Publications by authors named "Yutaka Osuga"

372 Publications

Endoplasmic reticulum stress: a key regulator of the follicular microenvironment in the ovary.

Mol Hum Reprod 2021 Jan;27(1)

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo, Tokyo 113-8655, Japan.

Intra-ovarian local factors regulate the follicular microenvironment in coordination with gonadotrophins, thus playing a crucial role in ovarian physiology as well as pathological states such as polycystic ovary syndrome (PCOS). One recently recognized local factor is endoplasmic reticulum (ER) stress, which involves the accumulation of unfolded or misfolded proteins in the ER related to various physiological and pathological conditions that increase the demand for protein folding or attenuate the protein-folding capacity of the organelle. ER stress results in activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which affect a wide variety of cellular functions. Recent studies have revealed diverse roles of ER stress in physiological and pathological conditions in the ovary. In this review, we summarize the most current knowledge of the regulatory roles of ER stress in the ovary, in the context of reproduction. The physiological roles of ER stress and the UPR in the ovary remain largely undetermined. On the contrary, activation of ER stress is known to impair follicular and oocyte health in various pathological conditions; moreover, ER stress also contributes to the pathogenesis of several ovarian diseases, including PCOS. Finally, we discuss the potential of ER stress as a novel therapeutic target. Inhibition of ER stress or UPR activation, by treatment with existing chemical chaperones, lifestyle intervention, or the development of small molecules that target the UPR, represents a promising therapeutic strategy.
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http://dx.doi.org/10.1093/molehr/gaaa088DOI Listing
January 2021

Use of selective PGE2 receptor antagonists on human endometriotic stromal cells and peritoneal macrophages.

Mol Hum Reprod 2021 Jan;27(1)

Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan.

Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to explore their potential as novel therapeutic strategies for endometriosis. The expression of PGE2 receptors (EP2 and EP4) in donated tissues from human ovarian endometriosis, adenomyosis and peritoneal endometriosis was examined using immunohistochemistry. Human endometriotic stromal cells (ESC) isolated from ovarian endometriotic tissue and peritoneal macrophages were treated with EP2 and EP4 antagonists. cAMP accumulation and the effect of EP antagonists were measured using cAMP assays. DNA synthesis in ESC was detected using bromodeoxyuridine incorporation analysis. Interleukin (IL)-6 and IL-8 protein levels in ESC supernatants were measured using ELISAs. mRNA expression level for aromatase by ESC, and selected cytokines by peritoneal macrophages was measured using RT-PCR. EP2 and EP4 receptors were expressed in cells derived from control and diseased tissue, ovarian endometriotic, adenomyotic and peritoneal lesions. A selective EP2 antagonist reduced DNA synthesis, cAMP accumulation and IL-1β-induced proinflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1β-induced IL-6 secretion and aromatase expression. In peritoneal macrophages, EP expression was elevated in endometriosis samples but the EP4 antagonist reduced cAMP levels and expression of vascular endothelial growth factor, chemokine ligand 2 and chemokine ligand 3 mRNA. EP2 and EP4 are functioning in endometriosis lesions and peritoneal macrophages, and their selective antagonists can reduce EP-mediated actions, therefore, the EP antagonists are potential therapeutic agents for controlling endometriosis.
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http://dx.doi.org/10.1093/molehr/gaaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846198PMC
January 2021

Postpartum Stanford type B aortic dissection in a woman with Loeys-Dietz syndrome who underwent a prophylactic aortic root replacement before conception: A case report.

Taiwan J Obstet Gynecol 2021 Jan;60(1):145-147

Departments of Obstetrics & Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

Objective: Loeys-Dietz syndrome (LDS) is associated with a higher risk of aortic dissections (ADs) during pregnancy and postpartum. However, there is limited evidence about the perinatal management of LDS patients who have undergone prophylactic aortic root replacements (ARRs) before conception.

Case Report: We present the case of a 28-year-old nulliparous pregnant woman with LDS with a pathogenic variant within exon 5 of TGFBR2 (c.1379G > T, p.[Arg460Leu]), who underwent an ARR at 20 years of age. Cardiac echocardiography did not show any significant changes in the aorta during pregnancy, and her blood pressure remained normal. She had a cesarean section at 37 weeks of gestation. She developed an acute Stanford type B AD extending from the aortic arch to the infrarenal aorta 8 days postpartum and underwent a total arch replacement.

Conclusion: This case report suggests that patients with LDS after prophylactic ARRs still possess a risk for Stanford type B ADs.
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http://dx.doi.org/10.1016/j.tjog.2020.10.005DOI Listing
January 2021

Induction of aryl hydrocarbon receptor in granulosa cells by endoplasmic reticulum stress contributes to pathology of polycystic ovary syndrome.

Mol Hum Reprod 2021 Jan 25. Epub 2021 Jan 25.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan.

Recent studies have uncovered the critical role of aryl hydrocarbon receptor (AHR) in various diseases, including obesity and cancer progression, independent of its previously identified role as a receptor for endocrine-disrupting chemicals (EDCs). We previously demonstrated that endoplasmic reticulum (ER) stress, a newly recognized local factor in the follicular microenvironment, is activated in granulosa cells from patients with polycystic ovary syndrome (PCOS) and a mouse model of the disease. By affecting diverse functions of granulosa cells, ER stress contributes to PCOS pathology. We hypothesized that expression of AHR and activation of its downstream signaling were upregulated by ER stress in granulosa cells, irrespective of the presence of EDCs, thereby promoting PCOS pathogenesis. In this study, we found that AHR, AHR nuclear translocator (ARNT), and AHR target gene cytochrome P450 1B1 (CYP1B1) were upregulated in the granulosa cells of PCOS patients and model mice. We examined CYP1B1 as a representative AHR target gene. AHR and ARNT were upregulated by ER stress in human granulosa-lutein cells (GLCs), resulting in an increase in the expression and activity of CYP1B1. Administration of the AHR antagonist CH223191 to PCOS mice restored estrous cycling and decreased the number of atretic antral follicles, concomitant with downregulation of AHR and CYP1B1 in granulosa cells. Taken together, our findings indicate that AHR activated by ER stress in the follicular microenvironment contributes to PCOS pathology, and that AHR represents a novel therapeutic target for PCOS.
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http://dx.doi.org/10.1093/molehr/gaab003DOI Listing
January 2021

Assisted reproductive technology in Japan: A summary report for 2018 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology.

Reprod Med Biol 2021 Jan 20;20(1):3-12. Epub 2020 Nov 20.

Department of Obstetrics and Gynecology Faculty of Medicine The University of Tokyo Tokyo Japan.

Purpose: Since 2007, the Japan Society of Obstetrics and Gynecology (JSOG) has collected cycle-based data for assisted reproductive technology (ART) in an online registry. Here, we present the characteristics and treatment outcomes of ART cycles registered during 2018.

Methods: The Japanese ART registry consists of cycle-specific information for all ART treatment cycles implemented at 621 participating facilities. We conducted descriptive analyses for such cycles registered for 2018.

Results: In total, 454 893 treatment cycles and 56 979 neonates were reported in 2018: both increased from 2017. The mean maternal age was 38.0 years (standard deviation ± 4.7). Of 247 402 oocyte retrievals, 118 378 (47.8%) involved freeze-all-embryos cycles; fresh embryo transfer (ET) was performed in 50 463 cycles: a decreasing trend since 2015. A total of 199 914 frozen-thawed ET cycles were reported, resulting in 69 357 pregnancies and 49 360 neonates born. Single ET (SET) was performed in 82.2% of fresh transfers and 83.4% of frozen-thawed cycles, with singleton pregnancy/live birth rates of 97.2%/97.2% and 97.0%/97.2%, respectively.

Conclusions: Total ART cycles and subsequent live births increased in 2018. SET was performed in over 80% of cases, and the mode of ET has shifted continuously from using fresh embryos to frozen-thawed ones compared with previous years.
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http://dx.doi.org/10.1002/rmb2.12358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812461PMC
January 2021

A low preoperative albumin-to-globulin ratio is a negative prognostic factor in patients with surgically treated cervical cancer.

Int J Clin Oncol 2021 Jan 21. Epub 2021 Jan 21.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: The albumin-to-globulin ratio reflects both the nutrition and inflammation and predicts prognosis in patients with various malignancies. However, in cervical cancer patients who undergo surgery, its significance has yet to be established.

Methods: A total of 247 cervical cancer patients who received surgical treatment at our institution between 2005 and 2017 were enrolled in this study. Preoperative data, such as the levels of serum albumin and serum globulin as well as the albumin-to-globulin ratio along with the other clinicopathological characteristics were retrospectively assessed, and their association with the overall survival was analyzed.

Results: Overall, 49 cases of recurrence and 26 deaths were observed during the median follow-up time of 58.6 months. A low albumin-to-globulin ratio (< 1.345) as well as low albumin (< 3.25 g/dL) and high globulin levels (≥ 3.25 g/dL) were significantly associated with poor prognosis. According to the multivariate analysis, a low albumin-to-globulin ratio was an independent prognostic factor for overall survival (HR = 2.59, 95% CI 1.12-5.96, P = 0.026); however, low albumin or high globulin levels was not associated with the overall survival. Among the clinicopathological characteristics, older age, diabetes mellitus, hypertension, larger tumor size, and parametrial invasion were associated with a low albumin-to-globulin ratio.

Conclusion: A low albumin-to-globulin ratio was associated with a poor prognosis in patients with surgically treated invasive cervical cancer. Therefore, the albumin-to-globulin ratio may serve as a prognostic marker, which predicts a worse prognosis.
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http://dx.doi.org/10.1007/s10147-021-01861-8DOI Listing
January 2021

CD206+ macrophage is an accelerator of endometriotic-like lesion via promoting angiogenesis in the endometriosis mouse model.

Sci Rep 2021 Jan 13;11(1):853. Epub 2021 Jan 13.

Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.

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 < 0.05). In the endometriotic-like lesions in the DT group, a lower proliferation of endometriotic cells and the decrease of angiogenesis were observed. In the lesions, the mRNA levels of VEGFA and TGFβ1, angiogenic factors, in the DT group significantly decreased to approximately 50% and 30% of control, respectively. Immunohistochemical study revealed the expressions of VEGFA and an endothelial cell marker CD31 in lesions of the DT group, were dim compared to those in control. Also, the number of TGFβ1 expressing MΦ was significantly reduced compared to control. These data suggest that CD206+ MΦ promotes the formation of endometriotic-like lesions by inducing angiogenesis around the lesions.
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http://dx.doi.org/10.1038/s41598-020-79578-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807007PMC
January 2021

Endoplasmic reticulum stress: a key regulator of the follicular microenvironment in the ovary.

Mol Hum Reprod 2021 Jan 7. Epub 2021 Jan 7.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, Japan.

Intra-ovarian local factors regulate the follicular microenvironment in coordination with gonadotrophins, thus playing a crucial role in ovarian physiology as well as pathological states such as polycystic ovary syndrome (PCOS). One recently recognized local factor is endoplasmic reticulum (ER) stress, which involves the accumulation of unfolded or misfolded proteins in the ER related to various physiological and pathological conditions that increase the demand for protein folding or attenuate the protein-folding capacity of the organelle. ER stress results in activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which affect a wide variety of cellular functions. Recent studies have revealed diverse roles of ER stress in physiological and pathological conditions in the ovary. In this review, we summarize the most current knowledge of the regulatory roles of ER stress in the ovary, in the context of reproduction. The physiological roles of ER stress and the UPR in the ovary remain largely undetermined. On the other hand, activation of ER stress is known to impair follicular and oocyte health in various pathological conditions; moreover, ER stress also contributes to the pathogenesis of several ovarian diseases, including PCOS. Finally, we discuss the potential of ER stress as a novel therapeutic target. Inhibition of ER stress or UPR activation, by treatment with existing chemical chaperones, lifestyle intervention, or the development of small molecules that target the UPR, represents a promising therapeutic strategy.
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http://dx.doi.org/10.1093/molehr/gaaa088DOI Listing
January 2021

Recombinant Thrombomodulin Attenuates Preeclamptic Symptoms by Inhibiting High-Mobility Group Box 1 in Mice.

Endocrinology 2021 Apr;162(4)

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Preeclampsia (PE) is a common gestational complication that involves systemic endothelial dysfunction and inflammatory responses primarily due to placental damage. Recombinant thrombomodulin (rTM), a novel anticoagulant clinically used for disseminated intravascular coagulation, is reported to have a unique anti-inflammatory endothelial repair function by inhibiting proinflammatory mediator high-mobility group box 1 (HMGB1). Despite the severe patient outcomes, there are currently no effective therapeutic options to treat PE. Here, we verified the efficacy of rTM as a novel therapeutic agent for PE using a murine model and human trophoblast cells. We revealed the therapeutic potential of rTM in an angiotensin II(Ang II)-induced PE mouse model. Injection of rTM significantly attenuated clinical features of PE, such as hypertension, proteinuria, fetal growth restriction, and impaired placental vasculature. Elevation of maternal soluble fms-like tyrosine kinase-1 (sFlt-1), a well-accepted causal factor of PE that induces systemic endothelial dysfunction, was suppressed in response to rTM treatment. Supporting these findings, our in vitro experiments revealed that rTM reduces Ang II-triggered overproduction of sFlt-1 in human trophoblast cells. Moreover, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), well-known key inflammatory mediators in PE pathogenesis, were diminished by rTM. SiRNA knockdown experiments further determined that these processes were directly mediated by HMGB1. Our studies demonstrate that rTM exerts its clinical effect as HMBG1 inhibitor and ameliorates placental dysfunction, which is central to PE pathogenesis. Our findings suggest that rTM could be a promising therapeutic that significantly improve the outcomes of PE patients.
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http://dx.doi.org/10.1210/endocr/bqaa248DOI Listing
April 2021

Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion.

EMBO Rep 2021 Feb 5;22(2):e50927. Epub 2021 Jan 5.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Retinoblastoma protein (RB) encoded by Rb1 is a prominent inducer of cell cycle arrest (CCA). The hormone progesterone (P ) promotes CCA in the uterine epithelium and previous studies indicated that P activates RB by reducing the phosphorylated, inactive form of RB. Here, we show that embryo implantation is impaired in uterine-specific Rb1 knockout mice. We observe persistent cell proliferation of the Rb1-deficient uterine epithelium until embryo attachment, loss of epithelial necroptosis, and trophoblast phagocytosis, which correlates with subsequent embryo invasion failure, indicating that Rb1-induced CCA and necroptosis of uterine epithelium are involved in embryo invasion. Pre-implantation P supplementation is sufficient to restore these defects and embryo invasion. In Rb1-deficient uterine epithelial cells, TNFα-primed necroptosis is impaired, which is rescued by the treatment with a CCA inducer thymidine or P through the upregulation of TNF receptor type 2. TNFα is expressed in the luminal epithelium and the embryo at the embryo attachment site. These results provide evidence that uterine Rb1-induced CCA is involved in TNFα-primed epithelial necroptosis at the implantation site for successful embryo invasion.
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http://dx.doi.org/10.15252/embr.202050927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857437PMC
February 2021

National survey of bladder endometriosis cases in Japan.

J Obstet Gynaecol Res 2021 Jan 4. Epub 2021 Jan 4.

Department of Obstetrics and Gynecology, University of Tokyo, Tokyo, Japan.

Aim: We aimed to describe the clinical presentation, operative or medical management, and postoperative recurrence of bladder endometriosis (BE).

Methods: We conducted a national survey to investigate BE cases from 2006 to 2016 in Japan. Histologically diagnosed cases were extracted and then investigated for the following factors: age at diagnosis, body mass index, symptoms, imaging modalities, surgical therapy, hormonal therapy, follow-up period, and postoperative recurrence.

Results: Eighty-nine patients with pathologically benign BE were identified. Eighty patients underwent surgery, whereas nine did not. Moreover, 34 and 44 patients underwent transurethral resection (TUR) and partial cystectomy (PC), respectively. Cumulative recurrence rates were significantly higher with TUR than with PC (p < 0.05). The recurrence rate tended to be higher after laparoscopic PC (n = 24) than after open PC (n = 20), but the difference was not statistically significant (p = 0.0879). Of the nine nonsurgical patients, eight received hormonal therapy and one did not. Efficacy rates of dienogest, GnRH agonist, and OC were 85.7%, 66.7%, and 66.7%, respectively. Of five patients with BE extending to the ureter or ureteral orifices, two underwent PC and ureteroneocystostomy and one underwent total nephroureterectomy due to renal function loss.

Conclusion: To our knowledge, this is the first study to compare the postoperative recurrence of BE after TUR and PC. We found that cumulative recurrence rate is significantly lower after PC than after TUR. BE extending to the ureter or ureteral orifices is a very challenging condition. Further studies are required for the optimal management of BE.
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http://dx.doi.org/10.1111/jog.14656DOI Listing
January 2021

Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer.

Biomolecules 2020 12 16;10(12). Epub 2020 Dec 16.

Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.

The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still unknown. The purpose of this study was to investigate the role of SETD8 in HGSOC. We performed quantitative real-time PCR and immunohistochemistry to detect the expression of SETD8 in HGSOC samples and normal ovarian specimens. Then, we assessed the effect of the inhibition of SETD8 expression using small interfering RNA (siRNA) and a selective inhibitor (UNC0379) on cell proliferation and apoptosis in HGSOC cells. The expression of SETD8 was significantly upregulated in clinical ovarian cancer specimens compared to that in the corresponding normal ovary. In addition, suppression of SETD8 expression in HGSOC cells with either siRNA or UNC0379 resulted in reduced levels of H4K20 monomethylation, inhibition of cell proliferation, and induction of apoptosis. Furthermore, UNC0379 showed a long-term antitumor effect against HGSOC cells, as demonstrated by colony-formation assays. SETD8 thus constitutes a promising therapeutic target for HGSOC, warranting further functional studies.
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http://dx.doi.org/10.3390/biom10121686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766894PMC
December 2020

National survey of primary amenorrhea and relevant conditions in Japan.

J Obstet Gynaecol Res 2021 Feb 16;47(2):774-777. Epub 2020 Dec 16.

Department of Obstetrics and Gynecology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.

Aim: In Japan, most of the patients with primary amenorrhea or related conditions, such as delayed menarche, are diagnosed by pediatricians or gynecologists; accordingly, the number of the patients and the ratio of the causes were unclear. To clarify them, we conducted a nationwide survey in both the departments for the first time.

Methods: We sent a questionnaire about the patients with chief complaint of no menarche whose first visit was from January 2015 to December 2017, to 596 training institutions for specialist physicians of the Japan Society of Obstetrics and Gynecology and 152 facilities to which councilors of the Japanese Society for Pediatric Endocrinology belong.

Results: We received replies from 283 (37.8%) institutions. During the 3 years, 1043 patients first visited pediatrics or gynecology for no menarche. In 303 patients under 16 years old at the first visit, 177 (58.4%) patients had menarche by the age of 16. Of them, 41 (13.5%) patients had menarche spontaneously. Among 308 patients aged 16 to 17 at the first visit, 216 patients were 18 years or older at the survey. Of them, 124 (57.4%) patients had menarche by the age of 18, and 21 (9.7%) of them had menarche spontaneously. The causes of amenorrhea were detected in 462 patients. Abnormal karyotype including Turner syndrome was the most common at 122 (26.4%), followed by Mullerian agenesis at 73 (15.8%).

Conclusions: The first national survey revealed the number and causes of primary amenorrhea and related conditions. This report will provide better information for clinicians.
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http://dx.doi.org/10.1111/jog.14606DOI Listing
February 2021

Comprehensive immunohistochemical analysis of the gastrointestinal and Müllerian phenotypes of 139 ovarian mucinous cystadenomas.

Hum Pathol 2020 Dec 1;109:21-30. Epub 2020 Dec 1.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan; Asahi TelePathology Center, Asahi General Hospital, Asahi, Chiba, 289-2511, Japan.

Mucinous cystadenoma is one of the most common benign ovarian neoplasms. The immunophenotypes and histogenetic relationships of mucinous cystadenomas with a Müllerian-type epithelium have not been fully explored. We elucidated the direction of differentiation of the mucinous epithelium that constitutes mucinous cystadenomas. Special attention was paid to the existence of gastrointestinal (GI)-type mucinous epithelium, and its association with background Müllerian-type epithelium. Immunohistochemistry was performed in 139 cases of mucinous cystadenoma to evaluate the expression of Claudin-18 (CLDN18), a novel marker of gastric differentiation; CDX2, a marker of intestinal differentiation; and estrogen receptor (ER), a marker of Müllerian differentiation. We found that GI differentiation characterized by CLDN18 and/or CDX2 positivity was observed in mucinous epithelium of most mucinous cystadenomas (129/139 cases, 93%). In a subset of these cases, the tumor was composed of mucinous epithelium exhibiting an intermediate GI and Müllerian phenotype (CLDN18+/CDX2±/ER+). Of note, in 12 cases, a transition from background Müllerian-type epithelium to mucinous epithelium with GI differentiation was identified. A minor subset (6%) of mucinous cystadenomas was considered a pure Müllerian type because the epithelium exhibited a CLDN18-/CDX2-/ER + immunophenotype. In conclusion, mucinous cystadenomas consist of three major subtypes: GI, Müllerian, and intermediate types. Most mucinous cystadenomas are GI-type, and they should be considered a precursor of GI-type mucinous borderline tumors. The existence of intermediate-type mucinous cystadenomas, and areas of transition from Müllerian-type to GI-type epithelium suggest that GI-type mucinous epithelium can arise from Müllerian duct derivatives or surface epithelium exhibiting Müllerian metaplasia in the ovary.
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http://dx.doi.org/10.1016/j.humpath.2020.11.011DOI Listing
December 2020

Use of selective PGE2 receptor antagonists on human endometriotic stromal cells and peritoneal macrophages.

Mol Hum Reprod 2020 Dec 3. Epub 2020 Dec 3.

Obstetrics and Gynecology, the University of Tokyo, 7-3-1 Hongo Bunkyo Tokyo, Japan.

Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to explore their potential as novel therapeutic strategies for endometriosis. The expression of PGE2 receptors (EP2 and EP4) in donated tissues from human ovarian endometriosis, adenomyosis and peritoneal endometriosis was examined using immunohistochemistry. Human endometriotic stromal cells (ESC) isolated from ovarian endometriotic tissue and peritoneal macrophages were treated with EP2 and EP4 antagonists. cAMP accumulation and the effect of EP antagonists was measured using cAMP assays. DNA synthesis in ESC was detected using bromodeoxyuridine incorporation analysis. IL-6 and IL-8 protein levels in ESC supernatants were measured using ELISAs. mRNA expression level for aromatase by ESC, and selected cytokines by peritoneal macrophages was measured using RT-PCR. EP2 and EP4 receptors were expressed in cells derived from control and diseased tissue, ovarian endometriotic, adenomyotic, and peritoneal lesions. A selective EP2 antagonist reduced DNA synthesis, cAMP accumulation and IL-1β-induced pro-inflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1β-induced IL-6 secretion and aromatase expression. In peritoneal macrophages, EP expression was elevated in endometriosis samples but the EP4 antagonist reduced cAMP levels and expression of VEGF, CXCL2 and CXCL3 mRNA. EP2 and EP4 are functioning in endometriosis lesions and peritoneal macrophages, and their selective antagonists can reduce EP-mediated actions, therefore, the EP antagonists are potential therapeutic agents for controlling endometriosis.
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http://dx.doi.org/10.1093/molehr/gaaa077DOI Listing
December 2020

Fertility preservation in patients receiving gonadotoxic therapies for systemic autoimmune diseases in Japan.

Mod Rheumatol 2021 Jan 18:1-8. Epub 2021 Jan 18.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: Gonadotoxic therapies, mainly cyclophosphamide, are used for the treatment of various systemic autoimmune diseases. In Japan, the number of patients who undergo gonadotoxic therapy for autoimmune diseases, fertility preservation procedures performed in these patients, and problems associated with performing such procedures have not been reported. This study was performed to address these issues.

Methods: A questionnaire was sent to Certified Educational Facilities of the Japanese Society of Rheumatology, and a single rheumatologist at each center completed the questionnaire.

Results: A total of 63 facilities completed the questionnaire. Between April 2014 and March 2019, a total of 1302 men and premenopausal women had received gonadotoxic therapies for systemic autoimmune disease. Nearly half of the respondents reported that gonadotropin releasing hormone analog therapy was available in their area. However, the availability of other fertility preservation procedures was limited, and the number of patients undergoing fertility preservation procedures was limited. 85.7% of the respondents responded that measures to preserve fertility in patients receiving gonadotoxic therapies for autoimmune diseases were inadequate.

Conclusions: A substantial number of patients are receiving gonadotoxic therapies for the treatment of autoimmune diseases in Japan, and those patients may not be receiving adequate care regarding their fertility.
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http://dx.doi.org/10.1080/14397595.2020.1856020DOI Listing
January 2021

CD206+ M2-Like Macrophages Are Essential for Successful Implantation.

Front Immunol 2020 23;11:557184. Epub 2020 Oct 23.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, Toyama, Japan.

Macrophages (MΦs) play important roles in implantation. Depletion of CD11b+ pan-MΦs in CD11b-diphtheria-toxin-receptor (DTR) mice is reported to cause implantation failure due to decreased progesterone production in the corpus luteum. However, of the M1 and M2, the type of MΦs that is important for implantation is unknown. In this study, we investigated the role of M2 MΦ in implantation using CD206-DTR mice. To deplete M2-MΦ, female CD206-DTR C57/BL6 mice were injected with DT before implantation. These M2-MΦ depleted mice (M2(-)) were naturally mated with Balb/C mice. As the control group, female C57/BL6 wild type (WT) mice injected with DT were mated with male Balb/C mice. The number of implantation sites and plasma progesterone levels at implantation were examined. Implantation-related molecule expression was determined using quantitative-PCR and immunohistochemistry of uterine tissues. The mRNA expression in the endometrial tissues of 38 patients with implantation failure was examined during the implantation window. In WT mice, CD206+M2-like MΦs accumulated in the endometrium at the implantation period, on embryonic (E) 4.5. In M2(-), the implantation number was significantly lower than that in control ( < 0.001, 7.8 ± 0.8 vs. 0.2 ± 0.4), although the plasma progesterone levels were not changed. Leukemia inhibitory factor (LIF) and CD206 mRNA expression was significantly reduced ( < 0.01), whereas the levels of TNFα were increased on E4.5 ( < 0.05). In M2(-), the number of Ki-67+ epithelial cells was higher than that in control at the pre-implantation period. Accelerated epithelial cell proliferation was confirmed by significantly upregulated uterine fibroblast growth factor (FGF)18 mRNA (P < 0.05), and strong FGF18 protein expression in M2(-) endometrial epithelial cells. Further, M2(-) showed upregulated uterine Wnt/β-catenin signals at the mRNA and protein levels. In the non-pregnant group, the proportion of M2-like MΦ to pan MΦ, CD206/CD68, was significantly reduced ( < 0.05) and the TNFα mRNA expression was significantly increased ( < 0.05) in the endometrial tissues compared to those in the pregnant group. CD206+ M2-like MΦs may be essential for embryo implantation through the regulation of endometrial proliferation via Wnt/β-catenin signaling.
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http://dx.doi.org/10.3389/fimmu.2020.557184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644510PMC
October 2020

Secretory leukocyte protease inhibitor and progranulin as possible regulators of cervical remodeling in pregnancy.

J Reprod Immunol 2021 Feb 1;143:103241. Epub 2020 Nov 1.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Japan.

Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24-26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (<35 mm) and with a history of threatened PD. In women with short cervix, cervical SLPI concentrations were positively correlated with inflammatory cytokines, interleukin-6 (R = 0.75) and interleukin-8 (R = 0.71). In pregnant mice, cervical mRNA expressions of PGRN and SLPI were increased in response to progesterone supplementation and were suppressed by a progesterone antagonist, mifepristone. Lipopolysaccharide-induced inflammation caused remarkable upregulation in cervical SLPI mRNA level but not in PGRN. Progesterone and local inflammation are the factors controlling expression levels of PGRN and SLPI at the cervix. The observed relationship of PGRN and SLPI levels in the cervical mucus with PD-related clinical parameters supports that those anti-inflammatory molecules possibly play a significant role in appropriate regulation of cervical remodeling.
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http://dx.doi.org/10.1016/j.jri.2020.103241DOI Listing
February 2021

Association of Women's Health Literacy and Work Productivity among Japanese Workers: A Web-based, Nationwide Survey.

JMA J 2020 Jul 13;3(3):232-239. Epub 2020 Jul 13.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Introduction: This study examined the relationship between health literacy (HL), women's health, and work productivity (i.e., absenteeism or presenteeism) among female workers in Japan.

Methods: In February 2018, a web-based, nationwide survey was conducted among registered survey company monitors. The questionnaire included women's HL, absenteeism, presenteeism, health behaviors for menstrual abnormalities and premenstrual syndrome (PMS), and demographic information. Overall, 2,596 monitors were randomly invited, and the survey included the first 2,000 respondents (average age = 35.8 years, SD = 8.1). An analysis of covariance (ANCOVA) was conducted to compare adjusted work productivity between two groups: the low-HL group and the high-HL group. The results were adjusted for age, education, employment status, number of children, and the presence of underlying gynecological diseases. Logistic regression analyses were performed to determine any differences in health behaviors for menstrual abnormalities or PMS between the two groups. The results were adjusted for age, education level, number of children, and employment status.

Results: The ANCOVA showed that the high-HL group had significantly less presenteeism and better performance when experiencing PMS (p < 0.001 and p < 0.013, respectively) compared to the low-HL group after adjusting for covariates. However, the results showed no significant differences in absenteeism between the two groups. Logistic regression showed that the high-HL group had a significantly higher odds ratio (OR) than the low-HL group in terms of health behaviors for menstrual abnormalities or PMS (OR 2.82 and 1.86, respectively) after adjusting for covariates.

Conclusions: Women's HL may contribute to decreased presenteeism and better health behaviors regarding the use of medicine or medical services.
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http://dx.doi.org/10.31662/jmaj.2019-0068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590399PMC
July 2020

Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation.

Biomedicines 2020 Oct 31;8(11). Epub 2020 Oct 31.

Department of Obstetrics and Gynecology, Kitasato University School of Medicine, Kanagawa 252-0375, Japan.

Background: Relaxin (RLX)-2, produced by the corpus luteum and placenta, is known to be potentially effective in fibrotic diseases of the heart, lungs, kidneys, and bladder; however, its effectiveness in endometriosis has not yet been investigated. In the present study, we conducted a comprehensive study on the effect of RLX-2 on endometriosis. We checked the expressions of LGR-7, a primary receptor of RLX-2, in endometriomas using immunohistochemistry. Endometriotic stromal cells (ESCs) purified from surgical specimens were used in in vitro experiments. The effects of RLX-2 on ESCs were evaluated by quantitative-PCR, ELISA, and Western blotting. Gel contraction assay was used to assess the contraction suppressive effect of RLX-2. The effect of RLX-2 was also examined in the endometriosis mouse model. LGR-7 was expressed in endometriotic lesions. In ESCs, RLX-2 increased the production of cAMP and suppressed the secretion of interleukin-8, an inflammatory cytokine, by 15% and mRNA expression of fibrosis-related molecules, plasminogen activator inhibitor-1 (PAI-1), and collagen-I by approximately 50% ( < 0.05). In the gel contraction assay, RLX-2 significantly suppressed the contraction of ESCs, which was cancelled by removing RLX-2 from the medium or by adding H89, a Protein Kinase A (PKA) inhibitor. In ESCs stimulated with RLX-2, p38 MAPK phosphorylation was significantly suppressed. In the endometriosis mouse model, administration of RLX-2 significantly decreased the area of the endometriotic-like lesion with decreasing fibrotic component compared to non-treated control ( = 0.01). RLX-2 may contribute to the control of endometriotic lesion by suppressing fibrosis, scar formation, and inflammation.
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http://dx.doi.org/10.3390/biomedicines8110467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693148PMC
October 2020

Uterine Epithelial Progesterone Receptor Governs Uterine Receptivity Through Epithelial Cell Differentiation.

Endocrinology 2020 12;161(12)

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Progesterone receptor (PGR) is indispensable for pregnancy in mammals. Uterine PGR responds to the heightened levels of ovarian progesterone (P4) after ovulation and regulates uterine gene transcription for successful embryo implantation. Although epithelial and stromal P4-PGR signaling may interact with each other to form appropriate endometrial milieu for uterine receptivity and the subsequent embryo attachment, it remains unclear what the specific roles of epithelial P4-PGR signaling in the adult uterus are. Here we generated mice with epithelial deletion of Pgr in the adult uterus (Pgrfl/flLtfCre/+ mice) by crossing Pgr-floxed and Ltf-Cre mice. Pgrfl/flLtfCre/+ mice are infertile due to the impairment of embryo attachment. Pgrfl/flLtfCre/+ uteri did not exhibit epithelial growth arrest, suggesting compromised uterine receptivity. Both epithelial and stromal expressions of P4-responsive genes decreased in Pgrfl/flLtfCre/+ mice during the peri-implantation period, indicating that epithelial Pgr deletion affects not only epithelial but stromal P4 responsiveness. In addition, uterine LIF, an inducer of embryo attachment, was decreased in Pgrfl/flLtfCre/+ mice. The RNA-seq analysis using luminal epithelial specimens dissected out by laser capture microdissection revealed that the signaling pathways related to extracellular matrix, cell adhesion, and cell proliferation are altered in Pgr fl/flLtf Cre/+ mice. These findings suggest that epithelial PGR controls both epithelial and stromal P4 responsiveness and epithelial cell differentiation, which provides normal uterine receptivity and subsequent embryo attachment.
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http://dx.doi.org/10.1210/endocr/bqaa195DOI Listing
December 2020

Use of Cap Analysis Gene Expression to detect human papillomavirus promoter activity patterns at different disease stages.

Sci Rep 2020 10 22;10(1):17991. Epub 2020 Oct 22.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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.
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http://dx.doi.org/10.1038/s41598-020-75133-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582169PMC
October 2020

A case of hemorrhagic shock occurred during dienogest therapy for uterine adenomyosis.

J Obstet Gynaecol Res 2020 Oct 8. Epub 2020 Oct 8.

Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo, Japan.

We present a case of hemorrhagic shock occurred during dienogest therapy for uterine adenomyosis which necessitated an emergency hysterectomy. The patient was a 45-year-old woman with adenomyosis. Magnetic resonance imaging showed type I adenomyosis measuring 10 cm. She had a history of intimal thrombectomy of pulmonary embolism and had been receiving warfarin and aspirin until the onset of the hemorrhagic shock. Following 6-month of gonadotropin-releasing hormone analogue, dienogest was commenced. Nine months after switching to dienogest, the patient experienced a persistent abnormal uterine bleeding for 2 weeks, eventually causing a massive bleeding and was transferred to our emergency room. A diagnosis of hemorrhagic shock with a severe anemia (hemoglobin 3.6 g/dL) was made. Despite blood transfusion and warfarin antagonization, continuous bleeding ≥150 g/h was not controlled. Emergent hysterectomy was opted and enabled hemostasis. Although the number of patients with adenomyosis who can avoid surgery by dienogest is increasing, care must be taken during dienogest therapy, especially in patients with anticoagulants and after gonadotropin-releasing hormone analogue treatment. To prevent such a critical event, careful management including patient education should be carried out.
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http://dx.doi.org/10.1111/jog.14519DOI Listing
October 2020

Clinical practice guidelines for the treatment of extragenital endometriosis in Japan, 2018.

J Obstet Gynaecol Res 2020 Oct 20. Epub 2020 Oct 20.

Department of Obstetrics and Gynecology, University of Tokyo, Tokyo, Japan.

The aim of this publication is to disseminate the clinical practice guidelines for the treatment of intestinal, bladder/ureteral, thoracic and umbilical endometriosis, already published in Japanese, to non-Japanese speakers. For developing the original Japanese guidelines, the clinical practice guideline committee was formed by the research team for extragenital endometriosis, which is part of the research program of intractable disease of the Japanese Ministry of Health, Labor and Welfare. The clinical practice guideline committee formulated eight clinical questions for the treatment of extragenital endometriosis, which were intestinal, bladder/ureteral, thoracic and umbilical endometriosis. The committee performed a systematic review of the literature to provide responses to clinical questions and developed clinical guidelines for extragenital endometriosis, according to the process proposed by the Medical Information Network Distribution Service. The recommendation level was determined using modified Delphi methods. The clinical practice guidelines were officially approved by the Japan Society of Obstetrics and Gynecology and the Japan Society of Endometriosis. This English version was translated from the Japanese version.
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http://dx.doi.org/10.1111/jog.14522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756675PMC
October 2020

Extra-pelvic endometriosis: A review.

Reprod Med Biol 2020 Oct 16;19(4):323-333. Epub 2020 Jul 16.

Faculty of Medicine Department of Obstetrics and Gynecology University of Tokyo Tokyo Japan.

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.
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http://dx.doi.org/10.1002/rmb2.12340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542014PMC
October 2020

Nationwide survey of fertility preservation in patients with hematological malignancies in Japan.

Int J Clin Oncol 2021 Feb 17;26(2):438-442. Epub 2020 Oct 17.

Department of Obstetrics and Gynecoclogy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Worldwide, there has been a growing interest in oncofertility issues. In 2017, the Japanese Society of Clinical Oncology published clinical practice guidelines for fertility preservation (FP) in cancer patients. We conducted a questionnaire survey to explore the FP practices among hematologists before the publication of this guideline.

Methods: We sent 427 designated cancer hospitals in Japan a questionnaire about FP treatment for patients with hematological malignancies between January and December 2014.

Results: Of these, 137 institutions responded, and 81 (19.0%) were included in the analysis. A total of 324 female and 441 male patients, aged < 40 years, were treated. The percentage of patients informed about FP was higher in patients treated with hematopoietic cell transplant than those without. Female patients were less likely to be informed about FP than male patients. FP was performed in a total of 27 female patients: 20 oocyte cryopreservation, 2 embryo cryopreservation, 3 ovarian tissue cryopreservation, and 2 ovarian shielding during total body irradiation. Sperm cryopreservation was performed in 115 male patients.

Conclusions: Our findings indicate the reality of fertility preservation in 2014, before the guideline were issued. Further studies are warranted to investigate the improvement in fertility preservation since the guidelines were issued.
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http://dx.doi.org/10.1007/s10147-020-01801-yDOI Listing
February 2021

Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment.

Sci Rep 2020 09 23;10(1):15523. Epub 2020 Sep 23.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Although it has been reported that uterine signal transducer and activator of transcription 3 (STAT3) is essential for embryo implantation, the exact roles of uterine epithelial and stromal STAT3 on embryo implantation have not been elucidated. To address this issue, we generated Stat3-floxed/Ltf-iCre (Stat3-eKO), Stat3-floxed/Amhr2-Cre (Stat3-sKO), and Stat3-floxed/Pgr-Cre (Stat3-uKO) mice to delete Stat3 in uterine epithelium, uterine stroma, and whole uterine layers, respectively. We found that both epithelial and stromal STAT3 have critical roles in embryo attachment because all the Stat3-eKO and Stat3-sKO female mice were infertile due to implantation failure without any embryo attachment sites. Stat3-eKO uteri showed indented structure of uterine lumen, indicating the role of epithelial STAT3 in slit-like lumen formation in the peri-implantation uterus. Stat3-sKO uteri exhibited hyper-estrogenic responses and persistent cell proliferation of the epithelium in the peri-implantation uterus, suggesting the role of stromal STAT3 in uterine receptivity. In addition, Stat3-uKO female mice possessed not only the characteristic of persistent epithelial proliferation but also that of indented structure of uterine lumen. These findings indicate that epithelial STAT3 controls the formation of slit-like structure in uterine lumen and stromal STAT3 suppresses epithelial estrogenic responses and cell proliferation. Thus, epithelial and stromal STAT3 cooperatively controls uterine receptivity and embryo attachment through their different pathways.
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http://dx.doi.org/10.1038/s41598-020-72640-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511330PMC
September 2020

The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells.

Oncol Lett 2020 Nov 24;20(5):153. Epub 2020 Aug 24.

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Previous studies have suggested that histone methylation can modulate carcinogenesis and cancer progression. For instance, the histone methyltransferase SET and MYND domain containing 2 (SMYD2) is overexpressed in several types of cancer tissue. The aim of the present study was to determine whether SMYD2 could serve a therapeutic role in ovarian clear cell carcinoma (OCCC). Reverse transcription-quantitative PCR was used to examine SMYD2 expression in 23 clinical OCCC specimens. Moreover, OCCC cell proliferation and cell cycle progression were also examined following small interfering RNA-mediated SMYD2 silencing or treatment with a selective SMYD2 inhibitor. SMYD2 was significantly upregulated in clinical OCCC specimens, compared with normal ovarian tissue. In addition, SMYD2 knockdown decreased cell viability as determined via a Cell Counting Kit-8 assay. Moreover, the proportion of cells in the sub-G phase increased following SMYD2 knockdown, suggesting increased apoptosis. Treatment with the SMYD2 inhibitor LLY-507 suppressed OCCC cell viability. These results suggested that SMYD2 could promote OCCC viability, and that SMYD2 inhibition induced apoptosis in these cells. Thus, SMYD2 inhibitors may represent a promising molecular targeted approach for OCCC treatment.
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http://dx.doi.org/10.3892/ol.2020.12014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471656PMC
November 2020

Polyhydramnios is associated with postnatal dysphagia determining short-term prognosis of the newborn with 22q11.2 deletion syndrome - A case series analysis.

Taiwan J Obstet Gynecol 2020 Sep;59(5):744-747

Department of Obstetrics and Gynecology, Faculty of Medicine, Japan.

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.
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http://dx.doi.org/10.1016/j.tjog.2020.07.021DOI Listing
September 2020

Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: a randomized, double-blind, placebo-controlled study.

Fertil Steril 2021 Feb 7;115(2):397-405. Epub 2020 Sep 7.

Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Yonago, Japan.

Objective: To evaluate the efficacy and safety of three dose levels of relugolix, a gonadotropin-releasing hormone receptor antagonist, compared with placebo and leuprorelin in women with endometriosis-associated pain.

Design: Phase 2, multicenter, randomized, double-blind, placebo-controlled study.

Setting: Hospitals and clinics.

Patient(s): Adult premenopausal women with endometriosis who had dysmenorrhea and endometriosis-associated pelvic pain.

Intervention(s): During a 12-week treatment period, patients received relugolix 10 mg (n = 103), 20 mg (n = 100), or 40 mg (n = 103) as a daily oral dose; placebo (n = 97) as a daily oral dose; or leuprorelin 3.75 mg (n = 80) as a monthly subcutaneous injection.

Main Outcome Measure(s): Primary endpoint was the change from baseline in mean visual analog scale score for pelvic pain during 28 days before the end of treatment.

Result(s): The mean changes in mean visual analog scale score for pelvic pain were -3.8 mm in the placebo group; -6.2, -8.1, and -10.4 mm in the relugolix 10-mg, 20-mg, and 40-mg groups; respectively; and -10.6 mm in the leuprorelin group. The major adverse events with relugolix were hot flush, metrorrhagia, menorrhagia, and irregular menstruation, and bone mineral density decrease in a dose-response manner, which were also observed in the leuprorelin group with a frequency comparable with that in the relugolix 40-mg group.

Conclusion(s): Oral administration of relugolix alleviated endometriosis-associated pain in a dose-response manner and was generally well tolerated. Relugolix 40 mg demonstrated efficacy and safety comparable with those of leuprorelin.

Clinical Trial Registration Number: NCT01458301.
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http://dx.doi.org/10.1016/j.fertnstert.2020.07.055DOI Listing
February 2021