Endometriosis is a prevalent chronic inflammatory condition impacting 5–10% of reproductive-age women, commonly resulting in debilitating pelvic pain and infertility. Despite extensive research efforts, the precise underlying pathophysiology remains largely unclear. Emerging evidence increasingly suggests that cellular senescence, iron overload, and fibrosis collectively form a critical pathological axis that significantly contributes to the persistence and severity of the disease. However, the intricate mechanistic interplay between the immune system’s failure to effectively clear senescent cells, the damaging effects of iron-induced oxidative stress, and the subsequent fibrotic remodelling is still poorly understood. This narrative review highlights the interconnected roles of impaired immune clearance of senescent cells, iron accumulation, and fibrosis development in driving endometriosis pathogenesis. The review aims to clarify how iron overload and cellular senescence contribute to the progression of endometriosis. It also evaluates novel therapeutic strategies that target iron dysregulation and senescence pathways. By exploring this detrimental triad, we seek to identify potential new avenues for transforming the management of endometriosis, offering hope for more effective treatments to alleviate the significant burden on affected women.

This study aimed to predict the likelihood of natural conception among couples by using a machine learning (ML) approach based on sociodemographic and sexual health data. This marks a novel, non-invasive methodology for fertility prediction. This prospective study included 197 couples divided into two groups: 98 fertile couples (Group 1) who achieved natural conception within one year, and 99 infertile couples (Group 2) who were unable to conceive despite regular unprotected intercourse. Data were collected using a structured form capturing 63 variables from both partners. Using the Permutation Feature Importance method, 25 key predictors were selected. The variables included BMI, age, menstrual cycle characteristics, and varicocele presence. Five ML models were developed and their performance was evaluated using metrics such as accuracy, sensitivity, and specificity. The XGB Classifier showed the highest performance among the models tested with an accuracy of 62.5% and a ROC-AUC of 0.580, indicating limited predictive capacity. The selected predictors encompassed a balance of medical, lifestyle, and reproductive factors for both partners, emphasizing the couple-based approach. Key factors included BMI, caffeine consumption, history of endometriosis, and exposure to chemical agents or heat. This study assessed the use of ML to predict natural conception using sociodemographic and health data The key predictors identified emphasize the importance of couple-based and lifestyle factors in predicting natural conception. However, the predictive capacity of the models was limited, highlighting the need for future studies with larger datasets and expanded predictors to improve accuracy and facilitate AI integration into fertility assessment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43032-025-01927-2.

For women with idiopathic diminished ovarian reserve (DOR), direct start with IVF has been suggested to potentially shorten the time to pregnancy. Others however prefer intra-uterine insemination with ovarian stimulation (IUI + OS) due to the expected low response in IVF. In this pilot study, we determined the effect of these two strategies in women with DOR < 40 years. From a retrospective cohort, we included 135 women that met the diagnostic criteria of DOR. Patients were randomly referred to two different outpatient clinics in the Netherlands between 2012–2018 because of subfertility. Primary outcome was clinical pregnancy; secondary outcomes included ongoing pregnancies, live births, time to pregnancy and pregnancy-related complications. An instrumental variable analysis was used to assess the average effect of treatment with IUI + OS followed by IVF (protocol A) compared to IVF alone (protocol B) and correct for (unknown) confounders. Treatment protocol A was performed in 72.6% patients in Centre 1 and 30.6% in Centre 2. In Centre 1 61.6% (45/73) women had a clinical pregnancy compared to 41.9% (26/62) in Centre 2 (difference 19.7% (95% CI 3.1%-36.3%), p = 0.02). Early miscarriage occurred in 24% of the women in Centre 1 in comparison to 45% of the women in Centre 2. There were no significant differences in pregnancy-related complications. This pilot study suggests that women < 40 with DOR, if treated with IUI + OS followed by IVF, have higher estimated cumulative clinical pregnancy success, with a trend towards higher ongoing pregnancies and live births, in comparison to women treated with IVF alone.

A 34-year-old woman with a long-standing history of recurrent implantation failure (RIF) and unexplained infertility presented for further evaluation. Molecular analysis revealed a significant disruption in the crosstalk between the Wnt/β-catenin and PI3K-AKT-mTOR signaling pathways, both essential for regulating endometrial receptivity and successful embryo implantation. Immunohistochemical testing showed a marked reduction in β-catenin nuclear translocation and a 65% decrease in AKT phosphorylation, leading to impaired cellular processes such as proliferation and differentiation. This disruption contributed to incomplete decidualization of the endometrium, which played a central role in her repeated implantation failures. Conventional fertility treatments, including hormone therapy and in vitro fertilization (IVF), were ineffective. Consequently, we explored targeted molecular therapies aimed at restoring functionality within these signaling pathways to enhance endometrial receptivity. This case underscores the critical role of the Wnt/β-catenin and PI3K-AKT-mTOR pathways in endometrial function and highlights the potential for novel therapeutic strategies in treating RIF by addressing specific molecular defects.

The transcriptomic analysis was used to explore the effect of electroacupuncture therapy with distant-approximal acupoints based on the hypothalamic-pituitary–testicular (HPT) on gene expression patterns and pathways in oligoasthenospermia (OAT) rats. In this study, the rat model of OAT after intragastric administration of adenine was selected as the research object, and randomly divided into a blank group (C), a model group (M), and a electroacupuncture therapy with distant-approximal acupoints group (D). After electroacupuncture intervention, the epididymal sperm quality and serum sex hormone levels of rats was detected and three tissue samples of HPT axis were taken, and differentially expressed genes (DEGs) were screened by transcriptome sequencing technology. GO functional annotation and KEGG pathway enrichment analysis were performed on the DEGs. The oxidative stress related indicators in serum and HPT axis were also detected to verify the transcriptomic analysis results. Compared with group C, group M rats showed a decrease in sperm count (p < 0.001), sperm survival rate (p < 0.001), and sperm motility rate (p < 0.001); the serum levels of GnRH in the group M rats decreased (p < 0.001), FSH increased (p < 0.001), LH increased (p < 0.001), and T decreased (p < 0.001). Compared with group M, group D rats showed an increase in sperm count (p < 0.01), sperm survival rate (p < 0.001), sperm motility rate (p < 0.001), an increase in GnRH levels (p < 0.001), a decrease in FSH levels (p < 0.01), a decrease in LH levels (p < 0.001), and an increase in T levels (p < 0.001). In bioinformatics analysis, compared with group M, we identified 1656, 518, 530 DEGs in the hypothalamus, pituitary, and testis in group D, respectively. Combining the go and KEGG analysis results, three oxidative stress signaling pathways that may be related to electroacupuncture intervention in OAT rats were screened. It mainly involves the glutamatergic synaptic pathway, the MAPK signaling pathway and the glutathione metabolism pathway. Six key genes (Gng12、Grin1、Gng7、Jun、Nf1 and Gstp1) were identified as key candidate genes regulating epididymal sperm quality on the HPT axis, which may affect the reproductive function of rats by affecting the process of oxidative stress in vivo. No matter in serum or in three tissues of HPT axis, GPX4 level in group M was decreased compared with Group K (p < 0.0001), while GPX4 level in group D was increased compared with group M (p < 0.0001). This study found that the effect of electroacupuncture therapy with distant-approximal acupoints based on the HPT axis in rats with OAT is related to the process of oxidative stress. And the main genes involved in the oxidative stress pathway were identified, which provided directions and ideas for subsequent research. But these results are only the preliminary results of transcriptomics, and relevant experiments need to be designed to further verify the mechanism of electroacupuncture therapy in rats with OAT.

The mouse uterus, which consists of single-layered epithelium and undifferentiated mesenchyme at birth, begins to differentiate in the postnatal period. The process of adenogenesis, defined as gland development, begins on the Postnatal (PN) Day 5, and this process is very evident on the PN Day 10. Although various signaling pathways effective in the adenogenesis process but the mechanism underlying this progress have not been clarified yet. Hippo signaling pathway have roles in many cellular functions, such as proliferation, differentiation and cell death. But the relationship between the Hippo signaling pathway and uterus adenogenesis is unknown. The objective of this study has been to determine if there is a change in the Hippo signaling pathway in mice with impaired gland development during the adenogenesis process. To that aim, we use mouse uterus with normal gland development (control group) and gland development inhibited by progesterone (experimental group). Animals were sacrificed on the PN Days 5, 10 and 15. YAP and p-YAP by immunohistochemistry and immunoblotting techniques to identify the main components of Hippo Signaling Pathway. YAP, LATS1, LATS 2, MST1, NF2 and TAZ used for the RT-qPCR methods. In conclusion, Hippo signaling pathway components were reduced during the adenogenesis process in mouse with impaired gland development. Graphical A summary of our study. When the control and experimental groups were compared, significant differences were observed in terms of the Hippo signaling pathway.Supplementary InformationThe online version contains supplementary material available at 10.1007/s43032-025-01793-y.

Endometrial polyps are hyperplastic overgrowths of the endometrium that contain both glands and stroma. Myoma uteri is the most common benign tumor of the female pelvis and uterus. HOXA10, which is involved during the organogenesis of the uterus in the embryonic period. The aim of this study was to compare the expression levels of infertility-related genes in endometrial tissue obtained from patients with endometrial polyp and myoma uteri and from healthy controls. A total of 36 patients, including 15 women with endometrial polyp and 21 women with myoma uteri, and 23 healthy controls were enrolled in the study. All patients were evaluated using transvaginal ultrasonography. Endometrial tissue samples were collected from the patient and control groups between the 19th and 21st days of the menstrual cycle. Expression levels of the receptivity markers PROK1, PROKR1, PROK2, PROKR2 and HOXA10 genes were determined by RT- PCR. When the patients diagnosed with endometrial polyp and the healthy controls were compared, it was observed statistically significantly that the expression of PROKR1 increased in endometrium tissue of patients with endometrial polyp (p < 0.05). In patients diagnosed with myoma uteri, gene expression levels of endometrial PROKR1 was statistically significant increased and gene expression levels of PROK1, PROKR2, HOXA10 were found to be statistically significantly decreased compared to the controls (p < 0.05). Changes in the endometrial expression of the HOXA10 and prokineticin gene family in patients with myoma uteri and endometrial polyps may explain certain aspects of infertility in these patients.

Considering the similarity between the invasion processes of cancer cells and embryo implantation, three-dimensional culture models used to study cancer cell invasion can also be applied to embryo implantation studies. In our study, endometrial epithelial cell line (RL95-2) and spheroid-forming trophoblast-like choriocarcinoma cell line (JAR) were cultured on three different biocompatible tissue scaffolds: bacterial cellulose, collagen foam and collagen fibre. These scaffolds are frequently used in cancer cell metastasis and invasion studies, A three-dimensional endometrium-like culture system was established to quantitatively investigate the role of E-cadherin, N-cadherin, Vimentin, α-smooth muscle actin and Syndecan-1 proteins in the type 1 epithelial mesenchymal transition mechanism observed during the invasion step of the implantation process. Based on the findings from the three-dimensional cell culture, the bacterial cellulose scaffold promoted the proliferation of RL95-2 cells and delayed JAR spheroid formation. The collagen foam scaffold favored the proliferation of RL95-2 cells and accelerated JAR spheroid formation. The collagen fibre scaffold is important for supporting cell topography and, when combined with collagen foam, may offer a potential solution for investigating 3D endometrium-like culture systems. Immunocytochemical and immunofluorescence analyses showed that scaffolds modulate the invasion process by affecting the expression of epithelial mesenchymal transition proteins in cells. The findings suggest that different tissue scaffolds can produce varying effects in endometrium-like culture systems, and combinations of these materials may yield more effective results in future studies. This research represents a critical step in studying cell behavior in 3D culture systems and elucidates the mechanism of endometrial invasion.

The study aimed to investigate the expression of nuclear actor-k-gene binding(NF-κB) and immediate early response 3(IER3) in ovarian endometrioid cysts and its correlation with the recurrence of the ovarian endometrioid cyst. From January 2018 to March 2019, a total of 88 patients who underwent laparoscopic ovarian cyst excision due to ovarian endometrioid cyst in Changzhou Maternity and Child Health Care Hospital were selected. Clinical data of the patients were collected. The patient's Revised American Fertility Society (R-AFS) score, least function(LF) score, and endometriosis fertility index (EFI) were calculated. Immunohistochemistry was performed to detect the expression of IER3 and NF-κB. The receiver-operating characteristic (ROC) curve was used to evaluate the predictive value of IER3 and NF-κB expression on postoperative recurrence. Cox regression was fitted to analyze the influencing factors of ovarian endometrioid cyst recurrence. The expression of NF-κB was positively correlated with IER3 (P < 0.001). ROC curve showed that NF-κB combined with IER3 had higher predictive value for disease recurrence. Multivariate Cox regression showed that the IER3 expression intensity > 4.5 (HR = 3.418,95%CI: 1.227 ~ 9.523, P = 0.019) and the NF-κB expression intensity > 4.5 (HR = 5.491,95%CI: 1.600 ~ 18.838, P = 0.007) were independent risk factors for recurrence, and EFI score (HR = 0.791,95%CI: 0.637 ~ 0.983, P = 0.035) was a protective factor for recurrence. Our results suggested that EFI score is a protective factor for recurrence. The expression levels of NF-κB and IER3 > 4.5 are correlated with the recurrence of ovarian endometrioid cysts and independent risk factors for recurrence.

Women with endometriosis were deemed more prone to COVID-19 infection in some reports. Considering that endometriosis-related aberrant immune response, understanding how COVID-19 vaccination influences its clinical status is crucial. The aim of this meta-analysis was the evaluate the susceptibility to COVID-19 infection and modifications of symptoms following COVID-19 vaccination in women with endometriosis. Electronic searches on EMBASE, MEDLINE, Scopus, Cochrane at CENTRAL, Scielo.br, LILACS and other databases were searched from inception to March 2024. Studies were eligible if they analyzed the incidence of infection in endometriosis women or the changes in symptoms after two doses of COVID-19 vaccine and had a control group. Four studies (2249 women) were included. No increased susceptibility to COVID-19 infection due to presence or absence of endometriosis was retrievable (risk ratio (RR) 1.42 [95% CI 0.88 to 2.27]; I2 = 33%). Patients with endometriosis did not experience an overall worsening of symptomatology relative to controls (RR 1.58 [95% CI 0.67 to 3.75]; I2 = 94%). An increase in the risk of dysmenorrhea worsening was noted (RR 1.88 [95% CI 1.11 to 3.17]; I2 = 63%). No other differences regarding menstrual flow (RR 1.25 [95% CI 0.70 to 2.23]; I2 = 78%), intermenstrual bleeding (RR 1.14 [95% CI 0.83 to 1.56]; I2 = 39%) and pelvic pain (RR 2.55 [95% CI 0.65 to 10.05]; I2 = 80%) compared to controls was retrievable. Therefore, mRNA vaccines do not seem to lead to worsening of symptomatology in endometriotic women. However, a slight temporary increase in dysmenorrhea may be present. Moreover, endometriosis does not seem to increase the risk of contracting COVID-19.