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Although it has been reported that hypoxia inducible factor 2 [alpha] (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone ([P.sub.4]) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2a-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2a (Hif2a-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2a (Hif2a-eKO mice) showed normal fertility, suggesting the importance of stromal HIF2[alpha] in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2a-uKO stroma at the attachment site, suggesting that stromal HIF2[alpha] regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2[alpha] allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal., Introduction Infertility is a worldwide issue estimated to affect up to 30% of couples in both developed and developing countries (1). Infertile patients undergoing in vitro fertilization and embryo transfer [...]

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 (Pgr fl/fl Ltf Cre/+ mice) by crossing Pgr -floxed and Ltf-Cre mice. Pgr fl/fl Ltf Cre/+ mice are infertile due to the impairment of embryo attachment. Pgr fl/fl Ltf Cre/+ uteri did not exhibit epithelial growth arrest, suggesting compromised uterine receptivity. Both epithelial and stromal expressions of P4-responsive genes decreased in Pgr fl/fl Ltf Cre/+ 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 Pgr fl/fl Ltf Cre/+ 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/fl Ltf  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. [ABSTRACT FROM AUTHOR]

Rationale, aims, and objectives: The aim of this observational study is to identify factors by which some pancreatic cystic lesions (PCLs) were undetectable at transabdominal ultrasonography (TAUS), using magnetic resonance imaging (MRI) as reference standard. Methods: The database for 781 consecutive subjects who underwent a health checkup including fat computed tomography and upper abdominal MRI as option was searched. The presence of fatty liver and fatty pancreas was diagnosed by TAUS, and atrophic pancreas was determined by reevaluating the image of the pancreas in the chest computed tomography for screening. Subjects with PCL detected and those undetected at TAUS were statistically compared in clinical characteristics. Results: The prevalence of PCL detected at MRI was 17.8% in the general population. Multivariate logistic regression analysis showed that fatty liver, body mass index, and the size of PCL were significantly associated with the factors influencing the visualization of PCL at TAUS (odds ratio [OR]: 0.337, 95% confidence interval [CI]: 0.154‐0.734, P = 0.006; OR: 0.852, 95% CI: 0.737‐0.985, P = 0.030; OR:1.120, 95% CI: 1.045‐1.200, P =.001). Thirty‐six PCLs (64.3%) in a total of 56 PCLs were undermeasured by TAUS. Additionally, nine (56%) out of 16 PCLs (≥ 15 mm) were undermeasured by 5 mm or more by TAUS, although a significantly higher detection rate was observed for PCLs (≥ 15 mm) in comparison with that for PCLs (< 15 mm) (80% vs 33.6%, P =.000). Conclusions: It should be noted that coexisting fatty liver may lower the detection of PCL, and its size may be underestimated by TAUS. [ABSTRACT FROM AUTHOR]

Embryo implantation is crucial for ensuring a successful pregnancy outcome and subsequent child health. The intrauterine environment during the peri-implantation period shows drastic changes in gene expression and cellular metabolism in response to hormonal stimuli and reciprocal communication with embryos. Here, we performed spatial transcriptomic analysis to elucidate the mechanisms underlying embryo implantation. Transcriptome data revealed that lipid metabolism pathways, especially arachidonic acid-related (AA-related) ones, were enriched in the embryo-receptive luminal epithelia. Cyclooxygenases (COXs), rate-limiting enzymes involved in prostaglandin production by AA, were spatiotemporally regulated in the vicinity of embryos during implantation, but the role of each COX isozyme in the uterus for successful pregnancy was unclear. We established uterine-specific COX2-knockout (uKO) and COX1/uterine COX2-double-KO (COX1/COX2-DKO) mice. COX2 uKO caused deferred implantation with failed trophoblast invasion, resulting in subfertility with reduced pregnancy rates and litter sizes. COX1/COX2 DKO induced complete infertility, owing to abrogated embryo attachment. These results demonstrate that both isozymes have distinct roles during embryo implantation. Spatial transcriptome and lipidome analyses revealed unique profiles of prostaglandin synthesis by each COX isozyme and spatiotemporal expression patterns of downstream receptors throughout the endometrium. Our findings reveal previously unappreciated roles of COXs at the fetomaternal interface to establish early pregnancy.

Functions of tumor suppressor p53 and its negative regulator mouse double minute 2 homolog (Mdm2) in ovarian granulosa cells remain to be elucidated, and the current study aims at clarifying this issue. Mice with Mdm2 deficiency in ovarian granulosa cells [ Mdm2-loxP/ progesterone receptor ( Pgr)-Cre mice] were infertile as a result of impairment of oocyte maturation, ovulation, and fertilization, and those with Mdm2/p53 double deletion in granulosa cells ( Mdm2-loxP/ p53-loxP/ Pgr-Cre mice) showed normal fertility, suggesting that p53 induction in the ovarian granulosa cells is detrimental to ovarian function by disturbing oocyte quality. Another model of Mdm2 deletion in ovarian granulosa cells ( Mdm2-loxP/ anti-Mullerian hormone type 2 receptor-Cre mice) also showed subfertility as a result of the failure of ovulation and fertilization, indicating critical roles of ovarian Mdm2 in ovulation and fertilization. Mdm2-p53 pathway in cumulus granulosa cells transcriptionally controlled an orphan nuclear receptor steroidogenic factor 1 (SF1), a key regulator of ovarian function. Importantly, MDM2 and SF1 levels in human cumulus granulosa cells were positively associated with the outcome of oocyte maturation and fertilization in patients undergoing infertility treatment. These findings suggest that the Mdm2-p53-SF1 axis in ovarian cumulus granulosa cells directs ovarian function by affecting their neighboring oocyte quality.-Haraguchi, H., Hirota, Y., Saito-Fujita, T., Tanaka, T., Shimizu-Hirota, R., Harada, M., Akaeda, S., Hiraoka, T., Matsuo, M., Matsumoto, L., Hirata, T., Koga, K., Wada-Hiraike, O., Fujii, T., Osuga, Y. Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality.