The effectiveness of relugolix compared with leuprorelin for preoperative therapy before laparoscopic myomectomy in premenopausal women, diagnosed with uterine fibroids: protocol for a randomized controlled study (MyLacR study).

BACKGROUND: The oral gonadotropin-releasing hormone antagonist relugolix, which temporarily stops menstruation, is used to treat heavy menstrual bleeding, pelvic pressure, and low back pain in women with uterine fibroids. Treatment can also help women recover from low hemoglobin levels and possibly shrink the fibroids. However, evidence of preoperative use of relugolix before laparoscopic myomectomy is limited. Nevertheless, the treatment could reduce interoperative blood loss, decrease the risk of developing postoperative anemia, and shorten the operative time. Thus, we aim to test whether 12-week preoperative treatment with relugolix (40 mg orally, once daily) is similar to or not worse than leuprorelin (one injection every 4 weeks) to reduce intraoperative blood loss. METHODS: Efficacy and safety of preoperative administration of drugs will be studied in a multi-center, randomized, open-label, parallel-group, noninferiority trial enrolling premenopausal women ≥ 20 years of age, diagnosed with uterine fibroids and scheduled for laparoscopic myomectomy. Participants (n = 80) will be recruited in the clinical setting of participating institutions. The minimization method (predefined factors: presence or absence of fibroids ≥ 9 cm and the International Federation of Gynecology and Obstetrics [FIGO] type 1-5 fibroids) with randomization is used in a 1:1 allocation. Relugolix is a 40-mg oral tablet taken once a day before a meal, for 12 weeks, up to the day before surgery. Leuprorelin is a 1.88 mg, or 3.75 mg subcutaneous injection, given in three 4-week intervals during patient visits before the surgery. For the primary outcome measure of intraoperative bleeding, the blood flow is collected from the body cavity, surgical sponges, and collection bag and measured in milliliters. Secondary outcome measures are hemoglobin levels, myoma size, other surgical outcomes, and quality-of-life questionnaire responses (Kupperman Konenki Shogai Index and Uterine Fibroid Symptoms-Quality of Life). DISCUSSION: Real-world evidence will be collected in a clinical setting to use pre-treatment with an oral gonadotropin-releasing hormone antagonist to reduce intraoperative bleeding in women who undergo laparoscopic myomectomy. TRIAL REGISTRATION: jRCTs031210564 was registered on 19 January 2022 in the Japan Registry of Clinical Trials ( https://jrct.niph.go.jp ).

Effectiveness of Prophylactic Laparoscopic Surgery for Benign Adnexal Mass during Pregnancy: A Single-center Retrospective Study.

Objectives: This study aimed to evaluate the effectiveness of prophylactic laparoscopic surgery for avoiding adnexal torsion in pregnant women with benign adnexal masses. Materials and Methods: This report contains two analyses, each for a different group of patients. Analysis 1: Surgical and pregnancy outcomes were examined among the 126 cases who underwent laparoscopic assisted cystectomy for adnexal masses during pregnancy in our hospital between January 2001 and December 2020. Analysis 2: The incidence of adnexal torsion during pregnancy was evaluated among the cases with adnexal masses ≥5 cm who opted for conservative follow-up in our hospital between January 2011 and December 2020. Results: In analysis 1, the most common pathological diagnosis was a mature cystic teratoma (76.2%). The mean gestational age at surgery was 13.1 ± 1.3 weeks. No cases were converted to laparotomy and oophorectomy. Regarding delivery outcomes, 97.4% of cases went on to have full-term deliveries. In Analysis 2, the incidence of adnexal mass ≥5 cm that did not resolve spontaneously during pregnancy was 89 cases (0.8%). The frequency of malignancy was 3 cases (0.03%). In 28 cases who opted for conservative treatment, 5 (17.9%) underwent emergency surgery for adnexal torsion. Conclusion: Prophylactic surgery for benign adnexal masses during pregnancy can be performed laparoscopically and preserved ovarian functions. In pregnant women with adnexal masses that do not resolve spontaneously, planning laparoscopic surgery is considered beneficial for complications, such as adnexal torsion.

Importance of optimal rewiring guided by 3-dimensional optical frequency domain imaging during double-kissing culotte stenting demonstrated through a novel bench model.

The usefulness of optical frequency domain imaging (OFDI) guidance on two-stenting at left main bifurcation has not been evaluated. Here, we used a novel bench model to investigate whether pre-defined optimal rewiring with OFDI-guidance decreases acute incomplete stent apposition (ISA) at the left main bifurcation segment. A novel bench simulation system was developed to simulate the foreshortening and overlapping of daughter vessels as well as left main bifurcation motion under fluoroscopy. Double-kissing (DK) culotte stenting was performed using the novel bench model under fluoroscopy with or without OFDI-guidance. In the OFDI-guidance group, if the guidewire did not pass through the pre-defined optimal cell according to the 3-dimensional OFDI, additional attempts of rewiring into the jailed side branch were performed. The success rate of optimal jailed side branch rewiring after implantation of the first and second stent under OFDI-guidance was significantly higher than that under only angio-guidance. After completion of the DK-culotte stenting, the incidence and volume of ISA at the bifurcation segment in the OFDI-guidance group was significantly lower than that in the angio-guidance group. Online 3-dimensional OFDI-guided DK-culotte stenting according to a pre-defined optimal rewiring point might be superior to only angio-guided rewiring for reducing ISA at the bifurcation.

Current state of management of struma ovarii and preoperative imaging features: A retrospective case series study of 18 patients at a single institution.

AIM: Even though 95% of struma ovarii are benign, it is often overtreated because of the difficulty to distinguish it from malignancy. In this study, our aim was to evaluate the current state of the preoperative diagnosis and the selection of the surgical procedure, and to improve preoperative diagnostic accuracy by retrospectively reviewing imaging findings. METHODS: We retrospectively reviewed the clinical course and imaging characteristics of 18 patients who were diagnosed postoperatively with struma ovarii, pathologically, at our institution between 2015 and 2021. RESULTS: The preoperative diagnoses included benign ovarian tumor in eight cases, borderline in four cases, and malignant in six cases. None of the cases were diagnosed as struma ovarii preoperatively. Of the seven patients who had confirmed a desire for future childbearing, four patients were suspected for borderline or malignant tumor preoperatively, and underwent abdominal adnexectomy. In patients without a desire for childbearing, laparoscopic surgery was performed in only 45% of the patients whose preoperative diagnosis was benign. On magnetic resonance imaging (MRI), 54% of the cases showed enhanced solid components, which is characteristic of malignant tumors, but diffusion restriction was observed in only 11%. On computed tomography (CT), 78% of the cases showed a high attenuation lesion reflecting thyroid tissue. CONCLUSIONS: Struma ovarii is difficult to distinguish from malignancy preoperatively, making the choice of surgical approach complicated. A comprehensive evaluation of diffusion-weighted MRI and CT findings may improve the accuracy of preoperative diagnosis of struma ovarii.

Taxonomic revision of the Tetraneura akinire species group (Insecta, Aphididae, Eriosomatinae), with description of a new species and a correction of a nomenclatural confusion.

Gall-forming aphid species Tetraneura nigriabdominalis and T. fusiformis and its closely related species are taxonomically revised. By referring to the original descriptions, the name T. nigriabdominalis (Sasaki, 1899) is discarded as an erroneous combination, and T. akinire Sasaki, 1904 is adopted as a valid name. The T. akinire species group is defined as having long claws in the first instar nymphs of the root generation. Of the T. akinire species group distributed in Korea and Japan, T. ovaliformis sp. nov., which induces globular galls on the leaves of Ulmus davidiana var. japonica, is described, and T. akinire and T. sorini Hille Ris Lambers, 1970 are redescribed. A molecular phylogeny based on partial sequences of mitochondrial cytochrome c oxidase subunit I (COI) indicates that T. akinire is composed of two clusters, one (type A) which is distributed widely from Europe to East Asia on Ulmus spp., and the other (type B) which is found in Hokkaido, northern Japan on U. davidiana var. japonica and in tropical regions as anholocyclic lineages. Tetraneura fusiformis Matsumura, 1917, which has often been treated as a junior synonym of T. nigriabdominalis, likely corresponds to type B. The taxonomic status of T. fusiformis is discussed and this species is tentatively considered as a junior synonym of T. akinire sensu novo.

Pyomyoma mimicking tubo-ovarian abscess: Two case reports.

Pyomyoma is an extremely rare complication, defined as an infection of a uterine leiomyoma. We describe two cases of pyomyoma that were initially considered to be tubo-ovarian abscesses but were later diagnosed as pyomyomas and managed with laparoscopic surgery. Case 1 was a 26-year-old nulliparous woman who was previously diagnosed with bilateral endometriomas and presented to the hospital with lower abdominal pain. Magnetic resonance imaging revealed bilateral endometrial cysts and a 4-cm mass consistent with a tubo-ovarian abscess. The patient experienced continuous pain, and the cyst in the left adnexa enlarged; thus, laparoscopic surgery was performed. The cystic tumor in her uterus contained purulent fluid. Therefore, an abscess in the degenerative subserous myoma was diagnosed. Case 2 was a 47-year-old nulliparous woman who had undergone total mastectomy and postoperative radiotherapy for breast cancer. She was undergoing hormone therapy when she presented to the hospital with lower abdominal pain, fever, and increased inflammatory markers. Computed tomography revealed a 7-cm tumor with rim enhancement in her left adnexa; therefore, a tubo-ovarian abscess was suspected. After admission, drainage was performed under transvaginal ultrasound guidance, and antibiotics were administered. However, these treatments did not relieve her abdominal pain. Emergency laparoscopic surgery was performed, and intraoperative findings demonstrated an abscess in the degenerative subserous myoma of the uterus with normal adnexa. Laparoscopic hysterectomy and bilateral salpingectomy were performed. Laparoscopic surgery was effective for both patients. Delayed diagnosis of pyomyoma can result in serious complications. Timely surgery with concomitant antibiotic treatment may facilitate good outcomes.

Electrostatic-triggered exothermic antibody adsorption to the cellulose nanoparticles.

Antibody-conjugated nanoparticles are used in a fields ranging from medicine to engineering. NanoAct® nanobeads are cellulose nanoparticles used in lateral flow assays that are highly water dispersible. In order to promote the adsorption of antibodies onto NanoAct® particles while maintaining their activity, we analyzed the adsorption onto NanoAct® particles thermodynamically and elucidated the adsorption mechanism. In an immunochromatographic assay, the amount of adsorbed antibody and the color intensity of the test line increased as the pH decreased. The zeta potential of the nanoparticles remained constant at around -30 mV over the pH range from 2 to 10. The model antibody had pI values between 6.2 and 6.8. Isothermal calorimetry analysis showed that adsorption of antibody to the NanoAct® particle is an endothermic reaction under low pH conditions, an exothermic reaction between pH 6 and pH 7, and a weakly exothermic reaction above pH 7. These data indicate that the changes in net charge of the antibody surface as a function of pH influence the pH dependence of antibody adsorption to the negatively charged NanoAct®. This suggests that increased positive charge on the antibody surface will result in a more sensitive NanoAct®-based immunoassay.

Monitoring drainage flow rate facilitates prompt intervention with re-laparoscopy for postoperative bleeding after laparoscopic gynecologic surgery: A case-control study.

INTRODUCTION: We aimed to identify the characteristics of cases involving postoperative bleeding after laparoscopic gynecologic surgery, and to clarify the optimal cutoff value of postoperative drainage and vital sign trends for predicting the need for re-laparoscopy. METHODS: Of 6366 patients with gynecologic benign pathologies who underwent laparoscopic surgery at our institution between 2009 and 2018, 13 (0.2%) required re-laparoscopy for postoperative bleeding. After reviewing the perioperative course in the re-laparoscopy group, we examined the postoperative total drainage volume (mL), drainage flow rate (mL/h), and vital sign trends in the re-laparoscopy group (n = 13) and among patients with substantial drainage volume ≥300 mL at 12 hours postoperatively but who did not need re-laparoscopy (observation group, n = 107). RESULTS: In the re-laparoscopy group, initial laparoscopic surgery included uterine surgery (myomectomy, n = 7; hysterectomy, n = 1), adnexal surgery (n = 3), and uterine plus adnexal surgery (n = 2). Postoperative bleeding sites included the uterine wound (n = 6), adnexal wound (n = 5), umbilical trocar site (n = 1), and mesentery (n = 1). The re-laparoscopy and observation groups did not differ regarding initial surgical characteristics or postoperative vital sign trends. For distinguishing between the re-laparoscopy and observation groups, the drainage flow rate was superior to total drainage volume. Continuous excessive drainage (flow rate >50 mL/h) at 3 hours postoperatively was associated with a remarkably increased risk for re-laparoscopy (odds ratio, 40.07; 95% confidence interval, 5.44 to 1776.41, P < 0.001). CONCLUSION: In cases with continuous excessive drainage later than 3 hours postoperatively (flow rate >50 mL/h) should be considered for exploratory re-laparoscopy to enable prompt diagnosis and intervention.

Exometabolomic Analysis of Decidualizing Human Endometrial Stromal and Perivascular Cells.

Differentiation of endometrial fibroblasts into specialized decidual cells controls embryo implantation and transforms the cycling endometrium into a semi-permanent, immune-protective matrix that accommodates the placenta throughout pregnancy. This process starts during the midluteal phase of the menstrual cycle with decidual transformation of perivascular cells (PVC) surrounding the terminal spiral arterioles and endometrial stromal cells (EnSC) underlying the luminal epithelium. Decidualization involves extensive cellular reprogramming and acquisition of a secretory phenotype, essential for coordinated placental trophoblast invasion. Secreted metabolites are an emerging class of signaling molecules, collectively known as the exometabolome. Here, we used liquid chromatography-mass spectrometry to characterize and analyze time-resolved changes in metabolite secretion (exometabolome) of primary PVC and EnSC decidualized over 8 days. PVC were isolated using positive selection of the cell surface marker SUSD2. We identified 79 annotated metabolites differentially secreted upon decidualization, including prostaglandin, sphingolipid, and hyaluronic acid metabolites. Secreted metabolites encompassed 21 metabolic pathways, most prominently glycerolipid and pyrimidine metabolism. Although temporal exometabolome changes were comparable between decidualizing PVC and EnSC, 32 metabolites were differentially secreted across the decidualization time-course. Further, targeted metabolomics demonstrated significant differences in secretion of purine pathway metabolites between decidualized PVC and EnSC. Taken together, our findings indicate that the metabolic footprints generated by different decidual subpopulations encode spatiotemporal information that may be important for optimal embryo implantation.

A case of left renal atrophy following the development of an infected giant retroperitoneal chylous cyst after laparoscopic para-aortic lymphadenectomy for endometrial cancer.

Chylous leakage is caused by interruption of lymphatic vessels carrying triglyceride-rich lymph during para-aortic lymph node dissection in patients with gynecological malignancies. Our search of literature revealed no report like our case that the renal atrophy was late onset after healing of the chylous cyst infection. A case is 60-year-old. She was preoperatively diagnosed with endometrial cancer, endometrioid carcinoma FIGO grade 3, stage IA of the FIGO system. Laparoscopic-modified radical hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy and partial omentectomy were performed. On the 16th postoperative day, a percutaneous drainage was performed, and revealed chylous effusion from the lymph cyst. The drainage tube was removed, and she discharged on the 34th postoperative day. On the 99th postoperative day, a follow-up plain CT to check for a recurrence of endometrial cancer revealed atrophy of left kidney. It is probable that the chylous leakage was the primary cause of renal atrophy. Therefore, it is crucial to prevent chylous leakage during surgery to avoid repeating the same complication again.

Comparison of effect of preoperative dienogest and gonadotropin-releasing hormone agonist administration on laparoscopic cystectomy for ovarian endometriomas.

PURPOSE: To compare the effects of preoperative dienogest (DNG) and gonadotropin-releasing hormone (GnRH) agonist administration on the improvement of preoperative symptoms and surgical outcomes in patients who underwent laparoscopic cystectomy for ovarian endometriomas. METHODS: Seventy patients who were scheduled for laparoscopic surgery were enrolled in the study. They were divided into two groups: 35 patients who received DNG for 4 months preoperatively (group D) and 35 patients who received low-dose sustained-release goserelin acetate for 4 months preoperatively (group G). Preoperative outcomes, including pain score associated with endometriosis, using the numerical rating scale (NRS), adverse events of hormonal therapy and Kupperman index (KI) before and after treatment, surgical outcomes including total surgical duration and blood loss, and postoperative recurrence of endometrioma were compared between the two groups. RESULTS: Regarding preoperative symptoms, NRS and KI at 4 months after preoperative hormonal therapy were significantly lower in group D than in group G (NRS, 5.3 ± 5.5 vs. 2.7 ± 3.9; P = 0.01; KI, 16.0 ± 11.0 vs. 9.2 ± 7.6; P = 0.006). Regarding adverse events, the incidence of hot flashes was significantly lower in group D than in group G (P < 0.001). Meanwhile, the incidence of breast pain and metrorrhagia was significantly higher in group D than in group G (P = 0.04 and P < 0.001, respectively). The total surgical duration and blood loss were not significantly different between the groups. At 12 months after surgery, ovarian endometrioma did not recur in either group. CONCLUSION: Preoperative administration of DNG is more valuable for patients with endometriosis and scheduled for laparoscopic surgery to improve symptoms with good efficacy and tolerability than the administration of GnRH agonist.

Resveratrol inhibits decidualization by accelerating downregulation of the CRABP2-RAR pathway in differentiating human endometrial stromal cells.

Pregnancy critically depends on the transformation of the human endometrium into a decidual matrix that controls embryo implantation and placenta formation, a process driven foremost by differentiation and polarization of endometrial stromal cells into mature and senescent decidual cells. Perturbations in the decidual process underpin a spectrum of prevalent reproductive disorders, including implantation failure and early pregnancy loss, emphasizing the need for new therapeutic interventions. Resveratrol is a naturally occurring polyphenol, widely used for its antioxidant and anti-inflammatory properties. Using primary human endometrial stromal cell (HESC) cultures, we demonstrate that resveratrol has anti-deciduogenic properties, repressing not only the induction of the decidual marker genes PRL and IGFBP1 but also abrogating decidual senescence. Knockdown of Sirtuin 1, a histone deacetylase activated by resveratrol, restored the expression of IGFBP1 but not the induction of PRL or senescence markers in decidualizing HESCs, suggesting involvement of other pathways. We demonstrate that resveratrol interferes with the reprogramming of the retinoic acid signaling pathway in decidualizing HESCs by accelerating down-regulation of cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor (RAR). Notably, knockdown of CRABP2 or RAR in HESCs was sufficient to recapitulate the anti-deciduogenic effects of resveratrol. Thus, while resveratrol has been advanced as a potential fertility drug, our results indicate it may have detrimental effects on embryo implantation by interfering with decidual remodeling of the endometrium.

Vitamin D Regulates Maternal T-Helper Cytokine Production in Infertile Women.

Vitamin D (VD) deficiency is associated with reproductive failure. However, the relationship between VD and maternal immunity remains unclear. We investigated the clinical efficacy of VD in maternal T-helper (Th) cytokines in 276 infertile women and examined for Th1 and Th2 cells based on the deficient, insufficient, and sufficient serum 25-hydroxyvitamin D3 (25[OH]VD) levels (<12, 12⁻30, and >30 ng/mL, respectively). Most infertile women had a low-level of VD (87.3%). Immunological tests of pre-/post-VD supplementation were performed in patients who were deficient and insufficient in VD. Of 23 patients, 11 (47.8%) exhibited sufficient VD levels after supplementation. Th1/Th2 cell ratio in patients with insufficient VD was significantly decreased after supplementation (p = 0.004). After supplementation, serum 25(OH)VD levels of the patients: 11 in the sufficient group showed significant decreases in Th1 cell level and Th1/Th2 cell ratio (p = 0.032 and 0.010, respectively), whereas no significant differences in Th1/Th2 cell ratio were recognized in the insufficient group. Furthermore, mid-luteal endometrial biopsies (n = 18) were processed for primary cultures and measured interferon [IFN]-γ and interleukin [IL]-4 in condition media. Decidualizing cultures with 1,25-dihydroxvitamin D3 (1,25[OH]2VD) decreased IFN-γ. Sufficient VD supplementation in women with insufficient VD may optimize maternal T-helper cytokines during pregnancy via rebalancing the Th1/Th2 cell ratio.

Predictive markers and prenatal management of isolated fetal complete atrioventricular block: A retrospective review at a single institution.

AIM: The study was conducted to determine an effective method for identifying patients at high risk of developing isolated complete atrioventricular block (CAVB) and to review the efficacy of prenatal anti-inflammatory treatment. METHODS: Fourteen CAVB cases and 76 anti-Ro-positive cases without CAVB were included in the study. Anti-Ro/La titers by double immunodiffusion and the prevalence of anti-52 kDa/60 kDa-Ro/48 kDa-La by Western blotting were compared between anti-Ro-positive women with and without CAVB. Outcomes of anti-Ro-positive CAVB cases were compared based on active prenatal anti-inflammatory treatment (plasma exchange or transplacental betamethasone). We evaluated the outcomes of five pregnancies from three women who had an affected child and underwent prophylactic plasma exchange (PEX) during subsequent pregnancy. RESULTS: Ten out of 14 patients with CAVB were positive for anti-Ro. Anti-Ro titers were significantly higher in patients with CAVB (CAVB median 64; without CAVB median 16; P < 0.01). All cases with CAVB showed high titers of anti-Ro (≥ 32×), whereas only 42% of cases without CAVB showed high titers (≥ 32×) (P < 0.001). The survival rate at one year was 80% in anti-Ro-positive CAVB cases with active prenatal anti-inflammatory treatment, but only 40% in cases that did not receive treatment. Recurrence was not observed in cases treated with prophylactic PEX. CONCLUSIONS: An anti-Ro level of 32× could be the threshold value for CAVB development. Prenatal anti-inflammatory treatment in patients with CAVB and prophylactic PEX in patients who had an affected child may have the potential to improve pregnancy outcomes.

Maternal peripartum septic shock caused by intrauterine infection with Edwardsiella tarda: A case report and review of the literature.

Edwardsiella tarda (E. tarda) is a rare pathogen in humans, especially during the peripartum period. Only a few cases of fatal neonatal infection with E. tarda have been reported. Herein, we describe a case of maternal septicemia caused by E. tarda following peripartum chorioamnionitis. The mother developed septic shock, disseminated intravascular coagulation and a post-cesarean wound hematoma with abscess. Her condition improved with multidisciplinary therapy including blood transfusion, antimicrobial agents, recombinant thrombomodulin and surgical debridement. E. tarda was isolated from the maternal blood, cesarean wound and neonatal skin, pharynx and gastric fluid. This case demonstrates that peripartum infection with E. tarda is a rare but life-threatening condition, not only for the neonate but also for the mother.

Verification of the airway securing capacity of a life jacket in a flood disaster.

OBJECTIVE: To verify the life jacket's airway-securing capacity to keep the nose and mouth out of the water in a flood disaster. DESIGN: Physical experiment. SETTING: University of Miyazaki. MATERIALS AND METHODS: We experimented with an open channel in which we created a wave and running water. In the channel, we observed a dummy attached to a balloon as a buoyant body. We used 170-, 220-, and 320-ml balloons. Experiment 1, we reproduced a tsunami. We created three sizes of wave. Experiment 2, we reproduced running water. When we installed an obstacle at the channel bottom, the current that submerged the dummy occurred downstream of the obstacle. We measured the submergence time of the dummy. RESULTS: For the medium-sized wave, the submergence time decreased as the balloon volume increased. For the largest wave, the submergence time was the shortest for a balloon of 220 ml, not 320 ml. Experiment 2, the submergence time decreased as the balloon volume increased. However, a dummy attached to a 320-ml balloon remained downstream of the obstacle. CONCLUSIONS: The biggest drawback is that the parameters of this study are not based on real-world experience. Therefore, if an evacuee with a life jacket is submerged in a flood disaster, we cannot easily decide whether the buoyancy is appropriate because in some situations, buoyancy adversely affected airway security. If we could decide buoyancy based on specific disaster conditions, the airway-securing capacity of a life jacket would improve.

Annual Report of the Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2015: Proposal of urgent measures to reduce maternal deaths.

Perinatal care in Japan has progressed rapidly in recent decades, remarkably reducing maternal, perinatal and neonatal mortality rates. This is attributable not only to the sustained efforts and dedication of past obstetricians and midwives, but also to the collective results achieved by the Japan Society of Obstetrics and Gynecology and healthcare administration, including research on advanced medical care, education, medical care improvements and establishing perinatal care centers. Although the maternal mortality rate was in steady decline until 2007 (3.1/100 000 births), it repeatedly fluctuated thereafter, plateauing at 3.4 per 100 000 births in 2013 and 2.7 per 100 000 births in 2014. Thus, the Perinatology Committee has analyzed the current situation of maternal deaths and has proposed countermeasures to reduce such death. The items deliberated upon by related subcommittees in 2015 are presented herein. The addition of indications for 'fibrinogen concentrate', 'eptacog alfa' and approval of the PGE2 vaginal tablet for cervical ripening were discussed in the subcommittee for unapproved drug review. Thus, a request for approval for health insurance coverage was submitted to the 'Evaluation committee on unapproved or off-label drugs with high medical needs' of the Ministry of Health, Labour and Welfare. Maternal and late-maternal deaths from suicide during the 10 years from 2005 to 2014 in Tokyo's 23 wards were jointly examined with the Tokyo Medical Examiner's Office. The suicide rate in the 23 wards is very high, at 8.7 per 100 000 births. Thus, the subcommittee for the reduction of maternal death discussed countermeasures for the eradication of maternal death and maternal suicide and the revision of death certificates.

Loss of Endometrial Plasticity in Recurrent Pregnancy Loss.

Menstruation drives cyclic activation of endometrial progenitor cells, tissue regeneration, and maturation of stromal cells, which differentiate into specialized decidual cells prior to and during pregnancy. Aberrant responsiveness of human endometrial stromal cells (HESCs) to deciduogenic cues is strongly associated with recurrent pregnancy loss (RPL), suggesting a defect in cellular maturation. MeDIP-seq analysis of HESCs did not reveal gross perturbations in CpG methylation in RPL cultures, although quantitative differences were observed in or near genes that are frequently deregulated in vivo. However, RPL was associated with a marked reduction in methylation of defined CA-rich motifs located throughout the genome but enriched near telomeres. Non-CpG methylation is a hallmark of cellular multipotency. Congruently, we demonstrate that RPL is associated with a deficiency in endometrial clonogenic cell populations. Loss of epigenetic stemness features also correlated with intragenic CpG hypomethylation and reduced expression of HMGB2, coding high mobility group protein 2. We show that knockdown of this sequence-independent chromatin protein in HESCs promotes senescence and impairs decidualization, exemplified by blunted time-dependent secretome changes. Our findings indicate that stem cell deficiency and accelerated stromal senescence limit the differentiation capacity of the endometrium and predispose for pregnancy failure.

Decidualization induces a secretome switch in perivascular niche cells of the human endometrium.

The endometrial perivascular microenvironment is rich in mesenchymal stem-like cells that express type 1 integral membrane protein Sushi domain containing 2 (SUSD2) but the role of these cells in the decidual transformation of this tissue in pregnancy is unknown. We used an antibody directed against SUSD2 (W5C5) to isolate perivascular (W5C5(+)) and nonperivascular (W5C5(-)) fibroblasts from mid-luteal biopsies. We show that SUSD2 expression, and hence the ratio of W5C5(+):W5C5(-) cells, changes in culture depending on cell-cell contact and activation of the Notch signaling pathway. RNA sequencing revealed that cultures derived from W5C5(+) progenitor cells remain phenotypically distinct by the enrichment of novel and established endometrial perivascular signature genes. In an undifferentiated state, W5C5(+)-derived cells produced lower levels of various chemokines and inflammatory modulators when compared with their W5C5(-) counterparts. This divergence in secretomes was switched and became more pronounced upon decidualization, which transformed perivascular W5C5(+) cells into the dominant source of a range of chemokines and cytokines, including leukemia inhibitory factor and chemokine (C-C motif) ligand 7. Our findings suggest that the decidual response is spatially organized at the embryo-maternal interface with differentiating perivascular cells establishing distinct cytokine and chemokine profiles that could potentially direct trophoblast toward maternal vessels and govern local immune responses in pregnancy.

Androgens modulate the morphological characteristics of human endometrial stromal cells decidualized in vitro.

The activated androgen receptor (AR) in decidualizing human endometrial stromal cells (HESCs) regulates genes involved in cytoskeletal organization, cell motility, and cell cycle progression. Androgens also enhance the secretion of prolactin, a widely used marker of decidualized HESCs. The purpose of the present study was to investigate the direct effects of androgens on the ultrastructural changes associated with decidual transformation of HESCs. Primary HESC cultures were established and propagated, and confluent cultures were decidualized for 6 days with 8-bromoadenosine 3',5'-cyclic monophosphate (8-br-cAMP) and progesterone (P4) in the presence or absence of dihydrotestosterone (DHT). Phase-contrast image analysis demonstrated that DHT increases the shape index of decidualizing cells, which was reversed upon cotreatment with the AR antagonist flutamide. Electron microscopy demonstrated that DHT enhances many of the ultrastructural changes induced by 8-br-cAMP and P4 in HESCs. Decidualizing cells are characterized by an abundant cytoplasm, multiple cell surface projections and, unlike undifferentiated HESCs, form 2 or more cell layers. The DHT further stimulated cytoplasmic expansion, lipid droplet formation, the production of an abundant extracellular matrix, and gap junction formation in decidualized HESCs. The present study demonstrates that androgen signaling has an impact on the morphological and ultrastructural changes associated with the decidual process. Our findings show that androgens promote the development and expansion of cytoplasmic organelles and gap junctions in decidualizing HESCs. These results suggest that androgens in early pregnancy play an important role in promoting the cellular transformation associated with decidualization.