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Aim: Endometrial changes in Japanese transgender men (TGM) on testosterone use remain elucidated. This study aims to present TGM with endometrial cancer and insights from a literature review of similar cases. Furthermore, we investigated the correlation between endometrial cancer and severe obesity in TGM who underwent gender‐affirming surgery. Methods: Between July 2020 and April 2023, two groups were assessed: 2 TGM with endometrial cancer and 43 TGM without cancer who underwent gender‐affirming surgery. A literature review for TGM with endometrial cancer was conducted. Clinical data were retrospectively collected, and histopathological evaluation of female genital organs was performed. Results: Two TGM with endometrial cancer and an additional four similar cases were identified through a literature search. These TGM had severe obesity (body mass index [BMI] ≥30 kg/m2) and long‐term testosterone use, indicating a possible link between endometrial cancer and these factors. Subsequently, we investigated the 43 TGM without cancer. We revealed 30% with obesity (BMI ≥25), only three cases of severe obesity (BMI ≥30), and a significant correlation between testosterone use duration and BMI in TGM without cancer. Histological examination revealed focal proliferative endometrium in 51% of cases and polycystic ovarian changes in 77%. Conclusions: Our observations suggest a potential link between severe obesity, prolonged testosterone use, and endometrial cancer in transgender men. Histological changes in the female genital tract highlighted frequent focal proliferative endometrium, even under testosterone therapy. Further research should focus on larger, multi‐institutional studies to confirm these findings and establish endometrial cancer screening for Japanese TGM. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome is caused by germline pathogenic variants in the DNA mismatch repair (MMR) genes predisposing carriers to colorectal and endometrial cancer. Genetic testing for Lynch syndrome, in the form of multigene panel testing, frequently identifies variants of uncertain clinical significance (VUS). These VUS have limited clinical actionability and create uncertainty for patients and clinicians regarding their risk of cancer. In this study, we tested carriers of germline VUS for features consistent with Lynch syndrome, namely (1) tumor microsatellite instability/MMR-deficiency, (2) the presence of a somatic second hit in the MMR gene harboring the VUS by tumor sequencing and (3) the presence of MMR-deficiency in normal colonic mucosa crypts or normal endometrial glands. Our findings showed that microsatellite instability/MMR-deficiency status and somatic second hits were consistent with MMR variant classifications as determined by the ACMG/InSiGHT framework. In addition to this, the presence of MMR-deficient crypts/glands were consistent with pathogenic variant classification. Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care. [ABSTRACT FROM AUTHOR]

Recurrent implantation failure (RIF) remains a challenging problem in assisted reproductive technology (ART). Further insights into uterine abnormalities that can disturb embryo implantation should be obtained. This review provides an overview of the effects of organic and non‐organic uterine disorders on endometrial receptivity. The results suggest that various uterine pathologies can lead to defective embryo implantation via multiple mechanisms. In particular, uterine adenomyosis dysregulates molecular and cellular interactions that are vital for successful embryo implantation with a background of chronic inflammation, which may be alleviated by pretreatment with a gonadotropin‐releasing hormone agonist. Uterine myomas can cause endometrial deformation and adverse alterations in uterine contractility. Nonetheless, the effectiveness of myomectomy remains debated, and endometrial polyp removal may be considered, particularly in patients with RIF. Chronic endometritis abrogates the appropriate uterine immunological environment critical for embryo implantation. Abnormal endometrial microbiota have been suggested to influence endometrial receptivity; however, supporting evidence is currently scarce. Platelet‐rich plasma therapy may be a potential treatment for thin endometria; nevertheless, further validation is required. Endometrial receptivity analysis can detect dysregulation of the window of implantation, and new non‐invasive methods for predicting endometrial receptivity have recently been proposed. However, numerous issues still need to be fully clarified. Further clinical and basic studies are necessary to investigate the pathophysiology of defective endometrial receptivity and identify optimal treatments for patients undergoing ART, especially those with RIF. [ABSTRACT FROM AUTHOR]

Background & Objective: Granulosa cells, the endometrium, and the placenta all play a role in the secretion of G-CSF in the reproductive tract. G-CSF affects immunological regulation, which is crucial for enhancing pregnancy viability and maintenance. To evaluate the effects of granulocyte-colony stimulating factor subcutaneous injection on the miscarriage rate, ongoing pregnancy rate, and livebirth rate after single and multiple doses of G-CSF factor. Materials & Methods: At the High Institute for Infertility Diagnosis and Assisted Reproductive Technologies at Al-Nahrain University, a prospective comparison study with a random sample selection was conducted from December 2021 to December 2022. It included 121 infertile women who had previously unsuccessful intracytoplasmic sperm injection (ICSI) procedures and who had finished ICSI protocols and reached the embryo transfer day. Patients were divided into three groups on the day of the embryo transfer: The non-G-CSF group (49 patients) received no additional treatment; the single-G-CSF group (31 patients) received a single subcutaneous injection of granulocyte-colony stimulating factor one hour after embryo transfer; and the multiple-G-CSF group (41 patients) received weekly injections of GCSF until a fetal heartbeat could be detected,starting one hour after the embryo transfer. Results: The multiple G-CSF group had better results in the miscarriage rate, ongoing pregnancy rate, and livebirth rate (23.5%, 34.1%, and 31.7%, respectively) when compared to the single G-CSF group (42.9%, 16.1, and 12.9%, respectively) and the non-G-CSF group (37.5%, 12.2%, and 10.2%, respectively).Conclusion: Multiple subcutaneous G-CSF doses can improve the miscarriage rate, ongoing pregnancy rate, and live birth rate. A single dose of G-CSF for infertile women has no appreciable benefits. [ABSTRACT FROM AUTHOR]

Context • In recent years, the number of women with unexplained infertility has increased, and clinicians consider poor endometrial receptivity (ER) to be one of the main reasons. ER can have great predictive value for in-vitro fertilization embryo transfer (IVF-ET)-induced pregnancy. Objective • The study intended to investigate the predictive value of ER—endometrial thickness (EMT) and type and hemodynamic parameters—using color-doppler ultrasound on the pregnancy outcome of IVF-ET for women of different ages. Design • The research team performed a prospective controlled study. Setting • The study took place at the Department of Reproductive Medicine at Hebei Reproductive Hospital in Shijiazhuang, China. Participants • Participants were 841 infertile patients undergoing IVF-ET treatment at the hospital between March 01, 2018 and December 30, 2018. The research team divided participants into two groups: (1) participants diagnosed as having a clinical pregnancy after IVF-ET became the pregnancy group, with 439 participants, and (2) participants who didn’t become pregnant became the nonpregnancy group, with 402 participants. Outcome Measures • The research team: (1) measured EMT, (2) determined endometrium types, (3) classified the intimal and subintimal blood flow, and (4) determined the hemodynamic parameters of the endometrium and subendometrium. The team also measured: (1) the systolic blood flow velocity (VS), (2) diastolic blood flow velocity (VD), and (3) average blood flow velocity (VM) three times and recorded the average value. Results • Statistically significant differences existed in the pregnancy and implantation rates among the different age groups for the groups with EMTs of <8 mm and 8-13 mm (P<.05). The results were similar in the endometrial Type A and endometrial Type B groups as well as between the endometrial blood flow Type 1 and Type 2 groups (P<.05). The distribution of endometrial blood flow types was significantly different between the groups (P = .002). In addition, statistically significant differences existed in the implantation rates between the <30 years and 30-34 groups in different blood-flow-type groups (P < .05). Based on the results of the ROC curve, high-quality embryos (0.566, 95%CI: 0.527-0.605) and endometrial blood flow types (0.554, 95%CI: 0.515-0.593) could not predict clinical pregnancy. Conclusions • The pregnancy and implantation rates increased between the <30 and 30-34 age groups and them decreased between the age groups as age increased. EMT, endometrial type, and blood flow type can be valuable parameters in predicting the implantation and pregnancy rates of patients of different ages. [ABSTRACT FROM AUTHOR]

Studying the underlying pathogenesis of disorders of the endometrium and of human pregnancy is challenging due to the lack of good in vivo and animal models. The development of organoid cultures has provided new opportunities to perform experiments in humans that recapitulate the in vivo situation. Endometrial organoids can be derived from tissues or menstrual fluid and respond robustly to ovarian hormones. Placental trophoblast organoids can only be generated from placentas under 9 weeks gestation. These assemble to form the structure of a placental villus. Modification of the culture conditions drives them to differentiate to the invading trophoblast that functions to transform the uterine spiral arteries. This process is critical for pregnancy success. These model systems will be transformative in understanding the biology of the female reproductive tract in health and disease. [ABSTRACT FROM AUTHOR]

Background: The positive effects of growth hormone (GH) on IVF are often attributed to improvements in oocyte and embryo quality. While emerging evidence emphasizes GH-induced improvements in the endometrium, these results are controversial.Objective and Rationale: This meta-analysis aimed to evaluate whether GH administration improved endometrial function and reproductive outcomes during IVF cycles and to thus guide clinical practice.Search Methods: A literature search in the Cochrane Central Register of Controlled Trials, PubMed and Embase was performed through to 30 November 2021, without language restrictions. Randomized controlled trials (RCTs) evaluating the effects of GH on IVF outcomes were included. Risk of bias and quality of evidence (QoE) were assessed according to the Cochrane Collaboration's tool and the Grading of Recommendations Assessment, Development and Evaluation system. Odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs) were assessed by random-effects models.Outcomes: A total of 25 trials with 2424 women were included. Seventeen RCTs with poor responders (n = 1723) showed that GH administration significantly increased endometrial thickness (EMT) (MD = 0.38, 95% CI: 0.18-0.59; moderate QoE), which contributed to an improved live birth rate (OR = 1.67, 95% CI: 1.13-2.49; very low QoE) and clinical pregnancy rate (CPR) (OR = 1.97, 95% CI: 1.43-2.72; low QoE). Subgroup analyses showed a dose- and time-dependent relationship between GH cotreatment and IVF outcomes; the optimal recommendation for improving CPR was consistent with that for EMT, rather than for oocytes and embryos. Hence, GH might improve fertility via effects on the endometrium. Administration of GH daily from the follicular phase of previous cycle until the hCG trigger with < 5 IU/day led to a thicker endometrium and a greater chance of becoming pregnant, while 5-10 IU/day or administration from the luteal phase of the previous cycle until the hCG trigger resulted in higher oocyte and embryo quality. Poor responders might benefit from cotreatment with the GnRH agonist long protocol more than other stimulation protocols. Pooled data from four trials (n = 354) on women with a thin endometrium indicated that improved endometrial function might be critical for improving reproductive outcomes during GH treatment, as no improvements in embryo quality were found. GH administration not only increased EMT (MD = 1.48, 95% CI: 1.21-1.75; moderate QoE) but also promoted endometrial morphology (OR = 2.67, 95% CI: 1.36-5.23; low QoE) and perfusion (OR = 5.84, 95% CI: 1.30-26.17; low QoE), thereby improving the CPR (OR = 2.71, 95% CI: 1.69-4.34; P < 0.0001; low QoE). There was insufficient evidence to reach a conclusion regarding the effects of GH in normal responders (n = 80). Due to obvious improvements in the CPR, women with a thin endometrium might be the most appropriate population to benefit from GH administration.Wider Implications: Improving endometrial function might be another vital mechanism by which GH improves IVF outcomes. Optimal treatment should be offered to the target population according to their personal conditions and needs. The QoE was moderate to very low, due to limited sample sizes and methodological problems; thus, the results should be interpreted with caution. More rigorous RCTs with large sample sizes are needed to confirm the effects and determine optimal GH protocols. [ABSTRACT FROM AUTHOR]

Background: The key oncogene B-cell lymphoma 6 (BCL6) drives malignant progression by promoting proliferation, overriding DNA damage checkpoints and blocking cell terminal differentiation. However, its functions in the placenta and the endometrium remain to be defined.Objective and Rationale: Recent studies provide evidence that BCL6 may play various roles in the human placenta and the endometrium. Deregulated BCL6 might be related to the pathogenesis of pre-eclampsia (PE) as well as endometriosis. In this narrative review, we aimed to summarize the current knowledge regarding the pathophysiological role of BCL6 in these two reproductive organs, discuss related molecular mechanisms, and underline associated research perspectives.Search Methods: We conducted a comprehensive literature search using PubMed for human, animal and cellular studies published until October 2021 in the following areas: BCL6 in the placenta, in PE and in endometriosis, in combination with its functions in proliferation, fusion, migration, invasion, differentiation, stem/progenitor cell maintenance and lineage commitment.Outcomes: The data demonstrate that BCL6 is important in cell proliferation, survival, differentiation, migration and invasion of trophoblastic cells. BCL6 may have critical roles in stem/progenitor cell survival and differentiation in the placenta and the endometrium. BCL6 is aberrantly upregulated in pre-eclamptic placentas and endometriotic lesions through various mechanisms, including changes in gene transcription and mRNA translation as well as post-transcriptional/translational modifications. Importantly, increased endometrial BCL6 is considered to be a non-invasive diagnostic marker for endometriosis and a predictor for poor outcomes of IVF. These data highlight that BCL6 is crucial for placental development and endometrium homeostasis, and its upregulation is associated with the pathogenesis of PE, endometriosis and infertility.Wider Implications: The lesson learned from studies of the key oncogene BCL6 reinforces the notion that numerous signaling pathways and regulators are shared by tumors and reproductive organs. Their alteration may promote the progression of malignancies as well as the development of gestational and reproductive disorders. [ABSTRACT FROM AUTHOR]

Background: Obesity has now been recognized as a high-risk factor for reproductive health. Although remarkable advancements have been made in ART, a considerable number of infertile obese women still suffer from serial implantation failure, despite the high quality of embryos transferred. Although obesity has long been known to exert various deleterious effects on female fertility, the underlying mechanisms, especially the roles of lipid metabolism in endometrial receptivity, remain largely elusive.Objective and Rationale: This review summarizes current evidence on the impacts of several major lipids and lipid-derived mediators on the embryonic implantation process. Emerging methods for evaluating endometrial receptivity, for example transcriptomic and lipidomic analysis, are also discussed.Search Methods: The PubMed and Embase databases were searched using the following keywords: (lipid or fatty acid or prostaglandin or phospholipid or sphingolipid or endocannabinoid or lysophosphatidic acid or cholesterol or progesterone or estrogen or transcriptomic or lipidomic or obesity or dyslipidemia or polycystic ovary syndrome) AND (endometrial receptivity or uterine receptivity or embryo implantation or assisted reproductive technology or in vitro fertilization or embryo transfer). A comprehensive literature search was performed on the roles of lipid-related metabolic pathways in embryo implantation published between January 1970 and March 2022. Only studies with original data and reviews published in English were included in this review. Additional information was obtained from references cited in the articles resulting from the literature search.Outcomes: Recent studies have shown that a fatty acids-related pro-inflammatory response in the embryo-endometrium boundary facilitates pregnancy via mediation of prostaglandin signaling. Phospholipid-derived mediators, for example endocannabinoids, lysophosphatidic acid and sphingosine-1-phosphate, are associated with endometrial receptivity, embryo spacing and decidualization based on evidence from both animal and human studies. Progesterone and estrogen are two cholesterol-derived steroid hormones that synergistically mediate the structural and functional alterations in the uterus ready for blastocyst implantation. Variations in serum cholesterol profiles throughout the menstrual cycle imply a demand for steroidogenesis at the time of window of implantation (WOI). Since 2002, endometrial transcriptomic analysis has been serving as a diagnostic tool for WOI dating. Numerous genes that govern lipid homeostasis have been identified and, based on specific alterations of lipidomic signatures differentially expressed in WOI, lipidomic analysis of endometrial fluid provides a possibility for non-invasive diagnosis of lipids alterations during the WOI.Wider Implications: Given that lipid metabolic dysregulation potentially plays a role in infertility, a better understanding of lipid metabolism could have significant clinical implications for the diagnosis and treatment of female reproductive disorders. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a type of specific molecules that control the activities of the uterus, such as the process of cellular maturing and evolution. A lot of substances like growth factors, cytokines, and transcription factors play a role in embryo-endometrial interaction. MiRNAs could regulate various these factors by attaching to the 3' UTR of their mRNAs. Moreover, current research show that miRNAs participate in formation of blood vessels in endometrium (miR-206, miR-17-5p, miR-16-5p…), decidualization (miR-154, miR-181, miR-9…), epithelial-mesenchymal transition (miR-30a-3p), immune response (miR-888, miR-376a, miR-300…) embryo attachment (miR-145, miR-27a,451…) and pinopod formation (mir-223-3p, mir-449a, mir-200c). In this study, the focus is on the role of miRNAs in managing the uterus' receptivity to an embryo and its ability to facilitate attachment. More specifically, we are exploring the mechanisms by which miRNAs regulate the presence of specific molecules involved in this crucial physiological process., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Study Question: Can a functional in vitro model, containing the main cellular components of the uterine wall, be generated from cells derived from patient tissues?, Summary Answer: We present a three-dimensional (3D) physiologically relevant, organ-on-a-chip model of the uterine wall containing primary endometrial and myometrial cellular participants, generated from human uterine tissue., What Is Known Already: As a highly dynamic reproductive organ, the human uterus plays fundamental physiological roles in menstruation and childbirth. The endometrial-myometrial junction (EMJ) defines the interface between the inner mucosal layer (endometrium) and outer smooth muscle zone (myometrium) that comprises the uterine wall. The EMJ is implicit in several uterine pathologies of unknown aetiology, including adenomyosis and abnormally invasive placenta; however, despite this, no patient-derived in vitro models of the uterine wall containing all EMJ participants currently exist., Study Design, Size, Duration: We employed microfluidic technology to characterize multiple miniaturized models of the uterine wall. Protocols were tested that included variations in the seeding order of endometrial and myometrial fractions, and the addition of a low viscosity extracellular matrix to influence cell behaviour. Ultimately, functional hormone responses of patient-derived uterine wall models were assessed., Participants/materials, Setting, Methods: Endometrial (n = 9) and myometrial biopsies (n = 4) were enzymatically dissociated to create epithelial, stromal and myometrial cellular fractions. Cell suspensions were seeded into non-adhesive poly(dimethylsiloxane) microfluidic devices containing 5 × 5 microwell arrays. The fate of individual cell types was monitored in real-time using fluorescent tracers, and cell phenotype was characterized by immunocytochemistry. Model functionality was assessed by measuring Ca2+ responses to agonist stimulation, and both insulin-like growth factor binding protein 1 (IGFBP-1) and osteopontin secretion in response to hormone stimulation., Main Results and the Role of Chance: When subjected to microfluidic culture in isolation, endometrial stromal cells and smooth muscle myocytes formed compact spheroids, whilst epithelial cells produced diffuse aggregates. Tri-cultures were established by sequential seeding of individual or combined cell fractions at various ratios. Regardless of the protocol, epithelial cells localized to the outer periphery of tri-culture spheroids, which varied in morphology across the protocols. Incorporation of 5% [v/v] Matrigel® improved the reproducibility of 3D aggregates which exhibited robust self-assembly of a stromal/smooth muscle core encased in epithelium. Exposure of tri-cultures to oestradiol, medroxyprogesterone acetate and cyclic adenosine monophosphate (cAMP) increased secretion of IGFBP-1, which indicates stromal decidualization, and enhanced epithelial cell osteopontin secretion. Stimulation with endothelin-1 induced Ca2+ signalling in myocytes., Limitations, Reasons for Caution: Endometrial and myometrial tissue was collected from relatively few donors. Myometrial tissue was collected from pregnant donors, which may have influenced the myocyte phenotype. Furthermore, endometrial tissue sampling was from women not having a hysterectomy, thus may not include the deeper basalis region, which may limit the physiological mimicry of the final models., Wider Implications of the Findings: Our novel approach to modelling the uterine wall in 3D captures all of the main cell types in a medium-throughput system, enabling the screening of hundreds of cultures in parallel from a single biopsy. This system shows great promise for examining the cellular interplay between physiological cues and EMJ pathologies, such as the impact of uterine peristalsis and cyclical hormones on the pathogenesis of adenomyosis., Study Funding/competing Interest(s): C.B. was supported by an Organ-on-a-Chip Technologies Network Pump Priming Project grant. C.J.H. was supported by a Wellbeing of Women project grant (RG2137), SRI/Bayer and Wellcome Trust IFFS3. D.K.H. was supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). M.Z. is Director and Co-Founder of ScreenIn3D Limited. The other authors declare no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

The human endometrium, the innermost lining of the uterus, is the anatomic prerequisite for pregnancy. It is the only dynamic tissue that undergoes more than 400 cycles of regeneration throughout the reproductive life of women. Key to this function are endometrial stem cells as well as cell adhesion molecules. Melanoma cell adhesion molecule (MCAM/CD146/MUC18) is a membrane glycoprotein of the mucin family and a key cell adhesion protein, highly expressed by endometrial cells. CD146 is a significant molecule pivotal in endometrial physiology, assisting tissue regeneration and angiogenesis. Endometrium also acts as a culprit in causing several endometrial dysfunctions, such as endometriosis, endometrial hyperplasia, and endometrial carcinoma, due to interrupted molecular and functional mechanisms. Though most of the endometrial dysfunctions arise as a result of endocrine disturbance, it has a major pathological role associated with angiogenesis. It has already been proven that CD146 is a potential marker for the diagnosis of angiogenic dysfunctions and malignancy, including endometrial cancer. However, its mechanistic role in causing the pathology is a mystery. This chapter explores the role of CD146 in normal and pathological endometrial conditions and the therapeutic implications of CD146., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Pericytes are versatile cells integral to the blood vessel walls of the microcirculation, where they exhibit specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, and maintaining homeostasis and are involved in the tissue repair process. The human endometrium is a unique and complex tissue that serves as a natural scar-free healing model with its cyclical repair and regeneration process every month. The regulation of pericytes has gained increasing attention due to their involvement in various physiological and pathological processes. However, endometrial pericytes are less well studied compared to the pericytes in other organs. This review aims to provide a comprehensive overview of endometrial pericytes, with a focus on elucidating their physiological function and potential implications in uterine disorders.

According to the current data, the endometrium acts as a "sensor" of embryo quality, which promotes the implantation of euploid embryos and prevents the implantation and/or subsequent development of genetically abnormal embryos. The present review addresses the nature of the "sensory function" of the endometrium and highlights the necessity for assessing its functional status. The first section examines the evolutionary origin of the "sensory" ability of the endometrium as a consequence of spontaneous decidualization that occurred in placental animals. The second section details the mechanisms for implementing this function at the cellular level. In particular, the recent findings of the appearance of different cell subpopulations during decidualization are described, and their role in implantation is discussed. The pathological consequences of an imbalance among these subpopulations are also discussed. Finally, the third section summarizes information on currently available clinical tools to assess endometrial functional status. The advantages and disadvantages of the approaches are emphasized, and possible options for developing more advanced technologies for assessing the "sensory" function of the endometrium are proposed.

Immune cells are essential for endometrial receptivity to embryo implantation and early placental development. They exert tissue-remodeling and immune regulatory roles-acting to promote epithelial attachment competence, regulate the differentiation of decidual cells, remodel the uterine vasculature, control and resolve inflammatory activation, and suppress destructive immunity to paternally inherited alloantigens. From a biological perspective, the endometrial immune response exerts a form of "quality control"-it promotes implantation success when conditions are favorable but constrains receptivity when physiological circumstances are not ideal. Women with recurrent implantation failure and recurrent miscarriage may exhibit altered numbers or disturbed function of certain uterine immune cell populations-most notably uterine natural killer cells and regulatory T cells. Preclinical and animal studies indicate that deficiencies or aberrant activation states in these cells can be causal in the pathophysiological mechanisms of infertility. Immune cells are, therefore, targets for diagnostic evaluation and therapeutic intervention. However, current diagnostic tests are overly simplistic and have limited clinical utility. To be more informative, they need to account for the full complexity and reflect the range of perturbations that can occur in uterine immune cell phenotypes and networks. Moreover, safe and effective interventions to modulate these cells are in their infancy, and personalized approaches matched to specific diagnostic criteria will be needed. Here we summarize current biological understanding and identify knowledge gaps to be resolved before the promise of therapies to target the uterine immune response can be fully realized. [ABSTRACT FROM AUTHOR]

Menstruation is a physiological process that is typically uncomplicated. However, up to one third of women globally will be affected by abnormal uterine bleeding (AUB) at some point in their reproductive years. Menstruation (that is, endometrial shedding) is a fine balance between proliferation, decidualization, inflammation, hypoxia, apoptosis, haemostasis, vasoconstriction and, finally, repair and regeneration. An imbalance in any one of these processes can lead to the abnormal endometrial phenotype of AUB. Poor menstrual health has a negative impact on a person's physical, mental, social, emotional and financial well-being. On a global scale, iron deficiency and iron deficiency anaemia are closely linked with AUB, and are often under-reported and under-recognized. The International Federation of Gynecology and Obstetrics have produced standardized terminology and a classification system for the causes of AUB. This standardization will facilitate future research endeavours, diagnosis and clinical management. In a field where no new medications have been developed for over 20 years, emerging technologies are paving the way for a deeper understanding of the biology of the endometrium in health and disease, as well as opening up novel diagnostic and management avenues. [ABSTRACT FROM AUTHOR]

Objective. This study aims to explore the effect of the prescription for Zhujingqiaoyun receptivity in patients with infertility. Methods. This project is a prospective randomized controlled clinical study, including infertility diagnostic criteria and dialectical kidney deficiency patients. 60 cases were randomly divided into 2 groups: the control group, where medication complex packing estradiol tablets were given, and the treatment group, on the basis of the control group, which was given Zhujingqiaoyun receptivity plus or minus. Transvaginal ultrasound was used to observe the endometrial thickness, endometrial volume, endometrial blood supply, and other aspects of patients in the two groups to evaluate the endometrial receptivity before and after treatment, and to record the pregnancy rate and safety of patients in the two groups after three menstrual cycles. Results. There was no significant difference in age, course of disease, and endometrial thickness between the two groups (P > 0.05). Before and after treatment, the endometrial thickness of the two groups increased significantly, and the uterine artery blood flow pulsatility index (PI) and resistance index (RI) decreased significantly (P < 0.05). The endometrial volume in the control group was significantly lower than that in the treatment group, and the difference was statistically significant (P < 0.05). The endometrial FI and VFI in the control group were significantly lower than those in the treatment group, and the difference was statistically significant (P < 0.05). In the treatment group, 30 cases were treated for 3 months, and 11 of those were pregnant (36.7%). There were 30 cases in the control group, and 5 cases were pregnant (16.67%). Both groups had good safety. SPSS 22.0 statistical software was used for the chi-square test. Conclusion. Zhujingqiaoyun receptivity on endometrial receptivity can treat infertility patients with good efficacy, increasing endometrial thickness and reducing uterine artery blood flow index. It is worthy of clinical promotion to improve pregnancy rates. [ABSTRACT FROM AUTHOR]

In the United Kingdom, between 2012 and 2017 the annual number of frozen-thawed embryo replacement (FER) cycles doubled, while fresh cycles declined. With FER now accounting for 34% of IVF cycles, the aim of this UK-wide survey of IVF clinics was to determine current trends in the management of FER. A senior clinician in each of the 84 UK IVF clinics was asked to complete an online survey between September 2018 and February 2019 focussing on their clinic's first-line protocols for FER. Sixty-five clinics (77%) responded, accounting for approximately 24,419 FER cycles annually. In ovulatory women, 69% of clinics favour medicated, 26% natural cycle and 5% modified natural cycle FER. In medicated FER, 61% of clinics undertake blastocyst transfer on the sixth day of progesterone administration, 21% on the fifth, 13% on the seventh, 3% on the fourth and 2% on the third. The preferred route of progesterone in medicated FER is vaginal, favoured by 82% of clinics. For pituitary suppression, 55% of clinics favour GnRH-agonist, 11% GnRH-antagonist and 34% oestrogen-only. In natural cycle FER, 31% always, 44% sometimes and 25% never give supplementary luteal support. In summary, the results illustrate wide variation in practice and highlight key research priorities. [ABSTRACT FROM AUTHOR]

Background: Suboptimal endometrial receptivity is a key factor behind in vitro fertilisation (IVF) implantation failure. Direct clinical tests of the endometrium of natural killer (NK) cells and endometrial receptivity analysis (ERA) are controversial. Aims: To examine the current practice of endometrial receptivity tests (NK cells and ERA) and immunological treatments (corticosteroids, anticoagulants, antiplatelets, intravenous immunoglobulin, Intralipid, other) among fertility specialists in Australia and New Zealand. Methods: A prospective 23‐item web‐based survey was distributed by email via the Fertility Society of Australia and New Zealand, between August and October 2020. Data were collected and analysed using Qualtrics. Results: Of 238 fertility specialists, 90 completed the survey (response rate 37.8%). ERA (48/90, 53.3%) was most commonly ordered, followed by uterine NK (uNK) (36/90, 40.0%) and peripheral blood NK (pNK) (12/90, 13.3%). For all tests, the most common indication was recurrent implantation failure (RIF) (41/48, 22/36, 6/12; 85.4%, 61.1%, and 50.0%, respectively for ERA, uNK and pNK). Of those that did not offer these tests, the main reason cited was insufficient evidence (30/42, 47/54, 68/78; 71.4%, 87.0%, and 87.0%). A third of specialists offered empirical immunological treatment for RIF (30/90, 33.3%): anticoagulants (28/30, 93.3%), antiplatelets (27/30, 90.0%), and corticosteroids (25/30; 83.3%). The majority of specialists (56/90, 62.2%) stated they had refused a patient request for endometrial testing or treatment. Conclusions: Tests for presumed endometrial receptivity pathology are often used in Australia and New Zealand. Immunological treatments for RIF are commonly employed empirically, without strong evidence of their effectiveness or safety. Further studies should focus on education and clinical adherence to evidence‐based guidelines. [ABSTRACT FROM AUTHOR]

During the first trimester of pregnancy, cytotrophoblasts (CTBs) differentiate into extravillous trophoblasts (EVTs). EVTs migrate from villus to decidua, invade maternal spiral arteries (SAs) and more strikingly, they migrate against blood flow along the vessels and replace endothelial cells (ECs), completing SA remodeling. Studies have indicated that trophoblast cells are mechanosensitive. They assemble ECs, which can align in the direction of fluid flow. However, how they sense blood flow and transform mechanical stimulations into chemical signals remain largely unexplored. What factors trigger their motility? what are the potential and major factors that guide them to find their path and empower them to migrate against flow? To answer these intricate questions, this review provides some of the novel aspects and sheds new insights into clinical applications. [ABSTRACT FROM AUTHOR]

Background: Human endometrium remains a poorly understood tissue of the female reproductive tract. The superficial endometrial functionalis, the site of embryo implantation, is repeatedly shed with menstruation, and the stem cell-rich deeper basalis is postulated to be responsible for the regeneration of the functionalis. Two recent manuscripts have demonstrated the 3D architecture of endometrial glands. These manuscripts have challenged and replaced the prevailing concept that these glands end in blind pouches in the basalis layer that contain stem cells in crypts, as in the intestinal mucosa, providing a new paradigm for endometrial glandular anatomy. This necessitates re-evaluation of the available evidence on human endometrial regeneration in both health and disease in the context of this previously unknown endometrial glandular arrangement.Objective and Rationale: The aim of this review is to determine if the recently discovered glandular arrangement provides plausible explanations for previously unanswered questions related to human endometrial biology. Specifically, it will focus on re-appraising the theories related to endometrial regeneration, location of stem/progenitor cells and endometrial pathologies in the context of this recently unravelled endometrial glandular organization.Search Methods: An extensive literature search was conducted from inception to April 2021 using multiple databases, including PubMed/Web of Science/EMBASE/Scopus, to select studies using keywords applied to endometrial glandular anatomy and regeneration, and the references included in selected publications were also screened. All relevant publications were included.Outcomes: The human endometrial glands have a unique and complex architecture; branched basalis glands proceed in a horizontal course adjacent to the myometrium, as opposed to the non-branching, vertically coiled functionalis glands, which run parallel to each other as is observed in intestinal crypts. This complex network of mycelium-like, interconnected basalis glands is demonstrated to contain endometrial epithelial stem cells giving rise to single, non-branching functionalis glands. Several previous studies that have tried to confirm the existence of epithelial stem cells have used methodologies that prevent sampling of the stem cell-rich basalis. More recent findings have provided insight into the efficient regeneration of the human endometrium, which is preferentially evolved in humans and menstruating upper-order primates.Wider Implications: The unique physiological organization of the human endometrial glandular element, its relevance to stem cell activity and scarless endometrial regeneration will inform reproductive biologists and clinicians to direct their future research to determine disease-specific alterations in glandular anatomy in a variety of endometrial pathological conditions. [ABSTRACT FROM AUTHOR]

Endometriosis (EMS) is a prevalent disease in women characterized by the presence of endometrial stroma and glands outside the uterus. Recent studies have showed that EMS is correlated with the resistance of endometrial stromal cells (ESCs) to ferroptosis, an iron-dependent nonapoptotic cell death. Fibulin-1 (FBLN1) is a newly identified target regulated by progesterone in the process of ESC decidualization. However, the role of FBLN1 in regulating ESC ferroptosis and EMS remains unclear. In the present study, the gene expression profiles of GSE58178, GSE23339, and GSE25628 were downloaded from the Gene Expression Omnibus (GEO) database, and the commonly differential genes were identified using Venn diagram analysis. The role of FBLN1 in ESC viability and migration was evaluated using Cell Counting Kit-8, transwell, and western blot analysis. We found that the FBLN1 expression was increased significantly in eutopic and ectopic endometrial tissues of patients with EMS compared with normal endometrium. FBLN1 overexpression in normal ESCs (NESCs) promoted cell viability and migration, whereas FBLN1 inhibition in ectopic ESCs (EESCs) decreased cell viability and migration. Furthermore, FBLN1 inhibition facilitated EESC death by triggering ferroptosis, as evidenced by increased Fe2+, lipid ROS, and malondialdehyde (MDA) level and decreased glutathione peroxidase 4 (GPX4) expression and glutathione (GSH) level. Mechanistically, FBLN1 interacted with EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) and increased the protein stability of EFEMP1. More importantly, EFEMP1 silencing repressed the effect of FBLN1 on regulating EESC ferroptosis, death, and migration. Taken together, these results verify the role of the FBLN1/EFEMP1/ferroptosis pathway in the pathogenesis of EMS, and silencing of FBLN1/EFEMP1 might be an effective approach to treat EMS. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the efficacy and safety of Yushen Tongluo Granule (YSTLG) combined with clomiphene citrate (CC) in the treatment of anovulatory infertility. Methods. This randomized, double-blinded, placebo-controlled clinical trial was carried out in the Department of Obstetrics and Gynecology and the Department of Traditional Chinese Medicine (TCM). During the 3 menstrual cycle intervention periods, all subjects received 50 mg/day CC from day 5 until day 9 of the menstruation. If no ovulation, the amount of CC per cycle increased 50 mg/day until 150 mg/day. Participants in the experimental group received YSTLG, while participants in the control group received YSTLG placebo. The granules were orally taken from the end of menstruation until ovulation. When one leading follicle attained a diameter of 18 mm or more, 5000 U human chorionic gonadotropin (hCG) was given intramuscularly. The primary outcome measure was the ovulation rate, and follicular development was monitored by transvaginal ultrasound on the 10th day of the cycles until ovulation. Secondary outcome measures including the overall curative effect, endometrial thickness, and pregnancy outcomes were also compared between the two groups. Results. The ovulation rate in the experimental group was higher than that in the control group (P < 0.05). Compared with the control group, the overall curative effect of the experimental group was better than that of the control group (P < 0.05), and the endometrial thickness in the ovulation phase was significantly thicker than that in the control group (P < 0.01). There was no significant difference in pregnancy rate and miscarriage rate between the experimental group and control group (P > 0.05). Conclusion. The combined YSTLG and CC used to treat anovulatory infertility can improve the ovulation rate without affecting endometrial thickness, which is efficacious and safe. [ABSTRACT FROM AUTHOR]

Aim: The primary aim of the study was to investigate the effect of cesarean scar diverticulum on the reproductive outcome of embryo transfer. The secondary aim was to assess the impact of endometrial cavity fluid on the reproductive outcome of embryo transfer among patients with a cesarean scar diverticulum. Methods: This was a retrospective cohort study. The study included 1538 patients, of whom 215 patients with an existing cesarean scar diverticulum and 1323 patients without cesarean scar diverticulum. A subgroup analysis of the impact of endometrial cavity fluid on the reproductive outcome of frozen embryo transfers among patients with a cesarean scar diverticulum was also conducted. Results: The odds of clinical pregnancy in the noncesarean section diverticulum group was higher than that in the diverticulum group (odds ratio [OR]: 1.72, 95% confidence interval [CI]: 1.27–2.34 and adjusted OR: 1.71, 95% CI: 1.25–2.34). The odds of live birth in the noncesarean section diverticulum group was also significantly higher than that in the cesarean section diverticulum group (OR: 1.61, 95% CI: 1.15–2.24 and adjusted OR: 1.59, 95% CI: 1.14–2.23). The existence of endometrial cavity fluid during endometrial preparation significantly reduced the pregnancy and live birth rate of frozen embryo transfer among the patients with cesarean section diverticulum. Conclusion: The presence of cesarean section scar diverticulum had an adverse impact on the pregnancy and live birth rate after in vitro fertilization. The endometrial cavity fluid among the patients with cesarean section scar diverticulum accounted for the reduced pregnancy and live birth rate partly. [ABSTRACT FROM AUTHOR]

Objective: To analyze the impact on live birth rates (LBRs) of the individualized luteal phase support (termed iLPS) in patients with low serum progesterone (P) levels compared with patients without iLPS.Design: Retrospective cohort study, December 1, 2018, to May 30, 2019.Setting: Private medical center.Patient(s): A total of 2,275 patients checked for serum P on the day of blastocyst transfer were analyzed. During the study period, 1,299 patients showed serum P levels of ≥9.2 ng/mL, whereas 550 showed serum P levels of <9.2 ng/mL and received iLPS. Additionally, a historical group of 426 patients with serum P levels of <9.2 ng/mL but no iLPS were used for comparison. Eligible patients were aged ≤50 years with adequate endometrium morphology after receiving estrogens. Luteal phase support was provided with micronized vaginal P (MVP) to all women. Patients with personalized initiation of exogenous P according to the endometrial receptivity assay test, polyps, fibroids distorting the cavity, or hydrosalpinx were not included in the analysis.Intervention(s): As routine practice since December 2018, patients with low serum P levels received an iLPS with a daily injection of 25 mg of subcutaneous P from the day of embryo transfer (ET) in addition to standard LPS (400 mg of MVP twice a day).Main Outcome Measure(s): Live birth rate.Result(s): The LBR was 44.9% in the iLPS cases vs. 45.0% in patients with normal serum P levels (crude odds ratio [OR], 1.0; 95% confidence interval [CI], 0.82-1.22). By regression analysis, low serum P levels did not affect the LBR after adjusting for possible confounders (age, oocyte origin, fresh vs. frozen, day of ET, embryo quality, number of embryos transferred) (adjusted OR, 0.99; 95% CI, 0.79-1.25). Similarly, no differences were observed in other pregnancy outcomes between groups. The LBR was significantly higher in the group of patients who received additional subcutaneous P (iLPS) compared with the historical group with low serum P levels and no iLPS (44.9% vs. 37.3%; OR, 1.37; 95% CI, 1.06-1.78). In the overall population, patients showing P levels of <9.2 ng/mL on the day of ET were slightly younger and had higher body mass index and lower estradiol and P levels during the proliferative phase compared with patients with P levels of ≥9.2 ng/mL. No differences were observed with regard to the time in between the last dose of MVP and the serum P determination. After a multivariable logistic regression analysis, only body mass index and estradiol levels in the proliferative phase reminded statistically significant. Significant differences in the LBR were observed between patients with serum P levels of <9.2 ng/mL without iLPS and patients with serum P levels of ≥9.2 ng/mL when using either own or donated oocytes.Conclusion(s): Individualized LPS for patients with low serum P levels produces LBRs similar to those of patients with adequate serum P levels. [ABSTRACT FROM AUTHOR]

Recurrent implantation failure (RIF) is a poorly defined clinical scenario marked by failure to achieve pregnancy after multiple embryo transfers. The causes and definitions of implantation failure are heterogeneous, posing limitations on study design as well as the interpretation and application of findings. Recent studies suggest a novel, personalized approach to defining RIF. Here, we review the implantation physiology and definitions of the implantation rate, failure, and RIF. [ABSTRACT FROM AUTHOR]

The development of endometrial receptivity is crucial for successful embryo implantation and the initiation of pregnancy. Understanding the molecular regulatory processes that transform the endometrium into a receptive phase is essential for enhancing implantation rates in fertility treatments, such as in vitro fertilization (IVF). Long non-coding RNAs (lncRNAs) play a pivotal role as gene regulators and have been examined in the endometrium. This review offers current insights into the role of lncRNAs in regulating endometrial receptivity. Considering the significant variation in endometrial remodeling among species, we summarize the key events in the human endometrial cycle and discuss the identified lncRNAs in both humans and other species, which may play a crucial role in establishing receptivity. Notably, there are 742 lncRNAs in humans and 4438 lncRNAs that have the potential to modulate endometrial receptivity. Additionally, lncRNAs regulating matrix metalloproteinases (MMPs) and Let-7 have been observed in both species. Future investigations should explore the potential of lncRNAs as therapeutic targets and/or biomarkers for diagnosing and improving endometrial receptivity in human fertility therapy.

The endometrium is an extremely important component of the uterus and is crucial for individual health and human reproduction. However, traditional methods still struggle to ideally repair the structure and function of damaged endometrium and restore fertility. Therefore, seeking and developing innovative technologies and materials has the potential to repair and regenerate damaged or diseased endometrium. The emergence and functionalization of various nanomedicine and biomaterials, as well as the proposal and development of regenerative medicine and tissue engineering techniques, have brought great hope for solving these problems. In this review, we will summarize various nanomedicine, biomaterials, and innovative technologies that contribute to endometrial regeneration, including nanoscale exosomes, nanomaterials, stem cell-based materials, naturally sourced biomaterials, chemically synthesized biomaterials, approaches and methods for functionalizing biomaterials, as well as the application of revolutionary new technologies such as organoids, organ-on-chips, artificial intelligence, etc. The diverse design and modification of new biomaterials endow them with new functionalities, such as microstructure or nanostructure, mechanical properties, biological functions, and cellular microenvironment regulation. It will provide new options for the regeneration of endometrium, bring new hope for the reconstruction and recovery of patients' reproductive abilities., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Liu et al.)

The endometrium during the sexual cycle undergoes detachment, tissue remodeling, and differentiation during the menstrual cycle. Localized and transient destruction and regeneration of endometrial tissue are also essential for pregnancy. It is possible to attribute many causes of failure in infertility treatment to the implantation stage. To improve the success rate of plateau fertility treatment, it is important to understand the regeneration mechanism of the endometrium, a unique regenerative tissue in the human body. In association with cell proliferation, tissue remodeling requires the relocation of proliferative cells, and the steady-state epithelial cells need to be motile for the relocation. Transient add-on motile activity in epithelial cells is mediated by epithelial to mesenchymal transition (EMT) and reversible mesenchymal to epithelial transition (MET). The destruction and regeneration of endometrial tissue over a period of days to weeks requires a system with a rapid and characteristic mechanism similar to that of wound healing. Here, I review the relationship between the well-known phenomenon of EMT in wound healing and endometrial tissue remodeling during the sexual cycle and pregnancy establishment, which are automatically triggered by menstruation and embryonal invasion.

Endometrial receptivity is the ability of the endometrium to accept embryos. Thus, endometrial receptivity dysfunction is an important factor leading to embryo implantation failure. A good endometrial receptivity provides a suitable environment for embryo implantation, improving the embryo implantation rate. The "implantation window" stage, or the receptive stage of the endometrium, is regulated by various hormones, genes, proteins and cytokines, among which microRNAs (miRNAs) and their target genes have a regulatory effect on endometrial receptivity. This review outlines the relationship between endometrial receptivity and pregnancy, the mRNAs and related signalling pathways that regulate endometrial receptivity, and the regulatory role of miRNA in endometrial receptivity, providing a deeper understanding of the regulatory mechanisms of miRNA on endometrial receptivity in humans and animals and reference for the endometrial receptivity-related research.

Study Question: Can a co-culture of three cell types mimic the in vivo layers of the uterine wall?, Summary Answer: Three protocols tested for co-culture of endometrial epithelial cells (EEC), endometrial stromal cells (ESC), and myometrial smooth muscle cells (MSMC) led to formation of the distinct layers that are characteristic of the structure of the uterine wall in vivo., What Is Known Already: We previously showed that a layer-by-layer co-culture of EEC and MSMC responded to peristaltic wall shear stresses (WSS) by increasing the polymerization of F-actin in both layers. Other studies showed that WSS induced significant cellular alterations in epithelial and endothelial cells., Study Design, Size, Duration: Human EEC and ESC cell lines and primary MSMC were co-cultured on a collagen-coated synthetic membrane in custom-designed wells. The co-culture model, created by seeding a mixture of all cells at once, was exposed to steady WSS of 0.5 dyne/cm2 for 10 and 30 min., Participants/materials, Setting, Methods: The co-culture of the three different cells was seeded either layer-by-layer or as a mixture of all cells at once. Validation of the models was by specific immunofluorescence staining and confocal microscopy. Alterations of the cytoskeletal F-actin in response to WSS were analyzed from the 2-dimensional confocal images through the Z-stacks following a previously published algorithm., Main Results and the Role of Chance: We generated three multi-cell in vitro models of the uterine wall with distinct layers of EEC, ESC, and MSMC that mimic the in vivo morphology. Exposure of the mixed seeding model to WSS induced increased polymerization of F-actin in all the three layers relative to the unexposed controls. Moreover, the increased polymerization of F-actin was higher (P-value < 0.05) when the length of exposure was increased from 10 to 30 min. Furthermore, the inner layers of ESC and MSMC, which are not in direct contact with the applied shearing fluid, also increased their F-actin polymerization., Large Scale Data: N/A., Limitations, Resons for Caution: The mixed seeding co-culture model was exposed to steady WSS of one magnitude, whereas the uterus is a dynamic organ with intra-uterine peristaltic fluid motions that vary in vivo with different time-dependent magnitude. Further in vitro studies may explore the response to peristaltic WSS or other physical and/or hormonal perturbations that may mimic the spectrum of pathophysiological aspects., Wider Implications of the Findings: Numerous in vitro models were developed in order to mimic the human endometrium and endometrium-myometrium interface (EMI) region. The present co-culture models seem to be the first constructed from EEC, ESC, and MSMC on a collagen-coated synthetic membrane. These multi-cell in vitro models better represent the complex in vivo anatomy of the EMI region. The mixed seeding multi-cell in vitro model may easily be implemented in controlled studies of uterine function in reproduction and the pathogenesis of diseases., Study Finding/competing Interest(s): This study was supported in part by Tel Aviv University funds. All authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Insulin resistance and hormonal imbalances are key features in the pathophysiology of polycystic ovarian syndrome (PCOS). We have previously shown that Ficus deltoidea var. deltoidea Jack (Moraceae) can improve insulin sensitivity and hormonal profile in PCOS female rats. However, biological characteristics underpinning the therapeutic effects of F. deltoidea for treating PCOS remain to be clarified. This study aims to investigate the biochemical, hormonal, and histomorphometric changes in letrozole (LTZ)-induced PCOS female rats following treatment with F. deltoidea. Methods: PCOS was induced in rats except for normal control by administering LTZ at 1 mg/kg/day for 21 days. Methanolic extract of F. deltoidea leaf was then orally administered to the PCOS rats at the dose of 250, 500, or 1000 mg/kg/day, respectively for 15 consecutive days. Lipid profile was measured enzymatically in serum. The circulating concentrations of reproductive hormone and antioxidant enzymes were determined by ELISA assays. Ovarian and uterus histomorphometric changes were further observed by hematoxylin and eosin (H&E) staining. Results: The results showed that treatment with F. deltoidea at the dose of 500 and 1000 mg/kg/day reduced insulin resistance, obesity indices, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL), malondialdehyde (MDA), testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) to near-normal levels in PCOS rats. The levels of high-density lipoprotein cholesterol (HDL), estrogen, and superoxide dismutase (SOD) are also similar to those observed in normal control rats. Histomorphometric measurements confirmed that F. deltoidea increased the corpus luteum number and the endometrial thickness. Conclusions: F. deltoidea can reverse PCOS symptoms in female rats by improving insulin sensitivity, antioxidant activities, hormonal imbalance, and histological changes. These findings suggest the potential use of F. deltoidea as an adjuvant agent in the treatment program of PCOS. [ABSTRACT FROM AUTHOR]

Successful implantation requires endometrial receptivity. To investigate the mechanisms of miR-494-3p on endometrial receptivity, GnRHa's superovulation scheme was designed to reduce en- dometrial receptivity, and the pregnant mice were injected with miR-494-3p antagomir. The regulatory role of miR-494-3p was identified by RT-qPCR, uterine blastocyst count, scanning electron microscopy, hematoxylin-eosin (HE) staining, and Western blot. Results indicated that miR-494-3p antagomir in- creased uterine blastocysts numbers, promoted the pinocytosis expressions, and increased endometrial thickness. Besides, miR-494-3p antagomir significantly increased leukemia inhibitory factor (LIF), Ang-2 and VEGF protein expressions, and up-regulated p-AKT/AKT and p-mTOR/mTOR protein ratios in endometrium. Luciferase assay confirmed that LIF was a potential target of miR-494-3p. Subsequently, human endometrial epithelial cells (hEECs) were transfected with miR-494-3p inhibitor and PI3K in- hibitor (LY294002). The role of miR-494-3p was identified by RT-qPCR, CCK-8 assay, transwell assay and flow cytometry. Results indicated that miR-494-3p inhibitor significantly increased proliferation and invasion, and significantly inhibited apoptosis in hEECs, while LY294002 reversed its biological function. Overall, these results suggested that miR-494-3p is the key regulator of endometrial receptivity in mice, regulating this complex process through the PI3K/AKT/mTOR pathway. Understanding the role of miR-494-3p in endometrial receptivity is of great significance for exploring new targets for the diagnosis and treatment of early pregnancy failure, and improving the success rates of artificial reproduction. [ABSTRACT FROM AUTHOR]

Objective: To study the impact of the endometrial receptivity analysis (ERA) on live birth rates in frozen embryo transfer (FET) cycles.Design: Retrospective cohort study.Setting: A single, large, university-affiliated infertility practice.Patient(s): Autologous FET cycles between January 1, 2014, and June 30, 2019, were reviewed. Multiple covariates that impact outcomes were used for propensity score matching; 133 ERA patients were matched to 353 non-ERA patients. Patients were assigned to the ERA group if they had an ERA during treatment and underwent at least one "personalized" FET based on the ERA recommendations.Intervention(s): No interventions administered.Main Outcome Measure(s): Live birth rates per cycle in the FET cycle after ERA compared with that of matched non-ERA patients.Result(s): The live birth rates for the ERA group, 49.62%, and the matched non-ERA group, 54.96%, (odds ratio 0.8074; 95% confidence interval, 0.5424-1.2018) were not significantly different, nor was a difference seen in subanalyses based on prior number of FETs or receptivity status.Conclusion(s): The ERA identifies a patient's putative window of implantation with the goal of improving synchrony with the embryo, thereby achieving higher live birth rates. This study used propensity score matching to control for multiple covariates in a heterogenous group of patients to compare live birth rates. There was no difference in the live birth rate in patients who underwent the ERA compared with that of those who did not. [ABSTRACT FROM AUTHOR]

Objective: To define the transcriptomic signature with respect to human endometrial receptivity in Chinese women by next-generation sequencing and to develop a more refined and customized bioinformatic predictive method for endometrial dating in Chinese women.Design: Randomized.Setting: A tertiary hospital-based reproductive medicine center.Patient(s): Ninety healthy, fertile Chinese women.Intervention(s): Human endometrial biopsies.Main Outcome Measure(s): Gene expression of endometrial biopsies.Result(s): Ninety endometrial samples from healthy Chinese women during their menstrual cycles-including prereceptive (luteinizing hormone [LH] + 3 days/LH + 5 days), receptive (LH + 7 days), and post-receptive (LH + 9 days) phases-were subjected to transcriptomic analysis using messenger RNA (mRNA)-enriched RNA-Seq. Feature genes were obtained and used to train the predictor for endometrial dating, with 63 samples for the training set and 27 samples for the validation set. Differentially expressed genes (DEGs) were identified by comparing samples from different phases of the menstrual cycle. Based on the transcriptomic feature genes, we constructed a bioinformatic predictor for endometrial dating. The accuracy on assessment of the endometrium on days LH + 3, LH + 5, LH + 7, and LH + 9 was 100% in the training set and 85.19% in the validation set.Conclusion(s): Our transcriptomic profiling method can be used to monitor the window of implantation with regard to the endometrium in the Chinese population. This method potentially provides an evaluation of endometrial status, and can be used to predict a personal window of implantation by reproductive medicine clinicians. [ABSTRACT FROM AUTHOR]

The most common form of congenital adrenal hyperplasia is 21‐hydroxylase deficiency (21OHD). Women with 21OHD have reduced fertility because of excessive production of adrenal androgen and progesterone, which can inhibit folliculogenesis, disturb the normal gonadotropin secretion pattern and development of the endometrium, and affect endometrial receptivity. Here, we report on an infertile woman with 21OHD who initially showed normal progesterone levels and spontaneous ovulation with the treatment by an endocrinologist. However, in vitro fertilization and embryo transfer repeatedly failed because of a gradual elevation in progesterone, which was masked by fertility treatment. The case underlines that close coordination is required between the endocrinologist and reproductive specialist for the total treatment for woman with 21OHD. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved catabolic process and a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles. An increasing body of evidence has unveiled autophagy as an indispensable biological function that helps to maintain normal tissue homeostasis and metabolic fitness that can also lead to severe consequences for the normal cellular functioning when altered. Recent accumulating data point to autophagy as a key player in a wide variety of physiological and pathophysiological conditions in the human endometrium, one of the most proficient self-regenerating tissues in the human body and an instrumental player in placental species reproductive function. The current review highlights the most recent findings regarding the process of autophagy in the normal and cancerous endometrial tissue. Current research efforts aiming to therapeutically exploit autophagy and the methodological approaches used are discussed. Abbreviations: 3-MA: 3-methyladenine; ACACA (acetyl-CoA carboxylase alpha); AICAR: 5-aminoimidazole-4-carboximide riboside; AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; ATG3: autophagy related 3; ATG4C: autophagy related 4C cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; Baf A1: bafilomycin A1; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CACNA1D: calcium voltage-gated channel subunit alpha1 D; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CASP9: caspase 9; CD44: CD44 molecule (Indian blood group); CDH1: cadherin 1; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; CQ: chloroquine; CTNNB1: catenin beta 1; DDIT3: DNA damage inducible transcript 3; EC: endometrial cancer; EGFR: epidermal growth factor receptor; EH: endometrial hyperplasia; EIF4E: eukaryotic translation initiation factor 4E; EPHB2/ERK: EPH receptor B2; ER: endoplasmic reticulum; ERBB2: er-b2 receptor tyrosine kinase 2; ERVW-1: endogenous retrovirus group W member 1, envelope; ESR1: estrogen receptor 1; FSH: follicle-stimulating hormone; GCG/GLP1: glucagon; GFP: green fluorescent protein; GIP: gastric inhibitory polypeptide; GLP1R: glucagon-like peptide-1 receptor; GLS: glutaminase; H2AX: H2A.X variant histone; HIF1A: hypoxia inducible factor 1 alpha; HMGB1: high mobility group box 1; HOTAIR: HOX transcript antisense RNA; HSPA5: heat shock protein family A (HSP70) member 5; HSPA8: heat shock protein family A (HSP70) member 8; IGF1: insulin like growth factor 1; IL27: interleukin 27; INS: insulin; ISL: isoliquiritigenin; KRAS: KRAS proto-oncogene, GTPase; LAMP2: lysosomal-associated membrane protein 2; lncRNA: long-non-coding RNA; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK8: mitogen-activated protein kinase 8; MAPK9: mitogen-activated protein kinase 9; MPA: medroxyprogesterone acetate; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYCBP: MYC-binding protein; NFE2L2: nuclear factor, erythroid 2 like 2; NFKB: nuclear factor kappa B; NFKBIA: NFKB inhibitor alpha; NK: natural killer; NR5A1: nuclear receptor subfamily 5 group A member 1; PARP1: poly(ADP-ribose) polymerase 1; PAX2: paired box 2; PDK1: pyruvate dehydrogenase kinase 1; PDX: patient-derived xenograft; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIK3R1: phosphoinositide-3-kinase regulatory subunit 1; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PPD: protopanaxadiol; PRKCD: protein kinase C delta; PROM1/CD133: prominin 1; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RFP: red fluorescent protein; RPS6KB1/S6K1: ribosomal protein S6 kinase B1; RSV: resveratrol; SGK1: serum/glucocorticoid regulated kinase 1; SGK3: serum/glucocorticoid regulated kinase family member 3; SIRT: sirtuin; SLS: stone-like structures; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SQSTM1: sequestosome 1; TALEN: transcription activator-like effector nuclease; TGFBR2: transforming growth factor beta receptor 2; TP53: tumor protein p53; TRIB3: tribbles pseudokinase 3; ULK1: unc-51 like autophagy activating kinase 1; ULK4: unc-51 like kinase 4; VEGFA: vascular endothelial growth factor A; WIPI2: WD repeat domain, phosphoinositide interacting 2; XBP1: X-box binding protein 1; ZFYVE1: zinc finger FYVE domain containing 1. [ABSTRACT FROM AUTHOR]

Objective: To compare the live birth rate between patients who undergo personalized embryo transfer (pET) after endometrial receptivity array (ERA) versus frozen embryo transfer (FET) with standard timing in first single euploid FET cycles. To report the rate of displacement of the window of implantation (WOI) in an infertile population without a history of implantation failure.Design: Prospective cohort study of patients who underwent their first single euploid programmed FET.Setting: Private fertility clinic.Patient(s): Patients who underwent first autologous single euploid programmed FET between January 2018 and April 2019.Intervention(s): Endometrial biopsy with ERA followed by pET as indicated.Main Outcome Measure(s): Live birth rate and rate of receptive and nonreceptive ERA.Result(s): A total of 228 single euploid FET cycles were included in our analysis. Of those, 147 (64.5%) were ERA/pET cycles, and 81 (35.5%) were standard timing FET cycles. Endometrial receptivity array was receptive in 60/147 (40.8%) and nonreceptive in 87/147 (59.2%) patients. Nonreceptive ERAs were prereceptive in 93.1% of cases. The live birth rate did not differ between patients who underwent FET with standard timing and patients who underwent ERA/pET, 45/81 (56.6%) and 83/147 (56.5%), respectively.Conclusion(s): Our data do not support the routine use of ERA in an unselected patient population undergoing first autologous single euploid programmed embryo transfer. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of endometrial receptivity is still unclear and conflicting. Despite advances in embryo development during assisted reproductive technologies (ART) cycles, the intricate process of implantation is still matter for debate and research.Materials and Methods: Prospective case control of 169 subjects during ovarian controlled stimulation for ART. Endometrial receptivity assessment to predict clinical pregnancy with serial continuous biochemical (serum estradiol) and biophysical (endometrial volume and adjusted endometrial volume) parameters were used. Both parameters were compared between negative and positive outcome in terms of clinical pregnancy.Results: No statistical difference was noted between the two groups in terms of demographics and ART procedures and scores. Serum estradiol was significantly higher in the positive group from day 8 after ovarian controlled stimulation. Endometrial volume and adjusted endometrial volume were significantly higher in the positive group as soon as day 6 of ovarian controlled stimulation.Conclusions: Continuous serum estradiol and 3D endometrial volume and adjusted endometrial volumes may reflect endometrial changes during ART procedures and provide a useful real time tool for clinicians in predicting endometrial receptivity. [ABSTRACT FROM AUTHOR]

An increase of steroid hormones in controlled ovarian hyperstimulation (COH) procedures is reducing the success rate in assisted reproductive technology (ART), and this includes the pregnancy rate and/or implantation rate. Research has found that the decrease in the success rate occurred due to the decreased expression of the protein that is needed to prepare the endometrium so that the embryo could attach. The aim of the study was to analyse the changes in E-chaderin expression due to COH and its relations with increased level of steroid hormones as one of the proteins in the endometrium. There were 13 samples of stored biological tissue from Macaca nemestrina endometrial tissue; came from one group of natural cycles as the control group (n = 4) and three groups of stimulated cycles. The first stimulated cycle group was injected by a 30 IU dose of rFSH (n = 2). The second stimulated cycle group was injected by a 50 IU dose of rFSH (n = 4). The third stimulated cycle group was injected by a 70 IU dose of rFSH (n = 3). The expression of E-cadherin was measured by the immunohistochemistry (IHC) technique. Estradiol (E2) and progesterone (P4) levels were assessed using ELISA and have already been done. The IHC staining expression of E-cadherin was found in the cytoplasm of glandular epithelium. Immunostaining measurement used the H_SCORE. We found that the expression of E-cadherin within the group was not significantly different (p value: 0.178). Similarly, both the correlation between the estradiol level with E-cadherin and the correlation between the progesterone level with E-cadherin were not significantly different (p value: 0.872 and p value: 0.836). The conclusion is that the level of E-Cadherin expression in the endometrium that were taken in themiddle secretion phase not affected by the dose regimen that given. In addition, the level of expression is not influenced by the increase of serum E2 and P4 levels. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to compare in vitro fertilization (IVF) outcomes in patients who were administered dual trigger due to OHSS risk in the GnRH antagonist protocol with patients who were administered standard trigger. Materials and Methods: The medical files were retrospectively scanned for all the patients who were admitted to Inonu Unıversity department of obstetrics and gynecology.While the dual trigger group was composed of patients with OHSS risk who were stimulated with GnRH antagonist and received dual trigger(hCG + GnRHa) for final oocyte maturation, the age-matched (20-40) control group consisted of patients who were administered standard trigger (10000 IU uhCG or 500 μgrrhCG and obtained oocyte counts of 500 μgr recombinant hCG). Thetwo groups were compared in terms of the oocyte count, MII oocyte count, and pregnancy and birth outcomes. Results: There was no statistically significant difference between the two groups in terms of age, weight, height, BMI, duration of marriage, presence of previous pregnancy, number of previous parities, number of pre-existing children, number of previous abortus stories, number of smokers, duration of infertility, LH, E2, prolactin, TSH levels, infertility causes, and hCG dose endometrium thickness. The number of oocytes and MII oocytes obtained was significantly higher in the dual trigger group compared to the control group. There was no statistically significant difference between the two groups in terms of the number of pregnancies and number of deliveries. Conclusion: Although the number of oocytes and MII oocytes was higher in the dual trigger group compared to the control group, there was no significant difference in terms of the pregnancy ratios and the number of deliveries. [ABSTRACT FROM AUTHOR]

Aim: Maternal complications caused by the cesarean delivery inhibit the capability of preserving the uterus and subsequent fertility. However, successful restoration of the incisional scar continuously still remains a challenge. This work was to evaluate the repairing effect of Human Wharton's Jelly Mesenchymal Stem Cells (hWJ‐MSC) on incisional scar of the uterine. Methods: Eighteen rats were randomly assigned into two groups and nine for each: one group injected with hWJ‐MSC in phosphate buffer saline (PBS) and the other injected with PBS for comparison. Results: With hWJ‐MSC in PBS injected, the uterine endometrium and myometrium with full‐thickness injury were restored and the functionality was greatly improved in comparison with the group only with PBS injected. Conclusion: The hWJ‐MSC can repair the injured uterine effectively by promoting the uterine endometrium and myometrium cells proliferation and according to the chi‐square analysis the pregnancy is improved. [ABSTRACT FROM AUTHOR]

Objective: Various stem cell-loaded scaffolds have demonstrated promising endometrial regeneration and fertility restoration. This study aimed to evaluate the efficacy of stem cell-loaded scaffolds in treating uterine injury in animal models., Methods: The PubMed, Embase, Scopus, and Web of Science databases were systematically searched. Data were extracted and analyzed using Review Manager version 5.4. Improvements in endometrial thickness, endometrial glands, fibrotic area, and number of gestational sacs/implanted embryos were compared after transplantation in the stem cell-loaded scaffolds and scaffold-only group. The standardized mean difference (SMD) and confidence interval (CI) were calculated using forest plots., Results: Thirteen studies qualified for meta-analysis. Overall, compared to the scaffold groups, stem cell-loaded scaffolds significantly increased endometrial thickness (SMD = 1.99, 95% CI: 1.54 to 2.44, P < 0.00001; I² = 16%) and the number of endometrial glands (SMD = 1.93, 95% CI: 1.45 to 2.41, P < 0.00001; I² = 0). Moreover, stem cell-loaded scaffolds present a prominent effect on improving fibrosis area (SMD = -2.50, 95% CI: -3.07 to -1.93, P < 0.00001; I² = 36%) and fertility (SMD = 3.34, 95% CI: 1.58 to 5.09, P = 0.0002; I² = 83%). Significant heterogeneity among studies was observed, and further subgroup and sensitivity analyses identified the source of heterogeneity. Moreover, stem cell-loaded scaffolds exhibited lower inflammation levels and higher angiogenesis, and cell proliferation after transplantation., Conclusion: The evidence indicates that stem cell-loaded scaffolds were more effective in promoting endometrial repair and restoring fertility than the scaffold-only groups. The limitations of the small sample sizes should be considered when interpreting the results. Thus, larger animal studies and clinical trials are needed for further investigation., Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42024493132., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huang, Zheng, Shi and Xu.)

Development of the placenta must always be in advance of that of the embryo. Evidence from domestic species demonstrates that the placenta is capable of stimulating its own development through a signalling dialogue with the endometrial glands. Placental lactogens produced by the trophoblast lead to increased expression and release of uterine secretions and mitogenic growth factors, including epidermal growth factor, that have a close temporal and spatial relationship with trophoblast proliferation. Here, we review evidence that an equivalent mechanism operates in the human. The same repertoire of receptors is present on the endometrial gland cells, and the epithelial cells have long been known to adopt a hypersecretory phenotype following an implantation. Furthermore, early pregnancy hormones stimulate the secretion of glycodelin-A and osteopontin, two 'uterine milk proteins' that have multiple potential effects at the maternal-placental interface, from organoid cultures derived from endometrial glands. Prolactin appears to be an important stimulant, but unlike in domestic species the human trophoblast does not secrete this hormone. Instead, it is a major product of decidual cells. Hence, complications of pregnancy that have their pathophysiological roots in deficient trophoblast proliferation may be due primarily to problems of decidualisation. Ensuring the endometrium is in an optimal state pre-conceptionally should therefore be a priority for women's health. Trophoblast stemness and proliferative capacity show a sharp decline at the switch from histotrophic to haemotrophic nutrition. This may reflect the increase in oxygen concentration or loss of growth factor support. Either way, there are implications for adaptive growth of the organ. [ABSTRACT FROM AUTHOR]

Aim: This study was designed to evaluate the effects of intrauterine transplantation of menstrual blood stem cells (MenSCs) on endometrial thickness and pregnancy outcomes in patients with refractory intrauterine adhesion (IUA). Methods: This study included a group of infertile women (n = 12, age 22–40 years), with refractory IUA. Autologous MenSCs isolated from the women's menstrual blood were expanded in vitro and transplanted into their uteruses, followed by hormone replacement therapy. Transvaginal ultrasound examination was performed to assess the endometrial thickness. Transabdominal ultrasound was conducted to detect pregnancy outcome. Results: Autologous MenSCs were successfully isolated and expanded from menstrual blood and transplanted into the uterus of each patient. A significant improvement of the endometrial thickness was observed from 3.9 ± 0.9 to 7.5 ± 0.6 mm (P < 0.001). No adverse reaction was observed. The duration of menstruation was increased from 2.4 ± 0.7 to 5.3 ± 0.6 days (P < 0.001). Five out of 12 patients achieved clinical pregnancy and the pregnancy rate was 41.7%. Conclusions: Intrauterine transplantation of autologous MenSCs results in regeneration of endometrium, a prolongation of menstrual duration and an increase rate of pregnancy in patients with refractory IUA. [ABSTRACT FROM AUTHOR]

Women's health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of understanding of basic uterine and menstrual physiology. Menstrual health is an integral part of overall health because between menarche and menopause, most women menstruate. Yet for tens of millions of women around the world, menstruation regularly and often catastrophically disrupts their physical, mental, and social well-being. Enhancing our understanding of the underlying phenomena involved in menstruation, abnormal uterine bleeding, and other menstruation-related disorders will move us closer to the goal of personalized care. Furthermore, a deeper mechanistic understanding of menstruation-a fast, scarless healing process in healthy individuals-will likely yield insights into a myriad of other diseases involving regulation of vascular function locally and systemically. We also recognize that many women now delay pregnancy and that there is an increasing desire for fertility and uterine preservation. In September 2018, the Gynecologic Health and Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a 2-day meeting, "Menstruation: Science and Society" with an aim to "identify gaps and opportunities in menstruation science and to raise awareness of the need for more research in this field." Experts in fields ranging from the evolutionary role of menstruation to basic endometrial biology (including omic analysis of the endometrium, stem cells and tissue engineering of the endometrium, endometrial microbiome, and abnormal uterine bleeding and fibroids) and translational medicine (imaging and sampling modalities, patient-focused analysis of menstrual disorders including abnormal uterine bleeding, smart technologies or applications and mobile health platforms) to societal challenges in health literacy and dissemination frameworks across different economic and cultural landscapes shared current state-of-the-art and future vision, incorporating the patient voice at the launch of the meeting. Here, we provide an enhanced meeting report with extensive up-to-date (as of submission) context, capturing the spectrum from how the basic processes of menstruation commence in response to progesterone withdrawal, through the role of tissue-resident and circulating stem and progenitor cells in monthly regeneration-and current gaps in knowledge on how dysregulation leads to abnormal uterine bleeding and other menstruation-related disorders such as adenomyosis, endometriosis, and fibroids-to the clinical challenges in diagnostics, treatment, and patient and societal education. We conclude with an overview of how the global agenda concerning menstruation, and specifically menstrual health and hygiene, are gaining momentum, ranging from increasing investment in addressing menstruation-related barriers facing girls in schools in low- to middle-income countries to the more recent "menstrual equity" and "period poverty" movements spreading across high-income countries. [ABSTRACT FROM AUTHOR]