorly studied. In the present study, we examined the effects of UPA on the ovaries of rats. Rats were treated for 28 days with UPA, and the effects of UPA on ovarian tissue were examined histologically and the expression of antioxidant genes and cell death markers were also investigated. UPA treatment increased the number of primordial follicles at each treatment group, primordial follicles increased at all dose levels, but the size/magnitude of the effect decreased with the increasing dose. The number of primary and antral follicles tended to increase with increasing UPA levels. Furthermore, the decrease in primary follicle number could be attributed to the exhaustion of follicles, but the examination of proliferation markers, oxidative stress markers, and cell death markers revealed no remarkable toxic effects on ovarian tissues. These results suggest that UPA treatment promotes follicle development at each stage but inhibits ovulation by suppressing the LH surge, resulting in an increase in atretic follicles or unruptured luteinized cysts. These results suggest that UPA may not have both toxic effects on the ovary and a direct local effect on ovarian follicles, but we should be careful about the effects of prolonged UPA treatment in patients with uterine fibroids on their future fecundity.

DOI： 10.1016/j.reprotox.2024.108571

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It is unclear whether clinical background differs between endometriosis in adolescent patients with obstructive Müllerian anomalies and those without anomalies. The aim of the study is to identify the difference in clinical characteristics of endometriosis in patients with or without obstructive Müllerian anomalies. The study involved 12 patients aged under 24 years old who underwent primary surgery for obstructive Müllerian anomalies and 31 patients aged under 24 years old who underwent surgery for ovarian endometrioma. A total of 6 out of 12 cases with obstructive Müllerian anomalies developed endometriosis (4 Herlyn-Werner-Wunderlich syndrome, 2 non-communicating functional uterine horn, 2 cervical aplasia). The age at surgery was significantly younger in endometriosis with obstructive Müllerian anomalies, compared with those without obstructive Müllerian anomalies (17.8 ± 4.4 vs. 23.1 ± 1.3, p = 0.0007). The rate of endometrioma was 50.0% and the rate of hydrosalpinx was significantly higher (66.7% vs. 0%, p = 0.0002) in the group of obstructive Müllerian anomalies. The recurrence rate of endometriosis was 20.0% in the group of anomalies and 25.9% in the group of those without anomalies. Adolescent patients with obstructive Müllerian anomalies more easily developed endometriosis and co-occurred with higher rate of hematosalipinx.

DOI： 10.3390/biomedicines12030651

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Language：English   Publishing type：Research paper (scientific journal)  

Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multi‑omics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIP‑seq) and RNA sequencing (RNA‑seq). The expression of PRMT6 in EC was analyzed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6‑knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIP‑seq of H3K27ac antibodies and RNA‑seq. Finally, the downstream targets identified by multi‑omics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6‑KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIP‑seq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNA‑seq data demonstrated altered interferon‑related pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide‑3‑kinase regulatory subunit 1, following PRMT6‑KD. RT‑qPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6‑KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.

DOI： 10.3892/ijo.2024.5620

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OBJECTIVE: To quantitatively evaluate the effect of a booster vaccination dose against coronavirus disease 2019 (COVID-19) on menstrual cycle in a large-scale retrospective cohort study using a menstrual cycle tracking smartphone application (app). METHODS: Prospectively or retrospectively recorded data, including the start and finish dates of menstrual cycles, were collected with the app. Detailed data on vaccinations, side effects, and participants' characteristics were retrospectively collected from a questionnaire on the app. For each COVID-19 vaccination shot (first, second, and third), within-individual changes in menstrual cycle length up to the fourth postvaccination cycle were evaluated. RESULTS: Among the 7,376 and 6,873 participants who had the first and second COVID-19 vaccine doses in different menstrual cycles, respectively, menstrual cycles immediately after the vaccination (first postvaccination cycles) were an average of 0.22 days (95% CI, 0.06-0.39) and 0.37 days (95% CI, 0.20-0.54) longer than the prevaccination cycle. In contrast, among the 1,672 participants who received the first and second doses in the same cycle, the first postvaccination cycle was an average of 4.21 days (95% CI, 3.69-4.72) longer. The second to fourth postvaccination cycles returned to the level of the prevaccination cycle. However, among the 4,768 participants who had the third COVID-19 vaccine dose, the menstrual cycle immediately after the vaccination was an average of 1.20 days (95% CI, 1.00-1.40) longer, with prolongation of cycles of 0.27 days (95% CI, 0.10-0.44) to 0.41 days (95% CI, 0.22-0.59) persisting from the second to the fourth postvaccination cycle. CONCLUSION: The booster shot against COVID-19 may have a greater and longer-lasting effect on menstrual cycles than the primary-series shots. Although the effect size was small, evidence on the side effects of immunization on menstruation should be accumulated.

DOI： 10.1097/AOG.0000000000005476

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The diagnosis and treatment of relative energy deficiency in sport (RED-S) are challenging owing to variations in symptoms and the absence of specific guidelines. This study aimed to investigate differences in the diagnosis and follow-up of RED-S, its consequences, and related factors among sports medicine physicians with different backgrounds in Japan and the USA and examine the differences between the two countries. METHODS: An anonymous survey regarding the diagnosis and treatment processes of RED-S was distributed to sports medicine physicians via email. Respondents included 58 sports medicine physicians from the USA and 241 from Japan. RESULTS: The findings showed that 77.6% of the US physicians screened athletes for RED-S, whereas 17.5% of their Japanese counterparts did so. Moreover, 98.3% and 36.7% of the US and Japanese physicians, respectively, answered that they screened athletes for eating disorders upon suspicion of low energy availability. Logistic regression analysis revealed that the number of US sports medicine physicians who screened athletes for the female athlete triad (Triad) and RED-S (odds ratio [OR] = 12.78, P<0.001) and adhered to specific criteria for athlete suspension and return-to-play (OR=33.67, P<0.01) was higher than that of their Japanese counterparts. CONCLUSIONS: The prevalence of RED-S-related screening and treatment differed between US and Japanese sports medicine physicians. Educating sports medicine physicians about the diagnosis and treatment of athletes with possible signs of RED-S is important in treating female athletes and further investigations are required to identify why the physicians screened/not screened the athletes.

DOI： 10.23736/S0022-4707.23.15302-3

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Language：English   Publisher：(公社)日本産科婦人科学会  

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Language：English   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(一社)東京産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Hypothalamic amenorrhea leads to a hypoestrogenic state, causing decreased bone mineral density (BMD), while strong impact loading on bone has been shown to increase BMD. The purpose of this study is to compare BMD in female athletes based on menstrual status and their sports/events by impact loading characteristics. BMD at the lumbar spine was measured by dual-energy X-ray absorptiometry and hormone level. The subjects were classified into four groups and BMD and hormone levels were compared among the four groups, which were divided into amenorrheic athletes (AAs) and eumenorrheic athletes (EAs). This study recruited 410 female athletes (164 in the AAs and 246 in the EAs), 55 athletes in non-impact sports, 123 in low-impact sports, 141 in multidirectional sports, and 91 in high-impact sports. In the AAs group, BMD Z-score was lowest in low-impact sports (Z-score: -1.53 [-1.76, -1.30]), and was highest in high-impact sports (Z-score: 0.02 [-0.34, 0.38]). In multidirectional and high-impact sports, BMD Z-score in the AAs group did not show results lower than the average for non-athletes. When screening female athletes for low BMD, it is important to evaluate the risk of low BMD based on the impact loading characteristics of their sports/events, in addition to the menstrual state.

DOI： 10.1055/a-2161-5668

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Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jog.16014

Scopus

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Language：English   Publishing type：Research paper (scientific journal)  

The gut microbiome is implicated in the pathogenesis of polycystic ovary syndrome (PCOS), and prenatal androgen exposure is involved in the development of PCOS in later life. Our previous study of a mouse model of PCOS induced by prenatal dihydrotestosterone (DHT) exposure showed that the reproductive phenotype of PCOS appears from puberty, followed by the appearance of the metabolic phenotype after young adulthood, while changes in the gut microbiota was already apparent before puberty. To determine whether the prenatal or postnatal nurturing environment primarily contributes to these changes that characterize prenatally androgenized (PNA) offspring, we used a cross-fostering model to evaluate the effects of changes in the postnatal early-life environment of PNA offspring on the development of PCOS-like phenotypes and alterations in the gut microbiota in later life. Female PNA offspring fostered by normal dams (exposed to an abnormal prenatal environment only, fostered PNA) exhibited less marked PCOS-like phenotypes than PNA offspring, especially with respect to the metabolic phenotype. The gut microbiota of the fostered PNA offspring was similar to that of controls before adolescence, but differences between the fostered PNA and control groups became apparent after young adulthood. In conclusion, both prenatal androgen exposure and the postnatal early-life environment created by the DHT injection of mothers contribute to the development of PCOS-like phenotypes and the alterations in the gut microbiota that characterize PNA offspring. Thus, both the pre- and postnatal environments represent targets for the prevention of PCOS and the associated alteration in the gut microbiota in later life.

DOI： 10.3389/fcell.2024.1365624

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

症例は50歳、0妊0産で、多発子宮筋腫に対し腹腔鏡下子宮全摘術を行い、585gの検体を経腟的回収した。腟断端縫合後に出血の有無を確認した際に温存すべき右卵巣が意図せずに摘出されたことが判明し、経腟的回収時に子宮と共に卵巣を腟内に巻き込み骨盤漏斗靭帯が断裂したと推察した。500g超の子宮、未産婦で腟管が狭い症例は経腟的回収により合併症が生じる可能性があるため、経腹的回収など安全な方法を行う必要があると考えられた。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J02563&link_issn=&doc_id=20240202460015&doc_link_id=%2Fcj7sanai%2F2023%2F003902%2F015%2F0082-0086%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcj7sanai%2F2023%2F003902%2F015%2F0082-0086%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy  

DOI： 10.5180/jsgoe.40.1_15

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fendo.2024.1460934

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Language：English   Publishing type：Research paper (scientific journal)  

Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by permanent cell growth arrest, in the pathologies of various diseases. Moreover, several promising senolytics, including dasatinib and quercetin (DQ), which remove senescent cells, are being developed. In the present study, we investigated whether cellular senescence is involved in Cy-induced POI and whether DQ treatment rescues Cy-induced ovarian damage. Expression of the cellular senescence markers p16, p21, p53, and γH2AX was upregulated in granulosa cells of POI mice and in human granulosa cells treated with Cy, which was abrogated by DQ treatment. The administration of Cy decreased the numbers of primordial and primary follicles, with a concomitant increase in the ratio of growing to dormant follicles, which was partially rescued by DQ. Moreover, DQ treatment significantly improved the response to ovulation induction and fertility in POI mice by extending reproductive life. Thus, cellular senescence plays critical roles in Cy-induced POI, and targeting senescent cells with senolytics, such as DQ, might be a promising strategy to protect against Cy-induced ovarian damage.

DOI： 10.3390/ijms242417193

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Language：English   Publishing type：Research paper (scientific journal)  

The purpose of this study is to clarify the metabolic dependence of ovarian clear cell carcinoma (CCC) by comparing normal tissues and to examine the applicability of fluorescence imaging probe to exploit these metabolic differences. Enhanced glutathione synthesis was supported by the increased uptake of related metabolites and elevated expression levels of genes. Accumulation of intracellular iron and lipid peroxide, induction of cell death by inhibition of the glutathione synthesis pathway indicated that ferroptosis was induced. The activation of γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent imaging probe that recognizes γ-glutamyl transferase, which is essential for the synthesis of glutathione, was investigated in fresh-frozen surgical specimens. gGlu-HMRG detected extremely strong fluorescent signals in the tumor lesions of CCC patients, compared to normal ovaries or endometrium. These results revealed that CCC occurs in the stressful and unique environment of free radical-rich endometrioma, and that glutathione metabolism is enhanced as an adaptation to oxidative stress. Furthermore, a modality that exploits these metabolic differences would be useful for distinguishing between CCC and normal tissues.

DOI： 10.1038/s41598-023-47637-0

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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More specific screening systems for cervical cancer may become necessary as the human papillomavirus (HPV) vaccine becomes more widespread. Although p16/Ki-67 dual-staining cytology has several advantages, it requires advanced diagnostic skills. Here, we developed an automated on-chip immunostaining method using a microfluidic device. An electroactive microwell array (EMA) microfluidic device with patterned thin-film electrodes at the bottom of each microwell was used for single-cell capture by dielectrophoresis. Immunostaining and dual staining for p16/Ki-67 were performed on diagnosed liquid cytology samples using the EMA device. The numbers of p16/Ki-67 dual-stained cells captured by the EMA device were determined and compared among the cervical intraepithelial neoplasia (CIN) lesion samples. Seven normal, fifteen CIN grade 3, and seven CIN grade 2 samples were examined. The percentage of dual-positive cells was 18.6% in the CIN grade 2 samples and 23.6% in the CIN grade 3 samples. The percentages of dual-positive staining increased significantly as the severity of the cervical lesions increased. p16/Ki67 dual immunostaining using the EMA device is as sensitive as the conventional method of confirming the histopathological diagnosis of cervical samples. This system enables a quantified parallel analysis at the individual cell level.

DOI： 10.1038/s41598-023-44273-6

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Adenomyosis is a common gynecological disease in women of reproductive age and causes various symptoms such as dysmenorrhea and heavy menstrual bleeding. However, the influence of pregnancy on the progression of adenomyosis remains unclear. The insight into whether the size of adenomyosis is increased, decreased, or unchanged during pregnancy is also undetermined. The current study aimed to evaluate the influence of pregnancy in patients with symptomatic adenomyosis.

Methods

This study retrospectively enrolled patients diagnosed with adenomyosis by magnetic resonance imaging between 2015 and 2022 at The University of Tokyo Hospital. Uterine size changes were evaluated by two imaging examinations. In the pregnancy group, the patients did not receive any hormonal and surgical treatments, except cesarean section, but experienced pregnancy and delivery between the first and second imaging examinations. In the control group (nonpregnancy group), the patients experienced neither hormonal and surgical treatments nor pregnancy from at least 1 year before the first imaging to the second imaging. The enlargement rate of the uterine size per year (percentage) was calculated by the uterine volume changes (cm³) divided by the interval (years) between two imaging examinations. The enlargement rate of the uterine size per year was compared between the pregnancy group and the control group.

Results

Thirteen and 11 patients with symptomatic adenomyosis were included in the pregnancy group and in the control group, respectively. The pregnancy group had a lower enlargement rate per year than the control group (mean ± SE: −7.4% ± 3.6% vs. 48.0% ± 18.5%, P &lt; 0.001), indicating that the size of the uterus with adenomyosis did not change in the pregnancy group.

Conclusions

Pregnancy is associated with reduced progression of symptomatic adenomyosis.

DOI： 10.1186/s12884-023-05956-0

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Other Link： https://link.springer.com/article/10.1186/s12884-023-05956-0/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Minimally invasive surgery (MIS) has been introduced as an alternative to more radical surgical procedures. The Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy conducted a cross-sectional questionnaire survey to ascertain the status of MIS for endometrial cancer. METHODS: The survey was conducted between May 10 and June 30, 2022. The questionnaire included information on personal attributes, academic affiliations, qualifications, hysterectomies, and intraoperative procedures performed. RESULTS: The total number of questionnaire respondents was 436 (9.2% of the membership). The hysterectomy methods and percentage performed were as follows: simple total hysterectomy (equivalent to benign surgery), 3%; simple total hysterectomy with care to avoid shaving the cervix, 31%; extended total hysterectomy, 48%; and modified radical hysterectomy, 15%. An analysis of hysterectomies performed using MIS for endometrial cancer by qualified gynecologists of endoscopy or board-certified gynecologic oncologists showed a tendency not to choose simple total hysterectomy compared to the gynecologists who did not hold certification (p = 0.019, p = 0.045, and p = 0.010, respectively). Additionally, 67% of respondents did not use uterine manipulators, and 59% of the respondents did not perform lymph node dissection following the guidelines for treating endometrial cancer in Japan. CONCLUSION: This study provided the current status of MIS for endometrial cancer in Japan. The hysterectomy method, use of uterine manipulators, and criteria for omitting lymph node dissection were generally in agreement with the guidelines. Currently, an extra-fascial simple hysterectomy, including at least not shaving the cervix, was a major method for early invasive endometrial cancer using MIS.

DOI： 10.1111/jog.15728

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Language：Japanese   Publisher：(株)メディカ出版  

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Recently, artificial intelligence (AI) has been applied in various fields due to the development of new learning methods, such as deep learning, and the marked progress in computational processing speed. AI is also being applied in the medical field for medical image recognition and omics analysis of genomes and other data. Recently, AI applications for videos of minimally invasive surgeries have also advanced, and studies on such applications are increasing. In the present review, studies that focused on the following topics were selected: i) Organ and anatomy identification, ii) instrument identification, iii) procedure and surgical phase recognition, iv) surgery-time prediction, v) identification of an appropriate incision line, and vi) surgical education. The development of autonomous surgical robots is also progressing, with the Smart Tissue Autonomous Robot (STAR) and RAVEN systems being the most reported developments. STAR, in particular, is currently being used in laparoscopic imaging to recognize the surgical site from laparoscopic images and is in the process of establishing an automated suturing system, albeit in animal experiments. The present review examined the possibility of fully autonomous surgical robots in the future.

DOI： 10.3892/br.2023.1628

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Language：Japanese   Publisher：(一社)日本心身医学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I032926638

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AIM: Abnormal uterine bleeding, as proposed in 2007, is defined as unexpected uterine bleeding in women of reproductive age; the cause of the bleeding is categorized using the PALM-COEIN system. Identifying the diagnostic and treatment modalities for each cause might be intriguing. To summarize the options for abnormal uterine bleeding assessment, we employed text-mining analysis for each of its causes. METHODS: We analyzed abstracts based on PALM-COEIN from PubMed and Web of Science in March 2022. The literature was divided into categories; topics about the disorders were retrieved, and covalent network analysis was conducted to find information for evaluating abnormal uterine bleeding. RESULTS: Diagnostic approaches for PALM included histological and image analysis, including computerized tomography, magnetic resonance imaging, sonography, and hysteroscopy. The therapeutic approaches varied according to the cause. Diagnostic approaches for COEIN were mostly medical history interviews and blood sampling, and the therapeutic approaches for COEIN were ablation, hysteroscopy, and hormonal treatment. The PALM-COEIN classification co-occurrence search revealed each cause's diagnostic procedures, symptoms, and treatment procedures. CONCLUSION: Our text-mining methodology revealed comprehensive insights, important study themes, and clinical trends for abnormal uterine bleeding. A tailored approach to medical realities is required for treating abnormal uterine bleeding properly.

DOI： 10.1111/jog.15669

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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AIMS: This study aimed to develop a scale to screen for eating disorders in female athletes. METHODS: Preliminary survey: A total of 275 female athletes (mean age: 19.4 ± 1.0 years) and 7 female athletes diagnosed with eating disorders (mean age: 20.1 ± 2.5 years) were administered screening items prepared based on an existing scale, followed by exploratory factor analysis. Main survey: Six items, relating to three factors, were extracted, and 201 female athletes (mean age: 22.3 ± 4.8 years) and 6 female athletes diagnosed with current or a history of eating disorders (mean age: 18.8 ± 2.9 years) were queried. The diagnostic validity of the scale was then evaluated. RESULTS: Preliminary survey: Questions (α = 0.71) were extracted from six items, relating to three factors, and collectively termed the University of Tokyo's eating disorders inventory in female athletes (TEDIFA). To determine the scale cut-off score, ROC analysis was performed with the total score, and the cut-off and gray zone scores were set at 13 and 11, respectively. Main survey: At the cut-off score of 13, AUC, sensitivity, and specificity were 0.83 (p < 0.05), 75%, and 90%, respectively. CONCLUSIONS: The scale that was developed, TEDIFA, consisted of six items. The cut-off scores were set at 11 for the gray zone (sensitivity: 75%; specificity: 56%; accurate diagnosis rate: 60%), and 13 for positivity (sensitivity: 75%; specificity: 90%; accurate diagnosis rate: 87%), demonstrating the reliability and validity of the scale.

DOI： 10.1111/jog.15637

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BACKGROUND: Although it has been shown that amenorrhea associated with low energy availability or relative energy deficiency in sport affects body physiology in female athletes, the association between menstrual dysfunction during active sports careers and reproductive function after retirement is not clear. OBJECTIVE: To investigate the association between menstrual dysfunction during their active sports career and post-retirement infertility in female athletes. METHODS: A voluntary web-based survey was aimed at former female athletes who had become pregnant and gave birth to their first child after retirement. Nine multiple-choice questions were included, on maternal age, competition levels and menstrual cycles during active sports careers, time from retirement to pregnancy, the time of resumption of spontaneous menstruation after retirement, conception method, and mode of delivery, etc. Regarding cases of primary and secondary amenorrhea among the abnormal menstrual cycle group, only those whose spontaneous menstruation had not recovered from retirement to the time of pregnancy were included in the study. The association between the presence of abnormal menstrual cycles from active sports careers to post-retirement pregnancy and the implementation of infertility treatment was evaluated. RESULTS: The study population included 613 female athletes who became pregnant and gave birth to their first child after retiring from competitive sports. Of the 613 former athletes, the infertility treatment rate was 11.9%. The rate of infertility treatment was significantly higher in athletes with abnormal than normal menstrual cycles (17.1% vs. 10.2%, p = 0.0225). Multivariable logistic regression analysis showed that maternal age (adjusted odds ratio [OR] 1.194; 95% confidence interval [CI] 1.129, 1.262) and abnormal menstrual cycles (OR and 1.903; adjusted OR 1.105, 3.278) were the relevant factors for infertility treatment. CONCLUSION: It was suggested that menstrual dysfunction that persist from active sports careers to post-retirement may be a factor in infertility when trying to conceive after retirement.

DOI： 10.1080/00913847.2023.2199687

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AIM: Laparoscopic power morcellator (LPM) can be used for tissue retrieval through laparoscopic port site, but the dissemination of uterine and/or myoma tissues is a serious complication. To study the use of LPM for uterine fibroid treatment in Japan, we aimed to perform two national cross-sectional surveys comprising multiple questionnaires. METHODS: The first survey (2011-2013) was conducted in November 2014, and 203 medical institutions responded. The second survey (2017-2019) was conducted in December 2020, and 302 medical institutions were investigated. RESULTS: Overall, 72 104 and 120 425 surgeries and 0.04% and 0.05% cases of postoperative malignancy diagnosis were reported in the first and second surveys, respectively. Magnetic resonance imaging was performed in >90% of the cases in the first and second surveys as preoperative examinations. The frequency of LPM at hysterectomy was 8.9% and 4.6% and the frequency of LPM at laparoscopic myomectomy was 80.4% and 54.8% in the first and second surveys, respectively; both the parameters decreased in the second survey. CONCLUSIONS: It is impossible to completely exclude malignant diseases even if extensive preoperative diagnosis has been done before surgery. Therefore, the use of LPM in patients requires careful attention and informed consent in Japan.

DOI： 10.1111/jog.15492

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Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

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Language：English   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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BACKGROUND: Small cell carcinoma of the uterine cervix (SCCC) is a rare and highly malignant human papillomavirus (HPV)-associated cancer in which human genes related to the integration site can serve as a target for precision medicine. The aim of our study was to establish a workflow for precision medicine of HPV-associated cancer using patient-derived organoid. METHODS: Organoid was established from the biopsy of a patient diagnosed with HPV18-positive SCCC. Therapeutic targets were identified by whole exome sequencing (WES) and RNA-seq analysis. Drug sensitivity testing was performed using organoids and organoid-derived mouse xenograft model. RESULTS: WES revealed that both the original tumor and organoid had 19 somatic variants in common, including the KRAS p.G12D pathogenic variant. Meanwhile, RNA-seq revealed that HPV18 was integrated into chromosome 8 at 8q24.21 with increased expression of the proto-oncogene MYC. Drug sensitivity testing revealed that a KRAS pathway inhibitor exerted strong anti-cancer effects on the SCCC organoid compared to a MYC inhibitor, which were also confirmed in the xenograft model. CONCLUSION: In this study, we confirmed two strategies for identifying therapeutic targets of HPV-derived SCCC, WES for identifying pathogenic variants and RNA sequencing for identifying HPV integration sites. Organoid culture is an effective tool for unveiling the oncogenic process of rare tumors and can be a breakthrough for the development of precision medicine for patients with HPV-positive SCCC.

DOI： 10.1002/cam4.5588

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

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The Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy (JSGOE) introduced a system for the certification of laparoscopic surgeons in 2002 and a system for the certification of facilities in 2014. We examined the opinions of the members of the Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy (JSGOE) regarding the necessity of a certification training system and a technical certification system for robotic surgery skills in Japan. Members of the JSGOE were surveyed with two questionnaires. Overall, 870 and 519 participants responded to the first and second questionnaires, respectively. Half of the respondents indicated that both systems were necessary. The breakdown by age and qualifications showed that this was especially true for the younger generation and respondents with more experience with robotic surgery. Overall, 40% of the respondents judged that a certification system for robotic surgery alone (with or without certification in laparoscopic surgery but with a requirement of experience in laparoscopic surgery) would be necessary. The opinions of the JSGOE members on making a certification system for robotic surgery were split into two clear-cut camps. Thus, we must further seek the extent of public demand for using a public survey so that a final decision can be made on whether to establish this system.

DOI： 10.1007/s11701-022-01520-8

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Other Link： https://link.springer.com/article/10.1007/s11701-022-01520-8/fulltext.html

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

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DOI： 10.1111/jog.15669

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PURPOSE: The current definition of menstrual cycle length in a Japanese woman is different from those of WHO definition, and the original data are outdated. We aimed to calculate the distribution of follicular and luteal phases length in modern Japanese women with various menstrual cycles. METHODS: This study determined the lengths of the follicular and luteal phases of Japanese women using basal body temperature data collected via a smartphone application from 2015 to 2019, and the data were analyzed using the Sensiplan method. Over 9 million temperature readings from more than 80 000 participants were analyzed. RESULTS: The mean duration of the low-temperature (follicular) phase averaged 17.1 days and was shorter among participants aged 40-49 years. The mean duration of the high-temperature (luteal) phase was 11.8 days. The variance and maximum-minimum difference of the length of the low temperature period were significant in women under 35 years old than women aged more than 35 years. CONCLUSIONS: The shortening of the follicular phase in women aged 40-49 years implied a relationship with the rapid decline of ovarian reserve in these women, and the age 35 years old was turning point of ovulatory function.

DOI： 10.1002/rmb2.12516

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BACKGROUND: Human pluripotent stem cells (hPSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (PSCs) have the capacity of self-renewal and multilineage differentiation in vitro. Conventional hPSCs, which are in a primed state, can produce various types of differentiated cells. However, the variability in their degree of pluripotency and differentiation propensities, which is influenced by the inductive methods and culture conditions, limit their availability. Therefore, PSCs in a naïve state are a promising source of PSCs. METHODS: We recently developed a culture system for naïve hPSCs using an inhibitor of the NOTCH signaling pathway and a histone H3 methyltransferase disruptor. This culture system requires feeder cells for stably maintaining the naïve hPSCs. We aimed to develop a culture system for hPSCs that could maintain pluripotency under feeder-free conditions. RESULTS: We used two inhibitors to develop an alternative feeder-free culture system to obtain naïve hPSCs. The naïve cells underwent stable cellular proliferation and were positive for naïve stem cell markers; in addition, they could differentiate into the three germ layers. These feeder-free dome-shaped induced pluripotent stem cells (FFDS-iPSCs) have characteristics similar to that of naïve-like PSCs. CONCLUSIONS: The naive hPSCs under feeder-free conditions could ensure supply of cells for various applications in regenerative medicine and disease modeling.

DOI： 10.21037/sci-2022-043

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Dienogest (DNG) is widely used to treat dysmenorrhea associated with estrogen-dependent diseases such as endometriosis and adenomyosis. DNG becomes unnecessary after menopause when estrogen secretion declines drastically. However, there are no clear criteria for when to halt DNG in perimenopausal patients. Menstruation and dysmenorrhea often resume after discontinuation due to approaching menopause. This case-control study used serum estradiol and follicle-stimulating hormone (FSH) levels to predict whether menstruation would resume in perimenopausal women after discontinuation of DNG. The study enrolled patients aged ≥40 years with endometriosis and/or adenomyosis and who had either completed oral DNG therapy (DNG group) or had spontaneous menopause without hormone therapy (control group). We assessed estradiol and FSH values before DNG termination or the final menstrual period. DNG group members that resumed menstruation after DNG termination (D (+) group, n = 17) had significantly higher estradiol and lower FSH levels than those who did not (D (-) group, n = 22) up to four months before DNG termination but not from four to 12 months. Estradiol and FSH levels were not significantly different between the D (-) and control groups. Receiver operating characteristic curves created from the estradiol and FSH values indicated that menstruation resumed when levels were ≥17 pg/mL and <100 mIU/mL, respectively. In contrast, menstruation did not resume in cases of estradiol ≤20 pg/mL and FSH >80 mIU/mL. The study results provide useful criteria for deciding when to terminate DNG in perimenopausal patients that consider their tolerance for resuming menstruation. Applications to menopause-inducing therapy for uterine fibroids and other conditions are anticipated. Further large-scale studies are needed.

DOI： 10.1507/endocrj.EJ22-0158

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

The cellular origins of cervical cancer and the histological differentiation of human papillomavirus (HPV)-infected cells remain unexplained. To gain new insights into the carcinogenesis and histological differentiation of HPV-associated cervical cancer, we focused on cervical cancer with mixed histological types. We conducted genomic and transcriptomic analyses of cervical cancers with mixed histological types. The commonality of the cellular origins of these cancers was inferred using phylogenetic analysis and by assessing the HPV integration sites. Carcinogenesis was estimated by analyzing human gene expression profiles in different histological types. Among 42 cervical cancers with known HPV types, mixed histological types were detected in four cases, and three of them were HPV18-positive. Phylogenetic analysis of these three cases revealed that the different histological types had a common cell of origin. Moreover, the HPV-derived transcriptome and HPV integration sites were common among different histological types, suggesting that HPV integration could occur before differentiation into each histological type. Human gene expression profiles indicated that HPV18-positive cancer retained immunologically cold components with stem cell properties. Mixed cervical cancer has a common cellular origin among different histological types, and progenitor cells with stem-like properties may be associated with the development of HPV18-positive cervical cancer.

DOI： 10.1111/cas.15664

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15664

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AIM: Endometriosis is linked to asymptomatic atherosclerosis and increases the risk of cardiovascular disease (CVD). Vascular function tests are used to assess atherosclerosis, an important indicator of CVD development. In this study, we aimed to evaluate atherosclerosis-related biomarkers, such as vascular function tests and laboratory data, in perimenopausal women with endometriosis. METHODS: This prospective cohort study enrolled 207 women (≥40 years old) with endometriosis. Laboratory data, ankle brachial index (ABI), and cardio-ankle vascular index (CAVI) were evaluated. RESULTS: The mean age, CAVI, and ABI of the participants at the initial examination were 45.02 years, 6.9 ± 0.6, and 1.07 ± 0.06, respectively. In multiple regression analysis, no factor was associated with CAVI, but ABI was significantly correlated with elevated total cholesterol (TC), low-density lipoprotein cholesterol, and estradiol (partial regression coefficient [β] = -0.00074, p = 0.017; β = -0.00075, p = 0.033; and β = -0.00022, p = 0.015, respectively). The annual rate of change in CAVI showed a positive correlation with TC and pentosidine and a negative correlation with history of hormone therapy. Neither correlation was strong. In a comparison of three groups classified by the annual rate of change in CAVI, the group with the severe change had a higher level of pentosidine. In adjusted multinomial logistic regression analysis, high pentosidine levels were a risk factor for increased rate of change in CAVI. CONCLUSIONS: The association between CAVI and serum markers related to lipid metabolism and ovarian function was mild. Longitudinal analysis of CAVI showed an association with pentosidine, which may be helpful in assessing atherosclerosis risk in women with endometriosis during perimenopause.

DOI： 10.1111/jog.15447

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DOI： 10.1038/s41598-022-22413-8

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OBJECTIVE: To evaluate the phosphorylation of estrogen receptor α at serine-118 (phospho-ERα S118) in the endometrium, ovarian endometrioma, and deep infiltrating endometriosis (DIE). DESIGN: Experimental study. SETTING: University-affiliated hospital and academic research laboratory. PATIENT(S): Twenty-five patients underwent a hysterectomy, 18 patients underwent surgical removal of ovarian endometrioma, and 6 patients underwent DIE. INTERVENTION(S): Tissue samples were obtained from patients who underwent surgical procedures. MAIN OUTCOME MEASURE(S): Immunostaining for phospho-ERα S118, ERα, or phosphorylated p44/42 mitogen-activated protein kinase (phospho-p44/42 MAPK) was performed to evaluate the endometrium with or without endometriosis, ovarian endometrioma, and DIE. For in vitro analysis, endometrial epithelial cells (Ishikawa cells) were stimulated with estradiol (E2) or tumor necrosis factor alpha (TNFα), and the expression levels of phospho-ERα S118 and phospho-p44/42 MAPK were evaluated via Western blotting. RESULT(S): First, phospho-ERα S118 level was significantly higher in the glands and stroma of ovarian endometriosis samples than in those of endometrial and DIE samples. Second, colocalization of phospho-p44/42 MAPK and phospho-ERα S118 was observed in the glands of ovarian endometrioma. The proportions of cells strongly expressing phospho-p44/42 and phospho-ERα were 87% in phosphor-p44/42 MAPK-positive cells and 79% in phosphor-ERα-positive cells. Third, E2 stimulation significantly enhanced phospho-ERα S118 after 15 and 30 minutes in in vitro analysis using endometrial epithelial cells. Fourth, TNFα stimulation modestly but significantly enhanced phospho-ERα S118 after 15 and 30 minutes. Fifth, in Ishikawa cells, treatment with a p44/42 inhibitor (PD98059) significantly reduced phospho-ERα S118 by TNFα but not by E2. CONCLUSION(S): ERα-S118 phosphorylation was increased in ovarian endometriosis. Our findings may provide a new perspective for understanding the mechanism of increased ERα action in the pathophysiology of endometriosis.

DOI： 10.1016/j.xfss.2022.04.004

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The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.

DOI： 10.3390/cancers14215367

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The purpose of this study was to establish a new mouse model of endometriosis that mimics real-world women's health problems, in which women continue to be affected by endometriosis long before they wish to become pregnant, and to evaluate the impact of "chronic exposure to endometriosis" on perinatal outcome. Endometriosis was established by the intraperitoneal injection of homologous minced mouse uteri. Vehicle was injected for the control. Mating was initiated either 1 or 43 days after disease establishment (Young or Aged studies, respectively). Mice were sacrificed on 18 dpc. The number pups and resorptions were counted and pups' body weights (BW) were measured, and the endometriosis lesion was identified and weighted. In the Young study, the number of resorptions and BW were comparable between the groups. In the Aged study, the number of resorptions was significantly higher and BW was significantly lower in endometriosis than that in control. The total weight of endometriosis lesion per dam was significantly lower in the Aged compared to the Young endometriosis group; however, not a single mouse was found to have any lesions at all. These results suggest that in addition to the presence of endometriosis per se, "chronic exposure to endometriosis" prior to pregnancy affect perinatal outcomes.

DOI： 10.3390/biomedicines10102627

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AIM: To investigate the status of abnormal uterine bleeding (AUB) in Japan using the International Federation of Gynecology and Obstetrics (FIGO) classification (AUB system 1 and 2; PALM-COEIN) and to clarify the relationship between AUB symptoms and the diseases causing AUB. METHODS: In a nationwide study, we enrolled first-time patients who visited target facilities during two consecutive weeks from December 1, 2019 to January 31, 2020. The FIGO classification was used to investigate patients with symptoms and causative diseases of AUB. Based on the proportion of patients in the nationwide study, 373 cases were included in the detailed survey. Survey items included symptoms of AUB according to AUB system 1, examination details, and causative diseases according to the PALM-COEIN classification. RESULTS: Within the study period, we encountered 61 740 first-time patients, of which 8081 (13.1%) were diagnosed with AUB. Among them, 39.9% had abnormal menstrual cycles and 56.9% had abnormal menstrual bleeding. In the survey, PALM had the highest percentage of AUB-L and COEIN had the highest percentage of AUB-O. Correspondence analysis showed that COEIN was strongly associated with abnormal menstrual cycles and PALM with abnormal menstrual bleeding. CONCLUSION: We conducted the first nationwide survey of AUB in Japan. The FIGO classification was a useful tool for the diagnosis of AUB, with a strong correlation between symptoms of AUB by AUB system 1 and the causative disease of AUB by PALM-COEIN. Conversely, a high percentage of AUB-N and AUB-E suggests that AUB system 1 and PALM-COEIN are ambiguous as diagnostic tools.

DOI： 10.1111/jog.15464

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Homologous recombination (HR) is a major repair pathway of DNA double-strand breaks and is closely related to carcinogenesis. HR deficiency has been established as a therapeutic target. The aim of this study was to elucidate the functions of a novel HR factor, Mediator complex subunit 1 (MED1), and its association with BRCA1. Formation of the MED1/BRCA1 complex was examined by immunoprecipitation and GST-pull down assays. The transcription cofactor role of BRCA1 was evaluated using luciferase assays. The roles of MED1 on DNA damage response and HR were analyzed by immunofluorescence and HR assays. R-loop accumulation was analyzed using immunofluorescence. R-loop-induced DNA damage was analyzed by comet assays. Immunoprecipitation and GST-pull down assays demonstrated that MED1 is a novel binding partner of BRCA1 and binds to the BRCT domain. Luciferase assays showed that MED1 potentiated the transcription ability of BRCT by two-fold. In MED1-depleted cells, recruitment of HR genes, such as RPA and γH2AX, to DNA damage sites was severely impaired. HR assays showed that MED1 knockdown significantly decreased HR activity. R-loop nuclear accumulation and R-loop-induced comet tails were observed in MED1-depleted cells. We conclude that the transcription factor MED1 contributes to the regulation of the HR pathway and R-loop processing.

DOI： 10.1038/s41598-022-21495-8

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I032456132

Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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PURPOSE: This study investigated the association between menstrual symptoms and the intention to leave work among female nurses in Japan. METHODS: This cross-sectional study investigated female nurses (n = 317) at two university hospitals. The items measured were their characteristics (e.g., age, body mass index), "intention to leave" work, somatic symptoms related with menstruation, self-reported menstrual characteristics (e.g., pain), physical workloads (e.g., working hours and night shifts) and psychological workloads, measured with the Copenhagen Burnout Inventory (CBI), and the Job Content Questionnaire (JCQ). Participants with at least four somatic symptoms (e.g., cold, fatigue) which are present during their menstrual cycles were considered to have "somatic symptoms associated with menstruation." We also measured serum ovarian and gonadotropin-releasing hormones. RESULTS: Approximately 40% of women answered "intention to leave" work, and 17% had "somatic symptoms associated with menstruation." Multiple logistic regression analysis suggested that nurses reporting "somatic symptoms associated with menstruation" were more likely to have "intention to leave" work: the adjusted odds ratios (AOR, 95% confidence interval [CI]) were 2.15 (1.12-4.11) in the personal-burnout model, 2.23 (1.16-4.31) in the work-related burnout model, 2.91 (1.52-5.56) in the client-related burnout model; 2.96 (1.50-5.82) in the JCQ model. There was no association between serum and gonadotropin hormones and the intention to leave. CONCLUSION: Somatic symptoms with menstruation were associated with intention to leave work among female Japanese nurses. Intervention for somatic symptoms with menstruation might support nurses to continue work.

DOI： 10.1007/s00420-022-01905-0

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Language：Japanese   Publisher：(一社)東京産婦人科医会  

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Language：Japanese   Publisher：(公社)日本人間ドック学会  

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Endoplasmic reticulum (ER) stress activated in granulosa cells contributes to the pathophysiology of polycystic ovary syndrome (PCOS). In addition, recent studies have demonstrated that Notch signaling plays multiple roles in the ovary via cell-to-cell interactions. We hypothesized that ER stress activated in granulosa cells of antral follicles in PCOS induces Notch signaling in these cells, and that activated Notch signaling induces aberrant cumulus-oocyte complex (COC) expansion. Expression of Notch2 and Notch-target transcription factors was increased in granulosa cells of PCOS patients and model mice. ER stress increased expression of Notch2 and Notch-target transcription factors in cultured human granulosa-lutein cells (GLCs). Inhibition of Notch signaling abrogated ER stress-induced expression of genes associated with COC expansion in cultured human GLCs, as well as ER stress-enhanced expansion of cumulus cells in cultured murine COCs. Furthermore, inhibition of Notch signaling reduced the areas of COCs in PCOS model mice with activated ER stress in the ovary, indicating that Notch signaling regulates COC expansion in vivo. Our findings suggest that Notch2 signaling is activated in granulosa cells in PCOS and regulates COC expansion. It remains to be elucidated whether aberrant COC expansion induced by the ER stress-Notch pathway is associated with ovulatory dysfunction in PCOS patients.

DOI： 10.3390/biom12081037

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OBJECTIVES: This study aimed to evaluate the course of long-term conservative management of bladder endometriosis (BE). MATERIALS AND METHODS: We retrospectively reviewed 17 cases of BE conservatively managed without surgery in our facility. The following factors were analyzed: age, medical history, lesion size, symptoms, hormonal treatment, and follow-up outcomes. RESULTS: In this study, 15 patients received hormonal therapy and 2 did not. Oral contraceptive (OC), dienogest (DNG), and gonadotropin-releasing hormone agonist (GnRHa) were administered as the first regimen in 7, 5, and 3 patients, respectively. Of the 7 patients, OC administration was effective in alleviating urinary symptoms in all but 2 patients. Of 3 patients who received GnRHa, 2 switched to OC and then DNG, and 1 patient discontinued the treatment because of adverse effects. Of 5 patients who received DNG, all experienced symptom relief. DNG, OC, and GnRHa administration were effective and tolerable in 9 of 10 patients (90.0%), in 5 of 9 patients (55.6%), and in 2 of 3 patients (66.7%), respectively. In particular, 3 patients completed DNG treatment until menopause. The size of the BE lesion significantly decreased after 3 months of DNG administration, and the reduction effect was maintained until 48 months thereafter. CONCLUSION: This study proposed that hormonal therapy for BE is an effective option for those who are not planning to conceive or to undergo surgery. Specifically, DNG may be suitable for patients refusing surgery, considering the effectiveness and tolerance for long-term use.

DOI： 10.1016/j.tjog.2022.02.044

PubMed

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Language：Japanese   Publisher：日本女性骨盤底医学会  

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Language：Japanese   Publisher：(一社)東京産科婦人科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.rbmo.2022.07.006

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Language：English   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Publishing type：Research paper (scientific journal)  

DOI： 10.3390/endocrines3020020

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In women with endometriosis, the association between ovarian function, hormones, and bone mineral density (BMD) is unclear. Therefore, this study aimed to elucidate the association between changes in bone mineral density (BMD) and clinical data, such as ovarian reserves, in perimenopausal women with endometriosis. METHODS: In this prospective study, we evaluated 207 female patients who visited the Department of Obstetrics and Gynecology at the University of Tokyo Hospital between December 2015 and December 2020. We included patients aged ≥ 40 years with a history of endometriosis or who presented with endometriosis lesions. Patients with a history of smoking, steroid administration, autoimmune diseases, dyslipidaemia, and heart disease were excluded. During the study period, patients who underwent two tests, an initial and a follow-up test (n = 142, average age: 45.02 years, average BMD: 1.16 g/cm2), were evaluated at regular intervals based on the annual rate of change in BMD. RESULTS: There was a weak negative correlation between the follicle-stimulating hormone (FSH) and BMD and a weak positive correlation between the anti-Müllerian hormone (AMH) and BMD. The annual rate of change in BMD showed a very weak correlation with thyroid-stimulating hormone (TSH) levels. A large decline in BMD was associated with high TSH levels and higher average age at menopause. Patients with higher TSH exhibited a higher rate of decrease in BMD than those without. CONCLUSIONS: High FSH or low AMH levels are associated with decreased BMD. Decreased ovarian reserve is associated with decreased BMD in perimenopausal women with endometriosis. High TSH levels increase the risk of BMD loss. This finding may suggest that women with endometriosis should undergo bone scanning to rule out the possibility of reduced bone mass and subsequent increased risk of fracture.

DOI： 10.1186/s12905-022-01711-3

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Language：English   Publishing type：Research paper (scientific journal)  

Histone modification is the key epigenetic mechanism that regulates gene expression. Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that catalyzes dimethylation of histone H3 (H3R17) at arginine 17. Lately, it has been suggested that CARM1 is associated with human carcinogenesis, and the CARM1-selective inhibitor, TP-064, has been shown to be a potential therapeutic agent for multiple myeloma. However, the physiological significance of CARM1 in endometrial cancer remains unclear. Therefore, we aimed to explore the role of CARM1 and the effect of TP-064 in endometrial cancer. To this end, we analyzed CARM1 expression in endometrial cancer using quantitative real-time polymerase chain reaction and examined the antitumor mechanism with CARM1 knockdown endometrial cancer cells. Moreover, we evaluated the therapeutic capability of TP-064 in endometrial cancer cells. CARM1 was remarkably overexpressed in 52 endometrial cancer tissues compared to normal endometrial tissues. The growth of CARM1 knockdown endometrial cancer cells was suppressed and CARM1 knockdown induced apoptosis. TP-064 also inhibited endometrial cancer cell growth and declined the number of endometrial cancer cell colonies. These data suggest that CARM1 may be a powerful therapeutic target for endometrial cancer.

DOI： 10.1016/j.bbrc.2022.02.086

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Language：Japanese   Publisher：金原出版(株)  

DOI： 10.18888/sp.0000002119

CiNii Books

CiNii Research

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To report a case of pituitary functioning gonadotroph microadenoma accompanied by ovarian hyperstimulation syndrome (OHSS) in a woman of reproductive age. DESIGN: A case report. SETTING: Tertiary care unit of a university hospital. PATIENTS: A 42-year-old parous woman with bilateral ovarian enlargement presumed to be secondary to a functioning gonadotroph pituitary microadenoma. INTERVENTIONS: Oral contraceptives and endoscopic transsphenoidal surgery for adenoma that initially could not be visualized on a magnetic resonance imaging (MRI) scan. MAIN OUTCOME MEASURES: Medical and radiographic assessment of endogenously induced OHSS and its resolution after treatment. RESULTS: The patient was diagnosed with OHSS secondary to elevations in endogenous levels of follicle-stimulating hormone (FSH). The cranial contrast-enhanced MRI scan did not show any apparent tumor in the pituitary gland. She was, therefore, treated with oral contraceptives, which resulted in a modest resolution of ovarian enlargement; however, this treatment became ineffective 3 years later. A small pituitary adenoma (maximum diameter of 8 mm) was suspected on repeated MRI (2 years after the first MRI). Selective adenomectomy was performed, which resulted in normalization of the ovarian size and resumption of regular menstrual cycles. CONCLUSIONS: We report a case of a functional pituitary microadenoma secreting FSH in quantities significant enough to result in OHSS. The excessive FSH production was resistant to medical therapy; however, surgical treatment was ultimately successful.

DOI： 10.1016/j.xfre.2022.01.006

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Language：English   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：English   Publisher：(公社)日本産科婦人科学会  

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Ulipristal acetate (UPA), a selective progesterone receptor modulator, is used for the treatment of uterine fibroids and selectively inhibits the proliferation and inflammation of leiomyoma cells. As few studies have focused on the molecular biological mechanism of UPA in Ishikawa endometrial cancer cells, we aimed to identify the effects of UPA on these cells. Ishikawa cells were treated with different concentrations of UPA. Cell viability and colony formation assays were performed to assess the growth of cancer cells, whereas invasion and migration assays were used to measure cell motility and invasiveness. Western blotting, caspase 3/7 assay, TUNEL assay, and flow cytometry were performed to analyze apoptosis. Moreover, expression levels of the proinflammatory cytokines oncostatin M, its receptor, interleukin 6, and interleukin 8 were examined using quantitative real-time PCR. UPA decreased cell viability and growth, thereby inhibiting cell migration and invasion via induction of apoptosis. Contrary to expectation, stand-alone application of UPA increased the expression of the proinflammatory cytokines but concomitant use of UPA and the estrogen receptor antagonist ICI 182,720 decreased it. These data revealed a novel dual role of UPA: It could attenuate cell growth via activation of apoptosis while simultaneously provoking the activation of proinflammatory cytokines in endometrial cancer cells. These indicate that the combination of UPA and an estrogen receptor antagonist may be useful in suppressing the secretion of proinflammatory cytokines by UPA alone.

DOI： 10.1016/j.heliyon.2021.e08696

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Language：Japanese   Publisher：(一社)日本がん・生殖医療学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Autophagy, meaning "self-eating," is a cellular catabolic process that involves lysosomal degradation of cytoplasmic materials. Autophagy contributes to both quality control and energy supply of cells, which are associated with tumorigenesis and tumor development, respectively. Endometrial cancer (EC) is the most common gynecologic cancer, and its incidence is increasing. Although autophagy plays crucial roles in several types of cancer, such as pancreatic ductal adenocarcinoma, its role in EC has not been clearly demonstrated. Activation of the PI3K/AKT/mTOR pathway, which functions to suppress autophagy, is an initial step in type 1 endometrial carcinogenesis, whereas a loss-of-function mutation of TP53, which augments autophagy via p16 induction, is the main cause of type 2 endometrial carcinogenesis. Mutations in autophagy-related genes, including ATG4C, RB1CC1/FIP200, and ULK4, have been reported in EC; thus, an aberrant autophagy mechanism may be involved in endometrial carcinogenesis. Furthermore, the biguanide diabetes drug metformin, treatment with which enhances autophagy via AMPK-mediated mTOR inactivation, has been reported to reduce the risk of EC. These findings suggest that autophagy negatively regulates endometrial carcinogenesis, and autophagy inducers may be useful for chemoprevention of EC. In contrast, autophagy appears to promote EC once it is established. Consistent with this, treatment with chloroquine, an autophagy inhibitor, is reported to attenuate EC cell proliferation. Moreover, chemotherapy-induced autophagy triggers chemoresistance in EC cells. As autophagy has a tumor-promoting function, the combination of chemotherapy and autophagy inhibitors such as chloroquine could be a potent therapeutic option for patients with EC. In conclusion, autophagy plays a dual role in the prevention and treatment of EC. Therefore, targeting autophagy to prevent and treat EC requires diametrically opposed strategies.

DOI： 10.3389/fcell.2022.839416

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd  

DOI： 10.1186/s12905-021-01462-7

Scopus

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Publishing type：Research paper (scientific journal)  

DOI： 10.3390/endocrines2040041

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jri.2021.103371

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1096/fj.202101051r

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.202101051R

Language：Japanese   Publisher：(株)医学書院  

DOI： 10.11477/mf.1409210524

CiNii Books

CiNii Research

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01564&link_issn=&doc_id=20211028090011&doc_link_id=10.11477%2Fmf.1409210524&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1409210524&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：日本生殖免疫学会  

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.molpharmaceut.1c00514

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

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Language：Japanese   Publisher：東北連合産科婦人科学会・北日本産科婦人科学会  

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Language：Japanese   Publisher：東北公衆衛生学会  

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Language：Japanese   Publisher：日本子宮鏡研究会  

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Recent studies have uncovered the critical role of aryl hydrocarbon receptor (AHR) in various diseases, including obesity and cancer progression, independent of its previously identified role as a receptor for endocrine-disrupting chemicals (EDCs). We previously showed that endoplasmic reticulum (ER) stress, a newly recognized local factor in the follicular microenvironment, is activated in granulosa cells from patients with polycystic ovary syndrome (PCOS) and a mouse model of the disease. By affecting diverse functions of granulosa cells, ER stress contributes to PCOS pathology. We hypothesized that expression of AHR and activation of its downstream signaling were upregulated by ER stress in granulosa cells, irrespective of the presence of EDCs, thereby promoting PCOS pathogenesis. In this study, we found that AHR, AHR nuclear translocator (ARNT), and AHR target gene cytochrome P450 1B1 (CYP1B1) were upregulated in the granulosa cells of PCOS patients and model mice. We examined CYP1B1 as a representative AHR target gene. AHR and ARNT were upregulated by ER stress in human granulosa-lutein cells (GLCs), resulting in an increase in the expression and activity of CYP1B1. Administration of the AHR antagonist CH223191 to PCOS mice restored estrous cycling and decreased the number of atretic antral follicles, concomitant with downregulation of AHR and CYP1B1 in granulosa cells. Taken together, our findings indicate that AHR activated by ER stress in the follicular microenvironment contributes to PCOS pathology, and that AHR represents a novel therapeutic target for PCOS.

DOI： 10.1093/molehr/gaab003

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Language：English   Publishing type：Research paper (scientific journal)  

Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to explore their potential as novel therapeutic strategies for endometriosis. The expression of PGE2 receptors (EP2 and EP4) in donated tissues from human ovarian endometriosis, adenomyosis and peritoneal endometriosis was examined using immunohistochemistry. Human endometriotic stromal cells (ESC) isolated from ovarian endometriotic tissue and peritoneal macrophages were treated with EP2 and EP4 antagonists. cAMP accumulation and the effect of EP antagonists were measured using cAMP assays. DNA synthesis in ESC was detected using bromodeoxyuridine incorporation analysis. Interleukin (IL)-6 and IL-8 protein levels in ESC supernatants were measured using ELISAs. mRNA expression level for aromatase by ESC, and selected cytokines by peritoneal macrophages was measured using RT-PCR. EP2 and EP4 receptors were expressed in cells derived from control and diseased tissue, ovarian endometriotic, adenomyotic and peritoneal lesions. A selective EP2 antagonist reduced DNA synthesis, cAMP accumulation and IL-1β-induced proinflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1β-induced IL-6 secretion and aromatase expression. In peritoneal macrophages, EP expression was elevated in endometriosis samples but the EP4 antagonist reduced cAMP levels and expression of vascular endothelial growth factor, chemokine ligand 2 and chemokine ligand 3 mRNA. EP2 and EP4 are functioning in endometriosis lesions and peritoneal macrophages, and their selective antagonists can reduce EP-mediated actions, therefore, the EP antagonists are potential therapeutic agents for controlling endometriosis.

DOI： 10.1093/molehr/gaaa077

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Endometrial cancer is a ubiquitous gynecological disease with increasing global incidence. Therefore, despite the lack of an established screening technique to date, early diagnosis of endometrial cancer assumes critical importance. This paper presents an artificial-intelligence-based system to detect the regions affected by endometrial cancer automatically from hysteroscopic images. In this study, 177 patients (60 with normal endometrium, 21 with uterine myoma, 60 with endometrial polyp, 15 with atypical endometrial hyperplasia, and 21 with endometrial cancer) with a history of hysteroscopy were recruited. Machine-learning techniques based on three popular deep neural network models were employed, and a continuity-analysis method was developed to enhance the accuracy of cancer diagnosis. Finally, we investigated if the accuracy could be improved by combining all the trained models. The results reveal that the diagnosis accuracy was approximately 80% (78.91-80.93%) when using the standard method, and it increased to 89% (83.94-89.13%) and exceeded 90% (i.e., 90.29%) when employing the proposed continuity analysis and combining the three neural networks, respectively. The corresponding sensitivity and specificity equaled 91.66% and 89.36%, respectively. These findings demonstrate the proposed method to be sufficient to facilitate timely diagnosis of endometrial cancer in the near future.

DOI： 10.1371/journal.pone.0248526

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Language：English   Publishing type：Research paper (scientific journal)  

The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still unknown. The purpose of this study was to investigate the role of SETD8 in HGSOC. We performed quantitative real-time PCR and immunohistochemistry to detect the expression of SETD8 in HGSOC samples and normal ovarian specimens. Then, we assessed the effect of the inhibition of SETD8 expression using small interfering RNA (siRNA) and a selective inhibitor (UNC0379) on cell proliferation and apoptosis in HGSOC cells. The expression of SETD8 was significantly upregulated in clinical ovarian cancer specimens compared to that in the corresponding normal ovary. In addition, suppression of SETD8 expression in HGSOC cells with either siRNA or UNC0379 resulted in reduced levels of H4K20 monomethylation, inhibition of cell proliferation, and induction of apoptosis. Furthermore, UNC0379 showed a long-term antitumor effect against HGSOC cells, as demonstrated by colony-formation assays. SETD8 thus constitutes a promising therapeutic target for HGSOC, warranting further functional studies.

DOI： 10.3390/biom10121686

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Language：English   Publishing type：Research paper (scientific journal)  

Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to explore their potential as novel therapeutic strategies for endometriosis. The expression of PGE2 receptors (EP2 and EP4) in donated tissues from human ovarian endometriosis, adenomyosis and peritoneal endometriosis was examined using immunohistochemistry. Human endometriotic stromal cells (ESC) isolated from ovarian endometriotic tissue and peritoneal macrophages were treated with EP2 and EP4 antagonists. cAMP accumulation and the effect of EP antagonists was measured using cAMP assays. DNA synthesis in ESC was detected using bromodeoxyuridine incorporation analysis. IL-6 and IL-8 protein levels in ESC supernatants were measured using ELISAs. mRNA expression level for aromatase by ESC, and selected cytokines by peritoneal macrophages was measured using RT-PCR. EP2 and EP4 receptors were expressed in cells derived from control and diseased tissue, ovarian endometriotic, adenomyotic, and peritoneal lesions. A selective EP2 antagonist reduced DNA synthesis, cAMP accumulation and IL-1β-induced pro-inflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1β-induced IL-6 secretion and aromatase expression. In peritoneal macrophages, EP expression was elevated in endometriosis samples but the EP4 antagonist reduced cAMP levels and expression of VEGF, CXCL2 and CXCL3 mRNA. EP2 and EP4 are functioning in endometriosis lesions and peritoneal macrophages, and their selective antagonists can reduce EP-mediated actions, therefore, the EP antagonists are potential therapeutic agents for controlling endometriosis.

DOI： 10.1093/molehr/gaaa077

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Conventional human pluripotent stem cells (hPSCs), known for being in a primed state, are pivotal for both basic research and clinical applications since such cells produce various types of differentiated cells. Recent reports on PSCs shed light on the pluripotent hierarchy of stem cells and have promoted the exploration of new stem cell states along with their culture systems. Human naïve PSCs are expected to provide further knowledge of early developmental mechanisms and improvements for differentiation programmes in the regenerative therapy of conventionally primed PSCs. However, practical challenges exist in using naïve-state PSCs such as determining the conditions for hypoxic culture condition and showing limited stable cellular proliferation. Here, we have developed new leukemia inhibitory factor dependent PSCs by applying our previous work, the combination of dibenzazepine and a DOT1L inhibitor to achieve the stable culture of naïve-state PSCs. The potential of these cells to differentiate into all three germ layers was shown both in vitro and in vivo. Such new naïve-state PSCs formed dome-shaped colonies at a faster rate than conventional, primed-state human induced PSCs and could be maintained for an extended period in the absence of hypoxic culture conditions. We also identified relatively high expression levels of naïve cell markers. Thus, non-hypoxia treated, leukemia inhibitory factor-dependent PSCs are anticipated to have characteristics similar to those of naïve-like PSCs, and to enhance the utility value of PSCs. Such naïve PSCs may allow the molecular characterization of previously undefined naïve human PSCs, and to ultimately contribute to the use of human pluripotent stem cells in regenerative medicine and disease modelling.

DOI： 10.1016/j.reth.2020.08.001

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Previous studies have suggested that histone methylation can modulate carcinogenesis and cancer progression. For instance, the histone methyltransferase SET and MYND domain containing 2 (SMYD2) is overexpressed in several types of cancer tissue. The aim of the present study was to determine whether SMYD2 could serve a therapeutic role in ovarian clear cell carcinoma (OCCC). Reverse transcription-quantitative PCR was used to examine SMYD2 expression in 23 clinical OCCC specimens. Moreover, OCCC cell proliferation and cell cycle progression were also examined following small interfering RNA-mediated SMYD2 silencing or treatment with a selective SMYD2 inhibitor. SMYD2 was significantly upregulated in clinical OCCC specimens, compared with normal ovarian tissue. In addition, SMYD2 knockdown decreased cell viability as determined via a Cell Counting Kit-8 assay. Moreover, the proportion of cells in the sub-G1 phase increased following SMYD2 knockdown, suggesting increased apoptosis. Treatment with the SMYD2 inhibitor LLY-507 suppressed OCCC cell viability. These results suggested that SMYD2 could promote OCCC viability, and that SMYD2 inhibition induced apoptosis in these cells. Thus, SMYD2 inhibitors may represent a promising molecular targeted approach for OCCC treatment.

DOI： 10.3892/ol.2020.12014

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

女性は加齢に伴いエストロゲンの分泌が減少するが、外因性にエストロゲンを投与するホルモン補充療法を行うことで、身体における好影響が期待できる。女性と男性の性差を含めたエストロゲンの作用について触れ、周閉経期以降の女性のアンチエイジング治療としてのホルモン補充療法と、その他のエストロゲンに関連した治療手段などについて概説した。

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J04290&link_issn=&doc_id=20201106170007&doc_link_id=%2Fai1aamdd%2F2020%2F001605%2F010%2F0610-0620%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai1aamdd%2F2020%2F001605%2F010%2F0610-0620%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

Advanced clear cell carcinomas originating from both ovaries and kidneys with cancerous peritonitis have poor prognoses. Murine double-minute 2 (MDM2) is a potential therapeutic target for clear cell ovarian carcinomas with WT TP53. Herein, we characterized the antiangiogenic and antitumor effects of the MDM2 inhibitors DS-3032b and DS-5272 in 6 clear cell ovarian carcinoma cell lines and 2 clear cell renal carcinoma cell lines, as well as in clear cell ovarian carcinomas s.c. xenograft and ID8 (murine ovarian cancer cells with WT TP53) cancer peritonitis mouse models. In clear cell ovarian carcinoma s.c. xenograft mouse models, DS-3032b significantly reduced WT TP53 clear cell ovarian carcinoma- and clear cell renal carcinoma-derived tumor volumes. In ID8 mouse models, DS-5272 significantly inhibited ascites production, reduced body weight, and significantly improved overall survival. Additionally, DS-5272 reduced the tumor burden of peritoneal dissemination and decreased CD31+ cells in a dose-dependent manner. Furthermore, DS-5272 significantly decreased vascular endothelial growth factor concentrations in both sera and ascites. Combined therapy with MDM2 inhibitors and everolimus showed synergistic, and dose-reduction potential, for clear cell carcinoma treatment. Our findings suggest that MDM2 inhibitors represent promising molecular targeted therapy for clear cell carcinomas, thereby warranting further studies to evaluate the efficacy and safety of dual MDM2/mTOR inhibitors in clear cell carcinoma patients.

DOI： 10.1111/cas.14583

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: Women undergoing infertility treatment often need to balance work and fertility treatment. Therefore, we evaluated the quality of life (QOL) and impact of infertility treatment on Japanese working women and their careers. METHODS: We conducted an online questionnaire at 18 clinics in Japan. Responses were collected from 835 women, 713 of whom were working. The participants were divided into three groups based on treatment stage. Data were collected using the FertiQoL and an original questionnaire created by the authors. The Mann-Whitney U test and a multinomial logistic analysis were used. RESULTS: Approximately 90% of the participants felt that treatment could hinder their work and 8% had quit their jobs. Low QOL was associated with sadness and despair due to infertility and mood disorders, disruptions to life and work, and the complicated medications and procedures involved in treatment. Social isolation and the effect of fertility treatment on daily life and work strongly hindered the careers of working women in the third stage of treatment (in vitro fertilization and intracytoplasmic sperm injection). Approximately 70% of the participants required support to subsidize treatment costs and sought shorter working hours and flextime systems. Only 55% informed their workplaces about the fertility treatment, but about 70% easily gained understanding by informing them. CONCLUSIONS: For many working women, infertility treatment posed barriers to their careers, which could explain the low QOL. Urgent introduction of a support system is necessary in Japan, and understanding and social acceptance of infertility appears to be important.

DOI： 10.1111/jog.14387

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese   Publisher：金原出版(株)  

DOI： 10.18888/sp.0000001392

CiNii Books

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BACKGROUND: Approximately 10% of female athletes have a history of stress fractures, which most commonly occur between the ages of 16 and 17 years old. PURPOSE: We investigated whether tartrate-resistant acid phosphatase 5b (TRACP-5b), which is a bone resorption marker, can serve as a valid predictor of stress fractures in female athletes in their teens and 20s. METHODS: Three hundred and sixteen elite female athletes were recruited between 2013 and 2015. Serum TRACP-5b and various hormones were examined in blood samples. The serum TRACP-5b level was compared between athletes with and without stress fractures within 3 months after the initial collection of their blood samples. RESULTS: The 316 athletes were divided into two age groups: 13-19 years old and 20-29 years old. Thirty-six athletes (11.4%) experienced new stress fractures within 3 months after the initial collection of their blood samples. The median serum TRACP-5b level was significantly higher in teenage athletes with new stress fractures than in teenage athletes without new stress fractures. In univariate logistic regression analysis, the Z-score of serum TRACP-5b was a significant predictive factor of stress fractures in teenage athletes only (odds ratio: 1.87; 95% CI: 1.31-2.66; P < 0.0012). CONCLUSION: For teenage female athletes, TRACP-5b is a predictor of the risk of stress fractures, and measuring TRACP-5b levels may be useful to prevent stress fractures.

DOI： 10.1111/jog.14256

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BACKGROUND: The effects of transdermal estradiol treatment (HT) in amenorrheic athletes (AA) with low body weight (BW) and low bone mineral density (BMD) are unknown. PURPOSE: To investigate whether HT increases BMD in AA with low BW and to compare the results with levels in AA who have recovered spontaneous menstruation (SM). METHODS: Female athletes (n = 151) were recruited at the Japan Institute of Sports Sciences and the University of Tokyo. All participants were divided into four groups: an AA group (untreated group) (n = 36), a HT group (n = 55), a SM group (n = 21), and an eumenorrheic athletes (EA) group (n = 39). Height, body weight, blood tests, and dual-energy X-ray absorptiometry were measured at baseline and after 12 months. The HT group was treated daily for 12 months with transdermal estrogen therapy. In addition, participants received oral progestin for 7 days once every 3 months. RESULTS: After 12 months, BMD in the AA group was significantly lower than at baseline; however, BMD in the other three groups was significantly higher than at baseline. The ratio of the change in BMD values before and after 12 months was -1.6 ± 3.2% for the AA group, 5.3 ± 8.7% for the HT group, 11.1 ± 8.9% for the SM group, and 2.3 ± 5.7% for the EA group. The rate of change in BMD values in the SM group was greater than that in the HT group. CONCLUSION: HT increased BMD in AA with low BW, and the increase in those with SM was greater than that in those treated with HT.

DOI： 10.1111/sms.13679

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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When the presence of endometriotic lesions are not evident by hematoxylin and eosin staining, CD10 is used to highlight and confirm the presence of endometriotic stroma. However, CD10 is not specific only to the endometrial stroma but is also expressed in many other cells. Recently, interferon-inducible transmembrane protein 1 (IFITM1) was reported as a highly specific immunohistochemical marker of normal endometrial stroma and endometrial stromal neoplasm. In this study, we examined the expression of IFITM1 and CD10 in 18 cases of ovarian endometriosis and 44 cases of extragenital endometriosis. Among the 62 patients, 62 (100.0%) were positive for IFITM1 and 60 (96.8%) for CD10, and CD10 was negative in 2 cases that were positive for IFITM1. Additionally, we found that IFITM1 sensitivity was unaffected by the presence or absence of hormonal therapy. To the best of our knowledge, this represents the first demonstration of IFITM1 as a highly sensitive stromal marker of ovarian and extragenital endometriosis.

DOI： 10.1007/s43032-020-00189-4

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In cases of extragenital endometriosis or microscopic endometriosis lesions, pathological diagnosis can be challenging because endometriotic stroma and glands represent only a minor component of fibrotic endometriotic lesions. For better accuracy of diagnosis, the development of a sensitive and specific epithelial marker is beneficial. Previous studies showed that PAX8 is a highly sensitive and specific marker for primary and metastatic Mullerian epithelial tumors. Therefore, we sought to examine whether PAX8 is a highly sensitive marker for glands in extragenital endometriosis. Eight and 47 samples of ovarian endometrioma and extragenital endometriosis, respectively, were evaluated in this study. We calculated the percentage of samples positively immunostained for PAX8, CD10, estrogen receptor (ER), and progesterone receptor (PR). PAX8 was positive for endometriotic epithelial cells in 95.7% (45/47) of extragenital endometrioses and in 100% (8/8) of ovarian endometrioses. CD10 was positive for endometriotic stromal cells in 97.9% (46/47) of extragenital endometrioses. PAX8 was strongly positive for glands, even in a CD10-negative case. The expression of PAX8, CD10, and PR was not affected by preoperative hormonal therapy, and the positive rate of ER staining was significantly reduced by preoperative hormonal therapy. In conclusion, PAX8 is a highly sensitive epithelial marker for extragenital endometriosis. This specific expression was maintained under hormonal therapy. It is noteworthy that extragenital endometriosis maintains the expression of this lineage marker, although it occurs at various sites, and its cause and mechanism of development might be different. PAX8 nuclear expression can be useful in detecting extragenital endometriosis in clinical practice.

DOI： 10.1007/s43032-020-00186-7

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A diagnostic biopsy for endometrial cancer is performed via dilation and curettage (D&C). However, D&C may miss endometrial cancer lesions due to of its 'blind' approach. Hysteroscopy is a useful method that can be used to detect endometrial cancer lesions. In addition, office hysteroscopy is easy to be scheduled and does not require anesthesia. The patient was a 40-year-old woman with suspected endometrial cancer; however, it could not be diagnosed by D&C and biopsy using hysteroscopy during hospitalization. Office hysteroscopy during the proliferative phase indicated that the suspicious endometrial cancerous lesion was minimal at the isthmus of the uterus with atypical vessels and a white spot, for which biopsy was performed. Pathological diagnosis was endometrioid carcinoma with squamous differentiation, G1. Therefore, total laparoscopic hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy were performed. In this case, it was difficult to detect minimal lesion in the secretory phase because the endometrial thickness hid the endometrial cancer. It is easy to perform office hysteroscopy in the proliferative phase. This case indicated that office hysteroscopy is a useful method to diagnose and perform biopsy for minimal lesions.

DOI： 10.3892/mco.2020.2053

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Language：Japanese  

DOI： 10.11477/mf.1409210105

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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OBJECTIVES: To evaluate the anti-inflammatory and anti-angiogenetic effects of Tokishakuyakusan (TSS), a traditional Japanese medicine (Kampo), and its ingredients, ferulic acid (FA) and paeoniflorin (PA) on endometriotic stromal cells (ESC) and peritoneal macrophages. STUDY DESIGN: Endometriotic tissues were obtained from 16 patients and peritoneal macrophages were obtained from 11 patients that had undergone laparoscopic surgery for ovarian endometriosis. ESC isolated from endometriotic tissues and peritoneal macrophages were cultured, and pre-treated with 300 μg/mL of TSS, 500 μM FA or 50 μM PA. ESC and peritoneal macrophages were then stimulated with IL-1β. Concentrations of IL-8 and VEGF protein in supernatants were then detected and measured using specific ELISAs. TSS (4 g/kg body weight) was orally administered to female Sprague-Dawley rats. The concentration of FA in plasma and uteri was measured using liquid chromatography-mass spectrometry with tandem mass spectrometry (LC-MS/MS). RESULTS: TSS and FA but not PA decreased the secretion of inflammatory cytokine (IL-8) and angiogenic factor (VEGF) in ESC. TSS and FA also suppressed the secretion of inflammatory cytokine (IL-8) from peritoneal macrophages. FA was detected in plasma and in uterine tissues after the oral administration of TSS to rats. CONCLUSIONS: Our study demonstrates that TSS has anti-inflammatory and anti-angiogenic effects on endometriosis related cells by controlling inflammatory cytokine and growth factor secretion from cells, and these effects, at least partially, may be due to the direct effects of the TSS ingredient FA.

DOI： 10.1016/j.jri.2020.103104

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Language：Japanese   Publisher：(一社)関東連合産科婦人科学会  

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Language：Japanese   Publisher：「産婦人科の進歩」編集室  

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Language：Japanese   Publisher：秋田県公衆衛生学会  

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Rikkunshito, a traditional Japanese herbal medicine, improves appetite via activation of gastrointestinal hormone ghrelin pathway. The function of ghrelin is mediated by growth hormone secretagogue receptor (GHSR1a), and ghrelin has been known to possess diverse physiological functions including growth suppression of some cancer cells. Considering that increased ghrelin signaling by Rikkunshito could enhance sirtuin1 (SIRT1) activity in nervous system, we aimed to investigate the effect of Rikkunshito in ovarian cancer cells. Ovarian cancer cell lines were treated with Rikkunshito, and cellular viability, gene expressions and epithelial-mesenchymal transition (EMT) status were investigated. To investigate the involvement of SIRT1 by Rikkunshito in SKOV3 cancer cells, endogenous expression of SIRT1 was depleted using small interfering RNA (siRNA). Treatment with Rikkunshito elevated ghrelin, GHSR1a and SIRT1, while cellular viability was decreased. The treatment of Rikkunshito also inhibited cellular migration and invasion status in a dose-dependent manner, and these effects were translated to the enhanced EMT status, although the role of SIRT1 was not determined. Our study revealed a novel function of Rikkunshito in enhancing EMT status of ovarian cancer cells. Therefore, we would like to propose that Rikkunshito may be used as a novel adjunctive therapy in chemotherapy of ovarian cancer because platinum-based chemotherapy frequently used for the treatment of ovarian cancer inevitably impairs appetite.

DOI： 10.1507/endocrj.EJ19-0368

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Language：Japanese   Publisher：金原出版(株)  

DOI： 10.18888/sp.0000001234

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Language：Japanese   Publisher：(一社)日本衛生学会  

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DOI： 10.34433/j00525.2020202556

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Language：Japanese   Publisher：(一社)日本衛生学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, and we previously found that androgens activate endoplasmic reticulum (ER) stress in granulosa cells from patients with PCOS. In addition, recent studies demonstrated the accumulation of advanced glycation end products (AGEs) in granulosa cells from PCOS patients, which contribute to the pathology. Therefore, we hypothesized that androgens upregulate the receptor for AGEs (RAGE) expression in granulosa cells by activating ER stress, thereby increasing the accumulation of AGEs in these cells and contributing to the pathology. In the present study, we show that testosterone increases RAGE expression and AGE accumulation in cultured human granulosa-lutein cells (GLCs), and this is reduced by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Knockdown of the transcription factor C/EBP homologous protein (CHOP), an unfolded protein response factor activated by ER stress, inhibits testosterone-induced RAGE expression and AGE accumulation. The expression of RAGE and the accumulation of AGEs are upregulated in granulosa cells from PCOS patients and dehydroepiandrosterone-induced PCOS mice. Administration of the RAGE inhibitor FPS-ZM1 or TUDCA to PCOS mice reduces RAGE expression and AGE accumulation in granulosa cells, improves their estrous cycle, and reduces the number of atretic antral follicles. In summary, our findings indicate that hyperandrogenism in PCOS increases the expression of RAGE and accumulation of AGEs in the ovary by activating ER stress, and that targeting the AGE-RAGE system, either by using a RAGE inhibitor or a clinically available ER stress inhibitor, may represent a novel approach to PCOS therapy.

DOI： 10.1210/endocr/bqaa015

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Language：Japanese   Publisher：(有)フジメディカル出版  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Endometriosis exerts detrimental effects on ovarian physiology and compromises follicular health. Granulosa cells from patients with endometriosis are characterized by increased apoptosis, as well as high oxidative stress. Endoplasmic reticulum (ER) stress, a local factor closely associated with oxidative stress, has emerged as a critical regulator of ovarian function. We hypothesized that ER stress is activated by high oxidative stress in granulosa cells in ovaries with endometrioma and that this mediates oxidative stress-induced apoptosis. Human granulosa-lutein cells (GLCs) from patients with endometrioma expressed high levels of mRNAs associated with the unfolded protein response (UPR). In addition, the levels of phosphorylated ER stress sensor proteins, inositol-requiring enzyme 1 (IRE1) and double-stranded RNA-activated protein kinase-like ER kinase (PERK), were elevated in granulosa cells from patients with endometrioma. Given that ER stress results in phosphorylation of ER stress sensor proteins and induces UPR factors, these findings indicate that these cells were under ER stress. H2O2, an inducer of oxidative stress, increased expression of UPR-associated mRNAs in cultured human GLCs, and this effect was abrogated by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Treatment with H2O2 increased apoptosis and the activity of the pro-apoptotic factors caspase-8 and caspase-3, both of which were attenuated by TUDCA. Our findings suggest that activated ER stress induced by high oxidative stress in granulosa cells in ovaries with endometrioma mediates apoptosis of these cells, leading to ovarian dysfunction in patients with endometriosis.

DOI： 10.1093/molehr/gaz066

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Human endometrium is a highly regenerative and dynamic tissue that undergoes cyclic changes during menstrual cycle. It has been reported that endometrial epithelium contains a population of progenitor/stem cells. Increasing amount of evidence indicates that progenitor/stem cells are involved in the pathogenesis of endometriosis. Proteins belonging to the aldehyde dehydrogenase 1 (ALDH1A) family have been reported to be markers of normal tissue stem cells and cancer stem cells. In this study, by using immunohistochemistry, we examined the expression of ALDH1A isozymes in human endometrial tissue, including that affected by endometriosis, and in ovarian endometrioma. Positive staining for ALDH1A isozymes was observed in the stroma of the endometrium and in endometriotic ovarian tissue. In the glands, expression patterns were distinct for different ALDH1A isozymes. ALDH1A1 and ALDH1A3 were highly expressed in the epithelium of stratum basalis of the endometrium and in the epithelium of ovarian endometrioma irrespective of the menstrual cycle, whereas ALDH1A2 was highly expressed only in the epithelium of endometrioma. Furthermore, ALDH1A1 co-localized with N-cadherin, which is a marker of endometrial epithelial progenitor cells, in the glands of stratum basalis. These findings support and reinforce the notion about the presence of progenitor/stem cells in endometrial glands in stratum basalis and in endometriotic glands, suggesting that these cells are involved in the physiology of the endometrium and in the pathology of endometriosis.

DOI： 10.1007/s43032-019-00041-4

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DOI： 10.1177/1745506520952003

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DOI： 10.3389/fendo.2020.591764

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BACKGROUND: Despite the huge burden of domestic work on women in Japan, its effects on their health have been poorly investigated. We aimed to assess the association between domestic work stress and self-rated psychological health among women. METHODS: We conducted a cross-sectional survey using an online social research panel in February 2018. Participants were 2,000 women with paid work (the "workers" group) and 1,000 women without paid work (the "homemakers" group), aged between 25 and 59 years old and living with a partner. Self-rated psychological health (Mental Health and Vitality scales of the Japanese SF-36), occupational and domestic work stress (the Brief Job Stress Questionnaire), the 10-item Work-Family Conflict Scale, and sociodemographic factors were assessed. RESULTS: The workers had lower domestic job control and higher support from a partner and their parents than the homemakers (p < 0.001), whereas domestic job demand and psychological health were similar between the groups. After adjustment for the covariates using multiple linear regression models, better psychological health was significantly associated with lower domestic job demand, higher domestic job control, and having a young child in both groups. In addition, work-family conflicts and occupational job stress among the workers and caregiving among the homemakers showed negative associations with psychological health. CONCLUSION: Self-rated psychological health in women was associated with domestic work stress regardless of employment status. To promote women's health, we need to take into account the effects of domestic work, work-family conflicts, and social support from families, as well as occupational factors.

DOI： 10.1186/s12199-019-0833-5

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: While the incidence of endometrial cancer continues to rise, the therapeutic options remain limited for advanced or recurrent cases, and most cases are resistant to therapy. The anti-tumor effect of many chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage in cancer cells; thus, activation of DNA damage response (DDR) pathways is considered an important factor affecting resistance to therapy. When some DDR pathways are inactivated, inhibition of other DDR pathways can induce cancer-specific synthetic lethality. Therefore, DDR pathways are considered as promising candidates for molecular-targeted therapy for cancer. The crosstalking ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 1 (ATR-Chk1) and ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 2 (ATM-Chk2) pathways are the main pathways of DNA damage response. In this study, we investigated the anti-tumor effect of inhibitors of these pathways in vitro by assessing the effect of the combination of ATM or ATR inhibitors and conventional DNA-damaging therapy (doxorubicin (DXR), cisplatin (CDDP), and irradiation) on endometrial cancer cells. Both the inhibitors enhanced the sensitivity of cells to DXR, CDDP, and irradiation. Moreover, the combination of ATR and Chk1 inhibitors induced DNA damage in endometrial cancer cells and inhibited cell proliferation synergistically. Therefore, these molecular therapies targeting DNA damage response pathways are promising new treatment strategies for endometrial cancer.

DOI： 10.3390/cancers11121913

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Language：Japanese  

DOI： 10.15106/j_naika124_2413

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Advanced glycation end products (AGEs) affect the follicular microenvironment. The close relationship between AGEs, proinflammatory cytokine production and activation of the unfolded protein response (UPR), which involves activating transcription factor 4 (ATF4), is crucial for regulation of various cellular functions. We examined whether accumulation of AGEs in follicles was associated with proinflammatory cytokine production and activation of the UPR in granulosa cells and decreased oocyte developmental competence. Concentrations of AGEs, soluble receptor for AGE (sRAGE), interleukin (IL)-6 and IL-8 in follicular fluid (FF) were examined by ELISAs in 50 follicles. mRNA expression of ATF4, IL-6 and IL-8 in cumulus cells (CCs) were examined by quantitative RT-PCR in 77 samples. Cultured human granulosa-lutein cells (GLCs) were treated with AGE-bovine serum albumin (BSA) alone or following transfection of ATF4-targeting small interfering RNA. The AGE concentration and the AGE/sRAGE ratio in FF were significantly higher in follicles containing oocytes that developed into poor-morphology embryos (group I) than those with good-morphology embryos (group II). When compared with sibling follicles from the same patients, the AGE/sRAGE and concentrations of IL-6 and IL-8 in FF, as well as ATF4, IL-6 and IL-8 mRNA expression in CCs, were significantly higher in group I follicles than group II. AGE treatment increased mRNA expression of ATF4, IL-6 and IL-8 in cultured GLCs. Knockdown of ATF4 abrogated the stimulatory effects of AGE on mRNA expression and protein secretion of IL-6 and IL-8. Our findings support the idea that accumulation of AGEs in follicles reduces oocyte competence by triggering inflammation via activation of ATF4 in the follicular microenvironment.

DOI： 10.1093/molehr/gaz050

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CONTEXT: The ovarian reserve is reduced in patients with endometriosis. We hypothesize that the phosphatidylinositol 3-kinase (PI3K)-phosphatase and tensin homolog deleted on chromosome 10 (PTEN) Akt-Forkhead box O (Foxo3) pathway is involved in reducing the ovarian reserve. OBJECTIVE: To elucidate the signaling mechanism by which endometriosis decreases ovarian reserve. DESIGN: Studies were conducted by using a mouse model for endometriosis and human ovaries. The endometriosis mouse model was established and ammonium trichloro (dioxoethylene-o,o') tellurate (AS101), an inhibitor of PI3K-PTEN-Akt pathway, was administered to experimental mice. Human ovaries were collected during surgery from patients with endometrioma or from patients with no ovarian pathology (control ovaries). The number of follicles and expression of Foxo3, PTEN, phosphorylated mammalian target of rapamycin and phosphorylated Akt by oocytes in primordial follicles in mouse and human ovaries were detected by immunohistochemical staining and evaluated. RESULTS: In the endometriosis mouse model, the proportion of primordial follicles was diminished, and the proportion of primary, secondary, antral, and growing follicles was increased in comparison with controls. In both mouse and human ovaries, the PI3K-PTEN-Akt-Foxo3 pathway was activated in samples from endometriosis. Administration of AS101 restored the proportion of primordial follicles in endometriotic mice ovaries to control levels. CONCLUSIONS: The current study describes the excessive activation of primordial follicles and the role of the PI3K-PTEN-Akt-Foxo3 pathway in the reduction of ovarian reserve associated with endometriosis. Our results suggest that a PI3K-PTEN-Akt inhibitor should be considered for further investigation as promising medicines for the prevention of the ovarian reserve reduction in patients with endometriosis.

DOI： 10.1210/jc.2019-00281

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Language：Japanese   Publisher：日本子宮鏡研究会  

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INTRODUCTION: PI3K pathway signaling has received attention as a molecular target in clear cell ovarian carcinoma (CCOC). MDM2 is one of the AKT effectors in the PI3K pathway, which binds to and degrades p53. In this study, we aimed to clarify the prognostic significance of PIK3CA and MDM2 expression, and potential therapeutic effect of a dual inhibition of the PI3K pathway and MDM2. MATERIALS AND METHODS: cDNA expression was evaluated by using microarray data using 75 samples of CCOC. DS-7423 (dual inhibitor of pan-PI3K and mTOR) and RG7112 (MDM2 inhibitor) were used on CCOC cell lines to evaluate cell proliferation, expression level of MDM2 related proteins, and apoptosis by MTT assay, western blotting, and flow cytometry. DS-7423 (3 mg/kg) and/or RG7112 (50 mg/kg) were orally administrated every day for three weeks, and the anti-tumor effect was evaluated using tumor xenografts, along with immunohistochemistry. RESULTS: Tumors with high expression of both PIK3CA and MDM2 showed significantly worse prognosis in expression array of 71 CCOCs (P = 0.013). Dual inhibition of the PI3K pathway by DS-7423 and MDM2 by RG7112 showed synergistic anti-proliferative effect in 4 CCOC cell lines without TP53 mutations. The combination therapy more robustly induced pro-apoptotic proteins (PUMA and cleaved PARP) with increase of sub G1 population and apoptotic cells, compared with either single agent alone. The combination therapy significantly reduced tumor volume in mice (P < 0.001 in OVISE, and P = 0.038 in RMG-I) without severe body weight loss. Immunohistochemistry from the xenograft tumors showed that the combination treatment significantly reduced vascularity and cell proliferation, with an increase of apoptotic cell death. CONCLUSION: A combination therapy targeting the PI3K pathway and MDM2 might be a promising therapeutic strategy in CCOC.

DOI： 10.1016/j.ygyno.2019.08.028

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Language：Japanese   Publisher：日本子宮鏡研究会  

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The ubiquitin-proteasome pathway plays an important role in the regulation of cellular proteins. As an alternative to the proteasome itself, recent research has focused on methods to modulate the regulation of deubiquitinating enzymes (DUBs) upstream of the proteasome, identifying DUBs as novel therapeutic targets in breast, endometrial, and prostate cancers, along with multiple myeloma. bAP15, an inhibitor of the 19S proteasome DUBs UCHL5 and USP14, results in cell growth inhibition in several human cancers; however, the mechanism remains poorly understood in ovarian cancer. Here, we found that aberrant UCHL5 expression predicted shorter progression-free survival (PFS) in a cohort of 1435 patients with ovarian cancer described in the Gene Expression Omnibus and The Cancer Genome Atlas databases. The subgroup of patients with TP53 mutations was significantly more likely to exhibit poor PFS (p <0.001). Moreover, we found bAP15 could suppress TP53-mutant ovarian cancer cell survival by regulating TGF-β signaling through inhibiting UCHL5 expression and dephosphorylating Smad2, consequently inducing apoptosis. bAP15 (2.5 and 5.0 mg/kg) also exerted significant anti-tumor effect on nude mice bearing subcutaneous SKOV3 xenografts. As activated TGF-β signaling is involved in ovarian cancer progression, these findings suggest that UCHL5 inhibition offers potential opportunities for a novel targeted therapy against TGF-β-activated ovarian cancer.

DOI： 10.18632/oncotarget.27219

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Language：Japanese   Publisher：金原出版(株)  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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AIM: This study aimed to describe the clinical presentation, diagnostic evaluation, and operative or medical management of inguinal endometriosis. METHODS: In this study, we retrospectively reviewed 20 cases of inguinal endometriosis in our facility, particularly on the clinical characteristics, diagnosis, and surgical and medical treatment. RESULTS: We retrospectively investigated the following items for each patient: age at diagnosis, surgical history, presence of extragenital endometriosis, symptoms, imaging modalities, surgical therapy, hormonal therapy, follow-up period, postoperative recurrence and time to recurrence. We identified 20 cases of inguinal endometriosis in our facility. First, 75% of the patients had right inguinal endometriosis. Second, T1-weighted or fat-saturated T1-weighted images showed hyperintensity in the lesions in 17 patients (17/18 patients, 94.4%). Third, in 5 of 6 patients who underwent surgical therapy, we performed radical surgery to excise the inguinal lesion including the round ligament. One patient had disease relapse. Fourth, in 6 of 7 cases, dienogest effectively improved pain without significant adverse effects, but oral contraceptive was effective in 1 of 4 patients without significant adverse effects. CONCLUSION: We retrospectively reviewed 20 patients with inguinal endometriosis in our facility. We have shown that magnetic resonance imaging can be a useful imaging modality to obtain a specific diagnosis of this disease. In addition, inguinal endometriosis can be managed with radical surgery to resect lesions including the round ligament and with hormonal treatment. In particular, dienogest ameliorated symptoms, which can be an option for patients who do not want surgery.

DOI： 10.1111/jog.14059

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BACKGROUND: The female athlete triad (Triad), defined by the American College of Sports Medicine as low energy availability (LEA) with or without disordered eating, menstrual dysfunction, and low bone mineral density (BMD), is associated with stress fractures and athletes aged 16-17 years are most susceptible. PURPOSE: To examine whether the Triad increases the risk of stress fractures, athletes were assigned to a "teenage" group and a "20s" group. METHODS: This prospective study enrolled 390 elite female athletes and was conducted from 2012 to 2016 at Japan Institute of Sports Sciences. Blood concentrations of various hormones were examined, and BMD was measured at the lumbar spine and throughout the whole body using dual-energy X-ray absorptiometry. LEA was defined as body weight ≤85% of the ideal body weight for teenage athletes, or BMI ≤17.5 for athletes in their 20s. Low BMD was defined as a BMD Z-score of <-1.0 in the lumbar spine and the whole body. RESULTS: Among 390 athletes enrolled, 36 developed new stress fractures within 3 months of registration. The risk for stress fractures due to the Triad in teenage athletes was higher than for athletes in their 20s. In teenage female athletes, secondary amenorrhea, low BMD for the whole body, and a low ratio of actual body weight to ideal body weight increased the risk for stress fractures by 12.9 times, 4.5 times, and 1.1 times, respectively. CONCLUSION: To prevent stress fractures in female athletes with the Triad, age of athletes should be taken into consideration.

DOI： 10.1111/sms.13464

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：(公社)日本産業衛生学会  

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Language：English   Publisher：(一社)日本癌学会  

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AIM: Oxidative stress (OS) is defined as an imbalance between oxidants and antioxidants in favor of the oxidants, and the disruption of redox signaling leads to molecular damages. This study was conducted to clarify the effect of OS in individual follicular fluid (FF) on oocyte fertilization and embryonic division. METHODS: A total of 124 patients who underwent assisted reproductive technology treatment in our hospital underwent intracytoplasmic sperm injection and 211 FF were collected. The ova were fertilized, and embryos were individually cultured until cleavage stage or blastocyst stage and classified according to the Veeck classification system or Gardner classification system. RESULTS: The follicular fluid corresponding to the ovum was analyzed by measuring the OS marker, the reactive oxygen metabolites (d-ROM test), and the antioxidant marker (biological antioxidant potential marker [BAP] test), and the relation between these markers and clinical parameters was analyzed. The value of d-ROM was correlated with the proper fertilization status and formation of good quality cleavage embryo, whereas the elevated value of BAP was observed in better embryonic development group. Oxidative stress index, defined as d-ROM/BAP × 100 clearly indicated that lower oxidative stress index was associated with better fertilization status and embryo development. CONCLUSION: Our results clearly indicate that the balance between OS and antioxidant capacity in FF at the time of oocyte retrieval is possibly important in the processes of fertilization and embryo division; thus, we propose that oxidative status and balance in FF might be used as novel biomarkers in assisted reproductive technology.

DOI： 10.1111/jog.14040

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The aim of this study was to clarify the expression of Ninj1 in endometriosis and adenomyosis lesions, and its inductive factor in human endometriotic stromal cells (ESCs). BACKGROUND: Nerve injury-induced protein 1 (Ninj1) is a molecule originally identified in dorsal root ganglion neurons and Schwann cells after nerve injury and promotes neurite outgrowth. The aim of this study was to clarify the expression of Ninj1 in endometriosis and adenomyosis lesions, and its inductive factor in human endometriotic stromal cells (ESCs). MATERIALS AND METHODS: Tissues were obtained with consent from patients diagnosed with ovarian endometrioma (n = 15 in total), peritoneal endometriosis (n = 5), adenomyosis (n = 5), and other gynecological disorders (n = 5, control) during surgery. Immunohistochemistry was conducted in order to detect Ninj1 protein expression in the lesion of endometriosis, adenomyosis, and eutopic endometrium. Nerve fibers in the ovarian endometrioma were detected by positive staining of PGP-9.5. To evaluate the effects of IL-1β on Ninj1 gene expression in endometriosis, ESCs isolated from ovarian endometrioma (n = 5) were treated with IL-1β (5 ng/mL) for 3 or 6 hours. Messenger RNA (mRNA) expression for Ninj1 was examined using quantitative RT-PCR. RESULTS: The Ninj1 protein was expressed by ovarian endometrioma, peritoneal endometriotic, and adenomyotic tissue. Nerve fibers were found in the areas of positive staining for Ninj1 in ovarian endometrioma. IL-1β, an indicator of inflammation in endometriosis, significantly increased Ninj1 mRNA expression by ESC. CONCLUSION: Our study demonstrates that Ninj1 is expressed in endometriosis and adenomyosis and is induced by the inflammatory stimuli. Given the neurogenetic property of Ninj1, our results imply that Ninj1, induced by inflammation in endometriosis lesion, may contribute to the pathogenesis of pain symptoms characteristic of endometriosis.

DOI： 10.1177/1933719118806395

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(一社)日本産科婦人科内視鏡学会  

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Language：Japanese   Publisher：(株)メジカルビュー社  

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Language：Japanese   Publisher：(株)メジカルビュー社  

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Language：English   Publishing type：Research paper (scientific journal)  

A 34-year-old woman presented our hospital with complaint of irregular menstruation and abnormal uterine bleeding lasting for a month. After her second parturition at the age of 27, her menstrual cycle had been regular, but it suddenly became irregular at the age of 30. Transvaginal ultrasound revealed the presence of ovarian mass, and the patient underwent diagnostic laparoscopic surgery. Bilateral ovaries temporally shrink after puncture but the size soon resumed. Gonadotropins were almost normal, but estradiol and PRL levels turned out to be elevated, and cabergoline treatment was initiated. After referral to our hospital, we found that the ovaries showed multifollicular appearance. Brain magnetic resonance imaging showed an 18-mm macroadenoma in the suprasellar area. To suppress the secretion of endogenous gonadotropins and estrogen, low-dose estrogen-progestin was prescribed. Surprisingly, the treatment temporarily reduced the size of the ovaries. The patient was referred to a neurosurgeon, and a functioning gonadotroph adenoma was suspected. After the resection of the pituitary tumor, her menstrual cycle became regular, and the size of bilateral ovaries became normal. We also noticed that her ovarian reserve judged by anti-Müllerian hormone had been almost diminished after the surgical treatment, probably reflecting the exhaustion of follicular pool. Women with multifollicular ovaries and elevated estradiol levels may have functioning gonadotroph adenomas, although the level of FSH is relatively normal, and ovarian reserve can be followed by measuring anti-Müllerian hormone.

DOI： 10.1507/endocrj.EJ19-0066

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The vital role of folic acid is to reduce the risk of having a neonate afflicted with neural tube defects. The prevalence of neural tube defects (myelomeningocele and anencephaly) has been reported in an incomplete form over the last 40 years in Japan. We aimed to evaluate the total number of neural tube defects including those delivered or terminated, to clarify the proportion of those terminated, and to internationally compare their prevalence. Through information on >311 000 deliveries obtained from 262 hospitals/clinics for 2 years of 2014 and 2015, we identified that the rate of total neural tube defects (termination of pregnancy, live births and stillbirths) was 8.29 per 10 000 deliveries for the year 2014 and was 8.72 for 2015, which were 1.5 and 1.6 times higher than the respective values (live births and stillbirths) reported. It is also observed that the ratio of the total number of myelomeningocele (termination of pregnancy, live births, and stillbirths) to that of anencephaly was approximately 1:1.2, that a half of pregnancies afflicted with neural tube defects were terminated, and that the proportion of termination of pregnancy due to myelomeningocele and due to anencephaly was 20% and 80%, respectively. Internationally, the real prevalence of neural tube defects in Japan was comparatively high, ranking fifth among the seven developed countries. In conclusion, the real prevalence of total neural tube defects was approximately 1.5 times higher than that currently reported by the Japan Association of Obstetricians and Gynecologists.

DOI： 10.1111/cga.12333

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Several specific tests for cervical screening have been developed recently, including p16/Ki67 dual immunostaining for diagnosing high-risk human papillomavirus positive squamous intraepithelial lesion in the cervix. However, manual screening of cells in an entire glass slide is currently a standard clinical procedure for quantification and interpretation of immunocytochemical features of the cells. Here, we developed a microfluidic device containing an electroactive microwell array with barriers (EMAB) for highly efficient single-cell trapping followed by on-chip immunofluorescence analysis with minimum loss of the sample. EMAB utilizes patterned electrodes at the bottom of cell-sized microwells to trap single cells using dielectrophoresis (DEP) and cell-holding structures behind the microwells to stabilize the position of trapped cells even without DEP. Using the device, we evaluated the performance of p16/Ki67 dual immunostaining of HeLa cells on the chip. The device shows 98% cell-trapping efficiency as well as 92% cell-holding efficiency against the fixed HeLa cells, and we successfully demonstrated high-efficiency on-chip immunofluorescence analysis with minimal loss of sample. p16/Ki67 dual immunostaining using EMAB may be useful for complementary tests for cervical screening in confirming the histopathological diagnosis.

DOI： 10.1063/1.5089796

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Language：Japanese   Publisher：日本エンドメトリオーシス学会  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：(株)医学書院  

CiNii Books

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Language：Japanese   Publisher：(株)診断と治療社  

CiNii Books

CiNii Research

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00525&link_issn=&doc_id=20190625080005&doc_link_id=%2Fae4sanke%2F2019%2F008607%2F006%2F0813-0816%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fae4sanke%2F2019%2F008607%2F006%2F0813-0816%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.1186/s12985-019-1180-2

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Language：Japanese   Publisher：(公社)日本婦人科腫瘍学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Dysfunction of histone methylation is known to be related to cancer progression. The histone methyltransferase SMYD2 methylates histone protein H3 and non-histone proteins, including poly ADP ribose polymerase 1 (PARP1). There have been reports of SMYD2 overexpression in several types of cancers. However, there are no reports regarding its role in high-grade serous ovarian carcinomas (HGSOCs). Therefore, we investigated the expression profile and conducted functional analysis on SMYD2 in HGSOC cells. In addition, we verified whether SMYD2 inhibition increases the susceptibility of HGSOC cells to PARP inhibitors. We analyzed the expression of histone methyltransferase SMYD2 by quantitative real-time polymerase chain reaction and immunohistochemistry using HGSOC clinical tissues (n = 35). We performed functional analyses, including cell proliferation assay, cell cycle analysis, and immunoblotting, after treatment with SMYD2 siRNAs and SMYD2 selective inhibitor LLY-507 in HGSOC cells. We also performed colony-formation assay after combination treatment with LLY-507 and PARP inhibitor olaparib in HGSOC cells. The expression profiles of SMYD2 showed significant overexpression of SMYD2 in HGSOC clinical tissues. The knockdown or inhibition of SMYD2 by siRNAs or LLY-507, respectively, suppressed cell growth by increasing the proportion of apoptotic cells. LLY-507 showed additive effect with olaparib in the colony-formation assay. These findings suggest that LLY-507 can be used alone or in combination with a PARP inhibitor for the treatment of patients with HGSOC.

DOI： 10.1016/j.bbrc.2019.03.155

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BACKGROUND: Wolf-Hirschhorn syndrome candidate gene-1 (WHSC1), a histone methyltransferase, has been found to be upregulated and its expression to be correlated with expression of enhancer of zeste homolog 2 (EZH2) in several cancers. In this study, we evaluated the role of WHSC1 and its therapeutic significance in ovarian clear cell carcinoma (OCCC). METHODS: First, we analyzed WHSC1 expression by quantitative PCR and immunohistochemistry using 23 clinical OCCC specimens. Second, the involvement of WHSC1 in OCCC cell proliferation was evaluated by MTT assays after siRNA-mediated WHSC1 knockdown. We also performed flow cytometry (FACS) to address the effect of WHSC1 on cell cycle. To examine the functional relationship between EZH2 and WHSC1, we knocked down EZH2 using siRNAs and checked the expression levels of WHSC1 and its histone mark H3K36m2 in OCCC cell lines. Finally, we checked WHSC1 expression after treatment with the selective inhibitor, GSK126. RESULTS: Both quantitative PCR and immunohistochemical analysis revealed that WHSC1 was significantly overexpressed in OCCC tissues compared with that in normal ovarian tissues. MTT assay revealed that knockdown of WHSC1 suppressed cell proliferation, and H3K36me2 levels were found to be decreased in immunoblotting. FACS revealed that WHSC1 knockdown affected the cell cycle. We also confirmed that WHSC1 expression was suppressed by EZH2 knockdown or inhibition, indicating that EZH2 is upstream of WHSC1 in OCCC cells. CONCLUSIONS: WHSC1 overexpression induced cell growth and its expression is, at least in part, regulated by EZH2. Further functional analysis will reveal whether WHSC1 is a promising therapeutic target for OCCC.

DOI： 10.1186/s12885-019-5638-9

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BACKGROUND: The recurrence rate after unilateral salpingo-oophorectomy (USO) for unilateral endometrioma has not been reported. We evaluated the rate of and risk factors for endometrioma recurrence after USO. METHODS: In this retrospective observational study, we enrolled 110 women (age, 35-45 years) who underwent laparoscopic USO (n = 50) or cystectomy (n = 60) for unilateral ovarian endometrioma from January 2010 through December 2012. We compared patients' characteristics between patients who underwent USO and those who underwent cystectomy. We also compared patients with and without an endometrioma recurrence after USO using univariate and multivariate stepwise logistic regression models to identify recurrence risk factors. Endometrioma recurrence was defined as an ovarian cyst (> 2 cm) with features typical of an endometrioma identified by postoperative transvaginal sonography. RESULTS: Endometrioma recurred in 8 (16%) patients after USO (mean follow-up, 46.0 ± 12.9 months [range, 15-73]). The post-USO cumulative recurrence rates at 12, 24, 36, and 60 months were 8.0, 10.2, 12.7, and 24.7%, respectively (Kaplan-Meier analysis). In logistic regression analysis, a contralateral side adhesion score ≥ 4 was an independent risk factor for endometrioma recurrence after USO (odds ratio, 19.48, 95% confidence interval, 1.59-237.72). The post-USO cumulative recurrence rates at 12, 24, 36, and 57 months were 19.5, 24.1, 31.0, and 54.0%, respectively, in cases with contralateral side adhesion scores ≥4, and 0.0, 0.0, 0.0, and 5.9%, respectively, in cases with scores < 4 (log-rank test, P = 0.0023). CONCLUSIONS: To our knowledge, this is the first report on the recurrence rate and risk factors associated with recurrence after USO. Endometrioma recurrence rates were 24.7% during the first 5 years after USO. The post-USO recurrence rate increased significantly in cases with contralateral side adhesions. Our findings could improve the planning of USO and patient selection for postoperative hormonal therapy.

DOI： 10.1186/s12905-019-0760-z

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(株)診断と治療社  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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When the presence of endometriotic lesions are not evident by hematoxylin and eosin staining, CD10 is used to highlight and confirm the presence of endometriotic stroma. However, CD10 is not specific only to the endometrial stroma but is also expressed in many other cells. Recently, interferon-inducible transmembrane protein 1 (IFITM1) was reported as a highly specific immunohistochemical marker of normal endometrial stroma and endometrial stromal neoplasm. In this study, we examined the expression of IFITM1 and CD10 in 18 cases of ovarian endometriosis and 44 cases of extragenital endometriosis. Among the 62 patients, 62 (100.0%) were positive for IFITM1 and 60 (96.8%) for CD10, and CD10 was negative in 2 cases that were positive for IFITM1. Additionally, we found that IFITM1 sensitivity was unaffected by the presence or absence of hormonal therapy. To the best of our knowledge, this represents the first demonstration of IFITM1 as a highly sensitive stromal marker of ovarian and extragenital endometriosis.

DOI： 10.1177/1933719119831782

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In cases of extragenital endometriosis or microscopic endometriosis lesions, pathological diagnosis can be challenging because endometriotic stroma and glands represent only a minor component of fibrotic endometriotic lesions. For better accuracy of diagnosis, the development of a sensitive and specific epithelial marker is beneficial. Previous studies showed that PAX8 is a highly sensitive and specific marker for primary and metastatic Mullerian epithelial tumors. Therefore, we sought to examine whether PAX8 is a highly sensitive marker for glands in extragenital endometriosis. Eight and 47 samples of ovarian endometrioma and extragenital endometriosis, respectively, were evaluated in this study. We calculated the percentage of samples positively immunostained for PAX8, CD10, estrogen receptor (ER), and progesterone receptor (PR). PAX8 was positive for endometriotic epithelial cells in 95.7% (45/47) of extragenital endometrioses and in 100% (8/8) of ovarian endometrioses. CD10 was positive for endometriotic stromal cells in 97.9% (46/47) of extragenital endometrioses. PAX8 was strongly positive for glands, even in a CD10-negative case. The expression of PAX8, CD10, and PR was not affected by preoperative hormonal therapy, and the positive rate of ER staining was significantly reduced by preoperative hormonal therapy. In conclusion, PAX8 is a highly sensitive epithelial marker for extragenital endometriosis. This specific expression was maintained under hormonal therapy. It is noteworthy that extragenital endometriosis maintains the expression of this lineage marker, although it occurs at various sites, and its cause and mechanism of development might be different. PAX8 nuclear expression can be useful in detecting extragenital endometriosis in clinical practice.

DOI： 10.1177/1933719119828095

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BACKGROUND: Age-associated infertility is a problem worldwide, and management of oxidative stress is known to be essential. Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway works as an essential defense mechanism against oxidative stress, and an oral drug Dimethylfumarate (DMF) is known to activate the pathway. METHODS: We tested the hypothesis that oral DMF could alleviate oxidative stress in the ovary, resulting in salvation of age-associated infertility in a mouse model of reproductive age, and we examined the effects of DMF administration. 20 mg/kg DMF was administrated to female mice from 32 to 48 weeks, and Nrf2 levels, antioxidant levels, ovarian reserve, DNA damage, and oxidative stress were examined. RESULTS: DMF administration resulted in elevated mRNA and protein levels of Nrf2, antioxidants, and telomere, and serum levels of Nrf2 and anti-mullerian hormone were also elevated. Results of TUNEL assay and Immunohistochemistry of mice ovarian tissues showed that DNA damage and oxidative stress were decreased by DMF administration, and significantly more oocytes were collected along with preservation of 60% more primordial follicles. CONCLUSIONS: Our data suggest that DMF administration activates the Nrf2/Keap1 pathway, elevate levels of antioxidants, and decrease DNA damage and oxidative stress, resulting in improved ovarian reserve in the mouse ovary.

DOI： 10.1186/s12958-019-0466-y

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AIM: To determine the efficacious treatment for infertile couples, we assessed the impact of infertility factors including endometriosis on assisted reproductive technology (ART) and non-ART treatment, and the effect of age in infertility treatment outcomes was also investigated. METHODS: The medical records of 1864 females, infertile patients from January 2000 to December 2015 at our hospital, were retrospectively reviewed under the approval of the Institutional Review Board. We extracted 10 representative factors and calculated the cumulative live birth rate (CLBR) in these patients. Multivariate analysis of ART and non-ART treatment was performed to assess the impact of infertility factors, and the age-related decline in cumulative live birth rate was calculated by creating eight age-stratified subgroups. RESULTS: In total, 21.9% and 49.4% of the patients conceived after being treated with non-ART and ART, respectively. Multivariate analysis revealed that age > 35, advanced endometriosis defined by the revised American Society for Reproductive Medicine classification system stages III to IV, and the past history or current presence of uterine fibroid had significantly negative impact on the outcome of non-ART. Age stratification revealed that advanced endometriosis adversely affected the outcome of non-ART, especially for patients in their 30s. Assisted reproductive technology treatment for patients with advanced endometriosis was shown to be efficacious because the negative impact had been diminished. CONCLUSION: Considering that non-ART treatment had limited role in patients with advanced endometriosis, prompt initiation of ART in these patients aged as young as 30 years can be recommended to achieve conception.

DOI： 10.1111/jog.13826

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FASEB journal : official publication of the Federation of American Societies for Experimental Biology  

Functions of tumor suppressor p53 and its negative regulator mouse double minute 2 homolog (Mdm2) in ovarian granulosa cells remain to be elucidated, and the current study aims at clarifying this issue. Mice with Mdm2 deficiency in ovarian granulosa cells [ Mdm2-loxP/ progesterone receptor ( Pgr)-Cre mice] were infertile as a result of impairment of oocyte maturation, ovulation, and fertilization, and those with Mdm2/p53 double deletion in granulosa cells ( Mdm2-loxP/ p53-loxP/ Pgr-Cre mice) showed normal fertility, suggesting that p53 induction in the ovarian granulosa cells is detrimental to ovarian function by disturbing oocyte quality. Another model of Mdm2 deletion in ovarian granulosa cells ( Mdm2-loxP/ anti-Mullerian hormone type 2 receptor-Cre mice) also showed subfertility as a result of the failure of ovulation and fertilization, indicating critical roles of ovarian Mdm2 in ovulation and fertilization. Mdm2-p53 pathway in cumulus granulosa cells transcriptionally controlled an orphan nuclear receptor steroidogenic factor 1 (SF1), a key regulator of ovarian function. Importantly, MDM2 and SF1 levels in human cumulus granulosa cells were positively associated with the outcome of oocyte maturation and fertilization in patients undergoing infertility treatment. These findings suggest that the Mdm2-p53-SF1 axis in ovarian cumulus granulosa cells directs ovarian function by affecting their neighboring oocyte quality.-Haraguchi, H., Hirota, Y., Saito-Fujita, T., Tanaka, T., Shimizu-Hirota, R., Harada, M., Akaeda, S., Hiraoka, T., Matsuo, M., Matsumoto, L., Hirata, T., Koga, K., Wada-Hiraike, O., Fujii, T., Osuga, Y. Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality.

DOI： 10.1096/fj.201801401R

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Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and growth arrest of antral follicles. Previously, we found that endoplasmic reticulum (ER) stress is activated in granulosa cells of antral follicles in PCOS, evidenced by activation of unfolded protein response (UPR) genes. Based on this observation, we hypothesized that ER stress is activated by androgens in granulosa cells of antral follicles, and that activated ER stress promotes apoptosis via induction of the UPR transcription factor C/EBP homologous protein (CHOP) and subsequent activation of death receptor (DR) 5. In this study, we found that testosterone induced expression of various UPR genes, including CHOP, as well as DR5, in cultured human granulosa-lutein cells (GLCs). Pretreatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) inhibited testosterone-induced apoptosis and expression of DR5 and CHOP. Knockdown of CHOP inhibited testosterone-induced DR5 expression and apoptosis, and knockdown of DR5 inhibited testosterone-induced apoptosis. Pretreatment with flutamide, as well as knockdown of androgen receptor, decreased testosterone-induced DR5 and CHOP expression, as well as apoptosis. Expression of DR5 and CHOP was upregulated in GLCs obtained from patients with PCOS, as well as in granulosa cells of antral follicles in ovarian sections obtained from patients with PCOS and dehydroepiandrosterone-induced PCOS mice. Treatment of PCOS mice with TUDCA decreased apoptosis and DR5 expression in granulosa cells of antral follicles, with a concomitant reduction in CHOP expression. Taken together, our findings indicate that ER stress activated by hyperandrogenism in PCOS promotes apoptosis of granulosa cells of antral follicles via induction of DR5.

DOI： 10.1210/en.2018-00675

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DOI： 10.1002/rmb2.12236

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This study aimed to evaluate the attitudes of male and female members of the public toward uterus transplantation (UTx), surrogacy, and adoption in Japan via a web-based survey. One thousand six hundred participants were recruited with equal segregation of age (20s, 30s, 40s, and 50s) and gender. We assessed the association between ethical view and gender, age, infertility, and the knowledge level of UTx, using a questionnaire. The findings were as follows. First, 36.5% and 31.0% of respondents agreed that UTx and gestational surrogacy should be approved, respectively. Second, the respondents would potentially choose to receive UTx (34.4%), gestational surrogacy (31.9%), and adoption (40.3%), if they or their partners experienced absolute uterine factor infertility. Third, 10.1%, 5.8%, and 14.3% of the respondents chose UTx, gestational surrogacy, and adoption as the most favorable option, respectively. Fourth, if their daughters suffered from absolute uterine factor infertility, 32.3% of female respondents might want to be donors, and 36.7% of male respondents might ask their wives to be donors. These data were affected by age, gender, infertility, or the knowledge level of UTx. UTx was a more acceptable option than gestational surrogacy and adoption. The effects of gender, age, infertility, and the level of knowledge of UTx are important in understanding the attitude toward UTx. On the other hand, there were concerns about the safety of UTx for recipients, donors, and babies. It is important to continue to understand public attitudes to inform the development and safety of UTx, which will enhance the discussion on the ethical consensus on UTx.

DOI： 10.1371/journal.pone.0223571

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Language：Japanese   Publisher：更年期と加齢のヘルスケア学会((NPO)更年期と加齢のヘルスケア)  

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Language：Japanese   Publisher：(一社)日本生殖医学会  

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Endometrioid endometrial carcinoma, commonly known as type 1 endometrial cancer, accounts for >80% of endometrial carcinomas and is dependent on estrogen. We recently reported on the prognostic significance of the BIRC5 survivin gene in endometrial cancer. Estradiol induces survivin expression in estrogen receptor-positive, but not in estrogen receptor-negative, cancer cells. Kaempferol, a bioflavonoid, reportedly inhibits estrogen receptor-α (ERα) in hormone receptor-positive breast cancer cells. However, whether kaempferol-mediated inhibition of ERα suppresses survivin and induces cell death in endometrial cancer remains unclarified. The present study evaluated the antitumor effects of kaempferol on endometrial cancer cells. Cell viability assays, flow cytometry analysis, western blotting and annexin V analyses were used to analyze the antitumor effects of kaempferol. The results demonstrated that kaempferol successfully suppressed the viability of two ER-positive endometrial cancer cell lines, with IC50 values of 83 and 65 µM. In addition, kaempferol induced sub-G1 cell accumulation and apoptotic cell death (P<0.01) in a dose-dependent manner. Treatment of cells with estradiol significantly induced co-expression of nuclear ERα and survivin proteins (P<0.001). Further evaluation revealed that kaempferol causes apoptotic cell death largely by suppressing ERα, survivin and Bcl-2 protein. Therefore, the results of the present study suggested that targeting ERα and survivin with kaempferol may be a novel therapeutic option against endometrial carcinoma.

DOI： 10.3892/ol.2018.9340

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AIM: Since 2014, Japan Society of Gynecologic and Obstetric Endoscopy and minimally invasive therapy (JSGOE) conducted a nationwide survey on gynecologic endoscopic surgery. We aimed to evaluate the current status and complications associated with endoscopic surgery by Japan gynecologic and obstetric endoscopy-database registry system (JOE-D). METHODS: Electrical medical records concerning the endoscopic surgery were generated from the daily use of reporting system. The subjects were all patients who underwent gynecologic endoscopic surgery. In addition to assessment of actual numbers, diagnosis, and operative methods, adverse events were registered. RESULTS: Total 203 970 patients performed laparoscopic, hysteroscopic and falloposcopic surgery for 3 years, 2014-2016. The numbers of endoscopic surgeries conducted in 2016 were increased more than 67 000, 13 000 or 450 cases, respectively. Incidence rates of complications involving these three types of surgeries in each year were approximately 3.1%. Incidences of intraoperative complications were relatively high in malignant diseases, laparoscopic-assisted vaginal hysterectomy (LAVH) and myomectomy (LAM). In total laparoscopic hysterectomy/laparoscopic hysterectomy (TLH/LH) performed from 2014 to 2016, ureteral injury as intra and postoperative complication occurred in 0.35%. In the past 3 years, the rates of vascular injury, urinary tract, and bowel injury as intraoperative complications caused by laparoscopic surgery were approximately 0.1%. In the hysteroscopic surgery, the rates of total intra- and postoperative complications were 0.78%. CONCLUSION: We exhibited the current status by the nationwide survey of gynecologic endoscopic surgery all over Japan. Severe intra or postoperative complications were identified over the 3 years at a rate of 0.04%.

DOI： 10.1111/jog.13774

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Purpose: To preoperatively predict the operative time (OT) for hysteroscopic myomectomy for G1 or G2 leiomyoma based on leiomyoma weight. Methods: The data from 544 patients who underwent one-step hysteroscopic myomectomy were analyzed retrospectively. A total of 340 patients with leiomyoma penetrating the intramural cavity were identified as suitable candidates for calculation of the OT based on leiomyoma weight; we considered leiomyoma weight to be the most objective parameter for evaluating leiomyoma tissues. Additionally, 460 patients with a single leiomyoma were analyzed to estimate the weight of the resected leiomyoma based on its diameter. Results: Considering total leiomyoma weight (TLW) and two additional coefficients (1.5: G2 leiomyoma, 0.75: vaginal parity of the patient), we demonstrated that our formula correlated well with OT (R2 = 0.72). TLW also correlated well with the cube of the average diameter (AD) of leiomyomas (R2 = 0.89). Predicting TLW significantly improved the application of specific coefficients depending on its value (1.0: AD 0.1-2.0 cm, 0.8: AD 2.1-3.0 cm, 0.7: AD 3.1-5.7 cm). Conclusion: The OT for hysteroscopic myomectomy of intracavital leiomyoma can be predicted prior to surgery using simple clinical information of the target leiomyoma and the patient.

DOI： 10.1002/rmb2.12228

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Increased neutrophil counts are a hallmark of a poor prognosis for cancer. We previously reported that KRAS promoted tumorigenesis and increased neutrophil counts in a mouse peritoneal cancer model. In the current study, we evaluated the role of increased neutrophils in cancer progression, as well as their influence on the intraperitoneal microenvironment. A mouse peritoneal cancer model was established using the KRAS-transduced mouse ovarian cancer cell line, ID8-KRAS. Neutrophil function was assessed by neutrophil depletion in ID8-KRAS mice. Neutrophil depletion markedly accelerated tumor formation; this was accompanied by an increase in interleukin-6 concentrations in ascites. Neutrophil depletion significantly decreased the amount of local and systemic CD8+ T cells, while increasing the amount of local CD4+ T cells, accompanied by an increased amount of monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) (P<0.05). The roles of peritoneal neutrophils (PENs) in CD8+ T cell activation were assessed in vitro. PENs of ID8-KRAS mice had a strong potential to enhance T cell proliferation with a higher expression of the T cell costimulatory molecules OX40 ligand (OX40L) and 4-1BB ligand (4-1BBL), as compared with peripheral blood neutrophils (PBNs). These findings suggest that neutrophils recruited into the KRAS-induced tumor microenvironment (TME) have antitumor properties with the potential to modulate the numbers of M-MDSCs and Tregs and activate CD8+ T cells through T cell costimulatory molecules.

DOI： 10.3892/ijo.2018.4504

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AIM: The objective of this study is to determine the factors associated with successful pregnancy in women of late reproductive age with uterine fibroids who undergo embryo cryopreservation before surgery (ECBS). METHODS: Patients who underwent in vitro fertilization treatment with controlled ovarian stimulation from November 2010 to January 2017 in our university hospital were included. Twenty-two patients older than 35 years of age at the first visit with cavity-distorting uterine fibroids underwent ECBS, a three-step therapeutic approach consisting of oocyte pick-up, myomectomy and embryo transfer (ET), which are performed in this order. We retrospectively calculated the pregnancy rate and determined the factors associated with successful pregnancy. RESULTS: The mean age at ET of the patients who underwent ECBS was 40.9 years, with a pregnancy rate per ET of 36.8% (21/57). Of 22 patients, 10 (45.5%) successfully continued pregnancy beyond 12 weeks of gestation (ongoing pregnancy). An ongoing pregnancy was observed only among the patients with more than three frozen embryos. The ongoing pregnancy rates of patients with ≤five fibroids and ≤5 cm in the maximal diameter were significantly higher compared to the respective remaining group (90.0% vs 14.3% and 87.5% vs 33.3%). CONCLUSION: ECBS is an effective strategy for infertile women of late reproductive age with cavity-distorting uterine fibroids, especially when it is applied to the patients who can freeze at least three embryos before myomectomy, with five or less fibroids smaller than 5 cm in the maximal diameter.

DOI： 10.1111/jog.13754

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Age-related fertility decline is hypothesized to occur mainly by the spontaneous exhaustion and deterioration of the ovarian follicle, and the accumulation of ovarian tissue damage resulting from the ovulation cycle may play roles in the process. In this study, we hypothesized that suppressing ovulation would exert protective effects against age-related fertility decline. To test this hypothesis, we established a mouse model in which oral contraceptives (OCs) were administered daily. Female C57BL/6N mice were administered OCs daily from the age of 2 months to 12 months as an ovulation suppression mouse model. Mouse fecundity was investigated by counting oocyte number after ovarian stimulation and by examining live fetuses after mating. We found that compared with control mice administered vehicle alone, 12-month-old mice administered 2-fold dose OCs used for treating humans exhibited a significantly greater average oocyte number after ovarian stimulation (8.5 ± 0.6 vs 5.9 ± 0.6, P < .01). In addition, spontaneous conception with living fetuses after mating was strikingly increased in 12-month-old mice administered OCs relative to controls (6.0 ± 1.2 vs 0.4 ± 0.3, P < .01). In the histological examination of mouse ovarian tissues, we did not detect a significant difference in ovarian follicle number, but reduced amount of brownish foamy fibrous tissues, which might reflect ovarian tissue damage, was detected in aged mice administered OCs. These results suggest the possibility that long-term OC administration might alleviate age-related fertility decline, and the improvement mechanism could be attributed to the prevention of ovarian tissue damage by suppressing ovulation.

DOI： 10.1177/1933719117746758

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：「産婦人科の進歩」編集室  

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Language：Japanese   Publisher：日本生殖内分泌学会  

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Language：Japanese   Publisher：(株)医学書院  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01564&link_issn=&doc_id=20180724120019&doc_link_id=10.11477%2Fmf.1409209473&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1409209473&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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AIM: Adenomyosis is a common gynecological disorder that causes dysmenorrhea, hypermenorrhea and metrorrhagia. Previously, we reported that 24 weeks of dienogest treatment is highly effective for pain in symptomatic adenomyosis. Up to present, there is no report that describes treatment of adenomyosis with long-term dienogest administration for more than 2 years. In this retrospective cohort study, we investigated the course of long-term dienogest treatment in patients with symptomatic adenomyosis. METHODS: This is a retrospective cohort study. Dienogest was continuously administered at a dose of 2 mg daily for patients with symptomatic adenomyosis. The outcome of long-term administration of dienogest was investigated, and the characteristics of patients were compared between discontinued cases and long-term administration cases. RESULTS: Two patients were excluded from this study because of transfer to another hospital or discontinuation due to infertility treatment. Twelve of 18 patients (66.7%) received dienogest until menopause or for a period of >80 months. Four cases (22.2%) discontinued dienogest treatment because of severe metrorrhagia. In the discontinued cases because of severe metrorrhagia, the pain score for dysmenorrhea and serum CA125 level at baseline significantly elevated, and the hemoglobin level at baseline and the frequency of type 2 adenomyosis significantly decreased, compared to those with long-term use. Moreover, long-term dienogest use did not decrease the serum estradiol level. CONCLUSION: Our report suggests that dienogest is tolerable for long-term use until menopause and can be an alternative treatment option in some patients, especially those with type 2 adenomyosis, to avoid hysterectomy.

DOI： 10.1111/jog.13674

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Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress (OS). It is well documented that equilibration status of OS plays fundamental roles in human reproductive medicine, and the physiological role of Nrf2 in ovarian granulosa cells (GCs) has not been determined yet. Herein we aimed to study the function of Nrf2 in GCs. Human ovarian tissues were subjected to immunohistochemistry to localize Nrf2 and Keap1 and we detected the expression of Nrf2 and Keap1 in the human GCs. Human luteinized GCs were isolated and cultured, and hydrogen peroxide (H2O2) or Dimethylfumarates (DMF), an activator of Nrf2, were added to GCs to analyze the relationship between Nrf2 and antioxidants by quantitative RT-PCR. The mRNA levels of Nrf2, catalase, superoxide dismutase 1 (SOD1), and 8-Oxoguanine DNA glycosylase (OGG1) were elevated by H2O2, and DMF treatment showed similar but pronounced effects through activation of Nrf2. To determine the relationship of Nrf2 and the generation of antioxidants, siRNAs were used and quantitative RT-PCR were conducted. Decreased expression of Nrf2 resulted in a decreased level of these antioxidant mRNA. Intracellular levels of ROS were investigated by fluorescence of 8-hydroxy-2'-deoxyguanosine and fluorescent dye, 2',7'-dichlorodihydrofluorescein diacetate after H2O2 and/or DMF treatment, and DMF treatment quenched intracellular ROS generation by H2O2. These results show that activation of Nrf2 might lead to alleviate OS in human GCs, and this could provide novel insight to conquer the age-related fertility decline that is mainly attributed to the accumulation of aberrant OS.

DOI： 10.1016/j.mce.2017.10.002

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Language：Japanese   Publisher：(株)診断と治療社  

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BACKGROUND: We present a minimal skin wound abdominal myomectomy performed in our hospital and attempt to identify the optimal range of this technique by considering the characteristics of target leiomyomas. In this procedure, we attempted to make the skin wound as small as possible, with a maximum length of approximately 5 cm. METHODS: In addition to introducing the minimal skin wound abdominal myomectomy, we retrospectively collected and analyzed the medical records of 76 patients treated with minimal skin wound abdominal myomectomy exclusively by the same physician at Maruyama Memorial General Hospital between January 2007 and December 2016. We statistically investigated relationships between ten factors, including body mass index; patient's age; patient's parity; administration of gonadotropin-releasing hormone analogue; presence of anemia; the uterine leiomyomas' number, size, weight, and location; operation time; and blood loss. RESULTS: First, we introduce a case in which we performed minimal skin wound abdominal myomectomy for a 36-year-old Japanese patient with a large leiomyoma (10 cm in diameter). Then, we assessed the impacts of patient characteristics and leiomyoma characteristics on operation time and blood loss for this surgical method. In a multivariate analysis, only the number of resected leiomyomas significantly affected massive bleeding. Other factors showed no difference on operation time and the amount of blood loss. CONCLUSIONS: Minimal skin wound abdominal myomectomy is safe and effective for use in many patients, because only the number of leiomyomas affects the amount of blood loss. No other factor affected operation time. We suggest the possibility that the expanded use of minimal skin wound abdominal myomectomy may reduce the number of patients waiting for long periods to undergo laparoscopic surgery and may optimize the use of medical resources in rural areas.

DOI： 10.1186/s13256-018-1703-2

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BACKGROUND: A previous report showed that a glucagon-like peptide-1 receptor (GLP-1R) agonist (exenatide) induced apoptosis in endometrial cancer cells. However, the pathophysiological role of GLP-1R in endometrial cancer has not been fully elucidated. Here, we investigated the effects of the GLP-1R agonist liraglutide in endometrial cancer cells and examined the association between GLP-1R expression and clinicopathological characteristics in endometrial cancer patients. METHODS: Human Ishikawa endometrial cancer cells were treated with different concentrations of liraglutide. To assess the effects of liraglutide, cell viability, colony formation, flow cytometry, Western blotting, and immunofluorescence assays were performed. Autophagy induction was examined by analyzing LC3 and p62 expression and autophagosome accumulation. Moreover, using a tissue microarray, we analyzed GLP-1R expression in 154 endometrial cancer tissue samples by immunohistochemistry. RESULTS: In accordance with the previous report, liraglutide inhibited Ishikawa cell growth in a dose-dependent manner. Liraglutide significantly induced autophagy, and phosphorylated AMPK expression was elevated. Immunohistochemical analysis revealed that GLP-1R expression was associated with positive estrogen receptor and progesterone receptor status, and higher GLP-1R expression was significantly correlated with better progression-free survival. CONCLUSIONS: The use of liraglutide to target autophagy in endometrial cancer cells may be a novel potential treatment for endometrial cancer. Furthermore, higher GLP-1R expression may be associated with better prognosis in endometrial cancer patients.

DOI： 10.1186/s12885-018-4570-8

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The female athlete triad (FAT) is defined by the American College of Sports Medicine (ACSM) as low energy availability (low EA), functional hypothalamic amenorrhoea and osteoporosis. In low EA, lutein dysfunction first develops, followed by anovulation and, subsequently, oligomenorrhea, leading to amenorrhea. Moreover, low estradiol concentrations due to amenorrhea decrease bone mineral density (BMD). In athletes with one of the factors of FAT, the risk of a stress fracture is 2.4-4.9 times higher and may increase the risk of fracture throughout the lifespan. Low EA is the starting point of FAT, and the FAT concept emphasizes the importance of energy intake that is commensurate with exercise energy expenditure in athletes. In amenorrheic athletes who undergo gynecological examination, it is important to appropriately evaluate whether the cause is low EA and to review exercise energy expenditure and energy intake. It remains difficult even for experts to calculate available energy using the ACSM definition formula when evaluating energy deficiency. Moreover, performing early FAT screening during teenage years and cooperation between the department of obstetrics and gynecology and sports dietitians are also issues. The aim of this paper is to review the management of FAT from the viewpoint of gynecologists.

DOI： 10.1111/jog.13614

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：Japanese   Publisher：(株)日本医事新報社  

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OBJECTIVES: To evaluate the clinical features of thoracic endometriosis syndrome (TES) represented by catamenial pneumothorax (CP), endometriosis-related pneumothorax (ERP), and catamenial hemoptysis (CH). STUDY DESIGN: In this retrospective study, we enrolled 25 patients with TES, 18 of whom had CP/ERP and 7 had CH, to investigate the clinical presentation, effectiveness of treatment, and recurrence rates in these disorders. RESULTS: The age at onset was significantly lower in patients with CH than in patients with CP/ERP (P < 0.05). In 94.4% of patients with CP/ERP, pneumothorax was observed on either the right side or bilaterally, however there was no tendency toward laterality of CH among our cases. In our study, patients with CP/ERP predominantly underwent surgical management and the recurrence rate during treatment was higher in patients with CP/ERP than in those with CH. We found that the recurrence frequency of CP/ERP was lowest under the combination therapy with thoracic surgery and postoperative hormonal therapy. CONCLUSION: Our findings suggest that CP/ERP and CH are different pathological conditions and CP/ERP is more difficult to manage than CH.

DOI： 10.1016/j.ejogrb.2018.04.021

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Language：Japanese   Publisher：(株)診断と治療社  

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Language：Japanese   Publisher：(一社)日本女性医学学会  

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Language：Japanese   Publisher：(株)医学書院  

DOI： 10.11477/mf.1409209375

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)東京産科婦人科学会  

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Language：Japanese   Publisher：(株)医学書院  

DOI： 10.11477/mf.1402225479

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Loss of p53 function due to human papillomavirus (HPV) infection induces resistance to apoptosis in cervical cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a p53-independent manner, may provide an alternative strategy for treating cervical cancer. Survivin, an antiapoptotic protein that is highly expressed in cancer cells, regulates apoptosis and the cell cycle. Here, we investigated the therapeutic potential of targeting survivin, while focusing on the TRAIL-induced apoptosis pathway. The viability and cell cycle of HPV16-positive CaSki and SiHa cells were assessed after survivin knockdown by small interfering RNA (si-survivin). E-cadherin expression was also assessed after si-survivin treatment, using western blotting. SiHa (a TRAIL-resistant cell line) was used for further studies. The small molecule YM155 and resveratrol (RVT; a polyphenol with the potential to suppress survivin expression) were used as survivin inhibitors. The effects of si-survivin and survivin inhibitors on TRAIL- or cisplatin (CDDP)-induced apoptosis were analyzed by annexin-V staining. si-survivin treatment decreased cell viability and led to G2/M arrest, accompanied by morphological changes and E-cadherin upregulation in both CaSki and SiHa cells. si-survivin and YM155 synergistically sensitized TRAIL-resistant SiHa cells to TRAIL-induced apoptosis (p < 0.05). However, si-survivin and YM155 only slightly increased CDDP-induced apoptosis. RVT markedly enhanced TRAIL-induced apoptosis by suppressing survivin expression. Targeting of survivin expression might be an ideal strategy for cervical cancer treatment as it would decrease viable cell number and enhance apoptosis sensitivity. Further, combination therapy with TRAIL, rather than CDDP, may be compatible with the proposed survivin-targeting strategy.

DOI： 10.18632/oncotarget.24413

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Language：Japanese   Publisher：(有)フジメディカル出版  

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Language：Japanese   Publisher：金原出版(株)  

DOI： 10.18888/sp.0000000338

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Cancer cell metabolism is currently considered to be context dependent, and metabolic reprogramming is being widely investigated. It is known that ovarian cancer often metastasizes to the omentum. Given that the omentum itself contains a high concentration of adipocytes, ovarian cancer is thought to be a good model for research into metabolic reprogramming (particularly the shift to lipid metabolism). The present study investigated the switch to lipid metabolism in the metabolic reprogramming of ovarian cancer cells. The present study first considered the possibility of epigenetic involvement. Using an open database (GSE 85293 and GSE2109), the methylation status and gene expression patterns of the primary tumor site (ovary) and the metastatic tumor site (omentum) were compared. However, no evidence was obtained regarding the involvement of epigenetics (at least in terms of DNA methylation). The influence of suspension in ascites on metabolism was then considered, and a suspension culture was used as an in vitro model. It was demonstrated that ovarian cancer cells that are detached from the primary site and suspended in ascites have enhanced lipid metabolism. Additionally, it was demonstrated that these cells express high levels of the cancer stem cell (CSC) marker cluster of differentiation 44 and c-kit in a balanced manner as they approach the omentum. Accordingly, these cells activate the mammalian target of rapamycin pathway, which is thought to be advantageous for cancer cell metastasis. In conclusion, the present study proposed one explanation for why ovarian cancer cells are likely to disseminate to the peritoneal cavity, and in particular to the omentum.

DOI： 10.3892/ol.2017.7388

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OBJECTIVE: The objective of this study was to examine public attitudes towards third-party reproduction and the disclosure of conception through third-party reproduction. METHODS: We conducted the web-based survey for the public attitude towards third-party reproduction in February 2014. Twenty-five hundred people were recruited with equal segregation of age (20s, 30s, 40s, and 50s) and gender. We analyzed the association between gender, age, infertility, and ethical view using a questionnaire regarding donor sperm, donor oocyte, donor embryo, gestational surrogacy, and disclosure to offspring. RESULTS: Of the respondents, 36.2% approved and 26.6% disapproved of gamete or embryo donation. The frequency of those who approved was lowest in females in the 50-59 year age group, and was significantly higher in males or females with infertility. Secondly, 40.9% approved and 21.8% disapproved of gestational surrogacy. The frequency of those who approved gestational surrogacy was higher in males or females with infertility. Thirdly, 46.3% of respondents agreed and 20.4% disagreed with "offspring have the right to know their origin". Those who disagreed were primarily in the 50-59 year age group of both genders, and disagreement was significantly higher in the infertility group compared with non-infertility group. CONCLUSION: In this study, public attitudes were affected by gender, age, and experience of infertility. These study findings are important in understanding the attitude towards third-party reproduction and disclosure to the offspring. Respondents having indecisive attitudes were >30%, which might indicate an increased requirement for information and education to enhance the discussion on the ethical consensus on third-party reproduction in Japan.

DOI： 10.1371/journal.pone.0198499

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Language：Japanese   Publisher：生命科学系学会合同年次大会運営事務局  

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Language：Japanese   Publisher：(株)医薬ジャーナル社  

DOI： 10.20837/4201801093

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DOI： 10.1038/s41598-017-11252-7

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DOI： 10.18632/oncotarget.16783

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DOI： 10.18632/oncotarget.16316

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Language：Japanese   Publisher：日本臨床分子医学会  

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DOI： 10.3892/ijo.2017.3891

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