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Chronic endometritis (CE) and endometrial dysbiosis (ED) are major causes of recurrent implantation failure (RIF). CE is diagnosed via hysteroscopy or the endometrial CD138 test; ED is examined using endometrial microbiome testing with next-generation sequencing. ED is characterized by a reduction in Lactobacillus species . However, correlations between the results of the three tests and the efficacy of treatment against CE and ED in pregnancy outcomes remain unclear. We analyzed 73 patients with RIF who underwent all three tests (hysteroscopy, endometrial CD138 test, and endometrial microbiome test). Patients with CE received antibiotics, whereas those with ED received antibiotics and vaginal Lactobacillus probiotics. The incidences of CE diagnosed using hysteroscopy and the CD138 test were 56.2 and 49.3%, respectively, and the prevalence of ED was 53.4%. No correlations were observed among the test-positive individuals in these three tests. Among patients with ED, 88.9% had a post-treatment clinical pregnancy, a significantly higher rate than that in patients without ED (p = 0.021). Multivariate analysis demonstrated that ED was associated with clinical pregnancy (odds ratio (OR): 6.29, p = 0.031). In conclusion, the three tests detected different populations of patients with RIF. ED diagnosed using the endometrial microbiome test was associated with favorable pregnancy outcomes after testing.

Adenomyosis often causes dysmenorrhea in women of reproductive age. Progestins such as levonorgestrel intrauterine system (LNG-IUS) are often used for treatment, but some patients experience progesterone resistance, showing poor treatment response. However, the clinical characteristics of progesterone-resistant and progesterone-sensitive patients with symptomatic adenomyosis remain unclear. We analyzed data of 69 patients with adenomyosis treated with LNG-IUS. Dysmenorrhea was quantified using linear visual analog scale (VAS) scoring, and progesterone resistance was interpreted as continued dysmenorrhea during LNG-IUS treatment. The rate of change in VAS scores of dysmenorrhea was calculated: patients with the bottom 25% improvement were defined as progesterone-resistant group, and those with the top 25% improvement as progesterone-sensitive group. The localization of adenomyosis lesions was evaluated by magnetic resonance imaging (MRI) and classified as advanced (localized in all layers of the myometrium), extrinsic (localized on the uterine serosa side), and intrinsic (localized on the endometrial side) subtypes. Progesterone-resistant group had a significantly lower incidence of intrinsic adenomyosis (7.7% vs. 69.2%, p  = 0.004) and a tendency toward a higher incidence of advanced adenomyosis (61.5% vs. 23.1%, p  = 0.111) compared with progesterone-sensitive group. Progesterone-sensitive group showed significant improvement of dysmenorrhea 1 month after starting LNG-IUS treatment ( p  < 0.001). These findings indicate that the responsiveness to LNG-IUS treatment can be determined 1 month after starting the treatment and that intrinsic adenomyosis is a favorable prognostic factor for progestin treatment with LNG-IUS, while advanced and extrinsic adenomyosis are predictors for progesterone resistance.

Background Adenomyosis is a common gynecological disease in women of reproductive age and causes various symptoms such as dysmenorrhea and heavy menstrual bleeding. However, the influence of pregnancy on the progression of adenomyosis remains unclear. The insight into whether the size of adenomyosis is increased, decreased, or unchanged during pregnancy is also undetermined. The current study aimed to evaluate the influence of pregnancy in patients with symptomatic adenomyosis. Methods This study retrospectively enrolled patients diagnosed with adenomyosis by magnetic resonance imaging between 2015 and 2022 at The University of Tokyo Hospital. Uterine size changes were evaluated by two imaging examinations. In the pregnancy group, the patients did not receive any hormonal and surgical treatments, except cesarean section, but experienced pregnancy and delivery between the first and second imaging examinations. In the control group (nonpregnancy group), the patients experienced neither hormonal and surgical treatments nor pregnancy from at least 1 year before the first imaging to the second imaging. The enlargement rate of the uterine size per year (percentage) was calculated by the uterine volume changes (cm 3 ) divided by the interval (years) between two imaging examinations. The enlargement rate of the uterine size per year was compared between the pregnancy group and the control group. Results Thirteen and 11 patients with symptomatic adenomyosis were included in the pregnancy group and in the control group, respectively. The pregnancy group had a lower enlargement rate per year than the control group (mean ± SE: −7.4% ± 3.6% vs. 48.0% ± 18.5%, P  < 0.001), indicating that the size of the uterus with adenomyosis did not change in the pregnancy group. Conclusions Pregnancy is associated with reduced progression of symptomatic adenomyosis.

Uterine inversion is a rare puerperal event in the third stage of labor. Nonpuerperal uterine inversion is even rarer and is mainly caused by uterine fibroids, uterine sarcoma, or endometrial cancer. This is the first report of uterine inversion caused by cervical cancer. A 67-year-old woman presented with a 10 cm pelvic mass. Contrast-enhanced magnetic resonance imaging revealed uterine inversion, which was preoperatively diagnosed to be caused by endometrial cancer and was treated using an extended abdominal hysterectomy. Postoperative histopathological examination revealed that the primary tumor was a squamous cell carcinoma with coexistent high-grade squamous intraepithelial lesions and small-cell neuroendocrine carcinoma. Immunostaining was diffusely positive for p16 and negative for estrogen receptors. The postoperative diagnosis was cervical squamous cell carcinoma. Our observations suggested that cervical carcinoma can cause uterine inversion by invading the corpus.

Embryo implantation is crucial for successful pregnancy, requiring appropriate uterine responses to implantation-competent blastocysts. Molecular communication at the maternal–fetal junction governs this process. Leukemia inhibitory factor (Lif) plays a pivotal role in implantation across species. Lif is abundantly expressed in the glandular epithelium during blastocyst-receptive phase and is induced in the stroma surrounding attached blastocysts. While diminished Lif expression leads to infertility, its influence on peri-implantation uteri remains unclear. Therefore, we investigated the role of Lif in uterine physiology using its uterine-specific knockout (uKO) and uterine epithelial-specific KO (eKO) in mice. Lif eKO and uKO mice displayed infertility owing to failed embryo attachment. Recombinant Lif supplementation rescued the reproductive phenotype of Lif eKO mice, but not Lif uKO mice; however, recombinant Lif injection rescued embryo attachment in Lif uKO mice. RNA-seq analysis indicated that Lif governs uterine epithelial genes, but not embryonic genes, to facilitate embryo attachment via activating nuclear Stat3. Concordantly, three-dimensional imaging of the uterine epithelium revealed that luminal closure and crypt formation are regulated by the uterine Lif–Stat3 axis as well as the presence of blastocysts. Collectively, our findings shed light on previously unknown mechanism on how Lif influences uterine functions molecularly and physiologically during early pregnancy.

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.

Macroautophagy (hereafter referred to as autophagy) requires the coordinated action of approximately 20 autophagy-related (ATG) genes. Duplication of ATG genes has had a major impact on the evolution of the autophagy pathway among major lineages. One duplication hotspot is in vertebrates. However, the exact duplication timing, post-duplication evolutionary divergence patterns, and its relation to functional differences among paralogs have not been investigated in detail. Here, we demonstrate that most ATG genes were likely duplicated by whole-genome duplication events near the root of vertebrates. We compared the sequence and gene expression divergence between paralogs and categorized the evolutionary fates (i.e., how ancestral function is divided between paralogs). Within the paralog pairs that evolved most asymmetrically, namely BECN, WIPI (WIPI1 and WIPI2), and ATG16, one paralog likely retained the ancestral function, allowing the other to evolve under less constraint. While no obvious asymmetry was observed between ATG9A and ATG9B in non-mammalian vertebrates, ATG9B experienced marked sequence divergence and expression level reduction in mammals, suggesting a shift in balance. Expression patterns among the ULK-1 (ULK1 and ULK2), GABARAP (GABARAP and GABARAPL1), and LC3 (LC3A and LC3B) pairs were more consistent with hypofunctionalization/dosage sharing, such that ancestral function depends on both paralogs. We also demonstrate that both ULK1 and ULK2 can support autophagy, whereas only BECN1, but not BECN2, has autophagic function and discuss the relationship between autophagic function and evolutionary divergence between paralogs. The present detailed analysis of ATG gene duplication in vertebrates provides a critical time-line for interpreting functional differentiation between homologs.

This retrospective study aimed to evaluate the effects of various patient characteristics, including cardiothoracic ratio (CTR), on vessel enhancement in coronary computed tomography (CT) angiography (CCTA). We screened the 306 patients who underwent CCTA with 80-detector row CT for clinical assessment due to suspected or confirmed coronary artery disease. The change in iodine dose per contrast enhancement (IDCE) (mgI/HU) was calculated as the product of 300 mgI multiplied by total body weight (TBW), divided by the change in Hounsfield unit (HU) obtained by subtracting the HU value. CTR was measured on CT images in scout view. Subsequently, we conducted linear regression analyses among age, sex, body size, CTR, heart rate, scan length, and scan start on IDCE. To evaluate the effects of age, sex, BSA, heart rate, scan length, scan start, and CTR on the IDCE, we used multivariate regression analysis. A significant positive correlation was observed between coronary artery IDCE and patient age ( r 2 = 0.07, p  < 0.01). Linear regression analysis revealed inverse correlations between coronary artery IDCE and height ( r 2 =  − 0.30), total body weight ( r 2 =  − 0.53), body mass index ( r 2 =  − 0.23), body surface area (BSA; r 2 =  − 0.56), lean body weight ( r 2 =  − 0.50), scan length ( r 2 =  − 0.01), and CTR ( r 2 =  − 0.02). There was no significant correlation between coronary artery IDCE and heart rate ( r 2 = 0.00, p  = 0.74) or scan start ( r 2 =  − 0.01, p  = 0.10). Standardized regression coefficients showed that the effect of BSA (− 0.71) was greater than that of other variables (CTR − 0.14, scan start − 0.10). The results of this study showed that patient BSA, CTR, and start scan significantly affect the IDCE of the coronary artery on CCTA images.