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Redox Biology May 2024Hypoxia-inducible factor 1 alpha (HIF-1α) is a major molecular mediator of the hypoxic response. In the endometrium, local hypoxic conditions induced by hormonal... (Review)
Review
Hypoxia-inducible factor 1 alpha (HIF-1α) is a major molecular mediator of the hypoxic response. In the endometrium, local hypoxic conditions induced by hormonal fluctuations and endometrial vascular remodeling contribute to the production of HIF-1α, which plays an indispensable role in a series of physiological activities, such as menstruation and metamorphosis. The sensitive regulation of HIF-1α maintains the cellular viability and regenerative capacity of the endometrium against cellular stresses induced by hypoxia and excess reactive oxygen species. In contrast, abnormal HIF-1α levels exacerbate the development of various endometrial pathologies. This knowledge opens important possibilities for the development of promising HIF-1α-centered strategies to ameliorate endometrial disease. Nonetheless, additional efforts are required to elucidate the regulatory network of endometrial HIF-1α and promote the applications of HIF-1α-centered strategies in the human endometrium. Here, we summarize the role of the HIF-1α-mediated pathway in endometrial physiology and pathology, highlight the latest HIF-1α-centered strategies for treating endometrial diseases, and improve endometrial receptivity.
PubMed: 38815332
DOI: 10.1016/j.redox.2024.103205 -
Frontiers in Medicine 2024Embryo implantation requires synchronous communication between the embryo and maternal endometrium. Inadequate maternal endometrial receptivity is one of the principal...
INTRODUCTION
Embryo implantation requires synchronous communication between the embryo and maternal endometrium. Inadequate maternal endometrial receptivity is one of the principal causes for embryo implantation failure [especially repeated implantation failure (RIF)] when biopsied good-quality euploid embryos are transferred. An RNA-seq-based endometrial receptivity test (rsERT) was previously established to precisely guide successful embryo implantation. In this study, we aimed to evaluate the effect of personalized embryo transfer (pET) via rsERT on the clinical outcomes in patients with RIF.
METHODS
A total of 155 patients with RIF were included in the present retrospective study and were divided into two groups: 60 patients who underwent rsERT and pET (Group rsERT) and 95 patients who underwent standard frozen embryo transfer (FET) without rsERT (Group FET). Reproductive outcomes were compared for patients who underwent rsERT-guided pET and standard FET.
RESULTS
Forty percent (24/60) of the patients who underwent rsERT were receptive, and the remaining 60% (36/60) were non-receptive. The positive human chorionic gonadotropin (β-hCG) rate (56.3% vs. 30.5%, = 0.003) and clinical pregnancy rate (43.8% vs. 24.2%, = 0.017) were significantly higher in Group rsERT patients than in FET group patients. Additionally, Group rsERT patients also showed a higher implantation rate (32.1% vs. 22.1%, = 0.104) and live birth rate (35.4% vs. 21.1%, = 0.064) when compared with FET patients, although without significance. For subpopulation analysis, the positive β-hCG rate, clinical pregnancy rate, implantation rate, and live birth rate of receptive patients were not statistically significant different from those of non-receptive patients.
CONCLUSIONS
The rsERT can significantly improve the pregnancy outcomes of RIF patients, indicating the clinical potential of rsERT-guided pET.
PubMed: 38813375
DOI: 10.3389/fmed.2024.1369317 -
Frontiers in Microbiology 2024The possibility that there is a resident and stable commensal microbiome within the pregnant uterus has been supported and refuted by a series of recent studies. One...
INTRODUCTION
The possibility that there is a resident and stable commensal microbiome within the pregnant uterus has been supported and refuted by a series of recent studies. One element of most of the initial studies was that they were based primarily on 16S rRNA gene sequencing from bacteria. To account for this limitation, the current study performed both bacterial culture and 16S rRNA gene sequencing in a side-by-side manner (e.g., same tissues isolated from the same animal).
METHODS
The uteruses of 10 mid-pregnant (156 ± 5 d of gestation) Holstein heifers and cows were collected following slaughter. The external surface of the reproductive tract (positive control for contamination during tissue collection) as well as tissues within the pregnant uterus (placentome, inter-cotyledonary placenta, inter-caruncular endometrium, amnionic fluid, allantoic fluid, fetal abomasum content, and fetal meconium) were sampled for bacterial culture and 16S rRNA gene sequencing.
RESULTS
There were 87 unique bacterial species cultured from the external surface of the pregnant reproductive tract (contamination control) and 12 bacterial species cultured from pregnancy tissues. Six out of 10 cattle (60%) exhibited bacterial growth in at least one location within the pregnant uterus. For the metataxonomic results (16S rRNA gene sequencing), a low targeted microbial biomass was identified. Analyses of the detected amplicon sequence variants (ASV) revealed that there were: (1) genera that were prevalent on both the external surface and within the pregnant uterus; (2) genera that were prevalent on the external surface but either not detected or had very low prevalence within the pregnant uterus; and (3) genera that were either not detected or had low prevalence on the external surface but found with relatively high prevalence within the pregnant uterus.
CONCLUSION
There are a small number of viable bacteria in the pregnant uterus. The 16S rRNA gene sequencing detected a microbial community within the pregnant uterus but with a low biomass. These results are consistent with recent studies of the pregnant bovine uterus and leave open the question of whether there is adequate microbial mass to significantly affect the biology of the normal healthy bovine pregnancy.
PubMed: 38812678
DOI: 10.3389/fmicb.2024.1385497 -
Clinical and Experimental Reproductive... Jun 2024The aim of this study was to compare the outcomes of in vitro fertilization (IVF) in patients with a poor ovarian response who used methyltestosterone, versus those...
OBJECTIVE
The aim of this study was to compare the outcomes of in vitro fertilization (IVF) in patients with a poor ovarian response who used methyltestosterone, versus those using a placebo, in an infertility clinic setting.
METHODS
This clinical trial included 120 women who had undergone IVF with intracytoplasmic sperm injection due to poor ovarian reserve and infertility. The study took place at the Yas Infertility Center in Tehran, Iran, between January 1, 2018 and January 1, 2019. In the intervention group, 25 mg of methyltestosterone was administered daily for 2 months prior to the initiation of assisted reproductive treatment. The control group was given placebo tablets for the same duration before starting their cycle. Each group was randomly assigned 60 patients. All analyses were performed using SPSS ver. 23 (IBM Corp.).
RESULTS
The endometrial thickness in the intervention group was 7.57±1.22 mm, whereas in the control group, it was 7.11±1.02 (
p =0.028). The gonadotropin number was significantly higher in the control group (64.7±13.48 vs. 57.9±9.25,p =0.001). However, there was no significant difference between the two groups in the antral follicular count. The chemical and clinical pregnancy rates in the intervention group were 18.33% and 15% respectively, compared to 8.33% and 6.67% in the control group. The rate of definitive pregnancy was marginally higher in the intervention group (13.3% vs. 3.3%, p=0.05).CONCLUSION
The findings of this study suggest that pretreatment with methyltestosterone significantly increases endometrium thickness and is associated with an increase in the definitive pregnancy rate.
PubMed: 38812245
DOI: 10.5653/cerm.2023.05946 -
Journal of Contemporary Brachytherapy Apr 2024To compare the dosimetric performance of vaginal intensity-modulated brachytherapy (IM-BRT) applicator and single- (SC-BRT) and multi-channel brachytherapy (MC-BRT)...
PURPOSE
To compare the dosimetric performance of vaginal intensity-modulated brachytherapy (IM-BRT) applicator and single- (SC-BRT) and multi-channel brachytherapy (MC-BRT) applicators for vaginal cuff brachytherapy (VC-BRT).
MATERIAL AND METHODS
Fifteen patients with uterine-confined endometrium cancer who received adjuvant VC-BRT were included in this study. IM-BRT, SC-BRT, and MC-BRT treatment plans were created for two different clinical target volume (CTV) definitions: 1. Standard CTV, called CTVs; and 2. Virtually defined CTV, called CTVv, with asymmetrical tumor extension > 5 mm in thickness. Plan comparison was performed using dose-volume histogram (DVH) and treatment planning parameters.
RESULTS
According to DVH analysis, D for CTVv and D for both CTVs and CTVv showed statistically significant differences between IM-BRT and SC-BRT plans, but there was no significant difference between IM-BRT and MC-BRT plans in terms of D and D for both CTVs and CTVv. Additionally, for CTVv plans, IM-BRT was found to be significantly superior to SC-BRT for the rectum (D, V, and V), bladder (D and V), and small bowel (D, V, and V). On the other hand, DVH parameters of the sigmoid showed large difference between IM-BRT and SC-BRT plans, but it was not statistically significant. Similarly, the use of IM-BRT applicator demonstrated a noticeable dose reduction in all defined OARs when compared with MC-BRT applicator, but statistically significant for the rectum V ( = 0.03) only.
CONCLUSIONS
While the IM-BRT applicator is still in pre-clinical phase, our investigation demonstrated the proof-of-concept in real patient treatment plans with promising dosimetric results compared with SC-BRT and MC-BRT plans in selected patient group.
PubMed: 38808211
DOI: 10.5114/jcb.2024.138979 -
Trials May 2024Embryo implantation remains a critical barrier in assisted reproductive technologies. One of the main causes of unsuccessful embryo implantation is window of...
Efficacy of endometrial receptivity testing for recurrent implantation failure in patients with euploid embryo transfers: study protocol for a randomized controlled trial.
BACKGROUND
Embryo implantation remains a critical barrier in assisted reproductive technologies. One of the main causes of unsuccessful embryo implantation is window of implantation (WOI) displacement, particularly in patients with recurrent implantation failure (RIF). Therefore, a reliable diagnostic tool for identifying the optimal WOI is essential. Previous data has suggested that a novel RNA-Seq-based endometrial receptivity testing (ERT) can diagnose WOI, guide personalized embryo transfer (pET), and improve pregnancy outcomes in patients with RIF compared to standard embryo transfer (sET). However, there is still a lack of evidence from randomized controlled trials (RCT) with sufficient power to determine whether pET based on ERT can increase the rate of live births as the primary outcome.
METHODS
This trial is a prospective, single-blind, parallel-group RCT (1:1 ratio of pET versus sET). Infertile women with RIF who intend to undergo frozen-thawed embryo transfer (FET) after preimplantation genetic testing for aneuploidy (PGT-A) with the availability of at least one euploid blastocyst for transfer will be enrolled and assigned into two parallel groups randomly. Participants in the intervention group will undergo ERT and then pET based on the results of ERT, while those in the control group will undergo sET. The primary outcome is live birth rate.
DISCUSSION
The findings of this study will provide evidence for the effect of pET guided by ERT on pregnancy outcomes in patients with RIF.
TRIAL REGISTRATION
Chinese Clinical Trial Registry ChiCTR2100049041. Registered on 20 July 2021.
Topics: Humans; Female; Embryo Implantation; Pregnancy; Embryo Transfer; Endometrium; Randomized Controlled Trials as Topic; Prospective Studies; Single-Blind Method; Live Birth; Infertility, Female; Adult; Pregnancy Rate; Treatment Outcome; China; Predictive Value of Tests
PubMed: 38807239
DOI: 10.1186/s13063-024-08125-6 -
Frontiers in Oncology 2024To explore the association between the Type and approach of hysterectomy and oncological survival of women with stage II cancer of the endometrium.
OBJECTIVE
To explore the association between the Type and approach of hysterectomy and oncological survival of women with stage II cancer of the endometrium.
PATIENTS AND METHODS
684 women with stage II endometrial cancer were included. Eligible cases were grouped by type of hysterectomy (simple hysterectomy or radical hysterectomy)and approach of hysterectomy (laparoscopy or laparotomy). The baseline characteristics were compared among groups. The survival outcomes (disease-free survival and overall survival) were calculated and compared among groups, and the underlying confounding factors were adjusted by the Cox proportional hazard regression analysis.
RESULTS
The radical hysterectomy group and the simple hysterectomy group had 217 cases and 467 cases, respectively. Between the groups, the difference in 5-year disease-free survival (87.3% versus 87.9%, HR=0.97, =0.87) and 5-year overall survival (83.8% versus 83.8%, HR=0.95, =0.95) was not statistically significant. The laparotomy group and the laparoscopy group had 277 cases and 407 cases, respectively. Between the groups, the difference in 5-year disease-free survival (88.7% versus 87.1%, HR=1.22, =0.34) and 5-year overall survival (85.5% versus 82.7%, HR=1.00, =0.99) was not statistically significant.
CONCLUSION
For long-term oncological survival, radical hysterectomy is not superior to total hysterectomy in stage II endometrial cancer. Also, for stage II cancer of the endometrium, laparoscopic hysterectomy is as oncologically safe as open hysterectomy.
PubMed: 38803540
DOI: 10.3389/fonc.2024.1404831 -
JBRA Assisted Reproduction May 2024The study aimed to evaluate the impact of CE on the expression of HOXA10 and HOXA11 during the late proliferative phase in the endometrium of infertile women.
OBJECTIVE
The study aimed to evaluate the impact of CE on the expression of HOXA10 and HOXA11 during the late proliferative phase in the endometrium of infertile women.
METHODS
A prospective, translational cohort study was conducted in partnership with the Hospital Universitário Antônio Pedro in Niterói and the Clínica Ginendo in Rio de Janeiro after approval by the Ethics Committee. The patients were selected to participate in the study after showing an indication for hysteroscopy. All participants were divided into three groups: infertile women with endometritis (n=10), infertile women without endometritis (n=17) and fertile women without endometritis (n=10). At hysteroscopy, two endometrial samples were obtaneid, with one sent for histopathological examination per the gynecologist's request and the other used for immunohistochemistry procedures to evaluate the expression of CD138, HOXA10 and HOXA11. CD138 was used to confirm the diagnosis of CE. The analysis of HOXA10 and HOXA11 was performed using the HScoring method for immunohistochemistry with polyclonal antibodies.
RESULTS
Women with and without endometritis had lower HOXA10 and HOXA11 expression values than women in the control group (fertile women without endometritis).
CONCLUSIONS
The expression of HOXA10 and HOXA11 during the proliferative phase is not significantly different between infertile women with endometritis and infertile women without endometritis. Translational studies with a larger number of patients should be performed.
PubMed: 38801313
DOI: 10.5935/1518-0557.20240035 -
Spatial Transcriptomic Analysis Identifies Epithelium-Macrophage Crosstalk in Endometriotic Lesions.BioRxiv : the Preprint Server For... May 2024The mechanisms underlying the pathophysiology of endometriosis, characterized by the presence of endometrium-like tissue outside the uterus, remain poorly understood....
The mechanisms underlying the pathophysiology of endometriosis, characterized by the presence of endometrium-like tissue outside the uterus, remain poorly understood. This study aimed to identify cell type-specific gene expression changes in superficial peritoneal endometriotic lesions and elucidate the crosstalk among the stroma, epithelium, and macrophages compared to patient-matched eutopic endometrium. Surprisingly, comparison between lesions and eutopic endometrium revealed transcriptional similarities, indicating minimal alterations in the sub-epithelial stroma and epithelium of lesions. Spatial transcriptomics highlighted increased signaling between the lesion epithelium and macrophages, emphasizing the role of the epithelium in driving lesion inflammation. We propose that the superficial endometriotic lesion epithelium orchestrates inflammatory signaling and promotes a pro-repair phenotype in macrophages, providing a new role for Complement 3 in lesion pathobiology. This study underscores the significance of considering spatial context and cellular interactions in uncovering mechanisms governing disease in endometriotic lesions.
PubMed: 38798560
DOI: 10.1101/2024.03.23.586434 -
Cellular and Molecular Life Sciences :... May 2024Ovarian endometriosis is a common gynecological disease, and one of its most significant symptoms is infertility. In patients with endometriosis, defects in endometrial...
Ovarian endometriosis is a common gynecological disease, and one of its most significant symptoms is infertility. In patients with endometriosis, defects in endometrial decidualization lead to impaired endometrial receptivity and embryo implantation, thus affecting early pregnancy and women's desire to have children. However, the mechanisms underlying the development of endometriosis and its associated defective decidualization are unclear. We find that NEK2 expression is increased in the ectopic and eutopic endometrium of patients with endometriosis. Meanwhile, NEK2 interacts with FOXO1 and phosphorylates FOXO1 at Ser184, inhibiting the stability of the FOXO1 protein. Importantly, NEK2-mediated phosphorylation of FOXO1 at Ser184 promotes cell proliferation, migration, invasion and impairs decidualization. Furthermore, INH1, an inhibitor of NEK2, inhibits the growth of ectopic lesions in mouse models of endometriosis and promotes endometrial decidualization in mouse models of artificially induced decidualization. Taken together, these findings indicate that NEK2 regulates the development of endometriosis and associated disorders of decidualization through the phosphorylation of FOXO1, providing a new therapeutic target for its treatment.
Topics: Female; Endometriosis; Forkhead Box Protein O1; Humans; Animals; Phosphorylation; Mice; NIMA-Related Kinases; Endometrium; Cell Proliferation; Cell Movement; Decidua; Adult; Disease Models, Animal
PubMed: 38795132
DOI: 10.1007/s00018-024-05270-8