Initiatives and achievements of the Japanese Society of Obstetrics and Gynecology, Obstetrics and Gynecology MIRAI Committee 2020.

BACKGROUNDS: In 2013, the total number of obstetrician-gynecologists decreased. The Japanese Society of Obstetrics and Gynecology established the Obstetrics and Gynecology MIRAI Committee in 2015. Within the MIRAI Committee, Japanese Trainees in Obstetrics and Gynecology (JTOG) was established; it was comprised of 20 promising young obstetrician-gynecologists recommended from regions across Japan. The office term is 2 years. OBJECTIVE: The purpose of this report is to learn and inform about the results of MIRAI's activities. METHODS: We surveyed the trends in new obstetrician-gynecologists and also matched each seminar participant with them. RESULT: The number of new memberships has been increasing since the nadir in 2016. In particular, there are over 100 more new physicians specializing in the field in 2020 than there were at the nadir in 2016. It was revealed that approximately 50% of the participants in the summer school specialized in obstetrics and gynecology. Furthermore, approximately 70% of POP2 participants specialized in obstetrics and gynecology, which shows that these two recruitment seminars are extraordinarily effective events that result in an increase in the number of new obstetricians and gynecologists. CONCLUSION: We conclude that the activities of this MIRAI Committee and JTOG have been effective. With the spread of COVID-19 and the inability of obstetrician-gynecologists and students/clinical trainees to perform social distancing, it is currently difficult to hold hands-on seminars. However, we hope that new JTOG members will be able to create a new seminar format.

Trophoblast-Specific Conditional Atg7 Knockout Mice Develop Gestational Hypertension.

Hypertensive disorder of pregnancy (HDP) is a serious pregnancy complication that is life threatening to both the mother and fetus. Understanding HDP pathophysiology is important for developing medical treatments. This study demonstrates the involvement of autophagy deficiency in adverse maternal and fetal outcomes using trophoblast-specific autophagy related (Atg)7, an autophagy-related protein, knockout mice. Atg7 conditional knockout (cKO) placentas were significantly smaller than controls in the spongiotrophoblast layer but not the labyrinth layer, which significantly elevated blood pressure in dams. A marker of autophagy deficiency, sequestosome 1/p62, was accumulated in giant trophoblast cells and in the spongiotrophoblast layer, accompanying increased apoptosis. However, neither proteinuria in dams nor fetal growth restriction was observed. Regarding trophoblast function, the number of trophoblasts migrating into the maternal decidua was significantly reduced, and the wall/lumen ratio of the spiral arteries was significantly increased in cKO placentas, suggesting shallow trophoblast invasion and inadequate vascular remodeling. The relative expression of placental growth factor mRNA was significantly decreased in cKO placentas compared with the control, likely causing poor placentation; however, other factors were unchanged in cKO placentas. This is the first report of autophagy deficiency leading to impaired placentation complicated by maternal HDP attributable to trophoblast dysfunction, and it suggests that placental autophagy is required for normal placentation.

Current Understanding of Autophagy in Pregnancy.

Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis under environmental stress. Intracellular control is exerted to produce energy or maintain intracellular protein quality controls. Autophagy plays an important role in embryogenesis, implantation, and maintenance of pregnancy. This role includes supporting extravillous trophoblasts (EVTs) that invade the decidua (endometrium) until the first third of uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions in early pregnancy. In addition, autophagy inhibition has been linked to poor placentation-a feature of preeclamptic placentas-in a placenta-specific autophagy knockout mouse model. Studies of autophagy in human placentas have revealed controversial results, especially with regard to preeclampsia and gestational diabetes mellitus (GDM). Without precise estimation of autophagy flux, wrong interpretation would lead to fixed tissues. This paper presents a review of the role of autophagy in pregnancy and elaborates on the interpretation of autophagy in human placental tissues.

Role of autophagy in oocytogenesis, embryogenesis, implantation, and pathophysiology of pre-eclampsia.

Autophagy is a well-conserved mechanism in cells from yeast to mammals, and autophagy maintains homeostasis against stress. The role of autophagy was originally shown to be a mechanism of energy production under starvation. In fact, multiple lines of evidence reveal that autophagy has numerous functions, such as protection from stress, energy regulation, immune regulation, differentiation, proliferation, and cell death. In the field of reproduction, the role of autophagy in implantation, embryogenesis, placentation, and delivery has become clearer. In addition, recent study has elucidated that the placenta has the ability to protect extraplacental cells from virus infection by activating autophagy. During resent research into autophagy, several issues have occurred in the interpretation of the autophagy status. In this review, we discuss the relation between autophagy and reproductive events, and show the importance of autophagy for placentation and pre-eclampsia.

Inhibition of autophagy in theca cells induces CYP17A1 and PAI-1 expression via ROS/p38 and JNK signalling during the development of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a clinical syndrome characterized by hyperandrogenism, oligo/anovulation, and polycystic ovary. Autophagy is an intracellular system that degrades cytosolic proteins and organelles. The relationship between autophagy and PCOS has not been clarified. We found that p62 and ubiquitin were significantly increased in theca cells of women with PCOS using immunohistochemistry. Autophagy inhibition by palmitic acid and chloroquine in bovine theca cells increased p62 and ubiquitin and induced the expression of cytochrome P450 17A1 (CYP17A1) and plasminogen activator inhibitor-1 (PAI-1) mRNA. Furthermore, palmitic acid and chloroquine exposure significantly increased reactive oxygen species (ROS) and activated p38 and c-Jun N-terminal kinase (JNK). Inhibition of p38 and JNK significantly reduced CYP17A1 and PAI-1 mRNA expression. We showed that inhibition of autophagy in theca cells may have contributed to the pathogenesis of PCOS, based on CYP17A1 and PAI-1 mRNA expression via the ROS/p38 and JNK signalling pathways.

Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts.

Pregnancy is a stress factor culminating into mild endoplasmic reticulum (ER) stress, which is necessary for placental development. However, excessive or chronic ER stress in pre-eclamptic placentas leads to placental dysfunction. The precise mechanisms through which excessive ER stress impacts trophoblasts are not well understood. Here, we showed that ER stress reduces the number of lysosomes, resulting in inhibition of autophagic flux in trophoblast cells. ER stress also disrupted the translocation of lysosomes to the surface of trophoblast cells, and inhibited lysosomal exocytosis, whereby the secretion of lysosomal-associated membrane protein 1 (LAMP1) into culture media was significantly attenuated. In addition, we found that serum LAMP1 and beta-galactosidase levels were significantly decreased in pre-eclampsia patients compared to normal pregnant women, potentially indicating lysosomal dysfunction through ER stress in pre-eclamptic placentas. Thus, we demonstrated that excessive ER stress essentially disrupts homeostasis in trophoblasts in conjunction with autophagy inhibition by lysosomal impairment.

Autophagy is a new protective mechanism against the cytotoxicity of platinum nanoparticles in human trophoblasts.

Nanoparticles are widely used in commodities, and pregnant women are inevitably exposed to these particles. The placenta protects the growing fetus from foreign or toxic materials, and provides energy and oxygen. Here we report that autophagy, a cellular mechanism to maintain homeostasis, engulfs platinum nanoparticles (nPt) to reduce their cytotoxicity in trophoblasts. Autophagy was activated by nPt in extravillous trophoblast (EVT) cell lines, and EVT functions, such as invasion and vascular remodeling, and proliferation were inhibited by nPt. These inhibitory effects by nPt were augmented in autophagy-deficient cells. Regarding the dynamic state of nPt, analysis using ICP-MS demonstrated a higher accumulation of nPt in the autophagosome-rich than the cytoplasmic fraction in autophagy-normal cells. Meanwhile, there were more nPt in the nuclei of autophagy-deficient cells, resulting in greater DNA damage at a lower concentration of nPt. Thus, we found a new protective mechanism against the cytotoxicity of nPt in human trophoblasts.

Chemical pleurodesis with autologous blood and freeze-dried concentrated human thrombin improved spontaneous pneumothorax and thoracic endometriosis: The first case involving a pregnant woman.

OBJECTIVE: Spontaneous pneumothorax combined with thoracic endometriosis is a rare condition during pregnancy. We present a case of chemical pleurodesis with autologous blood and freeze-dried concentrated human thrombin during pregnancy. CASE REPORT: This report presents a case of spontaneous pneumothorax combined with thoracic endometriosis that arose at 22 weeks' gestation in a 35-year-old female. The initial chest drainage was unsuccessful. At 25 weeks' gestation, video-assisted thoracoscopic surgery was performed and revealed endometriosis in the thoracic cavity. Since the leak persisted, chemical pleurodesis was performed with autologous blood and freeze-dried concentrated human thrombin at 28 weeks' gestation. The leak improved markedly and did not recur. CONCLUSION: This is the first case report about chemical pleurodesis with autologous blood and freeze-dried concentrated human thrombin during pregnancy. This procedure might contribute to the management of pneumothorax in pregnant women.

Autophagy regulation in preeclampsia: Pros and cons.

Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis against stress. This process has two main functions: producing energy and quality control of intracellular proteins. During early pregnancy, extravillous trophoblasts (EVTs) invade the uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions. Autophagy activation is observed in EVTs under these conditions, suggesting that EVTs use autophagy for adjusting to such harsh conditions. On the other hand, soluble endoglin, which is increased in sera in preeclamptic cases, inhibits autophagy in vitro, resulting in suppression of EVT functions, invasion and vascular remodeling. In addition, p62/SQSTM1, a substrate degraded by autophagy, accumulates in EVTs in preeclamptic placental biopsy samples, exhibiting impaired autophagy in vivo. There are, however, some opposing reports in which autophagy activation, an increase of autophagy vacuoles or LC3 dots, was more frequently observed in preeclamptic or FGR placentas than in normal pregnancy. Thus, changes in autophagy status are seen in preeclamptic placentas, but the mechanism by which autophagy modulates biological changes in the placentas is still unknown. Recently, there is increasing evidence that autophagy is involved in maintaining pregnancy. This review introduces the role of autophagy for maintaining pregnancy and its correlation with preeclampsia.

Prenatal diagnosis of enterolithiasis at 18 weeks: multiple foci of intraluminal calcified meconium within echogenic bowel.

Enterolithiasis is an uncommon finding of a dilated hyperechogenic bowel with multiple ball-like echogenic structures at a routine prenatal check-up using ultrasonography. We here report a case of prenatally diagnosed enterolithiasis at 18 weeks of gestation, showing multiple hyperechogenic foci rolling within the bowel fluid after peristalsis. The size of the dilated bowel gradually increased during pregnancy. Magnetic resonance image demonstrated the dilated lower bowel with blind-ending rectum. A postnatal contrast medium study with retrograde urethrography revealed a middle imperforate anus and a rectourethral fistula. A careful examination, even before 20 weeks of gestation, is extremely useful in demonstrating intraluminal coarse calcifications within an echogenic bowel.