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Abstract The cellular origin of clear cell ovarian carcinoma (CCOC), a major histological subtype of ovarian carcinoma remains elusive. Here, we explored the candidate cellular origin and identify molecular subtypes using integrated genomic/epigenomic analysis. We performed whole exome-sequencing, microarray, and DNA methylation array in 78 CCOC samples according to the original diagnosis. The findings revealed that ARID1A and/or PIK3CA mutations were mutually exclusive with DNA repair related genes, including TP53, BRCA1, and ATM. Clustering of CCOC and other ovarian carcinomas (n = 270) with normal tissues from the fallopian tube, ovarian surface epithelium, endometrial epithelium, and pelvic peritoneum mesothelium (PPM) in a methylation array showed that major CCOC subtypes (with ARID1A and/or PIK3CA mutations) were associated with the PPM-lile cluster (n = 64). This cluster was sub-divided into three clusters: (1) mismatch repair (MMR) deficient with tumor mutational burden-high (n = 2), (2) alteration of ARID1A (n = 51), and (3) ARID1A wild-type (n = 11). The remaining samples (n = 14) were subdivided into (4) ovarian surface epithelium-like (n = 11) and (5) fallopian tube-like (considered as high-grade serous histotype; n = 3). Among these, subtypes (1–3) and others (4 and 5) were found to be associated with immunoreactive signatures and epithelial-mesenchymal transition, respectively. These results contribute to the stratification of CCOC into biological subtypes.

Abstract 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.

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

Background Ectopic pregnancy (EP) can be treated surgically or nonsurgically. In many countries, methotrexate is frequently used as a first-line medical treatment, and its effect is similar to that of surgery in selected patients. We aimed to investigate national trends in the treatment of EP in Japan.Methods We conducted a retrospective observational analysis between 2010 and 2020 using a nationwide claims database that included inpatient data. We identified female inpatients with EP aged 15 to 49 years old. We analysed year-to-year treatment trends for EP, as well as year-to-year trends in methotrexate administration, with a focus on the site of the pregnancy. Patients who received methotrexate were divided into two groups: Those with and those without surgery after methotrexate use. We compared the characteristics of these groups and calculated the methotrexate success rate.Results We identified 53,653 patients with EP. The proportion of patients undergoing surgery increased from 79% in 2010 to 83% in 2020, whereas the proportion of methotrexate therapy decreased from 8.1% in 2010 to 5.1% in 2020. Regarding methotrexate use for the site of the pregnancy, there was a significant downward trend in methotrexate therapy for tubal pregnancies. Notably, the methotrexate success rate was 84% during the study period.Conclusions Surgery showed an increasing tendency over time, whereas methotrexate therapy showed a decreasing tendency for EP treatment in Japan. The efficacy of methotrexate in Japan was comparable to that observed in other countries.

Abstract 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.

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.

ObjectiveA Mediterranean dietary pattern, sleeping habits, physical activity, and lifestyle appear to affect reproductive health. There are few reports about whether fertility-specific quality of life (QOL) is linked to infertility treatment outcomes. The aim of this study is to investigate when lifestyle factors and fertility-specific QOL are comprehensively considered, which factors influence assisted reproductive technology (ART) outcomes.MethodsThis prospective cohort includes 291 women undergoing a first ART treatment at multiple centers in Japan and was designed to evaluate the influence of diet, physical activity, sleeping pattern, computer use duration, and fertility-specific quality of life tool (FertiQoL) score on ART treatment outcomes using a questionnaire. The primary endpoint was the good-quality blastocyst rate per oocyte retrieval and the secondary endpoints were a positive pregnancy test and gestational sac (GS) detection.ResultsThe good-quality blastocyst rate per oocyte retrieval tended to be negatively associated with frequent fish consumption. After all embryo transfer (ET) cycles, a positive pregnancy test tended to be positively associated with longer sleep and longer computer use (OR = 1.6, 95% CI = 0.9–2.7 and OR = 1.7, CI = 1.0–2.8, respectively) and negatively associated with a smoking partner (OR = 0.6, CI = 0.3–1.0). GS detection was positively and significantly associated with frequent olive oil intake and longer computer use (OR = 1.7, CI = 1.0–3.0 and OR = 1.7, CI = 1.0–3.0, respectively). After ET cycles with a single blastocyst, a positive pregnancy test was positively and significantly associated with longer computer use (OR = 2.0, CI = 1.1–3.7), while GS detection was significantly more likely in women with longer computer use (OR = 2.1, CI = 1.1–3.8) and tended to be more likely in women with a higher FertiQoL Total scaled treatment score (OR = 1.8, CI = 1.0–3.3). p < 0.05 was considered statistically significant and 0.05 ≤ p

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

Abstract Background Most women with anovulatory infertility show polycystic ovarian syndrome (PCOS), and androgen excess is known as a key factor involved in pathogenicity of PCOS. However, the mechanism of follicular developmental arrest in PCOS is not completely understood. The reproductive function of Neuropeptide Y (NPY) in the ovary during folliculogenesis was previously reported; NPY function in apoptosis and proliferation of granulosa cells (GCs) is follicular-stage dependent. The objective of this study was to investigate the role of NPY in ovarian follicular development and the pathogenesis of PCOS. Methods To simulate the PCOS phenotype using a rat model, 21-day old Sprague Dawley rats were implanted with dihydrotestosterone (DHT) capsule (83 µg/day) and euthanized after 28 days. mRNA and protein content of NPY and its receptors were assessed in GCs from DHT treated rats using RT-qPCR and Western blot, respectively. Proliferation and apoptosis of GCs was assessed using Ki67- and TUNEL assays. Finally, NPY levels were measured in human follicular fluid (FF) from matched PCOS and non-PCOS patients using ELISA. Results GCs from DHT treated rats (PCOS-GCs) contained significantly less NPY protein and Npy mRNA by 0.16- and 0.56-fold, respectively, and more NPY receptor type 2 and 5 protein by 2.21- and 3.17-fold, respectively, when compared to sham control. Addition of recombinant NPY to PCOS-GCs culture did not alter Ki67-positive but significantly decreased TUNEL-positive cells by 0.65-fold, but not to baseline levels. There was no significant difference in NPY levels in FF between PCOS and non-PCOS subjects. Conclusions These results indicate that DHT modulates expression of NPY and its receptors, NPY decreases DHT-induced GCs apoptosis. That alterations in NPY’s function might be involved in follicular developmental failure of PCOS.

Abstract Background Management of a bladder tumor during pregnancy is an uncommon clinical situation. Leiomyosarcoma of the urinary bladder is a rare histological type of bladder tumor and a rare secondary cancer in survivors of retinoblastoma (RB). However, there has been no report of RB-associated bladder leiomyosarcoma during pregnancy. Case presentation A 37-year-old pregnant woman with a medical history of RB in infancy presented with gross hematuria at the 17th week of gestation. Cystoscopy revealed a 40-mm papillary tumor on the left lateral wall of the urinary bladder. At the 25th week of gestation, she underwent transurethral resection of the bladder tumor, and the pathological diagnosis was bladder leiomyosarcoma with loss of RB1 expression. At the 31st week of gestation, she gave birth by caesarean section. One month after the delivery (to allow for involution of the uterus), she underwent partial cystectomy, and the specimen contained no residual leiomyosarcoma tissue. Conclusions We have reported a case of RB-associated bladder leiomyosarcoma that was successfully treated during and after pregnancy.

Abstract Infertility occurs in 15% of couples worldwide. Recurrent implantation failure (RIF) is one of the major problems in in vitro fertilization and embryo transfer (IVF–ET) programs, and how to manage patients with RIF to achieve successful pregnancy outcomes remains unresolved. Here, a uterine polycomb repressive complex 2 (PRC2)-regulated gene network was found to control embryo implantation. Our RNA-seq analyses of the human peri-implantation endometrium obtained from patients with RIF and fertile controls revealed that PRC2 components, including its core enzyme enhancer of zeste homolog 2 (EZH2)-catalyzing H3K27 trimethylation (H3K27me3) and their target genes are dysregulated in the RIF group. Although fertility of uterine epithelium-specific knockout mice of Ezh2 (eKO mice) was normal, Ezh2-deleted mice in the uterine epithelium and stroma (uKO mice) exhibited severe subfertility, suggesting that stromal Ezh2 plays a key role in female fertility. The RNA-seq and ChIP-seq analyses revealed that H3K27me3-related dynamic gene silencing is canceled, and the gene expression of cell-cycle regulators is dysregulated in Ezh2-deleted uteri, causing severe epithelial and stromal differentiation defects and failed embryo invasion. Thus, our findings indicate that the EZH2–PRC2–H3K27me3 axis is critical to preparing the endometrium for the blastocyst invasion into the stroma in mice and humans.

Abstract 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.

Abstract Polycystic ovarian syndrome (PCOS) is a complex multi-factorial syndrome associated with androgen excess and anovulatory infertility. In the current study, we investigated the role of dihydrotestosterone-induced exosomal miR-379-5p release in determining the destiny of the developing follicles. Our hypothesis was that androgen regulates granulosa cell miR-379-5p content by facilitating its exosomal release in a follicular-stage dependent manner, a process which determines granulosa cell fate. Compared to human non-PCOS subjects, individuals with PCOS exhibit higher follicular fluid free testosterone levels, lower exosomal miR-379-5p content and granulosa cell proliferation. Androgenized rats exhibited lower granulosa cell miR-379-5p but higher phosphoinositide-dependent kinase-1 (PDK1; a miR-379-5p target) content and proliferation. Androgen reduced granulosa cell miR-379-5p content by increasing its exosomal release in preantral follicles, but not in antral follicles in vitro. Studies with an exosomal release inhibitor confirmed that androgen-induced exosomal miR-379-5p release decreased granulosa cell miR-379-5p content and proliferation. Ovarian overexpression of miR-379-5p suppressed granulosa cell proliferation, and basal and androgen-induced preantral follicle growth in vivo. These findings suggest that increased exosomal miR-379-5p release in granulosa cells is a proliferative response to androgenic stimulation specific for the preantral stage of follicle development and that dysregulation of this response at the antral stage is associated with follicular growth arrest, as observed in human PCOS.

BACKGROUND: Adenomyosis is associated with unfavorable perinatal outcomes; however, the effect of an adenomyomectomy on pregnancy outcomes remains unclear. Pregnancy following an adenomyomectomy has been reported to be associated with a high risk for uterine rupture; however, the actual incidence remains unknown. OBJECTIVE: This study aimed to evaluate the effect of an adenomyomectomy on pregnancy outcomes by retrospectively comparing the pregnancy outcomes of women who underwent an adenomyomectomy with those of women with adenomyosis. STUDY DESIGN: This was a single-center retrospective study in which the pregnancy outcomes of women who underwent an adenomyomectomy and for whom complete resection of the affected tissue under laparotomy was achieved were compared with those of women with adenomyosis. The following pregnancy outcomes were examined: second-trimester miscarriage, preterm prelabor rupture of membranes, preterm delivery, spontaneous preterm delivery, preeclampsia, rate of cesarean delivery, blood loss during cesarean delivery, incidence of placenta accreta spectrum, neonatal body weight, and small for gestational age infants. RESULTS: A total of 18 pregnant women who underwent an adenomyomectomy and 105 pregnant women with adenomyosis were included in this study. All women who underwent an adenomyomectomy delivered via cesarean delivery, and among them, 1 had a uterine rupture at 30 weeks of gestation. Although there was no significant difference between pregnant women who underwent an adenomyomectomy and those with adenomyosis in the incidence of second-trimester miscarriage (0% [0/18] vs 7.6% [8/105], respectively; P=.22), preterm delivery (50% [9/18] vs 32% [34/105], respectively; P=.15), and spontaneous preterm delivery (6% [1/18] vs 15% [16/105], respectively; P=.26), a significant decrease in preterm prelabor rupture of membrane (0% [0/18] vs 12% [13/105], respectively; P

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.

Abstract Uterine sarcomas have very poor prognoses and are sometimes difficult to distinguish from uterine leiomyomas on preoperative examinations. Herein, we investigated whether deep neural network (DNN) models can improve the accuracy of preoperative MRI-based diagnosis in patients with uterine sarcomas. Fifteen sequences of MRI for patients (uterine sarcoma group: n = 63; uterine leiomyoma: n = 200) were used to train the models. Six radiologists (three specialists, three practitioners) interpreted the same images for validation. The most important individual sequences for diagnosis were axial T2-weighted imaging (T2WI), sagittal T2WI, and diffusion-weighted imaging. These sequences also represented the most accurate combination (accuracy: 91.3%), achieving diagnostic ability comparable to that of specialists (accuracy: 88.3%) and superior to that of practitioners (accuracy: 80.1%). Moreover, radiologists’ diagnostic accuracy improved when provided with DNN results (specialists: 89.6%; practitioners: 92.3%). Our DNN models are valuable to improve diagnostic accuracy, especially in filling the gap of clinical skills between interpreters. This method can be a universal model for the use of deep learning in the diagnostic imaging of rare tumors.

Abstract The purpose of this study was to establish a novel mouse model of adenomyosis suitable for longitudinal and quantitative analyses and perinatal outcome studies. Using a 30 G needle, the entire uterine wall of one horn was mechanically punctured at a frequency of 100 times/1 cm (adenomyosis horn). The other horn was left unpunctured (control horn). Balb/c mice were sacrificed on day 14 (D14) or day 65 (D65) (n = 3 each). The uterus was fixed, paraffin-embedded, sliced, and stained. Lesions were detected and counted, and their volumes were measured. Cell proliferation and fibrosis were assessed by Ki67 and Masson’s Trichrome staining, respectively. Blood vessels were detected using CD31 immunostaining. Some of the mice (n = 4), were mated and the date of delivery, litter size, number of implantations, and number and volume of postpartum lesions were measured. The number of lesions per horn did not differ between D14 and D65. The volume of the entire lesion was significantly greater on D65 than on D14 (p

Abstract 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.

Abstract Background Endometriosis is assumed to be involved in ovarian cancer development, which is called endometriosis-associated ovarian cancer (EAOC). Uterine endometrial cells may be the cell of origin of EAOC. Accumulated carcinogenic changes in the uterine endometrial cells may increase the risk of developing EAOC. To further understand the pathogenesis of EAOCs, we focused on the clinicopathological characteristics of EAOCs in endometrial cancer patients with concomitant endometriosis. Methods We retrospectively reviewed 376 patients who were surgically treated for stage I–III endometrial cancer. Clinicopathological characteristics were compared between patients with and without endometriosis. Furthermore, the incidence of simultaneous endometrial and ovarian cancer (SEOC) and the histological characteristics of SEOC were compared between the two groups. Results Among 376 patients with endometrial cancer, 51 had concomitant endometriosis. Patients with endometriosis were significantly younger and more frequently had endometrioid G1/G2 tumors than those without endometriosis. The incidence of SEOCs was significantly higher in endometrial cancer patients with endometriosis than those without it (p

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.

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.

Abstract Endometriosis, which exhibits enigmatic pathological features such as stromal fibrosis and proliferation of ectopic epithelial cells, is known as a refractory disease. Mesenchymal stem cells modulate the fibrosis in stromal tissues through their trophic and immunomodulatory properties. To investigate the potential of stem cells in treating endometriosis, we examined the secondary morphology and molecular alterations in endometriosis-like lesions after the administration of adipose tissue-derived stem cells (ASCs) to an experimental murine model of endometriosis. The infused ASCs were found integrated in the endometriosis-like lesions. Accompanied by the suppression of stromal fibrosis and proliferation of endometriotic epithelial cells, the infusion of ASCs with stemness potential (early passage of ASCs) suppressed the growth of endometriosis-like lesions and inhibited the expression of pro-inflammatory and pro-fibrotic cytokines, whereas no significant attenuation of endometriosis-like lesions occurred after the infusion of ASCs without stemness potential (late passage of ASCs). Accordingly, the trophic and immunomodulatory properties of ASCs may regulate fibrosis in endometriosis-like lesions, suggesting that regenerative medicine could be recognized as an innovative treatment for patients with endometriosis through the accumulation of evidence of preclinical efficacy.

Abstract 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.

This large multi-center retrospective study examined whether artificial oocyte activation (AOA) using Ca2+ ionophore following ICSI improves the live birth rate for couples with previous ICSI cycles of unexplained low fertilization rate. In this large-scale multi-center retrospective study conducted in Japan, data were collected from Keio University and 17 collaborating institutions of the Japanese Institution for Standardizing Assisted Reproductive Technology. Between January 2015 and December 2019, 198 couples were included in this study. Oocytes for both the intervention and control groups were procured from the same pool of couples. Oocytes obtained from ICSI cycles with no or low fertilization rate (

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, affecting up to 15% of women in this group, and the most common cause of anovulatory infertility. Although its etiology remains unclear, recent research has revealed the critical role of endoplasmic reticulum (ER) stress in the pathophysiology of PCOS. ER stress is defined as a condition in which unfolded or misfolded proteins accumulate in the ER because of an imbalance in the demand for protein folding and the protein-folding capacity of the ER. ER stress results in the activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which regulates various cellular activities. In principle, the UPR restores homeostasis and keeps the cell alive. However, if the ER stress cannot be resolved, it induces programmed cell death. ER stress has recently been recognized to play diverse roles in both physiological and pathological conditions of the ovary. In this review, we summarize current knowledge of the roles of ER stress in the pathogenesis of PCOS. ER stress pathways are activated in the ovaries of both a mouse model of PCOS and in humans, and local hyperandrogenism in the follicular microenvironment associated with PCOS is responsible for activating these. The activation of ER stress contributes to the pathophysiology of PCOS through multiple effects in granulosa cells. Finally, we discuss the potential for ER stress to serve as a novel therapeutic target for PCOS.

A uterine artery pseudoaneurysm (UAP) is a life-threatening complication during pregnancy and postpartum. Early diagnosis of exophytic UAP rupture is difficult due to the absence of vaginal bleeding. This study reports the case of a 31-year-old postpartum woman who presented with abdominal pain and fever seven days after vaginal delivery, without symptoms of maternal shock. Ultrasonography revealed a ruptured exophytic UAP with hemoperitoneum, which was confirmed using computed tomography. Interventional radiology confirmed that the site of the pseudoaneurysm was at the level of the uterine artery bifurcation, and embolization was performed immediately after diagnosis using a coil and n-butyl-2-cyanoacrylate. The patient’s symptoms were relieved, and she was discharged 12 days after the embolization. At eight months postpartum, the UAP was not visible on transvaginal ultrasonography. Exophytic UAP can occur even in the absence of specific risk factors such as cesarean section or endometriosis, and the UAP may not necessarily rupture immediately after delivery. Obstetricians must remain aware of the possibility of exophytic UAP rupture manifesting as abdominal pain with postpartum fever, rather than as unstable vital signs. This is the first report of an exophytic UAP that occurred at the level of the uterine artery bifurcation. Identification of the sites where exophytic UAP can occur can aid in the early diagnosis of the condition.

Abstract Purpose To evaluate clinical outcomes after endometrial receptivity analysis (ERA). Methods This was a multicenter, retrospective cohort study involving 861 women who underwent ERA testing at certified fertility clinics in Japan, and who received subsequent personalized blastocyst embryo transfers (ET) between 2018 and 2020. Clinical outcomes, including pregnancies, miscarriages, and live births, were evaluated according to receptivity status for ERA. Results Mean patient age was 37.7 years (SD = 4.0), and the median number of previous ETs was 2 (interquartile range, 2–3). 41.0% (353/861) of patients were non‐receptive for ERA testing. Clinical pregnancy, miscarriage, and live birth rates for personalized blastocyst ET were 44.5% (226/508), 26.1% (59/226), and 26.8% (136/508) for receptive patients, and 43.1% (152/353), 28.3% (43/152), and 28.9% (102/353) for non‐receptive patients, all statistically nonsignificant. Multiple logistic regression demonstrated similar nonsignificant associations between receptivity and clinical outcomes. Greater patient age, smoking, and longer duration of infertility were significantly and negatively associated with receptivity, whereas a history of delivery was positively associated and statistically significant. Conclusions Clinical outcomes after ERA testing were similar between receptive and non‐receptive patients. Further prospective study including an appropriate comparison group are warranted to evaluate the efficacy of ERA testing.

Abstract Purpose Since 1986, the Japan Society of Obstetrics and Gynecology assisted reproductive technology (ART) registry system has collected data on national ART use and outcomes trends in Japan. Herein, we describe the characteristics and outcomes of ART cycles registered during 2020 and compare the results with those from 2019. Methods and Results In 2020, 621 ART facilities participated in the registration. The total number of registered cycles was 449 900, and there were 60 381 live births, which decreased from the previous year (1.79% and 0.36% decrease, respectively). The number of freeze‐all in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles increased in 2020, and the number of neonates born was 2282 for IVF‐embryo transfer (ET) cycles and 2596 for ICSI cycles, which had decreased from the previous year. Frozen–thawed ET (FET) cycles had slightly increased from 2019 (0.04%). In 2020, 215 285 FET cycles were conducted, resulting in 76 196 pregnancies and 55 503 neonates. Single ET was performed in 81.6% of fresh transfers and 85.1% of frozen–thawed cycles, respectively, resulting in over 97% singleton pregnancies/livebirths rates. Conclusion Despite the COVID‐19 pandemic during 2020, the overall number of ART cycles and neonates born demonstrated only a slight decrease in 2020 compared with 2019.

Abstract Purpose To evaluate the short‐term efficacy and safety of a combined mifepristone‐misoprostol regimen in individuals seeking medical abortion at up to 63 days of gestational age. Methods This open‐label, multicenter, prospective study evaluated the short‐term efficacy and safety of medical abortion, with the primary outcome being the abortion success rate 24 h after misoprostol administration. The participants received 200 mg of mifepristone orally and 800 μg of misoprostol buccally in the hospital/clinic 36–48 h later. Bleeding and lower abdominal pain, which are the main symptoms associated with medical abortion, were recorded. Results The abortion success rate was 93.3% (95% confidence interval [CI]: 87.3–97.1%) within 24 h of misoprostol administration, 63.3% (95% CI: 54.05–71.94%) within 4 h, and 90.0% (95% CI: 83.18–94.73%) within 8 h. The median time from misoprostol administration to a successful abortion was 3.93 h. Bleeding was most commonly observed 0–4 h prior to the confirmation of gestational sac (GS) expulsion. The most intense lower abdominal pain occurred 0–1 h before the confirmation of GS expulsion. Conclusion The combined regimen of mifepristone and buccal misoprostol for medical abortion showed short‐term efficacy and a favorable safety profile.

Abstract 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.

Hyperreactio luteinalis (HL) is a rare condition that presents as bilateral ovarian enlargement during pregnancy. Typically, it is thought to be caused by increased production of human chorionic gonadotropin (hCG) associated with gestational trophoblastic diseases or multiple pregnancies. The prognosis is relatively good, with many cases resulting in term birth. However, some obstetric complications, such as preeclampsia (PE) and preterm births, have been reported. We present a serious case of HL with subsequent PE that resulted in preterm delivery at 31 weeks of gestation. The soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high at the onset of PE at 24 weeks of gestation, followed by a modest decline, which then increased in proportion to the exacerbation of symptoms. Since HL cases have also been reported to be associated with PE, repeated measurement of the sFlt-1/PlGF ratio proved useful for better pregnancy management.

Abstract Background Pseudomyxoma peritonei is a rare disease condition mainly caused by primary mucinous tumors from the appendix and rarely from the ovary, such as when mucinous ovarian tumors arise from within a teratoma. Molecular analyses of pseudomyxoma from the appendix showed that KRAS and GNAS pathogenic variants are common genetic features of pseudomyxoma peritonei. However, the origin of the tumors is difficult to be identified via genetic variants alone. This study presents a case of pseudomyxoma peritonei of ovarian origin, which was diagnosed by comprehensive genomic profiling with ploidy analysis in a series of primary, recurrent, and autopsy tumor specimens. Case presentation A 40-year-old woman was diagnosed with Stage IC2 mucinous ovarian tumor of borderline malignancy with mature cystic teratoma, upon clinical pathology. Immunohistochemical analysis suggested that the mucinous tumor was derived from the intestinal component of an ovarian teratoma. Three years later, intraperitoneal recurrence was detected, which subsequently progressed to pseudomyxoma peritonei. Genomic analysis detected KRAS (G12D), GNAS (R201C), and FBXW7 (R367*) variants in the primary tumor. In addition, the tumor showed aneuploidy with loss of heterozygosity (LOH) in all its chromosomes, which suggested that the primary ovarian tumor was derived from germ cells. Existence of one Barr body suggested the existence of uniparental disomy of the tumors throughout the genome, instead of a haploid genotype. All three pathogenic variants remained positive in the initial recurrent tumor, as well as in the paired DNA from the whole blood in pseudomyxoma peritonei. The pathogenic variant of KRAS (G12D) was also identified in the autopsy specimen of the appendix by droplet digital polymerase chain reaction. Conclusions This study pathologically and genetically confirmed that the primary ovarian borderline tumor was derived from the intestinal component of an ovarian teratoma, and that the subsequent pseudomyxoma peritonei progressed from the primary ovarian tumor. Integrative genomic analysis was useful to identify cellular origin of tumors, as well as to precisely interpret the process of disease progression.

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.

Abstract Introduction Previous studies have shown that individuals with human papillomavirus (HPV)‐related cervical lesions have different prognoses according to the HPV genotype. However, these studies failed to account for possible diagnostic misclassification. In this retrospective cohort study, we aimed to clarify the natural course of cervical lesions according to HPV genotype to account for any diagnostic misclassification. Materials and Methods Our cohort included 729 patients classified as having cervical intraepithelial neoplasia (CIN). HPV was genotyped in all patients, who were followed up or treated for cervical lesions at the University of Tokyo Hospital from October 1, 2008 to March 31, 2015. Hidden Markov models were applied to estimate the diagnostic misclassification probabilities of the current diagnostic practice (histology and cytology) and the transitions between true states. We then simulated two‐year transition probabilities between true cervical states according to HPV genotype. Results Compared with lesions in patients with other HPV genotypes, lesions in HPV 16‐positive patients were estimated to be more likely to increase in severity (i.e., CIN3/cancer); over 2 years, 17.7% (95% confidence interval [CI], 9.3%–29.3%) and 27.8% (95% CI, 16.6%–43.5%) of those with HPV 16 progressed to CIN3/cancer from the true states of CIN1 and CIN2, respectively, whereas 55%–70% of CIN1/2 patients infected with HPV 52/58 remained in the CIN1/2 category. Misclassification was estimated to occur at a rate of 3%–38% in the current diagnostic practice. Conclusion This study contributes robust evidence to current literature on cervical lesion prognosis according to HPV genotype and quantifies the diagnostic misclassification of true cervical lesions.

Machino et al discover that low expression of microtubule affinity-regulating kinase 3 (MARK3) correlates with poor prognosis in high-grade serous ovarian carcinoma (HGSOC) patients. They find that the LKB1-MARK3 axis is activated by metabolic stress to block the cell cycle at the G2/M checkpoint, and characterise other MARK3 regulated pathways through RNA and ATAC sequencing.

Abstract Background Menstrual symptoms have been identified as a substantial burden among women of reproductive age, affecting their health status and quality of life globally. A range of menstrual symptoms have been studied as they affect the health-related quality of life (HRQoL), showing variations across specific menstrual symptoms and study settings. A major concern is demonstrated due to menstrual symptoms in women’s professional and social life, and consequently societal and economic loss for women and the society at large. Yet evidence is scarce that estimates the index form HRQoL score related to menstrual symptoms that is needed for health economic evaluations. Methods This study aims to investigate the association between menstrual symptoms and the HRQoL among working women in Japan in an index form, using a self-reporting questionnaire (n = 6048). The EQ-5D-3L (EuroQoL 5-dimension 3-level) is used that is a widely used tool to measure health outcomes for health economic evaluations globally. Multivariate regression analysis is conducted to assess the association between the HRQoL score and specific nineteen physical and mental conditions related to menstruation (e.g., pain, heavy bleeding, concentration, negative affect). Results The index form HRQoL score for menstrual symptoms is estimated as 0.682 in the study population (where a score one suggests perfect health). The association of the HRQoL score varies substantially across the menstrual symptoms. Several of the physical conditions and disorders show a substantial negative association with the HRQoL score. Also, most of the mental and psychological issues are significantly and negatively related to the HRQoL score. Conclusions This study suggests that HRQoL is substantially and negatively affected by menstruation among working women in Japan. Distinct variations of negative influences across menstrual symptoms underscore the multi-dimensional nature of menstruation and consequently the need of collective interventions to address these difficulties. The evidence of HRQoL continues to be an important area for future research on women’s health and health economic evaluations to inform effective and efficient resource allocations for relevant health policies and financing strategies.

Abstract Background Relugolix is a once-daily, oral, nonpeptide, gonadotropin-releasing hormone receptor antagonist. The aim of this study was to evaluate safety of relugolix over 24 weeks in women with endometriosis-associated pain. Methods This phase 2, randomized, open-label, parallel-group extension study was conducted in 101 clinics in Japan. Patients (premenopausal females ≥ 20 years) who completed the preceding 12-week relugolix phase 2 study continued to receive relugolix (10 mg, 20 mg, or 40 mg), placebo, or leuprorelin (3.75 mg) for an additional 12 weeks. Relugolix was administered orally once daily, and leuprorelin subcutaneously once every 4 weeks. The primary outcome was safety, including bone mineral density (BMD) and treatment-emergent adverse events (TEAEs). Secondary endpoints included visual analog scale (VAS) scores for endometriosis-associated pain. Analysis sets were defined as all patients who were administered the study drug. Results Of 487 randomized patients in the preceding study, 397 enrolled in this extension study and continued to receive placebo (n = 77), relugolix 10 mg (n = 84), relugolix 20 mg (n = 78), relugolix 40 mg (n = 89), or leuprorelin (n = 69). Baseline characteristics were similar between extension study patients and patients in the preceding study. Frequency of TEAEs including metrorrhagia, menorrhagia, and hot flush was similar in the relugolix 40-mg and leuprorelin groups. Mean (SD) change in BMD from baseline at Week 24 was − 0.2 (1.99)% for placebo; − 1.6 (2.34)%, − 2.6 (2.94)%, and − 4.9 (2.91)% for the relugolix 10-mg, 20-mg, and 40-mg groups, respectively; and − 4.4 (2.16)% for leuprorelin. Mean ± SD change from baseline in mean VAS score (mm) for pelvic pain at end of treatment was − 3.2 ± 12.16 for placebo; − 6.8 ± 10.56, − 9.0 ± 11.84, and − 11.9 ± 11.26 for the relugolix 10-mg, 20-mg, and 40-mg groups, respectively; and − 12.7 ± 12.57 for leuprorelin. Estradiol levels decreased with increasing relugolix dose and remained below postmenopausal levels throughout the 24-week relugolix 40-mg treatment period. Conclusions Treatment with relugolix for 24 weeks was generally well tolerated and demonstrated similar pain reduction to leuprorelin in women with endometriosis. The dose-dependent loss in BMD observed with relugolix treatment was expected due to an induced hypoestrogenic state. Relugolix demonstrated a similar benefit/risk profile to injectable therapy in this phase 2 study. Trial registration NCT01452685 (ClinicalTrials.gov, registered 17/10/2011).

Abstract Purpose This study was conducted to investigate how the COVID‐19 pandemic has impacted reproductive medical providers’ behaviors and considerations, including their concerns regarding the necessity of fertility treatments. Methods A web‐based questionnaire was distributed to Japan Society of Fertilization and Implantation (JSFI) members from May 18 through May 31, 2020 to survey their professional behaviors and concerns during the COVID‐19 pandemic. Results Most survey participants reported a decrease in the number of patients and a decrease in their workload. Most also believe that the use of fertility treatments will return to the pre‐pandemic levels after the COVID‐19 pandemic ends. Additionally, more than half of the participants reported that they consider fertility treatment neither necessary nor unnecessary during the COVID‐19 pandemic. Conclusions At the institute where reproductive medical providers worked in Japan, the number of outpatients and the working time tended to decrease during the COVID‐19 pandemic. However, amid fears of infection during the COVID‐19 pandemic, the reproductive medical providers working at fertility institutes in Japan have remained engaged in their work with a sense of mission and hope.

Abstract In endometriosis, M2 MΦs are dominant in endometriotic lesions, but the actual role of M2 MΦ is unclear. CD206 positive (+) MΦ is classified in one of M2 type MΦs and are known to produce cytokines and chemokines. In the present study, we used CD206 diphtheria toxin receptor mice, which enable to deplete CD206+ cells with diphtheria toxin (DT) in an endometriosis mouse model. The depletion of CD206+ MΦ decreased the total weight of endometriotic-like lesions significantly (p

Abstract Transcription of human papillomavirus (HPV) genes proceeds unidirectionally from multiple promoters. Direct profiling of transcription start sites (TSSs) by Cap Analysis Gene Expression (CAGE) is a powerful strategy for examining individual HPV promoter activity. The objective of this study was to evaluate alterations of viral promoter activity during infection using CAGE technology. We used CAGE-based sequencing of 46 primary cervical samples, and quantitatively evaluated TSS patterns in the HPV transcriptome at a single-nucleotide resolution. TSS patterns were classified into two types: early promoter-dominant type (Type A) and late promoter-dominant type (Type B). The Type B pattern was more frequently found in CIN1 and CIN2 lesions than in CIN3 and cancer samples. We detected transcriptomes from multiple HPV types in five samples. Interestingly, in each sample, the TSS patterns of both HPV types were the same. The viral gene expression pattern was determined by the differentiation status of the epithelial cells, regardless of HPV type. We performed unbiased analyses of TSSs across the HPV genome in clinical samples. Visualising TSS pattern dynamics, including TSS shifts, provides new insights into how HPV infection status relates to disease state.

Abstract Background Extra‐pelvic endometriosis is a rare type of endometriosis, which occurs in a distant site from gynecological organs. The diagnosis of extra‐pelvic endometriosis can be extremely challenging and may result in a delay in diagnosis. The main objective of this review was to characterize abdominal wall endometriosis (AWE) and thoracic endometriosis (TE). Methods The authors performed a literature search to provide an overview of AWE and TE, which are the major types of extra‐pelvic endometriosis. Main findings Abdominal wall endometriosis includes scar endometriosis secondary to the surgical wound and spontaneous AWE, most of which occur in the umbilicus or groin. Surgical treatment appeared to be effective for AWE. Case reports indicated that the diagnosis and treatment of catamenial pneumothorax or endometriosis‐related pneumothorax (CP/ERP) are challenging, and a combination of surgery and postoperative hormonal therapy is essential. Further, catamenial hemoptysis (CH) can be adequately managed by hormonal treatment, unlike CP/ERP. Conclusion Evidence‐based approaches to diagnosis and treatment of extra‐pelvic endometriosis remain immature given the low prevalence and limited quality of research available in the literature. To gain a better understanding of extra‐pelvic endometriosis, it would be advisable to develop a registry involving a multidisciplinary collaboration with gynecologists, general surgeons, and thoracic surgeons.

Abstract Purpose The Japan Society of Obstetrics and Gynecology records online annual cycle‐based information for assisted reproductive technology (ART). This report presents the characteristics and treatment outcomes of ART cycles registered during 2019. Methods The Japanese ART registry includes cycle‐specific information from 619 participating facilities, including treatment and pregnancy outcomes. Descriptive analyses were conducted for cycles registered during 2019. Results In 2019, 458 101 treatment cycles and 60 598 neonates were reported, both of which increased from 2018. The number of fresh cycles, including in vitro fertilization and intracytoplasmic sperm injection, decreased, while frozen‐thawed embryo transfer (ET) cycles increased. The mean maternal age was 37.9 years (standard deviation ± 4.7). Of 239 348 oocyte retrievals, 123 690 (51.7%) involved freeze‐all‐embryos cycles; fresh ET was performed in 41 831 cycles (a decreasing trend since 2015). In 2019, there were 211 597 frozen‐thawed ET cycles, resulting in 74 882 pregnancies and 54 168 neonates born. Single ET was performed in 82.6% of fresh transfers and 85.1% of frozen‐thawed cycles, with singleton live birth rates of 97.3% for both. Conclusions The number of fresh cycles decreased but frozen cycles increased in 2019. Single ET was performed in >80% of cases, and the proportion of babies born from frozen‐thawed ET increased.

Abstract Purpose In 2017, the first guidelines for fertility preservation in cancer patients were published in Japan. However, the impact of the guidelines remains unknown. Therefore, the authors conducted a nationwide survey on cryopreservation procedures in the period from shortly before to after publication of the guidelines (2016–2019) and compared the results with our previous survey (2011–2015). The authors also surveyed reproductive specialists’ awareness of the guidelines and implementation problems. Methods The authors sent a questionnaire to 618 assisted reproductive technology facilities certified by the Japanese Society of Obstetrics and Gynecology. Results The authors received responses from 395 institutions (63.8%). Among them, 144 institutions conducted cryopreservation for cancer patients (vs. 126 in 2011–2015) and performed 2537 embryo or oocyte and 178 ovarian tissue cryopreservation procedures (vs. 1085 and 122, respectively). Compared with the previous period, indications were more varied and protocols for controlled ovarian stimulation were more standardized. Reproductive specialists’ interest in oncofertility was high, but many reported three main difficulties: selecting a treatment method, storing samples in the long term, and securing the necessary human resources. Conclusions The practice of fertility preservation in cancer patients in Japan has been considerably affected by the first Japanese guidelines.

Abstract Purpose The receptive endometrium is critical for blastocyst implantation. In mice, after blastocysts enter the uterine cavities on day 4 of pregnancy (day 1 = vaginal plug), blastocyst attachment is completed within 24 h, accompanied by dynamic interactions between the uterine luminal epithelium and the blastocysts. Any failures in this process compromise subsequent pregnancy outcomes. Here, we performed comprehensive analyses of gene expression at the luminal epithelium in the peri‐implantation period. Methods RNA‐seq combined with laser microdissection (LMD) was used to reveal unique gene expression kinetics in the epithelium. Results We found that the prereceptive epithelium on day 3 specifically expresses cell cycle‐related genes. In addition, days 3 and 4 epithelia express glutathione pathway‐related genes, which are protective against oxidative stresses. In contrast, day 5 epithelium expresses genes involved in glycolysis and the regulation of cell proliferation. The genes highly expressed on days 3 and 4 compared to day 5 are related to progesterone receptor signaling, and the genes highly expressed on day 5 compared to days 3 and 4 are associated with the ones regulated by H3K27me3. Conclusions These results suggest that specific gene expression patterns govern uterine functions during early pregnancy, contributing to implantation success.

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.

Uterine necrosis is a rare complication in uterine artery embolization (UAE) for postpartum hemorrhage (PPH). Preeclampsia (PE) is a condition characterized with systemic endothelial damage and intravascular volume depletion. Whether a patient with PE is at high risk for uterine necrosis after UAE for PPH has been unknown. A 30-year-old primipara woman was diagnosed with PE based on hypertension and proteinuria during delivery. UAE was performed for PPH after forceps delivery. After UAE, the patient presented with pleural effusion and massive ascites as well as persistent fever unresponsive to antibiotics. Ultrasonography and contrast-enhanced magnetic resonance imaging (MRI) led to the diagnosis of uterine necrosis, for which we performed total laparoscopic hysterectomy. It should be kept in mind that patients with PE associated with massive ascites may be at high risk for uterine necrosis after UAE due to decreased uterine perfusion. Therefore, it is important to pay attention to persistent symptoms such as fever and abdominal pain after UAE to diagnose uterine necrosis.

Objective: We experienced a case of 22q11.2 deletion syndrome (22qDS), with severe polyhydramnios, and dysphagia, which prompted us to review prognosis in neonates with 22qDS, with a focus on dysphagia. Case report: A patient was referred to our hospital at 35 gestational weeks because of polyhydramnios. After amniotic fluid reduction, labor was induced at 38 weeks. The neonate had serious dysphagia, and 22qDS was diagnosed postnatally by fluorescent in situ hybridization analysis. This prompted a retrospective analysis of 9 cases with 22qDS experienced in our facility. Three out of these nine cases showed polyhydramnios, and had severe dysphagia postnatally. In total, 4 cases had dysphagia, while mortality was observed in 2 of these 4 cases. Additionally, 5 cases without dysphagia had normal development and no major complications. Conclusion: Polyhydramnios associated with postnatal dysphagia might be a risk factor related to short-term prognostic outcomes in newborns with 22qDS.

Abstract HELLP syndrome is sometimes followed by massive bleeding, leading to DIC. In cases of intra‐abdominal compartment syndrome due to massive intra‐abdominal bleeding after cesarean section, if preeclampsia and partial HELLP syndrome persist, hematoma removal helps in the recovery from preeclampsia and partial HELLP syndrome.

Abstract Background Human papillomavirus (HPV) infection is a primary cause of cervical cancer. Although epidemiologic study revealed that carcinogenic risk differs according to HPV genotypes, the expression patterns of HPV-derived transcripts and their dependence on HPV genotypes have not yet been fully elucidated. Methods In this study, 382 patients with abnormal cervical cytology were enrolled to assess the associations between HPV-derived transcripts and cervical intraepithelial neoplasia (CIN) grades and/or HPV genotypes. Specifically, four HPV-derived transcripts, namely, oncogenes E6 and E6*, E1^E4, and viral capsid protein L1 in four major HPV genotypes—HPV 16, 18, 52, and 58—were investigated. Results The detection rate of E6/E6* increased with CIN progression, whereas there was no significant change in the detection rate of E1^E4 or L1 among CIN grades. In addition, we found that L1 gene expression was HPV type-dependent. Almost all HPV 52-positive specimens, approximately 50% of HPV 58-positive specimens, around 33% of HPV 16-positive specimens, and only one HPV18-positive specimen expressed L1. Conclusions We demonstrated that HPV-derived transcripts are HPV genotype-dependent. Especially, expression patterns of L1 gene expression might reflect HPV genotype-dependent patterns of carcinogenesis.