Background:Autoimmune thyroid disease (AITD) is the most common autoimmune disease in patients with Turner Syndrome (TS). There is a high prevalence of AITD in TS patients, it has an early age of onset and can present as severe thyroid dysfunction. The specific etiology of AITD in TS is not clear and may be associated with sex chromosome-related genetic defects, immune dysfunction, or sex hormone imbalance due to ovarian insufficiency. The aim of this study was to investigate the prevalence and related influencing factors of AITD in Chinese patients with TS. Methods:In total 63 female patients aged 14-32 diagnosed with TS received titer of thyroid autoantibodies and thyroid function examinations, including thyroid stimulating hormone (TSH), free tetraiodothyronine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), total triiodothyronine (TT3), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). The effects of age, body mass index (BMI), karyotype, fasting insulin, blood lipids and other factors that may affect thyroid function were analyzed, and the possible risk factors associated with AITD in TS patients explored. Results:Of the 63 TS patients, 24 (38.10%) had normal thyroid function and 39 (61.90%) patients had TgAb and/or TPOAb. Among the 39 women with positive thyroid autoantibodies, 10 had abnormal thyroid function, including 3 with hyperthyroidism and 7 with hypothyroidism. Patients with isochromosome X had an increased risk of developing AITD. Conclusions:The risk of AITD with TS correlates with the chromosomal karyotype, patients with isochromosome X have an increased risk of AITD. Patients with positive thyroid autoantibodies have a higher risk of thyroid dysfunction.

Despite occurring in up to 50% of the human population, menstruation is a fundamentally understudied process with limited treatment options when menstrual pathologies arise. Reasons for this deficit include the inherent ethical and technical constraints associated with researching menstruation. The multifactorial nature of many menstrual-related pathologies means in vivo research is necessary; however, this type of research is difficult in humans, and non-human species that menstruate naturally are often not suitable as research models. Consequently, most menstrual research relies on an artificially induced menstrual-like process in the non-menstruating laboratory mouse. This review investigates mouse models of menstruation and how specific technical variables are used to produce or modulate a menstrual-like process. The review describes two key categories of models, those that are ovariectomy-based versus those that are pseudopregnancy-based. The menstrual-like process occurring in these models varied slightly;the underlying reason for the variation is likely to be the method of progesterone withdrawal. Models that withdrew progesterone specifically had a far less rapid endometrial breakdown in comparison to those that withdrew all ovarian input. These outcomes suggest that a loss of ovarian factors other than progesterone is likely impacting the breakdown process. The review highlights the gaps in our understanding of the mechanisms of endometrial breakdown and repair in these proxies for menstruation and the subsequent impacts on any conclusions drawn from these models.

During uterine spiral artery remodeling, vascular smooth muscle cells (VSMCs) become disorganized and undergo phenotypic switching from a contractile to a more synthetic phenotype. We have previously reported that uterine natural killer cells induce this VSMC phenotypic switching by secreting angiopoietin-2 (Ang-2). Here, we identified the specific mechanisms by which Ang-2 plays a role in this phenomenon. VSMCs isolated from human umbilical arteries were used as an in vitro model to investigate the role of Ang-2 in phenotypic switching. Human decidua tissue from preeclamptic and control pregnancies was collected to compare the expression levels of related proteins. Ang-2 induced a more synthetic phenotype in VSMCs as evidenced by decreased contractile marker expression, increased proliferation and migration, and an altered cytoskeleton. VSMC expressed integrin β6 interacted directly with Ang-2 and induced phosphorylation of FAK (S910 and Y397), AKT (S473), and mTOR (S2448). Knockdown of FAK recovered the calponin loss induced by Ang-2 and resulted in lower EZH2 abundance. Inhibition of FAK and EZH2 both attenuated Ang-2-induced inhibition of the LC3 II/LC3 I ratio and ATG7 expression, and proliferation. Lipid peroxidation inhibition by ferrostatin-1 or the IL-8 receptor antagonist navarixin inhibited the Ang-2-induced migration. IL-8 secretion was significantly lower with lipid peroxidation inhibition. In preeclamptic decidua, there were more unremodeled spiral arteries, and the abundance of Ang-2 was dysregulated. Ang-2 dysregulation may disrupt spiral artery remodeling and contribute to preeclampsia. Ang-2 may be a novel therapeutic target for the treatment of pregnancy complications affected by incomplete spiral artery remodeling.

Microbial dysbiosis has an increasingly appreciated impact on carcinogenesis, and the cervicovaginal microbiome plays a critical role in microenvironmental inflammation. Here, we investigated the involvement of the female genital tract Peptostreptococcus species in gynecological cancer via indoleacrylic acid (IAA). IAA production from Peptostreptococcus species and the effect of bacterial culture on tumor growth in vivo were examined. The impact of IAA on cytokine production and indoleamine-2,3-dioxygenase 1 (IDO1) expression in an endometrial cancer (EC) cell line, as well as their effect on Treg and Teff cells, and M1 and M2 macrophage populations were examined in EC patients and tumor-grafted mice. Clinically, Peptostreptococcus species abundance, IAA, and IDO1 expression were verified in EC patients. The results showed that IAA production was induced in the uteri of BALB/c nude mice by Peptostreptococcus species transplantation, and the intratumoral injection of a conditioned medium from Peptostreptococcus cultures into tumor-grafted mice promoted tumor growth. IL-10 expression was upregulated by IAA; IFN-γ expression was increased by IL-10. IFN-γ induced IDO1 expression in the EC cell line. The co-culture of IDO1-expressing EC cells with peripheral blood mononuclear cells upregulated the Treg proportion and decreased the M1/M2 ratio. Clinically, P. anaerobius was more abundant amongst the uterine microbiota of EC patients than the control. The IAA, IDO1, and kynurenine/tryptophan ratios were all higher in EC tissue, and the M1/M2 ratio was lower. Our study sheds light on the link between IDO1 induction and uterine Peptostreptococcus dysbiosis and provides a potential rationale for the role of Peptostreptococcus species in immune tolerance induction in type I endometrial cancer.

OBJECTIVES:To evaluate the occurrence of retained products of conception (RPOC) after termination of pregnancy in the first trimester and to assess the vascular signals with transvaginal ultrasonography (TVUS) examination in the detection of retained products. METHODS:A retrospective cohort study was performed using TVUS examination in patients following termination of pregnancy. In cases of RPOC, 3 scales of vascular signal were identified: type 1, no or small amount, spot flow signals; type 2, medium amount, strip-like flow signals; type 3, rich amount, circumferential-like flow signals. The correlation between vascular signals and placenta accreta spectrum (PAS) staging was proposed by sonography and histopathology findings. RESULTS:The 3 vascular patterns were differently distributed within non-RPOC as well as RPOC patients with and without PAS: type 1 vascular signal detection rates of non-RPOC and RPOC were 97.8% (262/268) and 28.1% (18/64), respectively. Of 64 cases of RPOC, 48.4% (31/64) of the patients had type 2 vascular signals. Vascular signals were enhanced in RPOC with PAS patients whose diagnosis was confirmed by histopathology. CONCLUSIONS:The vascularity (amount of flow), vascular pattern (spot, strip- or circumferential-like flow), and the flow penetrating myometrium were significant findings for distinguishing concomitant RPOC with and without PAS. Additionally, RPOC may contribute to PAS progression, or PAS and RPOC in coordination strengthen the observed vascular signals.

Ovarian cancer is one of the most common gynecologic malignancies. Recurrence and metastasis often occur after treatment, and it has the highest mortality rate of all gynecological tumors. Cancer stem cells (CSCs) are a small population of cells with the ability of self-renewal, multidirectional differentiation, and infinite proliferation. They have been shown to play an important role in tumor growth, metastasis, drug resistance, and angiogenesis. Ovarian cancer side population (SP) cells, a type of CSC, have been shown to play roles in tumor formation, colony formation, xenograft tumor formation, ascites formation, and tumor metastasis. The rapid progression of tumor angiogenesis is necessary for tumor growth; however, many of the mechanisms driving this process are unclear as is the contribution of CSCs. The aim of this review was to document the current state of knowledge of the molecular mechanism of ovarian cancer stem cells (OCSCs) in regulating tumor angiogenesis.

Abnormal granulosa cell (GC) death contributes to cyclophosphamide (CTX) induced primary ovarian insufficiency (POI). To investigate the contribution of GCs to POI, gene profiles of GCs exposed to CTX were assessed using RNA-Seq and bioinformatics analysis. The results showed the differentially expressed genes (DEGs) were enriched in the ferroptosis-related pathway, which is correlated with upregulated heme oxygenase 1 (HO-1) and downregulated glutathione peroxidase-4 (GPX4). Using CTX-induced cell culture (COV434 and KGN cells), the levels of iron, reactive oxygen species (ROS), lipid peroxide, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were detected by DCFDA, MitoSOX, C11-BODIPY, MitoTracker, Nonylacridine Orange (NAO), JC-1 and transmission electron microscopy respectively. The results showed iron overload and disrupted ROS, including cytoROS, mtROS and lipROS homeostasis, were associated with upregulation of HO-1 and could induce ferroptosis via mitochondrial dysfunction in CTX-induced GCs. Moreover, HO-1 inhibition could suppress ferroptosis induced GPX4 depletion. This implies a role for ROS in CTX-induced ferroptosis and highlights the effect of HO-1 modulators in improving CTX-induced ovarian damage, which may provide a theoretical basis for preventing or restoring GC and ovarian function in patients with POI.

Introduction: Interleukin-1 beta (IL-1 beta) can promote cell migration, invasion and metastasis in various cancer cells. The mechanism of its role in human trophoblast has not been fully investigated. Therefore, we aimed to investigate the expression level of IL-1 beta in first trimester decidua and placenta and its potential role in regulation of extravillous trophoblast cell (EVT) invasion and migration. Methods: First trimester placenta and decidua were collected to study the expression levels of IL-1 beta and its receptors by immunohistochemical staining. Primary isolates of first trimester EVT or the HTR-8/SVneo trophoblast like cell line were used to assess migration and invasion. Matrix metalloproteinase levels were assessed by gelatin zymography and ELISA. The phosphorylation profile of signaling pathway proteins was detected with the Proteome Profiler Human Phospho-Kinase Array Kit. Differentially expressed proteins in cells was detected and verified by Western Blot. Results: IL-1 beta, its receptors and antagonist are expressed in first trimester placenta and decidua, exogenous IL-1 beta stimulates trophoblast cell outgrowth, migration and invasion through the ERK signaling pathway. IL-1 beta was significantly increased in the placenta at 6-7 weeks gestation compared with 8-9 weeks gestation (P < 0.0001). Transwell and RTCA assays indicated that IL-1 beta stimulates the invasion and migration of EVT. In addition, IL-1 beta promoted the phosphorylation of ERK 1/2. It also promoted the expression of MMP2 and MMP9 in EVT as demonstrated by gelatin zymography assay and enzyme linked immunosorbent assay. Discussion: This study demonstrated IL-1 beta expression in placenta and decidua, and that it regulates EVT invasion and migration.

During early pregnancy, fetal-derived extravillous trophoblast cells (EVT) from the placenta invade the maternal decidua and inner third of the uterus where they establish fetal tolerance and remodel the uterine spiral arteries, which ensures establishment of a successful pregnancy. Aberrant EVT invasion and spiral artery remodeling is associated with a number of pregnancy complications including miscarriage, preeclampsia, fetal growth restriction, and placenta accrete. During invasion of the maternal tissues, the EVT interact with a number of different cell types including the decidual leukocytes. EVT express HLA-C, HLA-G, HLA-E, and HLA-F and interact with uterine natural killer (uNK) cells through a series of different receptors. Epidemiological evidence suggests that different combinations of HLA-C and killer cell Ig-like receptor (KIR) haplotypes impact pregnancy success. Therefore, there is much interest in the functional consequence of interactions between EVT and uNK cells, and several different methodologies have been used to isolate these different cell types and their co-culture.

Keywords: advanced age, female infertility, pathological pregnancy, ovarian diseases, peripheral index

IntroductionSpontaneous miscarriage is a common complication of early pregnancy. Previous studies have shown that mitochondrial function plays an important role in establishment of a successful pregnancy. Cytochrome c oxidase subunit 4 isoform 1 (COX4I1), a component of electron transport chain complex Ⅳ, is required for coupling the rate of ATP production to energetic requirements. However, there is very limited research on its role in trophoblast biology and how its dysfunction may contribute to spontaneous miscarriage.MethodsPlacental villi (7-10 weeks gestational age) collected from either induced termination of pregnancy or after spontaneous miscarriage were examined for expression of COX4I1. COX4I1 was knocked down by siRNA transfection of primary isolates of EVT cells. Real-time cell analysis (RTCA) and 5-Ethynyl-2'-deoxyuridine (EdU) were used to detect changes in proliferation ability after COX4I1 knockdown of EVT cells. Migration and invasion indices were determined by RTCA. Mitochondrial morphology was observed via MitoTracker staining. Oxidative phosphorylation, ATP production, and glycolysis in COX4I1-deficient cells and controls were assessed by a cellular energy metabolism analyzer (Seahorse).ResultsIn placental villous tissue, COX4I1 expression was significantly decreased in the spontaneous miscarriage group. Knockdown of COX4I1 inhibited EVT cell proliferation, increased the migration and invasion ability and mitochondrial fusion of EVT cells. Mitochondrial respiration and glycolysis were impaired in COX4I1-deficient EVT cells. Knockdown of MMP1 could rescue the increased migration and invasion induced by COX4I1 silencing.DiscussionLow expression of COX4I1 leads to mitochondrial dysfunction in EVT, resulting in altered trophoblast function, and ultimately to pregnancy loss.

Breast cancer patients have high serum reactive oxygen species (ROS) levels, which exert toxicity on the ovary. However, it is still unclear whether tumor-derived ROS play a role in endometrial development and function in breast cancer. Breast cancer patients and healthy controls were recruited and endometrial thickness was measured by transvaginal ultrasound (TVUS). Xenograft tumors of the breast cancer cell line MDA-MB-231 in a female BALB/c nude mice model were established, and the therapeutic mechanism of vitamin C (VC) was investigated on uterine pathology in vivo and the contribution of co-culture of breast cancer cell and endometrial epithelial cell on this process was examined in vitro. Median thickness in endometria was lower in breast cancer patients and tumor-bearing mice compared to controls. A gene signature of uteri in tumor-bearing mice demonstrated differential expression of genes (DEGs) regulating extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT), and activation of TGF-beta and MAPK signaling pathways. In addition, ROS, EMT- and ECM-related protein levels were enhanced in uteri in tumor-bearing mice, as well as in Ishikawa cells which were co-cultured with MDA-MB-231 cells compared to controls. Supplementation with VC reduced endometrial damage, inhibited the EMT process and collagen deposition, and maintained better histologic architecture of uteri in tumor-bearing mice via inactivation of the TGF-beta 1/p38MAPK pathway. In women with breast cancer oxidative stress in the endometrium results in a fibrotic response as a consequence of EMT. VC could alleviate endometrial fibrosis via TGF-beta 1/p38MAPK pathway and provide new predictive and therapeutic targets for fertility preservation in younger breast cancer patients.

Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT can be driven by a number of mechanisms, including the TGF-β1 signalling pathway and/or by hypoxia. However, these drivers of EMT differ in their actions in regulating side population (SP) cell behaviour, even within SPs isolated from the same tissue. In this study we examined CoCl2 exposure and TGF-β driven EMT on SP cells of the MDA-MB-231 and MCF7 breast cancer cell lines. Both TGF-β1 and CoCl2 treatment led to the depletion of MDA-MB-231 SP. Whilst TGF-β1 treatment significantly reduced the MCF7 SP cells, CoCl2 exposure led to a significant increase. Single cell analysis revealed that CoCl2 exposure of MCF7 SP leads to increased expression of ABCG2 and HES1, both associated with multi-drug resistance. We also examined the mammosphere forming efficiency in response to CoCl2 exposure in these cell lines, and saw the same effect as seen with the SP cells. We suggest that these contrasting effects are due to ERα expression and the inversely correlated expression of TGFB-RII, which is almost absent in the MCF7 cells. Understanding the EMT-mediated mechanisms of the regulation of SP cells could enable the identification of new therapeutic targets in breast cancer.

Deep endometriosis (DE) is the most severe subtype of endometriosis, with the hallmark of lesions infiltrating adjacent tissue. Abnormal vascularisation has been implicated in contributing to endometriosis lesion development in general, and how vascularisation influences the pathogenesis of DE, in particular, is of interest. This systematic review followed the PRISMA guidelines to elucidate and examine the evidence for DE-specific vascularisation. A literature search was performed using MEDLINE, Embase, PubMed, Scopus, Cochrane CENTRAL Library and Europe PubMed Central databases. The databases were searched from inception to the 13 March 2023. A total of 15 studies with 1125 patients were included in the review. The DE lesions were highly vascularised, with a higher microvessel density (MVD) than other types of endometriotic lesions, eutopic endometrium from women with endometriosis and control tissue. Vascular endothelial growth factor, its major subtype (VEGF-A) and associated receptor (VEGFR-2) were significantly increased in the DE lesions compared to superficial endometriosis, eutopic endometrium and control tissue. Progestin therapy was associated with a significant decrease in the MVD of the DE lesions, explaining their therapeutic effect. This review comprehensively summarises the available literature, reporting abnormal vascularisation to be intimately related to the pathogenesis of DE and presents potentially preferential therapeutic targets for the medical management of DE.

Spiral artery remodeling is the process by which the uterine vessels become large bore low resistance conduits, allowing delivery of high volumes of maternal blood to the placenta to nourish the developing fetus. Failure of this process is associated with the pathophysiology of most of the major obstetric complications, including late miscarriage, fetal growth restriction and pre-eclampsia. However, the point at which remodeling 'fails' in these pathological pregnancies is not yet clear. Spiral artery remodeling has predominantly been described in terms of its morphological features, however we are starting to understand more about the cellular and molecular triggers of the different aspects of this process. This review will discuss the current state of knowledge of spiral artery remodeling, in particular the processes involved in loss of the vascular smooth muscle cells, and consider where in the process defects would lead to a pathological pregnancy.

Background Hearing loss (HL) is one of the main medical complications for Turner Syndrome (TS) patients, with an earlier presentation and higher incidence than normal women. However, the etiology of HL in TS is unclear. The aim of this study was to investigate the hearing status of TS patients in China and the influencing factors, so as to provide a theoretical basis for early intervention treatment for TS patients with HL. Methods In total 46 female patients aged 14–32 diagnosed with TS received tympanic membrane and audiological examinations, including pure tone audiometry and tympanometry. In addition, the effects of karyotype, sex hormone levels, thyroid function, insulin, blood lipids, bone mineral density, age and other factors on hearing levels were analyzed, and the possible risk factors associated with HL in TS patients were explored. Results In 9 patients (19.6%) had HL, including 1 (2.2%) with mild conductive hearing loss, 5 (10.9%) with mild sensorineural hearing loss, 3 (6.5%) with moderate sensorineural hearing loss. TS is often associated with age-related mid-frequency and high-frequency HL, and the incidence of HL increases with age. Compared with other karyotypes, patients with 45, X haplotype have an increased risk of mid-frequency HL. Conclusions Therefore, karyotype may be a predictor of hearing problems in TS.

The remodeling of uterine spiral arteries is a complex process requiring the dynamic action of various cell types. During early pregnancy, extravillous trophoblast (EVT) cells differentiate and invade the vascular wall, replacing the vascular smooth muscle cells (VSMCs). Several in vitro studies have shown that EVT cells play an important role in promoting VSMC apoptosis, however, the mechanism underlying this process is not fully understood. In this study, we demonstrated that EVT-conditioned media and EVT-derived exosomes could induce VSMC apoptosis. Through data mining and experimental verification, it was demonstrated that the EVT exosome miR-143-3p induced VSMC apoptosis in both VSMCs and a chorionic plate artery (CPA) model. Furthermore, FAS ligand was also expressed on the EVT exosomes and may play a co-ordinated role in apoptosis induction. These data clearly demonstrated that VSMC apoptosis is mediated by EVT-derived exosomes and their cargo of miR-143-3p as well as their cell surface presentation of FASL. This finding increases our understanding of the molecular mechanisms underlying the regulation of VSMC apoptosis during spiral artery remodeling.

EDITORIAL article Front. Immunol., 07 November 2023Sec. Immunological Tolerance and Regulation Volume 14 - 2023 | https://doi.org/10.3389/fimmu.2023.1330701