Endometriosis-associated Infertility Research Articles

Postoperative reproductive outcomes in patients with endometriosis-associated infertility: A single-centre retrospective study.

Endometriosis is a chronic inflammatory disease known to contribute to infertility. Laparoscopic excision of endometriotic lesions represents a standard treatment modality for symptomatic women. Our study aims to assess the potential benefits of laparoscopic excision of endometriosis in patients experiencing infertility associated with the condition, as well as to define the clinical factors that may impact the cumulative pregnancy rate. In this retrospective analysis, a total of 102 patients with endometriosis-related infertility were enrolled. All participants underwent reproductive surgery and were then categorized into two groups: those who conceived were assigned to Group A, while those who did not were assigned to Group B. The correlation between clinical factors and pregnancy rate was assessed using the log rank test, and both univariate and multivariate analyses were conducted utilizing the Cox regression model. Results The median age of the patients was 33.5 years, with a median follow-up duration of 70 months. Throughout the study period, 71 patients (69.6%) conceived (Group A), while the remaining 31 patients (30.4%) did not conceive (Group B), irrespective of the use of Assisted-Reproduction Technologies. The Cox regression model revealed that factors such as the duration of infertility, presence of deep infiltrating endometriosis, bowel endometriosis, rASRM stages, pelvic adhesions, and recurrent disease negatively impacted postoperative conception rates. Conversely, complete excision and coagulation of endometriotic lesions, as well as ablation of ovarian endometriomas, emerged as independent positive predictive factors for postoperative clinical pregnancy. The retrospective design of the study, as well as a small number of patients. Complete excision of endometriosis during reproductive surgery may yield a positive effect and optimize the likelihood of pregnancy in patients with endometriosis-related infertility.

Methyl 3,4-dihydroxybenzoate alleviates oxidative damage in granulosa cells by activating Nrf2 antioxidant pathway

Oxidative damage induced granulosa cells (GCs) apoptosis was considered as a significant cause of compromised follicle quality, antioxidants therapy has emerged as a potential method for improving endometriosis pregnancy outcomes. Here, we found that GCs from endometriosis patients show increased oxidative stress level. Methyl 3,4-dihydroxybenzoate (MDHB), a small molecule compound that is extracted from natural plants, reversed tert-butyl hydroperoxide (TBHP) induced GCs oxidative damage. Therefore, the aim of this study was to assess the protective effect of MDHB for GCs and its potential mechanisms. TUNEL staining and immunoblotting of cleaved caspase-3/7/9 showed MDHB attenuated TBHP induced GCs apoptosis. Mechanistically, MDHB treatment decreased cellular and mitochondria ROS production, improved the mitochondrial function by rescuing the mitochondrial membrane potential (MMP) and ATP production. Meanwhile, MDHB protein upregulated the expression of vital antioxidant transcriptional factor Nrf2 and antioxidant enzymes SOD1, NQO1 and GCLC to inhibited oxidative stress state, further beneficial to oocytes and embryos quality. Therefore, MDHB may represent a potential drug candidate in protecting granulosa cells in endometriosis, which can improve pregnancy outcomes for endometriosis-associated infertility.

A New Nomogram to Predict Spontaneous Pregnancy after Laparoscopy Combining Hysteroscopy in Women with Minimal to Mild Endometriosis-Associated Infertility

A New Nomogram to Predict Spontaneous Pregnancy after Laparoscopy Combining Hysteroscopy in Women with Minimal to Mild Endometriosis-Associated Infertility

In vitro fertilization for endometriosis-associated infertility: A literature review

In vitro fertilization for endometriosis-associated infertility: A literature review

A large-scale causal analysis of gut microbiota and endometriosis associated infertility: A Mendelian randomization study.

Endometriosis is a prevalent condition with notable impacts on fertility. Recent studies have implicated gut microbiota in the development of endometriosis associated infertility (EAI). This study employs Mendelian randomization (MR) to elucidate the causal relationship between specific gut microbes and EAI. Using MR, we selected single nucleotide polymorphisms associated with 211 gut microbiota taxa from large-scale genome-wide association studies summary data. We applied statistical methods including inverse variance weighting, weighted median, and MR-Egger for analysis. Outliers were identified through the leave-one-out method. MR-Egger intercept tests were conducted to address horizontal pleiotropy, while Cochran Q and P values assessed heterogeneity. The false discovery rate method was used for multiple testing correction. Sensitivity analysis and F statistics evaluated the reliability and potential biases of our results. The inverse variance weighting method indicated a significant association of the genus Actinomyces (OR = 1.657, 95% CI: 1.187-2.312, P = .00298) with an increased risk of EAI. Conversely, genera Holdemania (OR = 0.630, 95% CI: 0.444-0.894, P = .00969) and Ruminococcaceae NK4A214 group (OR = 0.689, 95% CI: 0.481-0.999, P = .0439) appeared as protective factors. MR-PRESSO global test and MR-Egger regression indicated no significant horizontal pleiotropy (P > .05). Leave-one-out analysis confirmed the robustness of these findings. Our study provides evidence of a causal relationship between specific gut microbiome taxa and EAI. These findings offer novel insights and may guide the development of new preventive and therapeutic strategies for managing EAI.

Endometriosis, staging, infertility and assisted reproductive technology: time for a rethink

How endometriosis causes infertility, with the exception of tubal dysfunction caused by adhesions, is unclear. The inflammatory milieu in the pelvis and impaired receptivity of the eutopic endometrium are considered to be possible factors. Anatomical staging systems fail to predict the fertility status of endometriosis patients. Data from assisted reproductive technology cycles consistently suggest that oocytes from patients with endometriosis have a normal potential to develop into euploid blastocysts. Moreover, oocyte or embryo recipients with endometriosis seem to have similar or slightly lower pregnancy and live birth rates compared with recipients without endometriosis, suggesting that eutopic endometrium is not or is only minimally affected, which may be caused by undiagnosed adenomyosis. In-vivo observations from women with endometriomas provide evidence against a detrimental effect of endometriomas on oocytes. Combined with the absence of an obvious improvement in fertility following the surgical destruction or excision of peritoneal endometriosis or from temporary medical suppression of the disease and the associated inflammation, the available evidence makes endometriosis-associated infertility questionable in the absence of tubal dysfunction caused by adhesions. It is likely that no anatomical staging will correlate with fertility beyond assessing tubal function. In patients with endometriosis assisted reproductive technology is as effective as for other indications.

The involvement of RNA N6-methyladenosine and histone methylation modification in decidualization and endometriosis-associated infertility.

Defective decidualization of endometrial stromal cells (ESCs) in endometriosis (EM) patients leads to inadequate endometrial receptivity and EM-associated infertility. Hypoxia is an inevitable pathological process of EM and participates in deficient decidualization of the eutopic secretory endometrium. Enhancer of zeste homology 2 (EZH2) is a methyltransferase which catalyses H3K27Me3, leading to decreased expression levels of target genes. Although EZH2 expression is low under normal decidualization, it is abundantly increased in the eutopic secretory endometrium of EM and is induced by hypoxia. Chromatin immunoprecipitation-PCR results revealed that decidua marker IGFBP1 is a direct target of EZH2, partially explaining the increased levels of histone methylation modification in defected decidualization of EM. To mechanism controlling this, we examined the effects of hypoxia on EZH2 and decidualization. EZH2 mRNA showed decreased m6 A modification and increased expression levels under hypoxia and decidualization combined treatment. Increased EZH2 expression was due to the increased expression of m6 A demethylase ALKBH5 and decreased expression of the m6 A reader protein YTHDF2. YTHDF2 directly bind to the m6 A modification site of EZH2 to promote EZH2 mRNA degradation in ESCs. Moreover, selective Ezh2 depletion in mouse ESCs increased endometrial receptivity and improved mouse fertility by up-regulating decidua marker IGFBP1 expression. This is the first report showing that YTHDF2 can act as a m6 A reader to promote decidualization by decreasing the stability of EZH2 mRNA and further increasing the expression of IGFBP1 in ESCs. Taken together, our findings highlight the critical role of EZH2/H3K27Me3 in decidualization and reveal a novel epigenetic mechanism by which hypoxia can suppress EM decidualization by decreasing the m6 A modification of EZH2 mRNA.

The treatment of endometriosis-associated infertility: Erratum.

The treatment of endometriosis-associated infertility: Erratum.

#334 : Tackling Complex Infertility Patient: A Case Report

Background: Infertility is a common problem presented in women with endometriosis especially as it is often associated with poor quality of life. Therefore, surgical Intervention has been considered as the first-line treatment of choice. On the other hand, surgery itself has detrimental effects on ovarian reserve and is associated with ovarian failure. Case Report: We present a case of a 39-year-old woman para 1 with multiple myoma uteri, bilateral endometriosis cyst, left hydrosalpinx, deep infiltrating endometriosis (DIE), and adhesion (Figure 1). She comes with a history of heavy abnormal uterine bleeding, lower abdominal pain, and unable to conceive 11 years after their first child despite adequate unprotected intercourse. The patient was anemic (Hemoglobin 7.30 g/dL) with low Anti Mullerian Hormone (AMH; 0.26 mg/ml). We decided to perform laparoscopic uterine myoma with multiple bilateral endometrial cysts, left salpingectomy, and adhesiolysis (Figure 2). Patient then underwent an ultra-long protocol with three cycles of leuprolide acetate 3.75 mg. Ovum pick-up was performed and we retrieved five M-II oocytes and from embryo culture, two embryos with good and moderate quality were collected for vitrification procedure. Prior frozen embryo transfer, extra acetylsalicylic acid 80 mg once a day and estradiol valerate 4 mg thrice a day were given for 18 days. The patient soon became pregnant after a few weeks of embryo transfer with βHCG of 185 mIU/m. Conclusion: Individualized treatment plans based on the patient’s symptoms and respective reproductive goals are important points to be discussed in endometriosis-associated infertility patients. Surgical intervention before IVF/ICSI is deemed as necessary to preserve ovarian reserve and to restore normal anatomy to increase the success rate of embryo implantation.

Signatures of necroptosis-related genes as diagnostic markers of endometriosis and their correlation with immune infiltration

BackgroundEndometriosis (EMS) occurs when normal uterine tissue grows outside the uterus and causes chronic pelvic pain and infertility. Endometriosis-associated infertility is thought to be caused by unknown mechanisms. In this study, using necroptosis-related genes, we developed and validated multigene joint signatures to diagnose EMS and explored their biological roles.MethodsWe downloaded two databases (GSE7305 and GSE1169) from the Gene Expression Omnibus (GEO) database and 630 necroptosis-related genes from the GeneCards and GSEA databases. The limma package in Rsoftware was used to identify differentially expressed genes (DEGs). We interleaved common differentially expressed genes (co-DEGs) and necroptosis-related genes (NRDEGs) in the endometriosis dataset. The DEGs functions were reflected by gene ontology analysis (GO), pathway enrichment analysis, and gene set enrichment analysis (GSEA). We used CIBERSORT to analyze the immune microenvironment differences between EMS patients and controls. Furthermore, a correlation was found between necroptosis-related differentially expressed genes and infiltrating immune cells to better understand the molecular immune mechanism.ResultsCompared with the control group, this study revealed that 10 NRDEGs were identified in EMS. There were two types of immune cell infiltration abundance (activated NK cells and M2 macrophages) in these two datasets, and the correlation between different groups of samples was statistically significant (P < 0.05). MYO6 consistently correlated with activated NK cells in the two datasets. HOOK1 consistently demonstrated a high correlation with M2 Macrophages in two datasets. The immunohistochemical result indicated that the protein levels of MYO6 and HOOK1 were increased in patients with endometriosis, further suggesting that MYO6 and HOOK1 can be used as potential biomarkers for endometriosis.ConclusionsWe identified ten necroptosis-related genes in EMS and assessed their relationship with the immune microenvironment. MYO6 and HOOK1 may serve as novel biomarkers and treatment targets in the future.

The role of the anti-Müllerian hormone/anti-Müllerian hormone receptor type II signaling pathway in the eutopic and ectopic endometrium in patients with deep endometriosis: A cross-sectional study

Aim. To analyze the profile of anti-Mllerian hormone (AMH) and the expression level of the transmembrane AMH receptor type II (AMHRII) in the eutopic and ectopic endometrium of patients with deep infiltrative endometriosis (DIE).&#x0D; Materials and methods. A comparative analysis of AMHRII expression in epithelial and stromal cells of eutopic and ectopic endometrial samples and the level of serum AMH in patients of reproductive age with DIE (n=50) and tuboperitoneal infertility (n=9) was performed.&#x0D; Results. AMHRII expression in eutopic endometrial stromal cells of DIE patients was significantly higher compared to glandular cells in all study groups (p0.5). AMHRII expression was found to be significantly higher in glandular cells of the eutopic endometrium compared to the ectopic endometrium of pelvic peritoneal foci in DIE patients: 1.600.77 and 1.090.68 points, respectively (p=0.001).&#x0D; Conclusion. The inhibitory effect of AMH on cell proliferation and the proven expression of AMHRII by eutopic and ectopic endometrioid cells may indicate the role of AMH in the pathogenesis of endometriosis and endometriosis-associated infertility.

Case Report: Implication of antiangiogenic therapy (bevacizumab) along with dichloroacetate therapy on endometriosis patient seeking infertility treatment

Endometriosis is a pervasive gynecological ailment which usually results in unease and infertility and is signified by an accumulation of endometrial-like tissue outside the uterus. Current endometriosis medications, which often entail surgical intervention and hormone therapy, are geared around easing discomfort as well as improving fertility.  However, alternative approaches targeting angiogenesis have shown promise in managing endometriosis-associated infertility. This case report highlights the implications of combining antiangiogenic therapy (bevacizumab) with dichloroacetate (DCA) therapy in a patient with endometriosis seeking infertility treatment. A 34-year-old woman presented with a five-year history of severe pelvic pain and primary infertility due to stage IV endometriosis. The patient sought other possibilities after repeated unsuccessful attempts using assisted reproductive technology. A revolutionary therapy strategy combining bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, and DCA, a metabolic modulator, has been proposed considering the potential significance of angiogenesis in endometriosis-related infertility. The patient underwent a six-month treatment regimen consisting of intravenous bevacizumab infusions combined with oral DCA administration. The theory behind this combination was to target the metabolic reprogramming typically associated with the disease in addition to altering the abnormal angiogenic signaling pathways that contribute to the pathogenesis of endometriosis. Given the scores on the visual analogue scale, the patient's pelvic pain substantially decreased during the time frame of treatment. Additionally, a notable improvement in ovarian reserve markers was observed, including an increase in anti-Müllerian hormone levels and the number of antral follicles. This case report suggests that the combination of bevacizumab and DCA may have a synergistic effect in managing endometriosis-associated infertility. This form of therapy may provide patients who have failed typical infertility treatment options with an innovative therapeutic approach since it targets both angiogenesis and metabolic changes.

Spatiotemporal Trends and Age-Period-Cohort Analysis for the Burden of Endometriosis-Related Infertility: An Analysis of the Global Burden of Disease Study 2019.

Endometriosis is a common nonfatal gynecological disease, and infertility is one of its main dangers. Endometriosis-related infertility causes serious damage to women's health and places a burden on women of reproductive age. The aim of this study was to describe the current burden of endometriosis-associated infertility and to analyze its spatiotemporal trends. Age-standardized prevalence rate (ASPR) data from 1990 to 2019 for Endometriosis-related primary infertility (ERPI) and secondary infertility (ERSI) were obtained from the Global Burden of Disease Study (GBD) 2019. These data spanning three decades cover the global, sociodemographic index (SDI) regions, GBD regions, and 204 countries and territories. Spatiotemporal trends were analyzed by calculating the estimated annual percentage change (EAPC) and using a time-period-cohort model. Globally, the ASPR of ERPI and ERSI showed a weak downward trend from 1990 to 2019, with EAPCs of -1.25 (95% CI: -1.39 to -1.11) and -0.6 (95% CI: -0.67 to -0.53), respectively. The spatiotemporal trends in ERPI and ERSI varied substantially between regions and age groups. When endometriosis-related infertility burden was linked to SDI values, a strong negative correlation was observed between the ASPR of ERSI and its EAPC and SDI values. When modeling with age-period-cohort, ERPI burden was found to be highest at ages 20-25 years, while ERSI burden was persistently higher at ages 20-45 years. Using 2000-2004 as the reference period, both ERPI and ERSI burden decreased with each year among women. Significant variability in burden between regions was found for the birth cohort factor. The global burden of endometriosis-related infertility declined minimally from 1990 to 2019. However, this burden varied considerably across regions, age groups, periods, and birth cohorts. The results of this study reflect spatiotemporal trends in the burden of endometriosis-related infertility over the study period and may be used to help improve health management, develop timely and effective prevention and control strategies, and provide epidemiologic theoretical evidence for reducing the burden for endometriosis-related infertility.

Exploring the Impact of Endometrioma Aspiration and Dienogest Combination Therapy on Cyst Size, Inflammatory Cytokines in Follicular Fluid and Fertility Outcomes.

Endometriomas (chocolate cysts) are cystic lesions that can develop on ovaries, and are characterized by the presence of ectopic endometrial tissue or similar tissue. Such lesions can cause a decline in the number and quality of oocytes, and lead to implantation failure. In this study, we retrospectively assessed the efficacy of repeated endometrioma aspiration and dienogest combination therapy in patients suffering endometriosis-associated infertility with endometriomas. A comparison was made between a treated group that underwent combination therapy followed by controlled ovarian hyperstimulation (COH) (n = 30) and a control group that did not undergo treatment (n = 40), at the IVF Osaka Clinic from September 2019 to September 2021. There were no differences in patient background between the two groups. A reduction in endometrioma size continued for 12 months after treatment. The numbers of follicles that developed to 15 mm or greater in size following COH and mature oocytes were significantly lower in the treated group compared to those in the control group. The levels of inflammatory cytokines in the follicular fluid significantly decreased in the treated group (p < 0.05). In patients in the treated group who underwent a second ova retrieval, the results were compared between those in the first ova retrieval (immediately after the end of treatment) and those in the second ova retrieval (four months after the first retrieval). The numbers of follicles following COH, retrieved, mature and fertilized ova were significantly increased in the second ova retrieval.

Impaired secretion of C-X-C motif chemokine ligand 10 by stimulation with a Toll-like receptor 4 ligand in endometrial epithelium of infertile patients with minimal-to-mild endometriosis

Successful embryo implantation requires transient, well-controlled inflammation in decidualizing cells. In mice, Toll-like receptor (TLR) 4 signaling in endometrial epithelial cells (EECs) by stimulation with factors present in seminal fluids has been shown to be a key upstream driver of a controlled inflammatory response. Clinical evidence supports that exposure of the female reproductive tract to seminal plasma promotes implantation success. We investigated the response of EECs to TLR2 (Pam3Csk4), TLR 3 (Poly I:C), and TLR4 (lipopolysaccharides [LPS]) ligands with respect to secretion of C-X-C motif chemokine ligand (CXCL) 10 (CXCL10) and interleukin-6 (IL-6) in infertile patients with minimal-to-mild endometriosis (EECs-endo) (n = 38) and those of healthy, fertile women (EECs-healthy) (n = 30). Stimulation with either Pam3Csk4, Poly I:C or LPS, significantly induced CXCL10 and IL-6 in EECs-healthy (p < 0.05). In EECs-endo, either Pam3Csk4 or Poly I:C significantly induced CXCL10 (p < 0.05), whereas no significant response was observed after stimulation with LPS. Neither LPS, Poly I:C, nor Pam3Csk4 significantly induced IL-6 secretion in EECs-endo. Secretion of CXCL10 in EECs-healthy after stimulation with LPS was significantly higher (p < 0.05) than that in EECs-endo. CXCL10 decreased cell proliferation of EECs from both groups. Activation of nuclear factor kappa light chain enhancer of activated B cells and signal transducer and activator of transcription 3 signalings was not impaired, but activation of p38 mitogen-activated protein kinases signaling by LPS stimulation was impaired in EECs-endo. The present findings suggested that an insufficient response of EECs to a TLR4 ligand may be involved in molecular mechanisms of endometriosis-associated infertility.

Modern concepts o f endometrial receptivity in endometriosis-associated infertility (analytical review)

Here we provide the recent information on the molecular profile of the endometrium and highlight the pathogenesis of infertility occurring during endometriosis. Because of individual features of each woman’s organism, there are no versatile diagnostic criteria for determining endometrial receptivity which plays one of the leading roles in implantation disorders. Although a lot of studies on the gene expression in endometriosis have been published to date, intricate gene-gene and gene-environment interactions frequently balance inherited or acquired alterations of gene expression in the endometrium. Hence, investigation of entire cell signaling pathways is preferrable over the general expression of gene expression within the endometrium. As eutopic and ectopic endometrium have largely similar histological appearance, the development of a single diagnostic test remains an unmet clinical need. Therefore, it is urgent to search for novel, evidence-based criteria for timely prediction and early diagnosis of endometriosis-associated infertility using minimally invasive examination methods.

Exosomal microRNAs in tubal fluid may be involved in damage to tubal reproductive function associated with tubal endometriosis

Research questionWhat is the effect of tubal endometriosis on tubal epithelial ultrastructure and is there a differential expression of exosomal microRNAs (miRNAs) in tubal fluid which may affect tubal infertility? DesignHuman fallopian tube epithelium and tubal fluid samples were obtained from patients with and without tubal endometriosis. Scanning electron microscopy and transmission electron microscopy were used to assess ultrastructural changes. Exosomal miRNAs in tubal fluid were extracted for microarray. ResultsEpithelial damage was visualized in the tubal endometriosis group using electron microscopy. The number of organelles decreased (P = 0.0314), and organelle structure was destroyed. A total of 14 differentially expressed exosomal miRNAs were detected in tubal fluid (fold change >2 and P < 0.05). Four miRNAs (miR-1273f, miR-5699-5p, miR-6087 and miR-6747-5p) were validated by quantitative real-time polymerase chain reaction. Bioinformatic analysis showed that most of the target genes participated in embryo transport, regulation of cell communication, anatomical structure morphogenesis and immune system processes. ConclusionsTubal endometriosis results in damage to the tubal epithelial ultrastructure in human specimens and the presence of differentially expressed exosomal miRNAs in tubal liquid. These findings help to clarify the pathogenesis of tubal endometriosis-associated infertility and the mechanisms driving tubal epithelial ultrastructure damage in tubal endometriosis.

P-322 Single-cell transcriptome analysis reveals endometrial immune microenvironment in minimal/mild endometriosis

Abstract Study question This study aimed to systematically understand the endometrial leukocyte types, inflammatory environment, and impaired receptivity at single-cell resolution. Summary answer These results provide new insights into the endometrial immune microenvironment and impaired endometrial receptivity in infertile women with minimal/mild endometriosis. What is known already Endometriosis is a common inflammatory disorder in women of reproductive age due to an abnormal endometrial immune environment and is associated with infertility. Study design, size, duration We profiled single-cell RNA transcriptomes of 138,057 endometrial cells from endometriosis patients (n = 6) and control (n = 7), respectively, using 10x Genomics platform. Participants/materials, setting, methods We profiled single-cell RNA transcriptomes of 138,057 endometrial cells from endometriosis patients (n = 6) and control (n = 7), respectively, using 10x Genomics platform. Main results and the role of chance We found that one cluster of epithelial cells that expressed PAEP and CXCL14 was mostly from the control during the window of implantation (WOI). This epithelial cell type is absent in the eutopic endometrium during the secretory phase. The proportion of endometrial immune cells decreased in the secretory phase in the control group, whereas the cycle variation of total immune cells, NK cells, and T cells was absent in endometriosis. Endometrial immune cells secreted more IL-10 in the secretory phase than in the proliferative phase in the control group; the opposite trend was observed in endometriosis. Proinflammatory cytokines levels in the endometrial immune cells were higher in endometriosis than in the control group. Trajectory analysis revealed that the secretory phase epithelial cells decreased in endometriosis. Ligand–receptor analysis revealed that 11 ligand-receptor pairs were upregulated between endometrial immune and epithelial cells during WOI. Limitations, reasons for caution Our study had some limitations, such as the small sample size and lack of validation experiments. Further studies are needed to demonstrated the conclusions of our bioinformatic analysis, like in situ validation of receptor-ligand pairs analysis. Therefore, more evidence is needed to clearly state the pathogenesis of endometriosis-associated infertility. Wider implications of the findings This database will provide an essential resource for understanding the eutopic endometrial inflammatory environment and defective endometrial receptivity in patients with endometriosis-associated infertility. Trial registration number 82071625

Higher miscarriage rate in subfertile women with endometriosis receiving unbiopsied frozen-warmed single blastocyst transfers.

Background: Assisted reproductive technology treatment is recommended to overcome endometriosis-associated infertility but current evidence is controversial. Endometriosis is associated with lower antral follicle count (AFC) and oocyte yield but similar clinical outcomes compared to controls. Unaffected ovarian stimulation response and embryological outcomes but lower clinical pregnancy and live birth rates and higher miscarriage rates have been reported, implying direct impact on endometrial receptivity. With evidence emerging on the benefit of frozen-warmed and blastocyst stage transfer, we investigated ART outcomes in endometriosis using homogeneous case-control groups. Methods: This is a retrospective observational case-control study including n = 66 frozen-warmed unbiopsied single blastocyst transfers of patients with endometriosis and n = 96 of women exhibiting idiopathic sterility. All frozen-warmed transfers followed artificial endometrial preparation. Results: In control women, the mean number of oocytes recovered at oocyte pick up was higher compared to women with endometriosis (15.3 ± 7.1 vs. 12.7 ± 5.2, p = 0.025) but oocyte maturation index (mature oocytes/total oocytes at oocyte pick up) was significantly higher for endometriosis (48.2% vs. 34.0%, p = 0.005). The same was shown for the subgroup of 44 endometriosis patients after endometrioma surgery when compared with controls (49.1% vs. 34.0%, p = 0.014). Clinical pregnancy rate was not higher in endometriosis but was close to significance (47.0% vs. 32.3%, p = 0.059) while live birth rate was comparable (27.3% vs. 32.3%, p = 0.746). Miscarriage rate was higher in the endometriosis group (19.7% vs. 7.3%, p = 0.018). A significantly higher AFC was observed in the control group in comparison with the endometriosis group (16.3 ± 7.6 vs. 13.4 ± 7.0, p = 0.014). Live birth rate did not differ when comparing all endometriosis cases (p = 0.746), ASRM Stage I/II and Stage III/IV (p = 0.348 and p = 0.888) with the control group but the overall pregnancy rate was higher in ASRM Stage I/II (p = 0.034) and miscarriage rate was higher in ASRM Stage III/IV (p = 0.030) versus control. Conclusion: Blastocyst transfers in women with endometriosis originate from cycles with lower AFC but higher share of mature oocytes than in control women, suggesting that endometriosis might impair ovarian reserve but not stimulation response. A higher miscarriage rate, independent of blastocyst quality may be attributed to an impact of endometriosis on the endometrium beyond the timing of implantation.

Integrative analysis of transcriptomic and metabolomic profiles reveals abnormal phosphatidylinositol metabolism in follicles from endometriosis-associated infertility patients.

Endometriosis is a common gynecological disorder that causes female infertility. Our recent research found that excessive oxidative stress in ovaries of endometriosis patients induced senescence of cumulus granulosa cells. Here, we analyzed the transcriptomic and metabolomics profiles of follicles in a mouse model of endometriosis and in patients with endometriosis and investigated the potential function of changed metabolites in granulosa cells. RNA-sequencing indicated that both endometriosis lesions and oxidative stress in mice induced abnormalities of reactive oxidative stress, steroid hormone biosynthesis, and lipid metabolism. The mouse model and women with endometriosis showed altered lipid metabolism. Nontargeted metabolite profiling of follicular fluid from endometriosis and male-factor infertility patients by liquid chromatography mass spectrometry identified 55 upregulated and 67 downregulated metabolites. These differential metabolites were mainly involved in steroid hormone biosynthesis and glycerophospholipid metabolism. Phosphatidylinositol (PI 16:0/18:2) was significantly elevated in follicular fluid from endometriosis patients compared with controls (p < 0.05), while lysophosphatidylinositol (LPI 18:2, 20:2, 18:1, 20:3 and 18:3) was reduced (p < 0.05). Upregulated PI and downregulated LPI correlated with oocyte retrieval number and mature oocyte number. LPI inhibited cellular reactive oxidative stress induced by hemin in granulosa cells. Cell proliferation inhibition, senescence, and apoptosis induced by hemin were partially reversed by LPI. Moreover, LPI administration rescued hemin blocking of cumulus-oocyte complex expansion and stimulated expression of ovulation-related genes. Transcriptomic Switching mechanism at 5' end of the RNA transcript sequencingand western blot revealed that LPI effects on granulosa cells were associated with its regulation of MAPK-ERK1/2 signaling, which was suppressed in the presence of hemin. In conclusion, our results revealed the dysregulation of lipid metabolism in endometriotic follicles. LPI may represent a novel agent for in vitro follicular culture that reverses the excessive oxidative stress from endometriotic lesions. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.