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.

Endometriosis is a chronic inflammatory disease that primarily affects women of reproductive age. The current hormonal treatments are unsuitable for women who wish to conceive, highlighting the need for non-hormonal therapeutic alternatives. In this study, we engineered outer membrane vesicle (OMV)-coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (OMV-NPs) as a potential therapy for endometriosis. These OMV-NPs were internalized by macrophages more efficiently than bacterial OMVs and preserved the immunostimulatory properties of OMVs. In vivo administration of OMV-NPs in mice achieved prolonged retention in the peritoneal cavity, with effective uptake by nearly 80 % of the peritoneal macrophages. Notably, treatment with OMV-NPs reprogrammed macrophages toward the M1 phenotype, resulting in a significant decrease in the M2 to M1 ratio within the peritoneal cavity and in endometriotic lesions. This shift from M2 to M1 was associated with reduced TGF-β1 production and suppressed myofibroblast activation, which led to substantial inhibition of endometriosis progression. Furthermore, immunohistochemical imaging of paired eutopic and ectopic endometrial tissues from endometriosis patients revealed a positive correlation between M2-polarized macrophages and fibrosis. This finding suggests that reprogramming macrophages with OMV-NPs could be a promising therapeutic approach for endometriosis.

Background: The possible impact of ovarian endometriomas (OMAs) on in vitro fertilization (IVF) outcomes remains controversial. Therefore, this study aimed to assess the impact of OMAs on IVF cycle parameters, including ovarian reserve and response to stimulation, embryo quality and pregnancy outcomes. Methods: This retrospective cohort study included 2067 patients undergoing their first IVF/ICSI cycles between January 2018 and December 2020. The study group included 154 infertile women who had OMAs. The control group consisted of 1913 women without endometriosis, and finally 305 women were matched according to maternal age, body mass index (BMI), and infertility duration by propensity score matching (PSM). Cumulative live birth rate (CLBR) was set as the primary outcome measure. Logistic regression analysis was conducted on the basis of clinical covariates assessed for their association with CLBRs. Subgroup analyses were performed to evaluate the effect of ovarian surgery, cyst size and laterality on CLBRs. Results: Women with OMAs had significantly lower ovarian reserve markers (AMH and AFC), number of follicles, oocytes, embryos, and top-quality embryos than women in the control group (p < 0.05). However, the CLBRs were comparable between the two groups (55.64% versus 54.34%, p = 0.806), regardless of previous history of ovarian surgery. Multivariate analysis revealed association between age (OR = 0.861; 95% CI [0.806–0.921]; p = 0.000), top-quality embryos (OR = 1.829; 95% CI [1.526–2.193]; p = 0.000) and the CLBRs. A negative correlation between OMA size and AFC levels in patients with unoperated OMAs was detected (r = -0.264, p = 0.007). Meanwhile, significant decrease in ovarian reserve with lower AFC, fewer oocytes, embryos and top-quality embryos were observed in patients with OMAs size ≥ 6 cm (p < 0.05). Moreover, ovaries with OMAs had a significantly lower AFC (P = 0.006) but similar number of oocytes when compared with contralateral ovaries without OMAs. Conclusion: Infertile women with OMAs were implicated in considerable decreases in ovarian reserve and response to stimulation, but no apparent adverse effects on oocyte quality or clinical outcomes. OMAs surgery and OMAs size may adversely affect ovarian reserve, but not CLBR.

Endometriosis (EMS) is an estrogen-dependent disease. However, little is known about the regulation of estrogen, a potential therapeutic target, in EMS, which remains very poorly managed in the clinic. We hypothesized that microRNAs (miRNAs) can be exploited therapeutically to regulate transcription factor 21 (TCF21) and steroidogenic factor-1 (SF-1) gene expression. In our study, paired eutopic and ectopic endometrial samples were obtained from women with EMS and processed by a standard protocol to obtain human endometrial stromal cells (EMs) for in vitro studies. We found that miR-92a-3p levels were decreased in ectopic endometrium and ectopic stromal cells (ESCs) compared with paired eutopic lesions. miR-92a-3p overexpression significantly suppressed the proliferation and migration of ESCs, whereas a decreased level of miR-92a-3p generated the opposite results. Next, we identified TCF21 as a candidate target gene of miR-92a-3p. In vitro cell experiments showed that miR-92a-3p negatively regulated the expression of TCF21 and its downstream target gene SF-1. Moreover, cell proliferation and invasion ability decreased after the silencing of SF-1 and increased after SF-1 overexpression. We also observed that silencing SF-1 while inhibiting miR-92a-3p partially blocked the increase in cell proliferation and invasion ability caused by miR-92a-3p knockdown while overexpressing both SF-1 and miR-92a-3p mitigated the impairment in cell proliferation and invasion ability caused by miR-92a-3p overexpression. Our results may provide a novel potential therapeutic target for the treatment of EMS.

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.

Diminished ovarian reserve (DOR) refers to a decrease in the number and/or quality of oocytes, leading to infertility, poor ovarian response and adverse pregnancy outcomes. Currently, the pathogenesis of DOR is largely unknown, and the efficacy of existing therapeutic methods is limited. Therefore, in-depth exploration of the mechanism underlying DOR is highly important for identifying molecular therapeutic targets for DOR. Our study showed that estrogen receptor beta (ERβ) mRNA and protein expression was upregulated in granulosa cells (GCs) from patients with DOR and in the ovaries of DOR model mice. Mechanistically, elevated ERβ promotes forkhead transcription factor family 3a (FOXO3a) expression, which contributes to autophagic activation in GCs. Activation of FOXO3a/autophagy signalling leads to decreased cell proliferation and increased cell apoptosis and ultimately leads to DOR. In a cyclophosphamide (Cy)-induced DOR mouse model, treatment with PHTPP, a selective ERβ antagonist, rescued fertility by restoring normal sex hormone secretion, estrus cycle duration, follicle development, oocyte quality and litter size. Taken together, these findings reveal a pathological mechanism of DOR based on ERβ overexpression and identify PHTPP as a potential therapeutic agent for DOR.