Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal–embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph–ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.

Although the human papillomavirus (HPV) vaccine is effective for preventing cervical cancers, this vaccine does not eliminate pre‐existing infections, and alternative strategies have been warranted. Here, we report that FOXP4 is a new target molecule for differentiation therapy of cervical intraepithelial neoplasia (CIN). An immunohistochemical study showed that FOXP4 was expressed in columnar epithelial, reserve, and immature squamous cells, but not in mature squamous cells of the normal uterine cervix. In contrast with normal mature squamous cells, FOXP4 was expressed in atypical squamous cells in CIN and squamous cell carcinoma lesions. The FOXP4‐positive areas significantly increased according to the CIN stages from CIN1 to CIN3. In monolayer cultures, downregulation of FOXP4 attenuated proliferation and induced squamous differentiation in CIN1‐derived HPV 16‐positive W12 cells via an ELF3‐dependent pathway. In organotypic raft cultures, FOXP4‐downregulated W12 cells showed mature squamous phenotypes of CIN lesions. In human keratinocyte‐derived HaCaT cells, FOXP4 downregulation also induced squamous differentiation via an ELF3‐dependent pathway. These findings suggest that downregulation of FOXP4 inhibits cell proliferation and promotes the differentiation of atypical cells in CIN lesions. Based on these results, we propose that FOXP4 is a novel target molecule for nonsurgical CIN treatment that inhibits CIN progression by inducing squamous differentiation.

Visualization of specific cells in the three-dimensional organ architecture is one of the key steps to develop our knowledge about pathophysiological mechanisms in various organs. In this study, we successfully obtained stereoscopic whole images of the intrauterine murine embryo and placenta through the uterus using a modified tissue clearing CUBIC method. By this procedure, we can recognize the three-dimensional relationships among various tissues within the pregnant uterus and analyze free-angle images of cross-sections with single-cell resolution using a computer system. Based on these data, we can select optimal cross-section angles and then produce the corresponding tissue slices that are adequate for further immunohistochemical examination. Furthermore, using transgenic mice, distinct images of an EGFP-positive embryo and the placenta can be obtained, confirming the precise three-dimensional location of invading trophoblasts in the feto-maternal interface in the uterus. These results indicate that this procedure will significantly contribute to analyzing pathophysiological mechanisms in reproductive organs.

Aim: To evaluate obstetric outcomes in embryo transfer (ET) during estrogen with progestin hormone replacement therapy (HRT) cycles using assisted reproductive technology (ART). Methods: Of the 118 singleton pregnancies conceived with ART and delivered between January 2015 and December 2017, we reviewed the data of 87 cases that had information on HRT at the time of ET. Data on pregnancy outcomes included the presence of small for gestational age fetuses, hypertensive disorders of pregnancy, placenta previa (including low-lying placenta), placental abruption and placenta accreta spectrum (including placenta accreta, placenta increta and placenta percreta). We investigated the relationship between HRT cycles and adverse placental outcomes (placenta accreta spectrum, placental abruption, placenta previa, hypertensive disorders of pregnancy and small for gestational age fetuses). We then analyzed the associations that correlated with adverse placental outcomes. Results: Patients with ET during HRT cycles were more likely to have placenta accreta spectrum. During the study period, 87 out of 118 singleton live births using ART had information on HRT (60 HRT cycles and 27 ovulation cycles). The incidence of placenta accreta spectrum was significantly higher in the HRT cycle group than in the ovulation cycle group (HRT cycle, 31.7% [19 of 60] vs ovulation cycle, 7.4% [2 of 27]; P < 0.01). Conclusion: The obstetric outcomes occurring in pregnancies involving HRT use may differ among ET cycles. ET during HRT cycles were associated with adverse obstetric outcomes due to placenta accreta spectrum. The potential interaction between HRT cycles and adverse placental events is novel and warrants further investigation.