Qing Xue

Endometriosis is a common gynecological disease in which lipid metabolic dysregulation has been increasingly implicated. However, the specific metabolic changes in ectopic lesions and stromal cells remain poorly understood. It is also unclear whether these changes contribute to lipid droplet accumulation or how this process is controlled at the transcriptional level. Here, we report that ectopic stromal cells exhibit broad lipid remodeling, showing changes in phosphatidylcholines, lysophosphatidylcholines, sphingomyelins (SMs), and acylcarnitines. Both ectopic lesions and ectopic stromal cells showed increased triacylglycerol and total cholesterol levels, lipid droplet accumulation, and reduced E2F transcription factor 1 (E2F1) expression. Integrated epigenomic and transcriptomic analyses of patient-derived ectopic stromal cells, together with mechanistic validation, revealed that E2F1 transcriptionally activates monoacylglycerol lipase gene (MGLL), which encodes monoacylglycerol lipase, a lipolytic enzyme involved in lipid mobilization. Both in vitro and in vivo experiments showed that down-regulation of E2F1 increased lipid droplet accumulation, whereas restoring MGLL expression partially reversed this effect. Consistently, targeted lipidomic analysis of ectopic stromal cells following MGLL knockdown showed increased levels of several diacylglycerol species and alterations in SM profiles. In summary, our findings suggest that E2F1 down-regulation reduces MGLL expression and impairs lipid mobilization, which may contribute to lipid droplet accumulation and endometriotic lesion growth.

Endometriosis is a common gynecological disease associated with pelvic pain and infertility. Despite several existing theories, the etiology and molecular mechanisms of endometriosis remain to be investigated. Here we report that transcription factor 21 (TCF21) regulates uterine development and endometriosis pathogenesis by promoting epithelial-to-mesenchymal transition (EMT) and cytoskeleton reorganization. Uterine-specific knockout of Tcf21 in mice promotes EMT of the endometrium and dysplasia of the uterus. Accordingly, patients with endometriosis exhibit high TCF21 expression and an expanded population of stromal cells in both eutopic and ectopic endometria. Integrative epigenomic and transcriptomic analyses in patient-derived ectopic stromal cells reveal that TCF21 transcriptionally activated a cohort of genes, including LIMK2, which is critically involved in cytoskeleton organization. Indeed, TCF21-activated LIMK2-cofilin signaling in stromal cells is associated with actin-cytoskeleton reorganization and increased cell invasion and adhesion. In a surgically constructed mouse model, depletion of Tcf21 in eutopic stromal cells alleviates endometriotic lesions, whereas treatment of mice with AAV-Pgr-Tcf21 leads to increased endometriosis incidence, which could be mitigated by administering the LIM kinase inhibitor LIMKi 3. These observations uncover the importance of the TCF21-LIMK2-cofilin axis in uterine development and endometriosis, supporting the pursuit of TCF21-LIMK2-cofilin targeting in the diagnosis and therapeutics of endometriosis.

Background Endometriosis is a chronic gynecological disorder affecting approximately 10% of women of reproductive age. It commonly presents with pelvic pain, dysmenorrhea, and infertility, imposing substantial physical, psychological, and social burdens. Current therapeutic options, such as surgical intervention and hormonal suppression, are constrained by adverse effects and high recurrence rates. Growing evidence implicates immune dysregulation, particularly of macrophages, in the pathophysiology of endometriosis. Main body This narrative review synthesizes foundational and clinical research on macrophages in endometriosis and integrates emerging evidence from single-cell RNA sequencing and spatial transcriptomics to refine current models of macrophage heterogeneity, ontogeny, and therapeutic opportunities. In endometriosis, macrophages adopt heterogeneous, context-dependent states rather than a simple binary pattern. Lesions contain macrophage populations that, through cytokines, chemokines, and growth factors, are implicated in chronic inflammation, impaired clearance of cellular debris, angiogenesis, neuroimmune interactions, extracellular-matrix remodeling, and fibrosis. These immune-mediated mechanisms support lesion survival and are thought to exacerbate symptoms. Recent studies have highlighted several therapeutic strategies aimed at modulating macrophage behavior, including the inhibition of their recruitment to ectopic sites, reprogramming of their functional phenotypes from pro-inflammatory to pro-resolving states, and targeting macrophage-related signaling pathways and immune checkpoints. These approaches are currently under preclinical and clinical investigation and hold promise for reducing disease recurrence and minimizing systemic side effects. Conclusion Macrophages are emerging as central players in the initiation and progression of endometriosis through their contributions to inflammation, lesion maintenance, and fibrogenesis. Targeting macrophage-mediated pathways offers a novel and potentially effective direction for immunomodulatory therapies. A deeper understanding of macrophage plasticity and function within the endometriotic milieu may pave the way for the development of more precise and durable treatment strategies to improve clinical outcomes.

Diminished ovarian reserve refers to the decrease in the quantity and quality of oocytes in the ovary which may cause poor fertility outcomes even with the help of assisted reproductive techniques. Most patients will undergo multiple cycles of IVF treatments. Compared to the live birth rate of a single oocyte retrieval cycle, the cumulative live birth rate across multiple cycles provides a more comprehensive reflection of treatment efficiency and a patient’s long-term outcomes, holding the following importance for clinical decision-making. This study aimed to evaluate the cumulative live birth rate of in vitro fertilization / intracytoplasmic sperm injection after multiple complete cycles in patients with diminished ovarian reserve. We performed a retrospective cohort study in female patients with diminished ovarian reserve undergoing in vitro fertilization / intracytoplasmic sperm injection cycle during the period from January 2016 to December 2020. All patients were followed up for 3 years until either discontinuation of treatments or delivery of one or more live infants. The conservative estimate of cumulative live birth rate and the optimal estimate of cumulative live birth rate were calculated. A total of 343 patients were included in this study, including 996 oocyte retrieval cycles. After one or more cycles of treatments, a total of 141 couples achieved live births during the study period, with a conservative estimate cumulative live birth rate of 41.1% and a optimistic estimate cumulative live birth rate of 81.0%. For women aged < 35 and 35 ~ 39, after 6 oocyte retrieval cycles, the conservative/optimistic estimates of the cumulative live birth rates reached 57.4/ 82.7% and 41.1/ 64.8%, respectively. For elderly women equal or over 40 years old, the conservative/optimistic estimates of the cumulative live birth rates after 6 oocyte retrieval cycles were only 14.7/ 26.0%. The multivariate analysis results showed that: age and the number of oocytes retrieved per cycle were significantly associated with live birth outcomes. For female diminished ovarian reserve patients younger than 40 years old, multiple cycles in vitro fertilization / intracytoplasmic sperm injection treatments can help to achieve satisfactory success rates. As for elder patients aged 40 or above, more than 4 cycles of in vitro fertilization / intracytoplasmic sperm injection may have limited benefits.

This study aimed to investigate the effect of ovarian endometriosis (OE) on ovarian reserve, as well as on cumulative clinical pregnancy rates (cCPR) and cumulative live birth rates (cLBR) in groups of younger women (those under 35 years) and older women (those aged 35 years and above) who are experiencing infertility and receiving treatment through in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). This retrospective analysis included a sample of 300 women diagnosed with OE and 2956 women without the condition, all of whom initiated their first IVF or ICSI cycle between January 2016 and December 2021. Participants were divided into two age categories: younger women (under 35 years) and older women (35 years and older). To establish a comparable baseline, a propensity score matching technique was utilized in a 1:1 ratio, considering age, body mass index, and duration of infertility to align women with OE against those without it. Both univariate and multivariate logistic regression analyses were applied to identify factors that influence cLBR. Furthermore, the ability of anti-Müllerian hormone (AMH) levels to predict cLBR was evaluated through receiver operating characteristic (ROC) curve analysis. Spearman's correlation was employed to examine the associations between age and AMH levels, as well as the relationship between cyst size and AMH levels. Women diagnosed with OE exhibited a significantly lower ovarian reserve, as indicated by reduced levels of AMH and a decreased antral follicle count, compared to those without the condition (P < 0.05). Within the younger age group, women with OE showed substantially lower cCPR and cLBR than their counterparts without OE (62.8% vs. 75.4%, P = 0.010; 56.1% vs. 67.6%, P = 0.025). In contrast, among older women, no significant differences in cCPR and cLBR were noted between those with OE and those without. Among younger women with OE, logistic regression analysis identified age, AMH levels, and the number of top-quality embryos as independent predictors of cLBR. ROC curve analysis determined an optimal AMH threshold of 1.835 ng/ml for predicting cLBR, with a sensitivity of 50.6% and specificity of 82.2%. AMH levels showed no correlation with age, but exhibited a negative correlation with cyst size. In contrast, among older women (≥ 35 years) with OE, AMH levels displayed a negative correlation with age but no significant association with cyst size. OE negatively impacts pregnancy outcomes in younger women, with AMH serving as an independent factor influencing cLBR.

Background: Poor ovarian response (POR) is a challenging condition in assisted reproduction technology. Oral contraceptives (OCs) are commonly used to suppress gonadotropin hormone release in POR patients to synchronize the development of antral follicles before ovarian stimulation. Nevertheless, the question of whether such approach confers advantageous outcomes has elicited inconclusive results in previous studies. Therefore, the objective of this study was to investigate the effect of OCs pretreatment in low prognosis patients stratified by Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) criteria. Methods: This retrospective cohort study included 2,222 patients undergoing their first IVF or ICSI cycle from January 2012 to April 2022. After propensity score matching, 369 patients were in the OC pretreatment group and 879 in the control group. Patients were divided into four subgroups based on the POSEIDON criteria. Comparisons of ovarian response and clinical outcomes were conducted, and multivariable logistic regression was used to assess the association between OCs pretreatment and live birth, clinical pregnancy, and pregnancy loss rates. Results: Patients in POSEIDON group 1 who received OCs pretreatment exhibited a significant reduction in the dose and duration of gonadotropin administration, along with an increase in the number of oocytes retrieved, 2 pronuclei, available embryos, and good quality embryos, indicating an improvement in their ovarian response to exogenous gonadotropins. Additionally, the live birth rate (P = 0.030) and clinical pregnancy rate (P = 0.012) were significantly higher in the OCs pretreatment group. Multivariate logistic regression analysis demonstrated a positive association between OCs pretreatment and live birth rate (P = 0.008) and clinical pregnancy rate (P = 0.008). However, in POSEIDON group 2 to group 4, there were no significant differences in ovarian response or clinical outcomes between the OCs pretreatment group and the control group. Conclusions: Administering OCs as pretreatment prior to ovarian stimulation using gonadotrophin releasing hormone antagonist protocol appears to be a more favorable approach than waiting for natural menses in low prognosis patients belonging to POSEIDON group 1.

Background: To evaluate the impact of embryo quality and quantity, specifically a poor quality embryo (PQE) in combination with a good quality embryo (GQE), by double embryo transfer (DET) on the live birth rate (LBR) and neonatal outcomes in patients undergoing frozen-thawed embryo transfer (FET) cycles. Methods: A study on a cohort of women who underwent a total of 1462 frozen-thawed cleavage or blastocyst embryo transfer cycles with autologous oocytes was conducted between January 2018 and December 2021. To compare the outcomes between single embryo transfer (SET) with a GQE and DET with a GQE and a PQE, propensity score matching (PSM) was applied to control for potential confounders, and a generalized estimating equation (GEE) model was used to determine the association between the effect of an additional PQE and the outcomes. Subgroup analysis was also performed for patients stratified by female age. Results: After PS matching, DET-GQE + PQE did not significantly alter the LBR (adjusted odds ratio [OR] 1.421, 95% CI 0.907–2.228) compared with SET-GQE in cleavage-stage embryo transfer but did increase the multiple birth rate (MBR, [OR] 3.917, 95% CI 1.189–12.911). However, in patients who underwent blastocyst-stage embryo transfer, adding a second PQE increased the live birth rate by 7.8% ([OR] 1.477, 95% CI 1.046–2.086) and the multiple birth rate by 19.6% ([OR] 28.355, 95% CI 3.926–204.790), and resulted in adverse neonatal outcomes. For patients who underwent cleavage-stage embryo transfer, transferring a PQE with a GQE led to a significant increase in the MBR ([OR] 4.724, 95% CI 1.121–19.913) in women under 35 years old but not in the LBR ([OR] 1.227, 95% CI 0.719–2.092). The increases in LBR and MBR for DET-GQE + PQE compared with SET-GQE in women older than 35 years were nonsignificant toward. For patients who underwent blastocyst-stage embryo transfer, DET-GQE + PQE had a greater LBR ([OR] 1.803, 95% CI 1.165–2.789), MBR ([OR] 24.185, 95% CI 3.285–178.062) and preterm birth rate (PBR, [OR] 4.092, 95% CI 1.153–14.518) than did SET-GQE in women under 35 years old, while no significant impact on the LBR ([OR] 1.053, 95% CI 0.589–1.884) or MBR (0% vs. 8.3%) was observed in women older than 35 years. Conclusions: The addition of a PQE has no significant benefit on the LBR but significantly increases the MBR in patients who underwent frozen-thawed cleavage-stage embryo transfer. However, for patients who underwent blastocyst-stage embryo transfer, DET-GQE + PQE resulted in an increase in both the LBR and MBR, which may lead to adverse neonatal outcomes. Thus, the benefits and risks of double blastocyst-stage embryo transfer should be balanced. In patients younger than 35 years, SET-GQE achieved satisfactory LBR either in cleavage-stage embryo transfer or blastocyst-stage embryo transfer, while DET-GQE + PQE resulted in a dramatically increased MBR. Considering the low LBR in women older than 35 years who underwent single cleavage-stage embryo transfer, selective single blastocyst-stage embryo transfer appears to be a more promising approach for reducing the risk of multiple live births and adverse neonatal outcomes.