Interoception, or the perception of internal somatic states, is crucial for signaling the individual to take care of the body when needed. It enables behavioral adaptations to sickness states, which further impact autonomic nervous system (ANS) activity. Whether acute inflammation affects interoceptive processing and how this relates to sickness behavior remains unknown. Therefore, we investigated interoceptive processing in participants undergoing experimental endotoxemia. In neuroimaging research, heartbeat-evoked potentials (HEP) - defined as event-related potentials time-locked to electrocardiogram (ECG) R-waves during electroencephalogram (EEG) recordings - have emerged as a promising metric for cardiac interoceptive processing. We analyzed the effects of intravenous administration of lipopolysaccharide (LPS; 0.4 ng/kg) or placebo, on HEP amplitudes and ANS functioning in healthy, female participants (n = 52) during 8 min resting-state EEG and ECG recordings before and 2 h after injections. Our results showed increased cortisol and cytokine levels in the LPS group, along with increased sympathetic and decreased parasympathetic activity 2 h after injections compared to the placebo group. Placebo-injected participants exhibited lower post injection-baseline differences in HEP amplitudes in an early timeframe (255-455 ms), indicating lower HEPs 2 h after administrations. Moreover, post-injection HEP amplitudes differed between groups, suggesting that while participants in the placebo group showed altered HEP amplitudes after injection, HEPs remained unresponsive to LPS administration. These findings are discussed in the context of predictive processing, expectation violation and attention direction to external and interoceptive cues. Future research should further investigate the role of LPS dose and explore behavioral measures of interoception under experimental inflammation.

This article aims to explore the relationship between the symptoms of PMS and changes of thalamic subregions.

71 patients diagnosed with PMS and 81 healthy controls (HCs) were included in the study. Participant status was determined using the Daily Record of Severity of Problems (DRSP) scale. All participants underwent functional and structural scans, and peripheral venous blood samples were collected to assess the cytokine and hormone levels. Resting-state functional connectivity (rsFC) and grey matter volume (GMV) of thalamic subregions were calculated from the MRI data. Correlation analyses were then conducted to investigate the associations between these neuroimaging indicators and the clinical features of PMS.

The rsFC analysis revealed that PMS patients showed lower rsFC between the middle frontal gyrus (MFG) and the left thalamic medial posterior and ventral nuclei while higher rsFC between the insula and the left lateral posterior(LP) nuclei compared to HCs. Additionally, the findings demonstrated a correlation between the DRSP scores and rsFC, while the DRSP scores were positively correlated with (TNF-α) levels. Furthermore, the rsFC was found to be correlated with part of the inflammatory cytokines.

The findings suggest that the observed functional connectivity alterations of the thalamus subregions are associated with the score of DRSP. This relationship appears to be largely dependent on the inflammation affecting the thalamic neural circuit, particularly the thalamic-MFG-insula network.

The menstrual cycle influences the risk of acquiring sexually transmitted infections (STIs), including those caused by the pathogen Chlamydia trachomatis (C. trachomatis). However, the underlying immune contributions are poorly defined. A mouse model simulating the repetitive immune-mediated process of menstruation could provide valuable insights into tissue-specific determinants of protection against chlamydial infection within the cervicovaginal and uterine mucosae of the female reproductive tract (FRT). Here, we used the pseudopregnancy approach for inducing menstruation in naïve C57Bl/6 mice and performed vaginal challenge with Chlamydia muridarum (C. muridarum) over the course of decidualization, endometrial tissue remodeling, and menstruation. This strategy identified that a time point over pseudopregnancy corresponding to the late luteal phase of the menstrual cycle correlated with reduced bacterial burden. By evaluating the early infection site following challenge at this time point, we found that a greater abundance of NK cell populations and proinflammatory signaling, including IFNγ, were strongly correlated with protection. FRT immune profiling in uninfected mice over pseudopregnancy or in pig-tailed macaques over the menstrual cycle identified periodic NK cell infiltration into the cervicovaginal tissues and luminal surface occurring over a similar time frame. Notably, these cell populations were transcriptionally distinct and enriched for programs associated with NK cell effector functions. Depletion of FRT NK cells during the late luteal phase resulted in a loss of protection, enabling productive infection following C. muridarum challenge. This study shows that the pseudopregnancy murine menstruation model recapitulates dynamic changes occurring in mucosal immune states throughout the FRT as a result of endometrial remodeling and identifies NK cell localization at the FRT barrier site of pathogen exposure as essential for immune protection against primary C. muridarum infection.

Endometrium is vital to the establishment of pregnancy through its cyclical regeneration, which, when disrupted, can lead to endometrial thinning and Asherman's syndrome (AS). AS is characterized by infertility, pelvic pain, menstrual irregularities, and placental complications. Currently, treatments such as hysteroscopic adhesiolysis and hormone replacement therapy have demonstrated variable efficacy with limited clinical evidence. Recent developments in cell therapy have introduced menstrual blood-derived mesenchymal stem cells (MenSCs) as a promising alternative therapeutic strategy. Menstrual blood offers a noninvasive, periodically available source of mesenchymal stem cells, MenSCs for endometrial regeneration. This review comprehensively examines the endometrial regenerative process, pathophysiology of AS, and therapeutic prospects of MenSCs, underscoring the need for continued research to optimize treatment strategies.

To investigate whether endometrial receptivity is affected in patients with endometriosis using podocalyxin (PCX) as a functional biomarker and to study how endometriotic lesions display PCX and the potential pathological implications.

We have previously reported that PCX, an anti-adhesion glycoprotein and barrier protector, is dynamically regulated in the endometrium and acts as a key negative regulator of epithelial receptivity. Early in the cycle both luminal epithelium (LE, lining the endometrial surface) and glandular epithelium (GE, residing within the tissue) strongly express PCX, but in the receptive window, PCX is selectively downregulated in LE, switching the endometrial surface to an adhesive state for embryo attachment/implantation; meanwhile, PCX expression is maintained in GE until postreceptivity. Here, we immuno-stained PCX in endometrial tissues and ectopic lesions biopsied across the menstrual cycle from patients with endometriosis (EOS, n = 41), and compared with endometrium of non-endometriosis controls (non-EOS, n = 55). We further investigated how PCX changes observed in ectopic lesions may influence their adhesive capacity.

Women without and with endometriosis.

Not applicable.

The window of endometrial receptivity might be shorter in patients with endometriosis; ectopic sites in addition downregulate PCX cyclically, mirroring the eutopic endometrial cells in preparing for receptivity to increase their adhesion potential.

Endometrial PCX levels were comparable between non-EOS and EOS early in the cycle, and in both groups, PCX is downregulated in LE during the expected window of receptivity; however, in EOS endometrium, PCX is reduced earlier in GE as if the receptive window were shorter. In endometriotic lesions, PCX was detected in endometrial LE- and GE-like cells plus mesothelial cells enveloping peritoneal organs, but PCX was cyclically lost specifically in LE-like cells and reduced in GE-like cells as seen in the eutopic endometrium, which however may increase their adhesion potential to nearby organs (overlaid by mesothelial cells). This speculation was further corroborated in an in vitro model showing endometrial epithelial cells with lower PCX were indeed more adhesive to mesothelial cells.

Endometrial receptivity is subtly affected in patients with endometriosis with a shorter window. Cyclic downregulation of PCX in ectopic sites may have pathological consequences.

This study aims to investigate the influence of ozone exposure on mouse corneas and human corneal epithelial cells (HCEC) to better understand its impact on corneal health and the underlying molecular mechanisms. Elevated cyclic ozone exposure was applied to both mouse corneas and HCECs to assess its effects on corneal structure and cellular response. Ozone exposure induced corneal stromal thinning (27.88 %), increased epithelial thickness (22.44 %), and disrupted epithelial barrier function. Inflammatory responses and nitrative stress, marked by inflammatory cell infiltration and heightened 3-nitrotyrosine levels, coupled with the upregulation of NLRP3, caspase-1 were observed in mice cornea. Additionally, ozone exposure induced diminished cell viability, nitrative stress, and activation of the NLRP3/caspase-1/GSDMD pathway in HCECs, which were mitigated by anti-nitration agent MnTMPyP treatment. In summary, the study elucidated the mechanisms underlying ozone-induced corneal toxicity, highlighting nitrative stress and NLRP3 inflammasome-mediated pyroptosis. These findings suggest the importance of minimizing ozone exposure and also provide potential therapeutic strategies targeting nitrative stress and inflammasome activation to prevent ozone-related tissue damage.

Women with premenstrual syndrome (PMS) are at increased risk for depression throughout their lives. White matter (WM) microstructure and inflammatory cytokine alterations have been proposed in its etiology.

To investigate whether WM, assessed using diffusion tensor imaging (DTI), and inflammatory cytokine levels are altered in PMS, and to examine the relationships between WM microstructure, inflammatory cytokines, and symptom severity.

Prospective.

Forty-two PMS patients and 58 healthy controls (HCs), categorized according to the daily record of severity of problems (DRSP).

3-T, echo planar imaging DTI.

Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured by using tract-based spatial statistics (TBSS). Venous blood was collected to measure cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Symptoms were assessed by using the DRSP.

Two-sample t test or Mann-Whitney U test were used to compare the DRSP and cytokines. Abnormal DTI metrics in WM were extracted and the differences between groups were analyzed by using two sample t-tests. Spearman's correlation (r) was used to assess the relationship between DTI metrics, cytokines, and DRSP. A P-value <0.05 with FDR correction was considered statistically significant.

Compared with HCs, PMS patients showed significantly lower FA in the corpus callosum and corona radiata, and significantly higher MD, AD, and RD in the corticospinal tract (CST), and significantly higher MD and RD in the anterior thalamic radiation (ATR). These differential metrics were significantly correlated with DRSP. Patients showed significantly higher IL-1β and TNF-α than HCs. Moreover, TNF-α correlated positively with MD, AD, and RD in both groups (r range, 0.256-0.315).

Alterations of WM microstructure and IL-1β and TNF-α may be associated with PMS symptom severity, and TNF-α may correlate with DTI metrics of CST and ATR pathways.

1 TECHNICAL EFFICACY: Stage 2.

The role of reactive oxygen species (ROS) in cellular senescence and inflammation has been extensively studied; however, the specific molecular mechanisms underlying these effects have yet to be fully elucidated. By applying a nucleotide pool detection system, oxidative microRNA sequencing, and cytokine chip detection techniques, we found that the levels of 8-oxo-guanosine triphosphate (8-oxo-GTP) increased with age and were positively correlated with elevated levels of oxidized microRNA and increased levels of inflammatory factors. During aging, guanine residues in the seed regions of miR-98-5p that regulates ICAM1, and miR-8085 that regulates CXCL16, were oxidized to 8-oxoguanine. This oxidation weakened the binding affinity of microRNAs to their target genes, thereby promoting the expression of ICAM1 and CXCL16. Oxidized microRNAs can regulate new target genes via o8G:A base mismatches. Our findings reveal that ROS-induced oxidative modifications of microRNAs reshape gene regulatory networks, activate inflammatory pathways, providing new insights into the mechanisms of age-related inflammation.

Cyclic exposure of the endometrium to ovarian sex steroids during the menstrual cycle induces a transition between proliferative and receptive states involving a different variety of cell types (ie, epithelial, stromal, endothelial, and immune cells) in preparation for embryo implantation during the narrow window of implantation. The study of the female reproductive system cells across these different phases contributes to our understanding of the healthy endometrium at the cellular level, supporting comparisons with pathological conditions, such as endometriosis, endometrial cancer, or Asherman's syndrome. Single-cell RNA sequencing technology represents a powerful tool that can discern the gene expression profiles of each cell within a tissue sample and has recently revealed the complex collaborations taking place between diverse cell types during the distinct endometrial phases. This review aims to summarize those studies that have employed single-cell RNA sequencing to deepen our understanding of the endometrium at single-cell resolution during the menstrual cycle. We discuss the transitions taken by distinct cell populations across the proliferative and secretory phases and the general importance of these transitions to successful embryo implantation. Furthermore, we analyze the use of single-cell RNA sequencing technology to study in vitro models of healthy endometrium and endometrial carcinoma. We believe that future studies using single-cell RNA sequencing will be essential to understanding the behavior of the endometrium as a whole and identifying potential avenues for the improved management of endometrial diseases.

This study aimed to investigate the effects of ubiquinol on menstrual symptoms.

This open-label trial involved 86 female healthcare workers aged 21-48 years. The study design included an observation period and a ubiquinol intake period. During the intake period, the participants consumed two soft capsules containing 75 mg of ubiquinol daily (i.e., 150 mg/day). At baseline and after the observation and intake periods, the participants underwent blood testing and completed the Pittsburgh Sleep Quality Index to evaluate their sleep condition. In addition, the Menstrual Distress Questionnaire was completed before, during, and after each of the first seven menses. All statistical analyses were performed, stratified by the median age of the participants.

Regarding the Menstrual Distress Questionnaire, in the younger group (age: <36 years), a significant improvement was observed in menstrual "Control" (p = 0.049) by ubiquinol intake. In the older group (age: ≥36), the effects of ubiquinol on the improvement of premenstrual "Negative affect" and "Control" scores reached significance (p = 0.02 and p < 0.01, respectively); further, menstrual "Control" score was significantly improved (p = 0.03). In addition, the Pittsburgh Sleep Quality Index showed a significant effect of ubiquinol in the older group.

This pilot study indicated that ubiquinol alleviated menstrual symptoms among premenopausal female healthcare workers. In those aged ≥36 years, ubiquinol intake may reduce premenstrual irritability and improve sleep quality.

Dysmenorrhea being an effect of uterine contractions in the endometrium is a consequential health concern that may hamper a woman quality of life and disrupt everyday activities. It is described as pain throughout the menstrual cycle which is one of the most prominent causes of pelvic pain in women. Traditional medicine and Ayurveda has for centuries stipulated and employed herbs to treat a variety of illnesses. These herbs contain various bioactive compounds that can be exploited to cure serious health complications of human body. The Purpose of this manuscript is to review every aspect of the menstrual cycle and its mechanism, as well as the application of various conventional treatments and herbal remedies. Numerous scientific studies have been carried out over the past several decades with the ultimate objective of preserving the traditional knowledge of medicinal herbs employed in food and medicine. Herbals like ginger, chamomile, fennel, saffron, onion, nimm primary compounds include Gingerols, terpenoids, flavonoids, coumarins, phyto-molecules, thiosulfanates that possess anti-inflammatory, anti-tumor activities, anti-hyperglycemia, and analgesic properties, which can lower the pain during dysmenorrhea. Literature was searched and data was collected related to herbs from different sources like Pubmed, Google scholar, Science direct. Despite many studies and research, there are many factors that need more information related to herbal medicines and it is necessary to acquire more knowledge about the pertinent hormonal balance induced by herbal remedies.

Large uterine fibroids (UFs) are clonal neoplasms of the uterus that form during the mid and late-aged women. Such women generally consume oral contraceptive pills, tranexamic acid, or NSAIDS to manage heavy menstrual bleeding (HMB) and associated complications while waiting for a conclusive procedure or avoiding hysterectomy. The procoagulant effect of these medicinal agents can result in venous stasis of the lower limbs, leading to deep vein thrombosis (DVT), a challenging complication with HMB. We examine the complicated state of heavy bleeding with thrombosis and explore better management options. It has been seen that women with hypothyroidism have an increased risk of getting DVT due to an alteration in the coagulation system. These incidences are mostly associated with higher uterine weight, which is related to the extrinsic compression of the inferior vena cava. In such cases, the occurrence of postoperative thrombosis is riskier if hysterectomy/myomectomy is the only option. Utilization of appropriate anticoagulants with modification of the steroid-hormone system using hormone agonists or antagonists (e.g., levonorgestrel intrauterine system, high-dose progestin-only therapy, danazol, aromatase inhibitors, Vitamin-D supplements or selective estrogen receptor modulators) could be an effective technique, but adverse consequences of continued use should be monitored. More research is needed into the basic biology associated with the role of growth factors and genetic alterations in these malignancies. The development of new leiomyomas following conservative therapy is also a significant issue.

We need to better understand how the menstrual cycle interacts with other biological systems, such the inflammation and immune response. One way to study this interaction is through C-reactive protein (CRP). Studies of CRP concentrations across the menstrual cycle have been inconsistent. This study explores menstrual cycle CRP variation in two geographically different samples of Polish and Polish American individuals.

Analyses were conducted on 76 Polish and 22 Polish American daily urine samples collected on the first day of menstruation until the start of their next period. CRP, estrone-3-glucuronide, and pregnanediol-3-glucuronide were assayed. Sample-specific linear mixed models were used to examine cycle effects and median CRP concentrations across cycle phases and between the start of menses and remainder of the cycle were compared using Kruskal-Wallace and Dunn tests.

Polish and Polish American samples had distinct menstrual cycle CRP phenotypes. The Polish sample did not show cycle effects. The Polish American LMM demonstrated that CRP decreases after the first 3 days of menses (estimate -0.17, t-value -5.2). The KW and Dunn tests supported this. CRP concentrations were higher during the early follicular (median 0.406, p < 0.05), specifically the first 3 days of menstruation (median 0.466, p < 0.01), and lower in the luteal (median 0.277, p < 0.05).

Results suggest that changes in CRP during menstrual cycle are not universal across populations. In the Polish American sample, CRP was highest during the early follicular, specifically the first 3 days of menstruation, suggesting a potential relationship between the menstrual cycle and inflammation.

There is an interplay between plasma cells, endometritis, and infertility, particularly in the context of in vitro fertilization (IVF) failure. This narrative literature review explains the pathophysiology of endometritis, detailing the involvement of various immune cells, cytokines, and chemokines in the regulation of inflammatory responses within the uterine endometrium. Here, we discuss the physiological role of plasma cells in immunity and their detection as markers of chronic endometritis, a disease associated with reproductive disorders. Our study also highlights the importance of CD138 immunohistochemical staining in the diagnosis of chronic endometritis, emphasizing the presence of plasma cells in endometrial tissue and its association with infertility and recurrent implantation failure. Of particular interest are the proposed diagnostic criteria for chronic endometritis based on the presence of plasma cells and studies that suggest a threshold for diagnosing this condition. We highlight the importance of examining the regenerative potential of endometrial stem cells in the treatment of infertility related to endometrial disorders.

Background/Objectives: Menstrual blood has recently emerged as a novel specimen for diagnostics, offering a non-invasive alternative to traditional blood testing methods. Despite the importance of vitamins and monitoring their levels in preventative healthcare measures, the feasibility of measuring them in menstrual blood has yet to be explored. In this study, we aimed to assess the potential of using menstrual blood for determining vitamin levels by comparing their levels in menstrual blood to those in matched capillary blood samples. Methods: A prospective, monocentric, observational study was conducted with healthy, reproductive-aged voluntary participants. Menstrual blood was collected from 30 participants using a menstrual cup, and the corresponding capillary blood samples were obtained using a finger prick. The samples were transferred to dried blood spot (DBS) cards and analyzed using mass spectrometry to determine vitamin levels. Statistical analyses were performed to compare menstrual blood vitamin A and D levels, and hemoglobin, to those in capillary blood. Results: The vitamin levels could be ascertained from the menstrual blood, and were observed to significantly correlate with those from the capillary blood for both vitamin A (r = 0.77, p < 0.001) and vitamin D (r = 0.66, p < 0.001), despite being statistically different. Conclusions: The results of this pilot study demonstrate the potential utility of menstrual blood in estimating vitamin A and D levels, illustrating the prospect of a non-invasive menstrual blood-based vitamin test following larger clinical and analytical validation studies.

Decidualization denotes the process of inflammatory reprogramming of endometrial stromal cells (EnSC) into specialized decidual cells (DC). During this process, EnSC are subjected to endoplasmic reticulum (ER) stress as well as acute cellular senescence. Both processes contribute to the proinflammatory mid-luteal implantation window and their dysregulation has been implicated in reproductive failure. Here, we evaluated the link between ER stress, decidual differentiation and senescence. In-silico analysis identified HSPA5 gene, codifying the ER chaperone BiP, as a potentially critical regulator of cell fate divergence of decidualizing EnSC into anti-inflammatory DC and pro-inflammatory senescent decidual cells (snDC). Knockdown of HSPA5 in primary EnSC resulted both in decreased expression of DC marker genes and attenuated induction of senescence associated β-galactosidase activity, a marker of snDC. Stalling of the decidual reaction upon HSPA5 knockdown was apparent at 8 days of differentiation and was preceded by the upregulation of ER stress associated proteins IRE1α and PERK. Further, HSPA5 knockdown impaired colony-forming unit activity of primary EnSC, indicative of loss of cellular plasticity. Together, our results point to a key role for HSPA5/BiP in decidual transformation of EnSCs and highlight the importance of constraining ER stress levels during this process.

Ovarian hormones are known to modulate the immune system in the female genital tract (FGT). We sought to define the impact of the menstrual cycle on the mucosal HIV target cell levels, and tissue-resident CD4 T cells.

Here, we characterized the distribution, phenotype, and function of CD4 T cells with special emphasis on HIV target cells (CCR5+ and α4β7+) as well as tissue-resident memory (TRM; CD69+ and CD103+) CD4 T cells in FGT of cycling women. Peripheral blood and Endocervical cells (EC-collected from cytobrush) were collected from 105 healthy women and performed multicolor flow cytometry to characterize the various subsets of CD4 T cells. Cervicovaginal lavage (CVL) were collected for cytokine analysis and plasma were collected for hormonal analysis. All parameters were compared between follicular and luteal phase of menstrual cycle.

Our findings revealed no significant difference in the blood CD4 T cell subsets between the follicular and luteal phase. However, in EC, the proportion of several cell types was higher in the follicular phase compared to the luteal phase of menstrual cycle, including CCR5+α4β7-cells (p=0.01), CD69+CD103+ TRM (p=0.02), CCR5+CD69+CD103+ TRM (p=0.001) and FoxP3+ CD4 T cells (p=0.0005). In contrast, α4β7+ CCR5- cells were higher in the luteal phase (p=0.0004) compared to the follicular phase. In addition, we also found that hormonal levels (P4/E2 ratio) and cytokines (IL-5 and IL-6) were correlated with CCR5+ CD4 T cells subsets during the follicular phase of the menstrual cycle.

Overall, these findings suggest the difference in the expression of CCR5 and α4β7 in TRM CD4 T cell subsets in endocervix of HIV seronegative women between the follicular and luteal phase. Increase in the CCR5+ expression on TRM subsets could increase susceptibility to HIV infection during follicular phase of the menstrual cycle.

For many years, it has been known that von Willebrand factor (VWF) interacts with factor VIII, collagen, and platelets. In addition, the key roles played by VWF in regulating normal hemostasis have been well defined. However, accumulating recent evidence has shown that VWF can interact with a diverse array of other novel ligands. To date, over 60 different binding partners have been described, with interactions mapped to specific VWF domains in some cases. Although the biological significance of these VWF-binding interactions has not been fully elucidated, recent studies have identified some of these novel ligands as regulators of various aspects of VWF biology, including biosynthesis, proteolysis, and clearance. Conversely, VWF binding has been shown to directly affect the functional properties for some of its ligands. In keeping with those observations, exciting new roles for VWF in regulating a series of nonhemostatic biological functions have also emerged. These include inflammation, wound healing, angiogenesis, and bone metabolism. Finally, recent evidence supports the hypothesis that the nonhemostatic functions of VWF directly contribute to pathogenic mechanisms in a variety of diverse diseases including sepsis, malaria, sickle cell disease, and liver disease. In this manuscript, we review the accumulating data regarding novel ligand interactions for VWF and critically assess how these interactions may affect cellular biology. In addition, we consider the evidence that nonhemostatic VWF functions may contribute to the pathogenesis of human diseases beyond thrombosis and bleeding.

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.

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.

Depression is the leading cause of disability worldwide, exerting a profound negative impact on quality of life in those who experience it. Depression is associated with disruptions to several closely related neural and cognitive processes, including dopamine transmission, fronto-striatal brain activity and connectivity, reward processing and motivation. Physical activity, especially aerobic exercise, reduces depressive symptoms, but the mechanisms driving its antidepressant effects are poorly understood. Here we propose a novel hypothesis for understanding the antidepressant effects of exercise, centred on motivation, across different levels of explanation. There is robust evidence that aerobic exercise decreases systemic inflammation. Inflammation is known to reduce dopamine transmission, which in turn is strongly implicated in effort-based decision making for reward. Drawing on a broad range of research in humans and animals, we propose that by reducing inflammation and boosting dopamine transmission, with consequent effects on effort-based decision making for reward, exercise initially specifically improves 'interest-activity' symptoms of depression-namely anhedonia, fatigue and subjective cognitive impairment - by increasing propensity to exert effort. Extending this framework to the topic of cognitive control, we explain how cognitive impairment in depression may also be conceptualised through an effort-based decision-making framework, which may help to explain the impact of exercise on cognitive impairment. Understanding the mechanisms underlying the antidepressant effects of exercise could inform the development of novel intervention strategies, in particular personalised interventions and boost social prescribing.

Administration of low-dose lipopolysaccharide (LPS) to healthy humans is a translational approach to analyze the effects of acute systemic inflammation and sickness behavior. Although studies documented that LPS-induced inflammation can alter social behavior, its impact on empathy remains poorly understood. In this double-blind, placebo-controlled study, 52 healthy female volunteers received an intravenous injection of either LPS (0.4 ng/kg body weight) or placebo and completed the Social Interaction Empathy Task (SIET) two hours after injection. Physiological responses (blood pressure, heart rate, body temperature, cytokines, cortisol) were analyzed along with sickness symptoms and mood before and after LPS or placebo administration. LPS application led to significant increases in plasma cytokines and sickness symptoms as well as low mood. Moreover, volunteers receiving LPS showed significantly less empathy for other's psychological pain than those who received placebo. Furthermore, LPS-injected volunteers with more severe sickness symptoms displayed higher pain ratings in the first-person perspective. Thus, low-grade inflammation reduces empathy for other's psychological pain which might reflect an adaptive strategy to save energy by not responding empathetically when sick oneself.

The menstrual cycle influences the risk of acquiring sexually transmitted infections (STIs), including Chlamydia trachomatis (C. trachomatis), although the underlying immune contributions are poorly defined. A mouse model simulating the immune-mediated process of menstruation could provide valuable insights into tissue-specific determinants of protection against chlamydial infection within the cervicovaginal and uterine mucosae comprising the female reproductive tract (FRT). Here, we used the pseudopregnancy approach in naïve C57Bl/6 mice and performed vaginal challenge with Chlamydia muridarum (C. muridarum) at decidualization, endometrial tissue remodeling, or uterine repair. This strategy identified that the time frame comprising uterine repair correlated with robust infection and greater bacterial burden as compared with mice on hormonal contraception, while challenges during endometrial remodeling were least likely to result in a productive infection. By comparing the infection site at early time points following chlamydial challenge, we found that a greater abundance of innate effector populations and proinflammatory signaling, including IFNγ correlated with protection. FRT immune profiling in uninfected mice over pseudopregnancy or in pig-tailed macaques over the menstrual cycle identified NK cell infiltration into the cervicovaginal tissues and lumen over the course of endometrial remodeling. Notably, NK cell depletion over this time frame reversed protection, with mice now productively infected with C. muridarum following challenge. This study shows that the pseudopregnancy murine menstruation model recapitulates immune changes in the FRT as a result of endometrial remodeling and identifies NK cell localization at the FRT as essential for immune protection against primary C. muridarum infection.

At menstruation, the functional layer of the human endometrium sheds off due to the trigger of the release of inflammatory factors, including interleukin 6 (IL-6), as a result of a sharp decline in progesterone levels, leading to tissue breakdown and bleeding. The endometrial mesenchymal stem-like cells (CD140b+CD146+ eMSC) located in the basalis are responsible for the cyclical regeneration of the endometrium after menstruation. Endometrial cells from the menstruation phase have been proven to secrete a higher amount of IL-6 and further enhance the self-renewal and clonogenic activity of eMSC. However, the IL-6-responsive mechanism remains unknown. Thus, we hypothesized that IL-6 secreted from niche cells during menstruation regulates the proliferation and self-renewal of eMSC through the WNT/β-catenin signaling pathway.

In this study, the content of IL-6 across the menstrual phases was first evaluated. Coexpression of stem cell markers (CD140b and CD146) with interleukin 6 receptor (IL-6R) was confirmed by immunofluorescent staining. In vitro functional assays were conducted to investigate the effect of IL-6 on the cell activities of eMSC, and the therapeutic role of these IL-6- and WNT5A-pretreated eMSC on the repair of injured endometrium was observed using an established mouse model.

The endometrial cells secrete a high amount of IL-6 under hypoxic conditions, which mimic the physiological microenvironment in the menstruation phase. Also, the expression of IL-6 receptors was confirmed in our eMSC, indicating their capacity to respond to IL-6 in the microenvironment. Exogenous IL-6 can significantly enhance the self-renewal, proliferation, and migrating capacity of eMSC. Activation of the WNT/β-catenin signaling pathway was observed upon IL-6 treatment, while suppression of the WNT/β-catenin signaling impaired the stimulatory role of IL-6 on eMSC activities. IL-6- and WNT5A-pretreated eMSC showed better performance during the regeneration of the injured mouse endometrium.

We demonstrate that the high level of IL-6 produced by endometrial cells at menstruation can induce the stem cells in the human endometrium to proliferate and migrate through the activation of the WNT/β-catenin pathway. Treatment of eMSC with IL-6 and WNT5A might enhance their therapeutic potential in the regeneration of injured endometrium.

The objective of this study was to evaluate the efficacy of electrotherapy and manual therapy for the treatment of women with primary dysmenorrhea.

Systematic searches were conducted in Scopus, Web of Science, PubMed, CINAHL, and MEDLINE. The articles must have been published in the last 10 years, had a sample exclusively of women with primary dysmenorrhea, had a randomized controlled trial design, and used interventions that included some form of manual therapy and/or electrotherapy techniques. Two reviewers independently screened articles for eligibility and extracted data. Difference in mean differences and their 95% CIs were calculated as the between-group difference in means divided by the pooled standard deviation. The I2 statistic was used to determine the degree of heterogeneity.

Twelve selected studies evaluated interventions, with 5 evaluating electrotherapy techniques and 7 evaluating manual therapy techniques. All studies analyzed identified improvements in pain intensity and meta-analysis confirmed their strong effect.

Manual therapy and electrotherapy are effective for the treatment of women with primary dysmenorrhea. Transcutaneous electrical nerve stimulation combined with thermotherapy and effleurage massage stands out for its effects on the intensity and duration of pain with the application of a few sessions and their long-term effects.

Manual therapy techniques and electrotherapy methods reduce the pain intensity of women with primary dysmenorrhea. Quality of life and degree of anxiety improved significantly with manual therapy interventions. Transcutaneous electrical nerve stimulation combined with thermotherapy and effleurage massage are the interventions with which positive effects were achieved with fewer sessions.

Primary dysmenorrhea (PD) is one of the most common reasons that affect the life quality of women during childbearing age. This research aims to explore the efficacy and curative effect characteristics of oral contraceptives and low-power visible-light-activated photodynamic therapy (PDT). Besides investigating the possible mechanism of PDT, we expected to find a treatment model with better efficacy and fewer side effects.

It was a multicenter, randomized, parallel-controlled study. Eligible participants were randomly assigned to three groups: placebo group, oral contraceptive (Marvelon) group, and the PDT group. They were treated continuously for three menstrual cycles and followed up for two cycles after treatment. The scores of the visual analog scale (VAS) and the concentration of pain-related small molecules in blood before and after treatment were recorded in each group, which can evaluate the therapeutic characteristics of different treatments.

Both Marvelon and PDT were effective. The effect of Marvelon appears quickly which can significantly relieve symptoms at the beginning, while PDT shows a relatively slow role. There was no significant difference in the final efficacy two cycles after treatment. The therapeutic effect was achieved by reducing the concentrations of prostaglandin 2 (PGE2) and endothelin (ET) in the blood.

Marvelon and PDT are effective methods for the treatment of PD. The long-term efficacy of the two is similar, while the therapeutic characteristics and the side effects are different. Patients can choose the suitable way according to their individual needs.

Several endocrine disrupting compounds released from plastics, including polyfluoroalkyl substances, bisphenols, flame retardants, phthalates and others, are of great concern to human health due to their high toxicity. This review discusses the effects of di-(2-ethylhexyl) phthalate (DEHP), the most common member of the phthalate family, on female reproduction. In vitro and in vivo studies link DEHP exposure to impaired hypothalamic-pituitary-ovarian s (HPO) axis function, alteration of steroid-hormone levels and dysregulation of their receptors, and changes in uterine morphophysiology. In addition, high urinary DEPH levels have been associated with several reproductive disorders in women, including endometriosis, fibromyoma, fetal growth restriction and pregnancy loss. These data suggest that DEHP may be involved in the pathophysiology of various female reproductive diseases. Therefore, exposure to these compounds should be considered a concern in clinician surveillance practices for women at reproductive age and should be regulated to protect their health and that of their progeny.

The endometrium is a resilient and highly dynamic tissue, undergoing cyclic renewal in preparation for embryo implantation. Cyclic endometrial regeneration depends on the intact function of several cell types, including parenchymal, endothelial, and immune cells, as well as adult stem cells that can arise from endometrial or extrauterine sources. The ability of the endometrium to undergo rapid, repeated regeneration without scarring is unique to this tissue. However, if this tissue renewal process is disrupted or dysfunctional, women may present clinically with infertility due to endometrial scarring or persistent atrophic/thin endometrium. Such disorders are rate-limiting in the treatment of female infertility and in the success of in vitro fertilization because of a dearth of treatment options specifically targeting the endometrium. A growing number of studies have explored the potential of adult stem cells, including mesenchymal stem cells (MSCs), to treat women with disorders of endometrial regeneration. MSCs are multipotent adult stem cells with capacity to differentiate into cells such as adipocytes, chondrocytes, and osteoblasts. In addition to their differentiation capacity, MSCs migrate toward injured sites where they secrete bioactive factors (e.g. cytokines, chemokines, growth factors, proteins and extracellular vesicles) to aid in tissue repair. These factors modulate biological processes critical for tissue regeneration, such as angiogenesis, cell migration and immunomodulation. The MSC secretome has therefore attracted significant attention for its therapeutic potential. In the uterus, studies utilizing rodent models and limited human trials have shown a potential benefit of MSCs and the MSC secretome in treatment of endometrial infertility. This review will explore the potential of MSCs to treat women with impaired endometrial receptivity due to a thin endometrium or endometrial scarring. We will provide context supporting leveraging MSCs for this purpose by including a review of mechanisms by which the MSC secretome promotes regeneration and repair of nonreproductive tissues.

The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained relatively stable until the pre-industrial era, characterized by late menarche, very young age at first birth, multiple pregnancies, and prolonged periods of lactational amenorrhoea. For hundreds of thousands of years, menstruators experienced few ovulatory cycles, even though they were genetically adapted to ovulate and menstruate every month. In the post-industrial era, the age at menarche gradually declined, the age at first birth progressively increased, and breastfeeding became optional and often of short duration. This created a mismatch between genetic adaptation and socio-environmental evolution, so that what was initially a probable reproductive advantage subsequently contributed to increased susceptibility to diseases associated with lifetime oestrogen exposure, such as ovarian, endometrial and breast cancer and, hypothetically, also those associated with the number of ovulatory menstruations, such as endometriosis and adenomyosis. The incidence of endometriosis shows a steep and progressive increase around the age of 25 years, but given the consistently reported delay in diagnosis, the actual incidence curve should be shifted to the left, supporting the possibility that the disease has its roots in adolescence. This raises the question of whether, from an evolutionary point of view, anovulation and amenorrhoea should not still be considered the physiological state, especially in the postmenarchal period. However, an increase in the frequency of endometriosis in recent decades has not been demonstrated, although this deserves further epidemiological investigation. In addition, as endometriosis occurs in a minority of individuals exposed to retrograde menstruation, other important pathogenic factors should be scrutinised. Research should be resumed to explore in more detail the transtubal reflux of not only blood, but also endometrial cells, and whether they are systematically present in the peritoneal fluid after menstruation. If repetitive ovulatory menstruation during the early reproductive years is shown to increase the risk of endometriosis and adenomyosis development and progression in susceptible individuals, hormonal interventions could be used as secondary prevention in symptomatic adolescents.

Abdominal pain due to menses (primary dysmenorrhea) is an extremely pervasive and debilitating symptom affecting up to 90% of menstruating individuals.

The objective of this randomized control trial was to investigate the effect of a commercial transcutaneous electrical nerve stimulation unit, Therabody PowerDot® (Therabody Inc., Los Angeles) on dysmenorrhea compared with non-steroidal anti-inflammatory drug use.

This was a randomized cross-over study.

A total of 47 participants agreed to participate in the study, with 34 completing it. Participants completed treatments across three consecutive menstrual cycles in randomized order: single-unit transcutaneous electrical nerve stimulation (Uno), dual unit transcutaneous electrical nerve stimulation (Duo), and non-steroidal anti-inflammatory drug use (Control). Upon onset of dysmenorrhea, participants applied transcutaneous electrical nerve stimulation to their abdomen for a minimum of 30 min. Control participants were instructed to take non-steroidal anti-inflammatory drugs as needed. Surveys were used to record pain before and after treatment. We hypothesized that the PowerDot would decrease self-reported pain scores, and decrease non-steroidal anti-inflammatory drug consumption during menses.

Participants experienced a statistically and clinically significant reduction in pain during the Control (-3.52 ± 1.9), Uno (-2.10 ± 1.6), and Duo (-2.19 ± 1.7) cycles (p < 0.001). The doses of non-steroidal anti-inflammatory drugs consumed during the Control cycle (3.5 ± 2.6), was significantly different as compared with that of Uno (1.5 ± 3.0), or Duo (1.1 ± 2.6) (p = 0.004).

Use of a commercial transcutaneous electrical nerve stimulation unit results in significant decrease in pain. Although not as robust as the relief in pain induced by non-steroidal anti-inflammatory drugs, the adverse events of transcutaneous electrical nerve stimulation are minimal in comparison. Therefore, transcutaneous electrical nerve stimulation appears to be a viable alternative to pain relief from dysmenorrhea.

NCT05178589.

Endometriosis is a prevalent gynecological condition associated with pelvic pain and infertility. Despite more than a century of research, the etiology of endometriosis still eludes scientific consensus. This lack of clarity has resulted in suboptimal prevention, diagnosis, and treatment options. Evidence of genetic contributors to endometriosis is interesting but limited; however, significant progress has been made in recent years in identifying an epigenetic role in the pathogenesis of endometriosis through clinical studies, in vitro cell culture experiments, and in vivo animal models. The predominant findings include endometriosis-related differential expression of DNA methyltransferases and demethylases, histone deacetylases, methyltransferases, and demethylases, and regulators of chromatin architecture. There is also an emerging role for miRNAs in controlling epigenetic regulators in the endometrium and endometriosis. Changes in these epigenetic regulators result in differential chromatin organization and DNA methylation, with consequences for gene expression independent of a genetic sequence. Epigenetically altered expression of genes related to steroid hormone production and signaling, immune regulation, and endometrial cell identity and function have all been identified and appear to play into the pathophysiological mechanisms of endometriosis and resulting infertility. This review summarizes and critically discusses early seminal findings, the ever-growing recent evidence of epigenetic contributions to the pathophysiology of endometriosis, and implications for proposed epigenetically targeted therapeutics.

The purpose of this systematic review and meta-analysis was to compile existing evidence on the significance of the NLR in predicting endometriosis in order to aid clinical decision-making and outcomes.

We searched ProQuest, Web of Science, and PubMed for related studies published before January 2, 2023. Standardized mean difference (SMD) with a 95% confidence interval (CI) was reported for each outcome. Because a significant level of heterogeneity was found, we used the random-effects model to calculate pooled effects. We used Newcastle-Ottawa Scale (NOS) for quality assessment.

Overall, 18 article with were included in the analysis. A random-effect model revealed that patients with endometriosis had elevated levels of NLR compared to healthy controls (SMD = 0.79, 95% CI = 0.33 to 1.25, P < 0.001). Patients with endometriosis had elevated levels of NLR compared to those with other benign tumors (SMD = 0.85, 95% CI = 0.17 to 1.53, P = 0.014). In addition, NLR level of patients with stage III and IV endometriosis was not different from that of patients with stage I and II endometrioma (SMD = 0.30, 95% CI = -0.14 to 0.74, P = 0.18). However, NLR level was not different between endometriosis patients with and without peritoneal lesions (SMD = -0.12, 95% CI = -0.34to 0.10, P = 0.28), between patients with and without endometrioma (SMD = 0.20, 95% CI = -0.15 to 0.55, P = 0.26) and between endometriosis patients with and without deep lesions (SMD = 0.04, 95% CI = -0.20 to 0.28, P = 0.72). The pooled sensitivity of NLR was 0.67 (95% CI = 0.60-0.73), and the pooled specificity was 0.68 (95% CI, 0.62-0.73).

NLR might be utilized in clinics as a possible predictor to help clinicians diagnose endometriosis in affected women.

What role, if any, does histone deacetylase 3 (HDAC3) play in adenomyosis-associated heavy menstrual bleeding (HMB)?

Seventy-two women with adenomyosis-associated HMB were recruited. Of these, 37 women reported moderate/heavy bleeding (MHB) and the remaining 35 women reported excessive bleeding (EXB). The stiffness of adenomyotic lesions and neighbouring endometrial-myometrial interface (EMI) was measured by transvaginal elastosonography, and full-thickness uterine tissue columns were processed for Masson trichrome staining and immunohistochemistry analyses. The protein expression levels of HDAC3 in endometrial cells cultured on substrates of different stiffnesses, and the protein concentrations of nuclear factor-κB (NF-κB) p65 subunit with HDAC3 suppression were evaluated. Mouse experiments were performed to assess the effect of adenomyosis on Hdac3 expression, endometrial repair and bleeding, and to evaluate the effect of HDAC3 inhibition on endometrial repair.

Compared with controls, the endometrial staining of HDAC3 was significantly lower in women with adenomyosis-associated HMB, concomitant with a greater extent of fibrosis. The stiffness of lesions and neighbouring EMI was significantly higher in the EXB group compared with the MHB group, as was the extent of fibrosis in lesions, their neighboring EMI and endometrium. Expression of HDAC3 was reduced significantly when endometrial epithelial cells were cultured in stiff substrates. Suppression of HDAC3 abrogated the activation and signalling of NF-κB. Mice with induced adenomyosis exhibited reduced Hdac3 staining and elevated fibrosis in endometrium, concomitant with disrupted endometrial repair and more bleeding. Hdac3 inhibition resulted in botched inflammation and increased bleeding.

Lesional fibrosis results in reduced endometrial HDAC3 expression and subsequent disruption in NF-κB signalling and inflammation, leading to adenomyosis-associated HMB.

Progestogens and androgens have been found in many plants, but little is known about their biosynthesis and the evolution of steroidogenesis in these organisms. Here, we show that the occurrence and biosynthesis of progestogens and androgens are conserved across the viridiplantae lineage. An UHPLC-ESI-MS/MS method allowed high-throughput analysis of the occurrence and chemical conversion of progestogens and androgens in 41 species across the green plant lineage. Dehydroepiandrosterone, testosterone, and 5α-dihydrotestosterone are plants' most abundant mammalian-like steroids. Progestogens are converted into 17α-hydroxyprogesterone and 5α-pregnane-3,20-dione. Androgens are converted into testosterone and 5α-dihydrotestosterone. 17,20-Lyases, essential for converting progestogens to androgens, seem to be most effective in monocot species. Our data suggest that the occurrence of progestogens and androgens is highly conserved in plants, and their biosynthesis might favor a route using the Δ4 pathway.

Menstruation is a specific physiological phenomenon in female humans that is regulated by complex molecular mechanisms. However, the molecular network involved in menstruation remains incompletely understood. Previous studies have suggested that C-X-C chemokine receptor 4 (CXCR4) is involved; however, how CXCR4 participates in endometrial breakdown remains unclear, as do its regulatory mechanisms. This study aimed to clarify the role of CXCR4 in endometrial breakdown and its regulation by hypoxia-inducible factor-1 alpha (HIF1A). We first confirmed that CXCR4 and HIF1A protein levels were significantly increased during the menstrual phase compared with the late secretory phase using immunohistochemistry. In our mouse model of menstruation, real-time PCR, western blotting, and immunohistochemistry showed that CXCR4 mRNA and protein expression levels gradually increased from 0 to 24 h after progesterone withdrawal during endometrial breakdown. HIF1A mRNA and HIF1A nuclear protein levels significantly increased and peaked at 12 h after progesterone withdrawal. Endometrial breakdown was significantly suppressed by the CXCR4 inhibitor AMD3100 and the HIF1A inhibitor 2-methoxyestradiol in our mouse model, and HIF1A inhibition also suppressed CXCR4 mRNA and protein expression. In vitro studies using human decidual stromal cells showed that CXCR4 and HIF1A mRNA expression levels were increased by progesterone withdrawal and that HIF1A knockdown significantly suppressed the elevation in CXCR4 mRNA expression. CD45+ leukocyte recruitment during endometrial breakdown was suppressed by both AMD3100 and 2-methoxyestradiol in our mouse model. Taken together, our preliminary findings suggest that endometrial CXCR4 expression is regulated by HIF1A during menstruation and may promote endometrial breakdown, potentially via leukocyte recruitment.

Matrix metalloproteinases (MMPs) and their major source, endometrial stromal cells (ESCs), play important roles in menstruation. However, other mechanisms in endometrial shedding may be unexplored. This study focused on four proteins: S100A8 and S100A9 (alarmins) are binding partners and induce MMPs, MMP-3 cycle-dependently plays a key role in the proteolytic cascade, and CD147, which has S100A9 as its ligand, induces MMPs. Immunostaining for these proteins was performed on 118 resected specimens. The percentage and location of each positive reaction in ESCs were measured and compared using Image J. The influence of leukocytes on S100A8 or S100A9 immunopositivity was also examined. From the premenstrual phase, S100A8 and MMP-3 began to have overlapping expressions in ESCs of the superficial layer, and ESC detachment was found within these sites. S100A9 was expressed from the late secretory phase and CD147 already from earlier. Later, the expression sites of S100A9 and CD147 included those of S100A8. Before menstruation, S100A8 or S100A9 expression was not affected by leukocytes. These results suggest that the local formation of S100A8/S100A9 complex, which occurs specifically in ESCs upon progesterone withdrawal, induces the local expression of MMP-3 and serves as a switch to the lysis phase.

Neutrophil recruitment and activation within the female genital tract are often associated with tissue inflammation, loss of vaginal epithelial barrier integrity, and increased risk for sexually transmitted infections, such as HIV-1. However, the direct role of neutrophils on vaginal epithelial barrier function during genital inflammation in vivo remains unclear. Using complementary proteome and immunological analyses, we show high neutrophil influx into the lower female genital tract in response to physiological surges in progesterone, stimulating distinct stromal, immunological, and metabolic signaling pathways. However, despite the release of extracellular matrix-modifying proteases and inflammatory mediators, neutrophils contributed little to physiological mucosal remodeling events such as epithelial shedding or re-epithelialization during transition from diestrus to estrus phase. In contrast, the presence of bacterial vaginosis-associated bacteria resulted in a rapid and sustained neutrophil recruitment, resulting in vaginal epithelial barrier leakage and decreased cell-cell junction protein expression in vivo. Thus, neutrophils are important mucosal sentinels that rapidly respond to various biological cues within the female genital tract, dictating the magnitude and duration of the ensuing inflammatory response at steady state and during disease processes.

Embryo implantation in humans is interstitial, meaning the entire conceptus embeds in the endometrium before the placental trophoblast invades beyond the uterine mucosa into the underlying inner myometrium. Once implanted, embryo survival pivots on the transformation of the endometrium into an anti-inflammatory placental bed, termed decidua, under homeostatic control of uterine natural killer cells. Here, we examine the evolutionary context of embryo implantation and elaborate on uterine remodelling before and after conception in humans. We also discuss the interactions between the embryo and the decidualising endometrium that regulate interstitial implantation and determine embryo fitness. Together, this Review highlights the precarious but adaptable nature of the implantation process.