Endometriosis In Infertile Patients Research Articles

Correlation of Glycolysis-immune-related Genes in the Follicular Microenvironment of Endometriosis Patients with ART Outcomes.

Endometriosis (EMT) -related infertility has been a challenge for clinical research. Many studies have confirmed that abnormal alterations in the immune microenvironment and glycolysis are instrumental in causing EMT-related infertility. Recently, our research team identified several key glycolysis-immune-related genes in the endometrial cells of EMT patients. This study aimed to further investigate the expression patterns of pyruvate dehydrogenase kinase 3 (PDK3), glypican-3 (GPC3), and alcohol dehydrogenase 6 (ADH6), which are related to glycolysis and immunity, in the follicular microenvironment of infertile patients with EMT using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR) assays. According to the results, compared to the patients with tubal factor infertility, the concentrations of PDK3 and GPC3 were considerably increased in the follicular environment of EMT patients, while ADH6 expression was significantly reduced. The number of oocytes retrieved, the transferable embryo rate, and the cumulative clinical pregnancy rate of EMT patients were significantly reduced, and there was a correlation with the level of PDK3, GPC3, and ADH6 in Follicular Fluid (FF). The area under the receiver operating characteristic (ROC) curve for predicting clinical pregnancy in infertile patients with EMT for PDK3, GPC3, ADH6, and their combination was 0.732, 0.705, 0.855, and 0.879, respectively (P < 0.05). In conclusion, our research indicates that glycolysis-immune-related genes may contribute to infertility in EMT patients through immune infiltration, and disruption of mitochondrial and oocyte functions. The combined detection of PDK3, GPC3, and ADH6 in FF helps to predict clinical pregnancy outcomes in infertile patients with EMT.

Oxidative stress markers cannot be used as endometriosis biomarkers in infertile patients

Objectives Endometriosis is a common benign gynaecological disease that significantly compromises the quality of life of patients. To date, invasive surgery is the method of choice to visually and histologically confirm endometriosis. Thus, there is a major interest to develop noninvasive diagnostic tools. Oxidative stress is one of the proposed mechanisms of pathogenesis and may be involved in pelvic pain, dysmenorrhea, dyspareunia, and infertility in endometriosis patients. Thus, markers of oxidative stress may serve as diagnostic biomarkers for endometriosis. Design This prospective case–control study assessed erythrocyte superoxide dismutase (SOD), erythrocyte glutathione peroxidase (GPX), serum hexanoyl lysine (HEL) and peritoneal fluid HEL. Participants/Materials, Setting, and Methods We enrolled 86 women with primary infertility; the case group included 57 women with endometriosis, and the control group included 29 women with unexplained primary infertility. All the patients underwent laparoscopy, and the diagnosis was confirmed histologically. RANDOX and RANSEL reagents were used to determine the levels of SOD and GPX, respectively, and ELISA was used to determine the levels of HEL. Results We found no statistically significant differences in the erythrocyte levels of GPX (p value 0.623) or SOD (p value 0.122) or the serum or peritoneal fluid levels of HEL (p value 0.562 and 0.329 accordingly). Conclusions SOD, GPX, and HEL levels most likely do not differ between patients with unexplained infertility and patients with endometriosis.

A cohort study on IVF outcomes in infertile endometriosis patients: the effects of rapamycin treatment

Research questionCan rapamycin, used as an anti-senescence drug before IVF cycles, improve the IVF outcomes of women with endometriosis by reducing oxidative stress and senescence? DesignThis retrospective analysis involved 168 endometriosis patients undergoing two successive IVF cycles. The treatment group (n = 80) received 3 months of rapamycin before the second IVF cycle, while the non-treatment group (n = 88) had no adjuvant treatment. The first and second IVF cycles were compared between and within groups. Follicular fluid from both IVF cycles (treatment group n = 28, non-treatment group n = 32) were tested for senescence-associated and oxidative stress-related markers. ResultsComparing the follicular fluid from the second cycles, the rapamycin treatment group showed decreased markers of oxidative stress (8-hydroxydesoxyguanosine, malondialdehyde) and increased antioxidant markers (superoxidase dismutase, glutathione peroxidase) (all P < 0.001); the expression of senescence-related markers p16 and p21 was also significantly lower in the treatment group than in the non-treatment group (P < 0.001). Comparing the second IVF cycles, the treatment group needed fewer days of ovarian stimulation, with increased numbers of oocytes obtained and mature oocytes compared with the non-treatment group (all P < 0.001). Furthermore, rates of fertilization, implantation and clinical pregnancy were significantly higher in the treatment group (P = 0.008, 0.034 and 0.038 respectively), as was the live birth rate (P = 0.003). No structural abnormalities were seen in fetuses born to women treated with rapamycin. ConclusionsThis study suggested an association between short-term rapamycin treatment and improved pregnancy outcomes via IVF. This result needs to be further investigated in prospective randomized controlled clinical trials.

P-329 Oocyte donation outcomes in endometriosis patients with multiple IVF failures

Abstract Study question What are the reproductive outcomes and the prognostic factors of live birth rates in endometriosis patients referred to oocyte donation after multiple in vitro fertilization(IVF)-failures? Summary answer In this specific population, oocyte donation appears to be a viable option to optimize the reproductive outcomes, as the cumulative live birth rate reaches 63.2%. What is known already Assisted Reproductive Technology(ART) is currently recognized as one of the main therapeutic options to manage endometriosis-related infertility, often resulting in satisfactory outcome. A burning issue in this field remains how to deal with patients undergoing recurrent ART failures. As there appear to be two main factors contributing to the failures, i.e., a deleterious effect of endometriosis on embryo implantation and altered oocyte and embryo quality, two competing therapeutic strategies can be considered:(i) endometriosis surgery and (ii) oocyte donation. However, no data has been published to date in the specific population of endometriosis patients with previous IVF failures, undergoing oocyte donation. Study design, size, duration Observational cohort study including fifty-seven women with endometriosis-related infertility and multiple IVF failures (≥ 2 failed IVF cycles) referred to oocyte donation who consulted at our institution between January 2013 and June 2022. Participants/materials, setting, methods Endometriosis was diagnosed based on published imaging criteria using transvaginal sonography and magnetic resonance imaging and confirmed histologically in women who had a history of surgery for endometriosis. The main outcomes measured were the clinical pregnancy rate (CPR) and the cumulative live birth rate (CLBR). We compared the characteristics of women who had a live birth versus those who did not using univariate and multivariate analysis to identify determinant factors of fertility outcome. Main results and the role of chance Fifty-seven patients underwent 90 oocyte donation cycles, after 244 failed autologous IVF cycles. The mean age of the population was 36.8 ± 3.3 years, with a mean infertility duration of 3.6 ± 2.2 years, and a mean number of autologous IVF/ICSI cycles of 4.4 ± 2.3 cycles per patient. Three patients (5.3%) had superficial endometriosis, 2 patients (3.5%) had ovarian endometriomas, and 52 patients (91.2%) had deep infiltrating endometriosis, among which 30 patients (57.7%) had bowel lesions. Thirty patients (52.6%) had associated adenomyosis. Overall, the CPR and the CLBR per patient were 49/57 (85.9%) and 36/57 (63.2%), respectively. After multivariate analysis, only being nulligravida (p = 0.002) remained an independent negative predictive factor of the live birth rate. Limitations, reasons for caution In 35.1% of patients there was no surgical/histological proof of endometriosis. However, for all the study participants, endometriosis was diagnosed and staged using patient interviews, clinical examination, and imaging techniques to assess for endometriosis phenotypes, which is in line with the structured diagnostic process acknowledged as being appropriate for endometriosis. Wider implications of the findings In this specific population, poor embryo quality may be the main limiting factor of ART success rates, rather than impaired endometrial receptivity. These data are reason for clinicians not to systematically refer infertile endometriosis patients with recurrent IVF failures to surgery. Trial registration number not applicable

Endometrial stromal PRMT5 plays a crucial role in decidualization by regulating NF-κB signaling in endometriosis

Decidualization is a prerequisite for successful embryo implantation, in which elongated fibroblast-like endometrial stromal cells differentiate into more rounded decidual cells. Accumulating evidence has stressed the important role of the defective eutopic endometrium in infertility in endometriosis patients. However, the role of arginine methylation in the process of physiological decidualization and pathological decidualization defects is not clear. Here, we observed that the expression level of PRMT5, the main type II PRMT, was decreased in the endometrium of endometriosis patients, predominantly in stromal cells. Compared with the undecidualized state, PRMT5 was increased in the stromal cells of normal secretory endometrium in humans and in the decidua of normal pregnant mice or mice with artificially induced decidualization. The inhibition of PRMT5 resulted in a significant decrease in uterine weight and decidualization-related regulator expression, including FOXO1, HOXA10 and WNT4, in mice and IGFBP1 and prolactin levels in human endometrial stromal cells. Transcriptome analysis showed that decreased PRMT5 activity led to NF-κB signaling activation by inducing p65 translocation to the nucleus, which was also observed in endometriosis patients. Finally, overexpression of PRMT5 rescued the defective expression of IGFBP1 and prolactin in primary endometrial stromal cells from endometriosis patients. Our results indicate that promotion of PRMT5 may provide novel therapeutic strategies for the treatment of decidualization defects in infertile women, such as those with endometriosis.

Assessment of TET1 gene expression, DNA methylation and H3K27me3 level of its promoter region in eutopic endometrium of women with endometriosis and infertility.

Endometriosis is the cause of infertility. The eutopic endometrium of women with endometriosis showed an aberrant expression pattern of multitude genes. The role of TET1 protein in the pathogenesis of endometriosis and related infertility is not sufficiently known. Further, knowledge on TET1 transcriptional control still remains incomplete. The aim of the study was assessment of TET1 gene expression, DNA methylation and H3K27me3 level of its promoter region in eutopic endometrium of women with endometriosis and infertility. The study included 44 infertile patients with endometriosis (IWE) and 77 infertile (IW) and fertile (FW) patients without endometriosis. The research material was eutopic endometrium. The TET1 mRNA level was analyzed by qPCR. Western blot was used to evaluate the level of TET1 protein. The level of DNA methylation and H3K27me3 level of TET1 gene's promoter region were assessed using HRM and ChIP qPCR, respectively. The level of TET1 expression (TET1 mRNA; TET1 protein level) was lower in IWE during the implantation window (p<0.001; p=0.0329). The level of TET1 DNA methylation was higher in the secretory endometrium in mild and advanced IWE (p<0.004; p<0.008). H3K27me3 level did not differ between the study groups. The diminished expression of TET1 gene during the secretory phase, may account for the aberrant process of embryonic implantation in infertile endometriosis patients. DNA hypermethylation of TET1 gene is a potential relevant regulator of its expression. H3K27me3 occupancy does not affect the expression of TET1 gene in our study group.

Identification of Potential Molecular Mechanism Related to Infertile Endometriosis.

ObjectivesIn this research, we aim to explore the bioinformatic mechanism of infertile endometriosis in order to identify new treatment targets and molecular mechanism.MethodsThe Gene Expression Omnibus (GEO) database was used to download MRNA sequencing data from infertile endometriosis patients. The “limma” package in R software was used to find differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was used to classify genes into modules, further obtained the correlation coefficient between the modules and infertility endometriosis. The intersection genes of the most disease-related modular genes and DEGs are called gene set 1. To clarify the molecular mechanisms and potential therapeutic targets for infertile endometriosis, we used Gene Ontology (GO), Kyoto Gene and Genome Encyclopedia (KEGG) enrichment, Protein-Protein Interaction (PPI) networks, and Gene Set Enrichment Analysis (GSEA) on these intersecting genes. We identified lncRNAs and miRNAs linked with infertility and created competing endogenous RNAs (ceRNA) regulation networks using the Human MicroRNA Disease Database (HMDD), mirTarBase database, and LncRNA Disease database.ResultsFirstly, WGCNA enrichment analysis was used to examine the infertile endometriosis dataset GSE120103, and we discovered that the Meorangered1 module was the most significantly related with infertile endometriosis. The intersection genes were mostly enriched in the metabolism of different amino acids, the cGMP-PKG signaling pathway, and the cAMP signaling pathway according to KEGG enrichment analysis. The Meorangered1 module genes and DEGs were then subjected to bioinformatic analysis. The hub genes in the PPI network were performed KEGG enrichment analysis, and the results were consistent with the intersection gene analysis. Finally, we used the database to identify 13 miRNAs and two lncRNAs linked to infertility in order to create the ceRNA regulatory network linked to infertile endometriosis.ConclusionIn this study, we used a bioinformatics approach for the first time to identify amino acid metabolism as a possible major cause of infertility in patients with endometriosis and to provide potential targets for the diagnosis and treatment of these patients.

Role of ultrasonographic parameters for predicting tubal involvement in infertile patients affected by endometriosis: A retrospective cohort study

IntroductionTransvaginal ultrasound is fundamental for the mapping of endometriosis, and the imaging criteria have been clearly described for different organs study. However, no specific ultrasonographic signs of tubal endometriosis have been reported, with the exception of hydrosalpinx, which is the expression of an extreme tubal damage and obstruction. The detection of tubal pathology in infertile patients is fundamental, therefore the aim of the study was to evaluate incidence of tubal endometriosis in infertile patients, and to analyze ultrasonographic signs useful for detection of this condition. Material and methodsIt is a single-center, retrospective cohort study. All 500 consecutive infertile women who underwent laparoscopic surgery for endometriosis were included. The preoperative workup included transvaginal ultrasound and was compared to intraoperative findings and histologic study. ResultsThe incidence of tubal endometriosis in our study was 8%. Using hydrosalpinx as the ultrasonographic marker for tubal involvement the overall pooled, sensitivity and specificity of TVU were 12% (95%CI, 5–23%) and 99% (95%CI, 98–100%), respectively.If at least one ultrasonographic parameter like hydrosalpinx, periadnexal adhesions or ovarian cyst was considered as a sign of tubal endometriosis, a sensitivity, VPN and specificity were 94% (95% IC, 85–98%), 97% (95%IC, 93–99%) and 31% (95%CI, 27–36%), respectively. DiscussionHydrosalpinx as ultrasonographic sign alone is characterized by a high specificity but low sensitivity for detection of tubal endometriosis; its sensitivity can be improved by the addition of other markers such as endometrioma and/or periadnexal adhesions.

Spontaneous and induced chromosomal aberrations in peripheral blood of women with endometriosis: evidence of genomic instability.

Endometriosis is a prevalent gynecological disease which can lead to certain types of cancers. We investigated the spontaneous and induced chromosomal aberrations in peripheral blood lymphocytes (PBL) of endometriosis patients. We performed a pilot study utilizing mitomycin C (MMC) to assess chromosomal instability in the peripheral blood of participants. The patient group consisted of 20 infertile endometriosis patients and the controls of 20 healthy fertile women. Blood samples were collected, and two distinct lymphocyte cultures were prepared to evaluate the baseline and the MMC induced chromosomal aberrations. The results showed a significant difference before and after MMC treatment in both groups (P<0.001) and also revealed that endometriosis patients are far more sensitive to MMC than controls (P<0.001). The significantly higher frequency of induced and spontaneous chromosomal aberrations in patients can be consider as a sign of genomic instability and the defect in DNA repair mechanisms, which can be both assumed as a driver of cancer development in endometriosis patients.

Treating Deep Endometriosis in Infertile Patients before Assisted Reproductive Technology.

Deep endometriosis (DE) causes infertility and pelvic pain. Surgical management of DE has become a topic of increasing interest in gynecological surgery. In women desirous of pregnancy, optimal management such as surgery versus first-line assisted reproductive technology (ART) for patients with severe endometriosis is strongly debated. Current guidelines and literature including retrospective and prospective studies in English available on DE surgery, infertility, and pregnancy outcomes following surgery were searched in Cochrane Library with DE, DIE, Infertility, “DE surgery and pregnancy outcomes,” and “Deep infiltrating endometriosis and assisted reproduction” as keywords. The purpose was to find evidence to answer the following clinical questions: How does DE affect fertility and pregnancy? What are the possible benefits of primary surgery for DIE before in vitro fertilization (IVF)? Several studies have recently concluded that surgical removal of DE nodules might actually have a favorable impact on IVF outcomes. This is in contradiction to European Society of Human Reproduction and Embryology statement which stated that there was no evidence supporting surgical management of DE prior to ART to improve pregnancy rate; several studies have suggested that the surgical removal of DE nodules might actually have a favorable impact on IVF outcomes. Treatment of DE affecting the rectovaginal septum or bowel requires complex surgery with considerable risk of complications. This review article tries to analyze the rationale of surgical treatment of DE before ART. A balance must be struck between exposing the patient to surgical risk and improvement in pain and fertility potential. Decisions should be tailored according to the individual needs of each woman and most importantly on the ability of the surgeons.

Inflammation to Infertility: Panoramic View on Endometriosis.

Endometriosis is a disease caused by the implantation of endometrial glands and stroma outside the uterine cavity. It affects 10% of the reproductive-age women this means that 190 million women are affected worldwide. The definitive diagnosis requires surgical exploration or a laparoscopy which is of a high expense. The pathogenesis of the disease is heterogeneous and poorly understood despite the progress in the research field. Infertility is one of the main symptoms of Endometriosis. The mechanism behind this remains unclear. Literature suggests that Endometriosis reduces implantation capacity, increases the risk of pregnancy loss, and causes anatomical obstruction imposed by endometriotic lesions. The disease has a high burden to it by decreasing the quality of women's life and imposing negative consequences for their productivity, social life, and emotional wellbeing. Since inflammation is considered the hallmark of endometriosis, it is worth looking at the mechanism of how inflammation is linked to infertility in endometriosis patients. In this study, we summarized the recent finding of how inflammation can affect oocyte, endometrium, hormones, and sperm.

Effect of GnRH agonist before IVF on outcomes in infertile endometriosis patients: a randomized controlled trial

Research questionDoes 3-months of gonadotrophin releasing hormone agonist (GnRHa) treatment before IVF improve clinical pregnancy rate in infertile patients with endometriosis? DesignSingle-blind, placebo-controlled clinical trial of 200 infertile women with endometriosis assigned to use GnRHa (study group) or placebo (control group) for 3 months before IVF. Clinical, embryological outcomes and stimulation parameters were analysed. Clinical pregnancy rate was the primary endpoint. In a subgroup of 40 patients, follicular fluid levels of oestradiol, testosterone and androstendione were measured. Gene expression profile of CYP19A1 was analysed in cumulus and mural granulosa cells. ResultsImplantation or clinical pregnancy rate were not significantly different between the two groups. Clinical pregnancy rates were 25.3% and 33.7% in the study and control groups, respectively (P = 0.212). Cumulative live birth rate was not significantly different: 22.0% (95% CI 13.0 to 31.0) in the study group and 33.7% (95% CI 24.0 to 44.0) in the control group (P = 0.077). Ovarian stimulation was significantly longer and total dose of gonadotrophins significantly higher in the study group (both P < 0.001). Serum oestradiol levels on the day of HCG were significantly lower in the study group (P = 0.001). Cancellation rate was significantly higher in the study group (P = 0.042), whereas cleavage embryos were significantly more numerous in the control group (P = 0.023). No significant differences in the expression of CYP19A1 gene in mural or cumulus granulosa cells or steroid levels in follicular fluid between the two groups were observed, but testosterone was significantly lower in the study group (P < 0.001). ConclusionThree-months of GnRHa treatment before IVF does not improve clinical pregnancy rate in women with endometriosis.

Placental Genetic Variants in the Upstream Region of the FLT1 Gene in Pre-eclampsia.

Background:Inflammatory responses within the peritoneal cavity may result in endometrial dysfunction in women with endometriosis. The true causes of this disease remain poorly understood. It is hypothesized that downstream toll-like receptors (TLRs) inflammatory cytokines in response to pathogens may be associated with endometriosis. So, this study was aimed at evaluating the expression of TLRs signaling and endometriosis-associated inflammatory responses.Methods:Totally, 20 infertile endometriosis patients and 20 normal women undergoing controlled ovarian stimulation were enrolled. The cellular pellet and supernatant were obtained by centrifugation of follicular fluid (FF). Evaluation of TLRs and their signaling pathway gene expression was performed on cellular pellets using quantitative-PCR. The supernatant was used for determination of cytokine protein expression by ELISA. The results are expressed as mean±SEM and a p<0.05 was considered statistically significant.Results:Quantitative-PCR analysis suggested that TLR1, 5, 6, 7, 8, 10, MYD88, NF-ĸB, IL-10 and TGF-β genes expression significantly increased in patients compared to the control group (p<0.05). TLR3, 9, INF-β genes expression was significantly lower in endometriosis than control group (p<0.05). There was no significant difference in the expression of TLR2, TLR4, TIRAP, TRIF, TRAM, and IRF3 between two groups. Also, significant increase in the levels of IL-6, IL-8 and MIF protein in FF of endometriosis group was detected in comparison with normal women (p<0.05).Conclusion:The expression of TLR downstream signaling in the follicular cells can initiate inflammatory responses and changes in the FF cytokine profile which in turn may induce endometriosis and infertility disorder.

Pregnancy Rates After Surgical Treatment of Deep Infiltrating Endometriosis in Infertile Patients With at Least 2 Previous In Vitro Fertilization or Intracytoplasmic Sperm Injection Failures

To assess the postoperative probabilities of pregnancy in patients with deep infiltrating endometriosis (DIE) and ≥2 previous in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) failures. Retrospective study using data prospectively recorded in the North-West Inter Regional Female Cohort for Patients with Endometriosis (CIRENDO) database. University tertiary referral center. Infertile patients under the age of 43 years, having undergone ≥2 previous IVF or ICSI failures, who were surgically managed for DIE. Complete excision of DIE. The pregnancy rate after surgery was assessed. One hundred and four infertile patients had surgery in 7 different centers participating in the database. Seventy-seven women intended to get pregnant postoperatively. Four patients who got pregnant by oocyte donation were excluded, resulting in a sample of 73 women. The mean patient age was 31.9 years (standard deviation [SD], 4.1), and the mean length of history of infertility was 48.4 months (SD, 26.5). Stage III and IV endometriosis were recorded in 83.6% of patients. The mean postoperative follow-up was 46.6 months (SD, 20.5). The postoperative pregnancy rate was 43.8% with a mean time from surgery to pregnancy of 11.1 months. 21.8% of pregnancies were spontaneous, 31.2% were obtained by IVF, 21.8% by frozen embryo transfer, 18.7% by IVF-ICSI, and 3.1% by intrauterine insemination. Multivariate analysis revealed that ovarian surgery, age ≥35 years old, and stage II endometriosis was associated with the probability of conception. Infertile women with ≥2 IVF-ICSI failures may be referred for surgery as it appears related to reasonable postoperative pregnancy rates, particularly when endometriomas surgery is either not required or not performed. Surgery for DIE does not routinely delay conception, as it usually occurs during the year following surgery.

HOXA-10 gene expression in ectopic and eutopic endometrium tissues: Does it differ between fertile and infertile women with endometriosis?

ObjectiveTo compare HOXA-10 gene expression in eutopic endometrium samples, between fertile and infertile endometriosis patients and the fertile control cases, and in endometrium and endometrioma specimens, between severe and moderate endometriosis cases. Study DesignProspective clinical study included women without infertility and endometriosis (Group 1); women without infertility but with endometrioma (Group 2); and infertile women with endometrioma (Group 3). In addition, the Group 2 and 3 cohort were assessed based on the findings obtained during laparoscopy, based on the (rAFS) scoring, as women with a rAFS score of 16–40 were evaluated in Group A, whereas those with rAFS score above 40 were considered in Group B. HOXA-10 gene expression was evaluated in both secretory endometrium tissue and endometrioma specimens. ResultsEutopic endometrium samples from group 2 (reference gene = 0,680 vs. target gene = 0,362) and group 3 (reference gene = 0,641 vs. target gene = 0,183) patients revealed a 1,871-fold and 3,509-fold decrease in HOXA-10 gene expression, respectively, as compared to group 1. Endometrial HOXA-10 gene expression was 1,778-fold down-regulated in group 3 women (reference gene = 1,510 vs. target gene = 0,850), when compared to group 2. Both eutopic endometrium and endometrioma tissue samples from severe endometriosis patients revealed 1,259-fold (reference gene = 1,523 vs. target gene = 1,210) and 1,338-fold (reference gene = 1,274 vs. target gene = 0,952), down-regulation in HOXA-10 gene expressions, respectively, as compared to moderate cases. ConclusionEndometrial HOXA-10 gene expression in women with endometriosis is significantly down-regulated than in those without endometriosis. Endometriosis patients with infertility have significantly lower levels of endometrial HOXA-10 gene expression than endometriosis without infertility; thus decreased expression of this gene may, directly or indirectly, be related with the endometriosis-associated infertility. Severe endometriosis cases express, in their both endometrium and endometrioma tissues, significantly lower levels of HOXA-10 gene than moderate endometriosis cases.

Abstract LB-375: The landscape of somatic mutations in uterine adenomyomas

Abstract Uterine adenomyosis is a relatively common disorder characterized by the abnormal presence of endometrial glands and stroma in the myometrium. The estimated prevalence of adenomyosis varies between 20-30% in hysterectomy specimens. Approximately 65% of the patients develop symptoms, including dysmenorrhea and heavy menstrual bleeding. Additionally, adenomyosis has been shown to significantly associate with peritoneal endometriosis in infertile patients. A circumscribed and nodular form of adenomyosis is called an adenomyoma (AM). This lesion is often misdiagnosed as uterine leiomyoma (ULM), a benign smooth muscle tumor of the uterus. To date, the molecular mechanisms underlying adenomyosis are rather poorly understood. The aim of this study was to investigate the molecular genetic background of uterine AMs by whole-exome sequencing, as well as to examine if the known ULM driver changes play a role in the genesis of AMs. This study focused on patients with nodular uterine AMs. A total of 16 AMs and matched normal myometrium samples from 14 hysterectomy patients entered exome sequencing. From each lesion, genomic DNA was extracted separately from both the myometrial and endometrial components. Coding regions were enriched using SeqCap EZ System (Roche Nimblegen) and sequencing was performed with Illumina HiSeq 4000. Comprehensive clinical information was available for 13 out of 14 patients. The average age at diagnosis was 45 years and at hysterectomy 49 years among patients. All patients had experienced dysmenorrhea (9/13, 69%), heavy menstrual bleeding (10/13, 77%), or both as symptoms. Endometriosis had been diagnosed in 62% (8/13) and infertility in 15% (2/13) of the patients. ULMs occurred in 8/14 (57%) patients. The average coverage of exome sequencing data was 44x for AMs. In each sample, 85% of targeted bases were covered with at least 10 reads. After filtering out germline variation, all AM samples displayed, on average, 16 somatic variants. The most prominent variants are validated in a set of additional adenomyosis samples. Based on our results, the genetic background of AMs differs from that of ULMs due to the lack of ULM driver changes: MED12 mutations, HMGA2 overexpression, and biallelic FH inactivation. Only one AM had a somatic missense mutation in MED12, and no HMGA2 overexpression was detected. Studies on FH inactivation are still ongoing. Knowledge of the molecular background of AMs is important for understanding the development of the condition and essential for improving the management of these lesions. This is the first exome sequencing study to our knowledge to comprehensively profile somatic variation in uterine AMs. Citation Format: Jaana Tolvanen, Hanna-Riikka Heinonen, Nanna Sarvilinna, Jari Sjöberg, Oskari Heikinheimo, Annukka Pasanen, Ralf Bützow, Lauri A. Aaltonen, Netta Mäkinen. The landscape of somatic mutations in uterine adenomyomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-375.

A preliminary evaluation of influence of body mass index on in vitro fertilization outcome in non-obese endometriosis patients

Background/aimsObese and overweight women experience a lower probability for pregnancy after IVF. However, despite the increasing prevalence of obesity, the large majority of infertile women are non-obese. One of the most common indications for IVF is endometriosis. Thought-provoking inverse correlation has been established between BMI and endometriosis. Lower BMI is a risk factor for development of endometriosis and a predictive factor for severe endometriosis. Since severe endometriosis carries lower reproductive chances, even after IVF, we preliminary tested a hypothesis that higher BMI among non-obese endometriosis patients improves IVF outcomes.MethodsPreliminary retrospective observational cross-sectional study was performed in women with endometriosis as a sole infertility cause who underwent IVF. During analyzed period we performed 2782 IVF procedures. In order to achieve highly homogenous study sample and to eliminate almost all confound factors that could lead to bias, we implemented strict study criteria. The number of eligible subjects was 156 and they were divided into underweight, normal weight and overweight groups. Primary outcomes were number of retrieved oocytes, good quality oocytes, embryos, and the rates of biochemical, clinical and ongoing pregnancies. For group comparisons, we used parametric test, analysis of variance, and non-parametric tests (Kruskal-Wallis test, Chi-square test). Logistic regression and General linear model was used to assess correlation between BMI and dependent variables (outcome and stimulation duration) when adjusted for age.ResultsEndometriosis as a single infertility factor among IVF couples had prevalence of 5.61%. Underweight women accounted for 10.26%, normal weight 71.15% and overweight 18.59% of study population. Significant differences were not found in number of retrieved oocytes (p = 0.880), good quality oocytes (p = 0.476), obtained embryos (p = 0.706), and biochemical (p = 0.298), clinical (p = 0.770) and ongoing (p = 0.822) pregnancy rates between study groups.ConclusionAlthough preliminary results do not support our hypothesis, increase in BMI did not adversely affect the outcome of IVF in non-obese endometriosis patients, which is in contrast to literature data as regards general population of infertile women undergoing IVF. Prospective studies with large number of patients with endometriosis or prospective case-control studies should address these issues and provide more comprehensive counseling of infertile endometriosis patients regarding achievement of optimal BMI prior to IVF with the intention of achievement higher pregnancy rates.

Peritoneal fluid cytokines related to endometriosis in patients evaluated for infertility

Our aim was to characterize peritoneal cytokine profiles in patients with infertility, with and without endometriosis, to illuminate potential differences in immune profiles that may reflect mechanistic differences between these two patient populations. Cross-sectional study. University hospital and research center. Women undergoing laparoscopy for infertility investigation (n = 107). Peritoneal fluid was collected during surgery. Clinical characteristics were registered preoperatively. We determined the concentration of 48 different cytokines from the peritoneal fluid with multiplex immunoassays. Associations between cytokines and clinical findings were assessed with logistic regression and partial least squares discriminant analyses (PLS-DA). Concentrations of SCGF-β, IL-8, HGF, and MCP-1 were significantly higher, while IL-13 was significantly lower in the endometriosis group compared with the group without endometriosis. Multiple stepwise logistic regression identified a combination of SCGF-β, IL-13, and G-CSF concentrations that predicted the presence of endometriosis with 86% sensitivity and 67% specificity. PLS-DA identified a class of 11 cytokines (SCGF-β, HGF, IL-13, MCP-1, CTACK, MCP-3, M-CSF, LIF, IL-5, IL-9, and IFN-a2) that were more characteristic of endometriosis than nonendometriosis patients. By combining univariate and multivariate analyses, profiles of cytokines more likely to be enriched or depleted in infertility patients with endometriosis compared with those without endometriosis were identified. These findings may inform future analyses of pathophysiological mechanisms of endometriosis in infertile patients, including dysregulated Th1/Th2 response and mobilization and proliferation of hematopoietic stem cells.

Strategies to Preserve and Optimize Fertility for Patients with Endometriosis

Endometriosis is commonly associated with dysmenorrhea, chronic pelvic pain, and infertility. When medical therapy fails, surgery is often recommended; unfortunately, endometriosis surgery can adversely impact fertility and ovarian reserve in women desiring future childbearing. This review will focus on mechanisms of infertility in endometriosis patients as well as strategies for optimizing fertility in endometriosis patients when surgery is indicated. In addition, fertility preserving techniques such as oocyte and ovarian tissue cryopreservation as well as issues relevant to in vitro fertilization for patients with endometriosis are discussed.

Combined treatment of endometriosis in infertile patients with gonadotropin-releasing hormone agonist or dienogest

Combined treatment of endometriosis in infertile patients with gonadotropin-releasing hormone agonist or dienogest