Endometriosis, a heterogeneous, inflammatory, and estrogen-dependent gynecological disease defined by the presence and growth of endometrial tissues outside the lining of the uterus, affects approximately 5-10% of reproductive-age women, causing chronic pelvic pain and reduced fertility. Although the etiology of endometriosis is still elusive, emerging evidence supports the idea that immune dysregulation can promote the survival and growth of retrograde endometrial debris. Peritoneal macrophages and natural killer (NK) cells exhibit deficient cytotoxicity in the endometriotic microenvironment, leading to inefficient eradication of refluxed endometrial fragments. In addition, the imbalance of T-cell subtypes results in aberrant cytokine production and chronic inflammation, which contribute to endometriosis development. Although it remains uncertain whether immune dysregulation represents an initial cause or merely a secondary enhancer of endometriosis, therapies targeting altered immune pathways exhibit satisfactory effects in preventing disease onset and progression. Here, we summarize the phenotypic and functional alterations of immune cells in the endometriotic microenvironment, focusing on their interactions with microbiota and endocrine and nervous systems, and how these interactions contribute to the etiology and symptomology of endometriosis.
Female ; Humans ; Endometriosis/metabolism* ; Killer Cells, Natural/metabolism* ; T-Lymphocytes/metabolism* ; Estrogens ; Endometrium/metabolism*

Corded and hyalinized endometrioid carcinoma (CHEC) is a morphologic variant of endo-metrioid adenocarcinoma. The tumor exhibits a biphasic appearance with areas of traditional low-grade adenocarcinoma merging directly with areas of diffuse growth composed of epithelioid or spindled tumor cells forming cords, small clusters, or dispersed single cells. It is crucial to distinguish CHEC from its morphological mimics, such as malignant mixed mullerian tumor (MMMT), because CHECs are usually low stage, and are associated with a good post-hysterectomy prognosis in most cases while the latter portends a poor prognosis. The patient reported in this article was a 54-year-old woman who presented with postmenopausal vaginal bleeding for 2 months. The ultrasound image showed a thickened uneven echo endometrium of approximately 12.2 mm and a detectable blood flow signal. Magnetic resonance imaging revealed an abnormal endometrial signal, considered endometrial carcinoma (Stage Ⅰ B). On hysterectomy specimen, there was an exophytic mass in the uterine cavity with myometrium infiltrating. Microscopically, most component of the tumor was well to moderately differentiated endometrioid carcinoma. Some oval and spindle stromal cells proliferated on the superficial surface of the tumor with a bundle or sheet like growth pattern. In the endometrial curettage specimen, the proliferation of these stromal cells was more obvious, and some of the surrounding stroma was hyalinized and chondromyxoid, which made the stromal cells form a cord-like arrangement. Immunostains were done and both the endometrioid carcinoma and the proliferating stroma cells showed loss of expression of DNA mismatch repair protein MLH1/PMS2 and wild-type p53 protein. Molecular testing demonstrated that this patient had a microsatellite unstable (MSI) endometrial carcinoma. The patient was followed up for 6 months, and there was no recurrence. We diagnosed this case as CHEC, a variant of endometrioid carcinoma, although this case did not show specific β-catenin nuclear expression that was reported in previous researches. The striking low-grade biphasic appearance without TP53 mutation confirmed by immunohistochemistry and molecular testing supported the diagnosis of CHEC. This special morphology, which is usually distributed in the superficial part of the tumor, may result in differences between curettage and surgical specimens. Recent studies have documented an aggressive clinical course in a significant proportion of cases. More cases are needed to establish the clinical behaviors, pathologic features, and molecular profiles of CHECs. Recognition of the relevant characteristics is the prerequisite for pathologists to make correct diagnoses and acquire comprehensive interpretation.
Female ; Humans ; Middle Aged ; Carcinoma, Endometrioid/surgery* ; Endometrial Neoplasms/pathology* ; Endometrium/metabolism* ; Adenocarcinoma/pathology* ; Stromal Cells/pathology*

OBJECTIVE: To analyze the difference in the gene expression, amino acid and carnitine levels in the cervical secretions between the endometria of pre-receptive and receptive stages, with an aim to provide clues for identifying new molecular markers for endometrial receptivity. METHODS: Fifty nine infertile women treated at the Department of Reproductive Medicine of Linyi People's Hospital from January 6, 2020 to January 31, 2022 were selected as as the study subjects, which were matched with 3 pairs (6 cases) of infertile women preparing for embryo transfer based on factors such as age, body mass index, and length of infertility. Endometrial tissue samples were collected for gene transcription and expression analysis. Twenty five women who had become pregnant through assisted reproductive technology were selected as the control group, and 28 non-pregnant women receiving ovulation monitoring at the Outpatient Department were enrolled as the case group. Status of endometrial receptivity was determined by ultrasonography. In the former group, endometrial tissues were sampled for sequencing, and GO and KEGG database enrichment analysis of differentially expressed genes was carried out. In the latter group, cervical secretions were collected, and amino acid and carnitine levels were measured by mass spectrometry. Statistical analysis was carried out using rank sum test, t test and chi-square test with SPSS v25.0 software. RESULTS: No difference was found in the clinical data of the patients with regard to age, body mass index, infertility years, AMH, FSH, LH, E2, and type of infertility. Compared with the receptive endometrial tissues, there were 100 significantly up-regulated genes and 191 significantly down-regulated genes in the pre-receptive endometrial tissue, with the most significantly altered ones being HLA-DRB5 and MMP10. The biological processes, molecular functions and pathways enriched by more differentially expressed genes in GO and KEGG were mainly immune regulation, cell adhesion and tryptophan metabolism. Analysis of secretion metabolism also revealed a significant difference in the levels of amino acids and carnitine metabolites between the two groups (P < 0.05), in particular those of Alanine, Valine, 3-hydroxybutyrylcarnitine (C4OH) + malonylcarnitine (C3DC)/captoylcarnitine (C10). CONCLUSION A significant difference has been discovered in the levels of gene transcription and protein expression in the endometrial tissues from the pre-receptive and receptive stages. The levels of amino acids and carnitine, such as Alanine, Valine, 3-hydroxybutyryl carnitine (C4OH)+malonyl carnitine (C3DC)/caproyl carnitine (C10), may be associated with the receptive status of the endometrium, though this need to be verified with larger samples.
Pregnancy ; Humans ; Female ; Infertility, Female/genetics* ; Endometrium/metabolism* ; Amino Acids/metabolism* ; Gene Expression ; Carnitine ; Alanine/metabolism* ; Valine/metabolism*

OBJECTIVE: To investigate the effects and mechanisms of Kindlin-2 on uterus development and reproductive capacity in female mice. METHODS: Cdh16-Cre tool mice and Kindlin-2^flox/flox mice were used to construct the mouse model of uterus specific knockout of Kindlin-2, and the effects of Kindlin-2 deletion on uterine development and reproduction capacity of female mice were observed. High expression and knockdown of Kindlin-2 in endometrial cancer cell lines HEC-1 and Ish were used to detect the regulation of mammalian target of rapamycin (mTOR) signaling pathway. In addition, uterine proteins of the female mice with specific knockout of Kindlin-2 and female mice in the control group were extracted to detect the protein levels of key molecules of mTOR signaling pathway and Hippo signaling pathway. RESULTS: The mouse model of uterine specific knockout of Kindlin-2 was successfully constructed. The knockout efficiency of Kindlin-2 in mouse uterus was identified and verified by mouse tail polymerase chain reaction (PCR), Western blot protein identification, immunohistochemical staining (IHC) and other methods. Compared with the control group, the female mice with uterus specific deletion of Kindlin-2 lost weight, seriously impaired reproductive ability, and the number of newborn mice decreased, but the proportion of the female mice and male mice in the newborn mice did not change. Hematoxylin eosin staining (HE) experiment showed that the endometrium of Kindlin-2 knockout group was incomplete and the thickness of uterine wall became thinner. In terms of mechanism, the deletion of Kindlin-2 in endo-metrial cancer cell lines HEC-1 and Ish could downregulate the protein levels of mTOR, phosphorylated mTOR, adenosine monophosphate-activated protein kinase (AMPK), phosphorylated AMPK and phosphorylated ribosomal protein S6 (S6), and the mTOR signal pathway was inhibited. It was found that the specific deletion of Kindlin-2 could upregulate the protein levels of Mps one binding 1 (MOB1) and phosphorylated Yes-associated protein (YAP) in the uterus of the female mice, and the Hippo signal pathway was activated. CONCLUSION Kindlin-2 inhibits the development of uterus by inhibiting mTOR signal pathway and activating Hippo signal pathway, thereby inhibiting the fertility of female mice.
AMP-Activated Protein Kinases/metabolism* ; Adenosine Monophosphate/metabolism* ; Animals ; Cadherins/metabolism* ; Cytoskeletal Proteins/metabolism* ; Endometrium/metabolism* ; Eosine Yellowish-(YS)/metabolism* ; Female ; Hematoxylin/metabolism* ; Hippo Signaling Pathway ; Male ; Mammals/metabolism* ; Mice ; Muscle Proteins ; Ribosomal Protein S6/metabolism* ; Sirolimus/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; YAP-Signaling Proteins

At present, endometriosis remains a worldwide health burden, with the main symptoms of dysmenorrhea, chronic pelvic pain, and infertility, markedly reducing the quality of life (de Ziegler et al., 2010). Although there is no proof that the disease is associated with high mortality, this disorder can significantly contribute to the deterioration of women's general well-being (McPeak et al., 2018). The main current treatment for endometriosis is surgery to remove endometriotic lesions; however, the recurrence rate following surgical treatment is as high as 21.5% at two years and 40.0%‍-‍50.0% at five years post-surgery (Koga et al., 2015). To prevent recurrence, adjuvant treatment with drugs after surgery is recommended to prolong relapse-free intervals. However, it is inconvenient for patients to continuously use such medications in terms of adverse effects and cost (Turk, 2002).
Endometriosis/pathology* ; Endometrium/pathology* ; Female ; Humans ; Ki-67 Antigen/metabolism* ; Quality of Life ; Recurrence ; Telomerase/metabolism* ; Up-Regulation

The synthesis and decomposition of glycogen adjust the blood glucose dynamically to maintain the energy supply required by the cells. As the only hormone that lowers blood sugar in the body, insulin can promote glycogen synthesis by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and increasing glucose transporter translocation, and inhibit gluconeogenesis to lower blood glucose. In the endometrium, glycogen metabolism is active, but gluconeogenesis does not occur. The glycogen metabolism in the endometrium is controlled not only by the classical glucose regulating hormones, but also by the ovarian hormones. The functional activities related to implantation of the endometrium during the implantation window require glucose as energy source. A large amount of glucose is used to synthesize glycogen in the endometrium before implantation, which could meet the increased energy demand for embryo implantation. In diabetes, glycogen metabolism in the endometrium is impaired, which frequently leads to implantation failure and early abortion. This article reviews the glycogen metabolism in the endometrium and discusses its role in embryo implantation, which provide new ideas for embryo implantation research and infertility treatment.
Blood Glucose/metabolism* ; Embryo Implantation ; Endometrium ; Female ; Glucose/metabolism* ; Glycogen/metabolism* ; Humans ; Insulin/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Pregnancy

OBJECTIVE: To explore the expression of CCN5 in endometriotic tissues and its impact on proliferation, migration and invasion of human endometrial stromal cells (HESCs). METHODS: We collected ovarian endometriosis samples from 20 women receiving laparoscopic surgery and eutopic endometrium samples from 15 women undergoing IVF-ET for comparison of CCN5 expression. Cultured HESCs were transfected with a recombinant adenovirus Ad-CCN5 for CCN5 overexpression or with a CCN5-specific siRNA for knocking down CCN5 expression, and the changes of cell proliferation, migration and invasion were evaluated using CCK-8 assay, wound healing assay and Transwell chamber assay. RT-qPCR and Western blotting were used to examine the expression levels of epithelial-mesenchymal transition (EMT) markers including E-cadherin, N-cadherin, Snail-1 and vimentin in HESCs with CCN5 overexpression or knockdown. RESULTS: CCN5 expression was significantly decreased in ovarian endometriosis tissues as compared with eutopic endometrium samples (P < 0.01). CCN5 overexpression obviously inhibited the proliferation, migration and invasion of HESCs, significantly increased the expression of E-cadherin and decreased the expressions of N-cadherin, Snail-1 and vimentin (P < 0.01). CCN5 knockdown significantly enhanced the proliferation, migration and invasion of HESCs and produced opposite effects on the expressions of E-cadherin, N-cadherin, Snail-1 and vimentin (P < 0.01). CONCLUSION CCN5 can regulate the proliferation, migration and invasion of HESCs and thus plays an important role in EMT of HESCs, suggesting the potential of CCN5 as a therapeutic target for endometriosis.
Cell Movement ; Cell Proliferation ; Endometriosis/metabolism* ; Endometrium/metabolism* ; Epithelial Cells ; Epithelial-Mesenchymal Transition ; Female ; Humans ; Stromal Cells

To investigate the role of prokineticin (PROK) 1 and prokineticin-receptor (PROKR) 1 in the pathogenesis of endometriosis and its clinical signifaicance.
 Methods: Quantitative real-time PCR (qPCR) and Western bloting were used to detect the expression of PROK 1 and PROKR 1 in eutopic and ectopic endometrium of endometriosis (n=22) and normal control endometrium (n=18). Endometrial stromal cells were isolated and cultured in 6 normal controls. The expression of PROK 1 mRNA was detected by qPCR after treated with estradiol (E2) or TNF-α.
 Results: PROK 1 and PROKR 1 mRNA were expressed in eutopic and ectopic endometrium of endometriosis and normal control endometrium, and the expression level gradually declined (P<0.05). The expression of PROKR-1 protein in eutopic and ectopic endometrium of endometriosis and normal control endometrium gradually declined (P<0.05). The expression of PROK-1 protein in normal control endometrial cells and eutopic endometrium cell was higher in secretory phase than in proliferative phase (P<0. 05). E2 did not change the expression of PROK 1, whereas TNF-α up-regulated the expression of PROK 1.
 Conclusion: PROK-1 and its receptors are involved in the pathogenesis and development of endometriosis. TNF-α can promote angiogenesis via up-regulating the expression of PROK 1.
Endometriosis ; Endometrium ; Female ; Gastrointestinal Hormones ; metabolism ; Humans ; RNA, Messenger ; Receptors, G-Protein-Coupled ; metabolism ; Vascular Endothelial Growth Factor, Endocrine-Gland-Derived ; metabolism

Antigens, Neoplasm ; genetics ; Apoprotein(a) ; genetics ; Carrier Proteins ; genetics ; Endometriosis ; metabolism ; pathology ; Endometrium ; metabolism ; pathology ; Female ; Humans ; Intracellular Signaling Peptides and Proteins ; genetics ; Membrane Proteins ; genetics ; Mutation, Missense ; genetics ; Nuclear Proteins ; genetics ; Ovarian Neoplasms ; metabolism ; pathology ; Proprotein Convertase 5 ; genetics ; Salivary Cystatins ; genetics ; Ubiquitin-Protein Ligases ; genetics ; Whole Exome Sequencing

To explore the mechanism for the role of autophagy in endometriosis, and to provide a theoretical basis for prevention and treatment of endometriosis.
 Methods: The endometrial CRL-7566 cells were treated with ATG5 siRNA, autophagic activator rapamycin and autophagic inhibitor 3-MA, respectively. The cell proliferation and invasion were detected by clonal formation, cell growth curve and MTT assay. The clinical specimens of endometriosis were collected from 20 cases. The expression of autophagy marker LC3II and autophagy substrate protein P62 were detected.
 Results: Rapamycin inhibited the proliferation and clonal formation of CRL-7566 cells, while autophagy inhibitor 3-MA and ATG5 siRNA showed opposite effect. Moreover, rapamycin inhibited filopodia growth in endometriosis, whereas overexpression of filopodia-relevant protein fascin-1 inhibited the decrease in invasiveness caused by rapamycin. In clinical samples, we also found a significant decrease of LC3II while an increase in P62 compared with the control group.
 Conclusion: Autophagy inhibition may contribute to an increase in endometrial cell proliferation and invasiveness. Autophagy activation could be a potential strategy for endometriosis therapy.
Autophagy ; drug effects ; genetics ; Carrier Proteins ; genetics ; metabolism ; Cell Line ; Cell Proliferation ; drug effects ; Endometriosis ; physiopathology ; Endometrium ; cytology ; Female ; Gene Expression Regulation ; Humans ; Microfilament Proteins ; genetics ; metabolism ; Microtubule-Associated Proteins ; genetics ; RNA-Binding Proteins ; genetics ; Sirolimus ; pharmacology