Pathophysiology and Clinical Implications of Ovarian Endometriomas.

Ovarian endometriomas affect many patients with endometriosis and have significant effects on quality of life, fertility, and risk of malignancy. Endometriomas range from small (1-3 cm), densely fibrotic cysts to large (20 cm or greater) cysts with varying degrees of fibrosis. Endometriomas are hypothesized to form from endometriotic invasion or metaplasia of functional cysts or alternatively from ovarian surface endometriosis that bleeds into the ovarian cortex. Different mechanisms of endometrioma formation may help explain the phenotypic variability observed among endometriomas. Laparoscopic surgery is the preferred first-line modality of diagnosis and treatment of endometriomas. Ovarian cystectomy is preferred over cyst ablation or sclerotherapy for enabling pathologic diagnosis, improving symptoms, preventing recurrence, and optimizing fertility outcomes. Cystectomy for small, densely adherent endometriomas is made challenging by dense fibrosis of the cyst capsule obliterating the plane with normal ovarian cortex, whereas cystectomy for large endometriomas can carry unique challenges as a result of adhesions between the cyst and pelvic structures. Preoperative and postoperative hormonal suppression can improve operative outcomes and decrease the risk of endometrioma recurrence. Whether the optimal management, fertility consequences, and malignant potential of endometriomas vary on the basis of size and phenotype remains to be fully explored.

Are women with endometriosis more likely to experience reduced physical performance compared to women without the condition?

Background: Endometriosis is a condition of the female reproductive system associated with pelvic pain. Chronic pain can affect physical performance by limiting the functional activities, thus, it is hypothesized that women with endometriosis may also present decreased functional capacity, decreased strength, and mobility. The objective of this study is to compare physical performance in women with and without endometriosis. Methods: This is a cross-sectional study composed of 115 women equally divided into two groups: the endometriosis group (EG), composed of women with a confirmed diagnosis of the disease by magnetic resonance imaging, and the comparator group (CG), consisting of women without suspicion of the disease. Physical performance (dependent variable) was assessed using hand dynamometry, the 6-min walk test (6MWT), gait speed, and the chair stands test. CG participants performed the tests during the luteal phase of the menstrual cycle. Descriptive statistics, unpaired t-tests, and chi-square tests were used to describe and compare the groups. Multiple linear regression tested the associations adjusted for covariates (age, income, education, age at menarche, and body mass index). Results: The EG had worse gait speed (mean difference: -0.11; 95% CI: [-0.18 to -0.04]), weaker grip strength (mean difference: -3.32; 95% CI: [-5.30 to -1.33]), shorter distance covered in the 6MWT (mean difference: -83.46; 95% CI: [-121.38 to -45.53]), and a lower number of repetitions in the chair stands test (mean difference: -8.44; 95% CI: [-10.64 to -6.25]) than the CG, even after adjusting for covariates. Conclusion: Grip strength, lower limb strength, mobility, and functional capacity were worse in women diagnosed with endometriosis. Women with endometriosis should be encouraged to engage in physical exercise, adopt healthy lifestyle habits, and participate in rehabilitation activities to control pain, with the aim of reducing functional impairments.

The Role of Long Noncoding RNAs in Endometriosis Progression.

Endometriosis (EMs) is a common gynecological disease with an increasing incidence in recent years. Because of the lack of specific molecular biological indicators in clinical practice, diagnosis is often delayed and the quality of life of patients is seriously reduced. Therefore, the discovery of effective molecular biomarkers is crucial for the early diagnosis and treatment of EMs patients. With the development of high-throughput sequencing technology, the mechanism of lncRNAs in EMs has been increasingly confirmed experimentally. This article summarizes the biological characteristics and functions of EMs-related lncRNAs, and introduces the mechanisms of EMs-related lncRNAs in the context of ceRNAs, in exosomes, under hypoxic conditions, and related antisense RNAs. The mechanism of the most popular imprinted gene H19 and metastasis-associated lung adenocarcinoma transcript 1 in EMs is then introduced. Finally, we explore the challenges of molecular biomarker EMs-related lncRNAs in the diagnosis and treatment of EMs, anticipating their potential value in clinical applications.

Serum kisspeptin levels in deep-infiltrating, ovarian, and superficial endometriosis: A prospective observational study.

The diagnosis of endometriosis may delay for many years due to non-deterministic symptoms and avoiding surgical interventions. Kisspeptins are hormones that interact with endometrial tissue to limit invasions during placentation and various cancers and are suggested to be also associated with endometriosis. This study evaluated if serum kisspeptin levels are associated with the invasion depth in endometriosis. Forty patients between 18 and 45 years of age and admitted to a tertiary-care Obstetrics and Gynecology Department between 2020 and 2021 with a diagnosis of endometriosis, and 40 patients without endometrioma were included in the study. Demographic, obstetric, clinical, and biochemical characteristics were evaluated in patients with superficial (SE) and deep infiltrating (DIE) endometriosis and healthy controls. Twenty patients (50%) had SE, 14 (35%) had DIE, and 22 (55%) had endometrioma in the patient group. Fertility rates were higher among controls, but similar between patients with SE and DIE. CA125 levels were significantly higher in the DIE group. SE and DIE groups had similar kisspeptin values, significantly higher than controls. CA125 and kisspeptin levels were not correlated in study groups. Serum kisspeptin levels were significantly different between endometriosis patients and healthy controls. However, kisspeptin levels were unable to differentiate endometriosis severity. Our results suggest that kisspeptins might play a role in the pathogenesis of endometriosis, which needs further assessment in more comprehensive studies.

Long noncoding RNA ADAMTS9-AS1 represses ferroptosis of endometrial stromal cells by regulating the miR-6516-5p/GPX4 axis in endometriosis.

Endometriosis (EMs) is one of the most frequent diseases of reproductive-age women and is characterized by the growth of endometrial tissues beyond the uterus. The enhanced proliferative and migratory potential of endometrial stromal cells (ESCs) plays an important role in the progression of EMs. Mounting studies have demonstrated that long noncoding RNAs (lncRNAs) exert an important role in regulating the development and progression of EMs. Given the aberrant expression of lncRNA ADAMTS9-AS1 in ectopic endometrium (ecEM), we investigated the biological effect of ADAMTS9-AS1 on ESC proliferation and migration and explored the underlying mechanism. The current data showed that ADAMTS9-AS1 expression was significantly upregulated in ecEM compared with eutopic endometrium (euEM) in patients with EMs and in a murine model of EMs. Functionally, ADAMTS9-AS1 knockdown in ectopic ESCs (EESCs) decreased cell viability and migration, whereas ADAMTS9-AS1 overexpression in normal ESCs (NESCs) enhanced cell viability and migration. More importantly, the effect of ADAMTS9-AS1 inhibition on decreasing ESC viability was significantly blocked by ferrostatin-1 (Fer-1, a ferroptosis inhibitor), and ADAMTS9-AS1 overexpression repressed erastin (a ferroptosis activator)-induced cell death. Furthermore, the regulatory role of ADAMTS9-AS1 in ferroptosis was defined and evidenced by increased reactive oxygen species (ROS) levels and malonyl dialdehyde (MDA) content and decreased expression of glutathione peroxidase 4 (GPX4) after ADAMTS9-AS1 inhibition. Mechanistically, ADAMTS9-AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-6516-5p to derepress the expression of GPX4, the critical repressor of ferroptosis. Taken together, these results demonstrate that upregulated ADAMTS9-AS1 accelerates ESC proliferation and migration by regulating miR-6516-5p/GPX4-dependent ferroptosis and may be a potential target for the treatment of EMs.

Quinagolide Treatment Reduces Invasive and Angiogenic Properties of Endometrial Mesenchymal Stromal Cells.

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment.

Diagnosis of presence and extent of deep infiltrating endometriosis by preoperative MRI-improvement of staging accuracy by expert training.

INTRODUCTION: This study evaluates the clinical utility of magnetic resonance imaging (MRI) for the determination of presence and extent of DIE with special emphasis on effects of MRI reporting training MATERIAL AND METHODS: Data from 80 patients with clinically suspected DIE presented at our certified endometriosis center between 2015 and 2018 were analyzed. For all patients an ENZIAN score (describing DIE related to individual anatomical localizations) was obtained based on the preoperative MRI findings. The intraoperatively determined ENZIAN score served as the reference for assessment of diagnostic performance of the MRI. RESULTS: Overall, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of DIE by MRI were 76.9%, 53.3%, 87.7% and 34.8%, respectively. Analysis by compartment revealed a sensitivity, specificity, PPV and NPV of 59.5%, 88.2%, 86.2% and 63.9%, respectively, for compartment A, with similar values for compartment B, and 50.0%, 88.9%, 64.7% and 81.4%, respectively, for the less often affected compartment C. Expert training (n = 32 before, n = 48 after) led to a considerable increase in sensitivities for the overall detection of DIE (84.6% vs. 65.4%, p = 0.071) and for the detection of DIE in compartment A (71.4% vs. 35.7%, p = 0.026), compartment B (66.7% vs. 37.5%, p = 0.057) and compartment C (75.0% vs. 20.0%, p = 0.010), without significant loss in specificity (all p > 0.50). DISCUSSION: After expert training, MRI has a good sensitivity with fair specificity regarding preoperative assessment of presence, location and extent of DIE.

Willingness of Women with Endometriosis Planning to Undergo IVF to Participate in a Randomized Clinical Trial and the Effects of the COVID-19 Pandemic on Potential Participation.

The Pre-IVF Treatment with a GnRH Antagonist in Women with Endometriosis (PREGnant) Trial (clinicaltrials.gov no. NCT04173169) was designed to test the hypothesis that 60-day pre-treatment with an oral GnRH antagonist in women with documented endometriosis and planning an IVF cycle will result in a superior live birth rate to placebo. Eight hundred fourteen women are required from 4 national sites. To determine the feasibility of using an electronic medical record (EMR)-based strategy to recruit 204 participants at the Colorado site, we conducted a survey of women within the UCHealth system. Eligible women, identified using relevant ICD-10 codes, were invited to complete a 6-question survey to assess planned utilization of IVF, potential interest in participation, and whether delays in treatment due to COVID-19 would influence their decision to participate. Of 6354 age-eligible women with an endometriosis diagnosis, 421 had a concurrent infertility diagnosis. After eliminating duplicates, 212 were emailed a survey; 76 (36%) responded, 6 of whom reported no endometriosis diagnosis. Of the remaining 70, 29 (41%) were planning fertility treatment; only 19 planned IVF. All 19 expressed interest in participation. COVID-19 delays in treatment were not considered as a factor affecting participation by 8/19; the remaining 11 felt that it would "somewhat" affect their decision. None reported that they would not consider participation because of COVID-19. EMR-based recruitment for an endometriosis clinical trial is feasible although the overall yield of participants is low. Delays in treatment due to COVID-19 did not appear to overly influence potential recruitment.

Central sensitization inventory in endometriosis.

ABSTRACT: A key clinical problem is identifying the patient with endometriosis whose pain is complicated by central nervous system sensitization, where conventional gynecologic treatment (eg, hormonal therapy or surgery) may not completely alleviate the pain. The Central Sensitization Inventory (CSI) is a questionnaire previously validated in the chronic pain population. The objective of this study was an exploratory proof-of-concept to identify a CSI cutoff in the endometriosis population to discriminate between individuals with significant central contributors (identified by central sensitivity syndromes [CSS]) to their pain compared to those without. We analyzed a prospective data registry at a tertiary referral center for endometriosis, and included subjects aged 18 to 50 years with endometriosis who were newly or re-referred to the center in 2018. The study sample consisted of 335 subjects with a mean age of 36.0 ± 7.0 years. An increasing number of CSS was significantly correlated with dysmenorrhea, deep dyspareunia, dyschezia, and chronic pelvic pain scores (P < 0.001), and with the CSI score (0-100) (r = 0.731, P < 0.001). Receiver operating characteristic analysis indicated that a CSI cutoff of 40 had a sensitivity of 78% (95% CI: 72.7%-84.6%) and a specificity of 80% (95% CI: 70.3%-84.5%) for identifying a patient with endometriosis with ≥3 CSS. In the group with CSI ≥ 40, 18% retrospectively self-reported pain nonresponsive to hormonal therapy and 40% self-reported daily pain, compared with 6% and 20% in the CSI < 40 group (P = 0.003 and 0.002, respectively). In conclusion, a CSI ≥ 40 may be a practical tool to help identify patients with endometriosis with pain contributors related to central nervous system sensitization.

Fibronectin Molecular Status in Plasma of Women with Endometriosis and Fertility Disorders.

The diagnosis of endometriosis and fertility disorders is difficult; therefore, it is necessary to look for reliable biomarkers. Analysis of the molecular status of fibronectin as a key player in repair and wound healing processes, as well as in coagulation and fibrinolysis pathways, is justified. ELISA and SDS-agarose immunoblotting were applied to determine the fibronectin concentration and presence and occurrence of soluble FN-fibrin complexes in the blood plasma of women with endometriosis (n = 38), fertility disorders (n = 28) and the healthy group (n = 25). The concentration of fibronectin in the blood plasma of women with endometriosis (292.61 ± 96.17 mg/L) and fertility disorders (287.53 ± 122.68 mg/L) was significantly higher than in the normal group (226.55 ± 91.98 mg/L). The presence of FN-fibrin complexes of 750, 1000, 1300, 1600 and 1900 kDa in the plasma of women with endometriosis and fertility disorders was shown. The presence of FN-fibrin complexes with a molecular mass of more than 1300 kDa in women with endometriosis and infertility and the complete absence of these complexes in healthy women may indicate an increased and chronic activation of coagulation mechanisms in these patients. The presence of complexes of high molecular mass may be one of the biomarkers of fertility disorders in women.

The Mechanism Exploration of Follicular Fluids on Granulose Cell Apoptosis in Endometriosis-Associated Infertility.

OBJECTIVE: To explore the mechanisms of follicular fluids (FFs) on granulose cell (GC) apoptosis in endometriosis-associated infertility. MATERIALS AND METHODS: 60 infertile women were enrolled. The FFs from 30 endometriosis-associated infertility (EI) patients were collected and processed by ELISA hormone assay and proteomic profiling. The ovary GCs collected from 30 tubal-associated infertility (TI) patients were cultured in follicular fluids of endometriosis-associated infertility patients (EI-FFs), and the apoptosis mechanisms were explored by flow cytometry assay, real-time PCR, Western blotting, and protein-protein interaction (PPI) network analysis. RESULTS: Our results showed that the expression of 22 specific proteins was significantly different in the FFs from EI and TI patients, and the level of testosterone and anti-Müllerian hormone was not obviously different between the two groups. EI-FFs could accelerate the apoptosis process of granulose cells of tubal-associated infertility patients (TI-GCs) by regulating the expression of 5 apoptosis-related proteins including BCL2, BAX, CASP3, CASP9, and TP53. The correlation of these 22 specific proteins and 5 apoptosis-related proteins was analyzed by PPI, and 5 protein biomarkers (INS, CXCL10, ICAM1, WIF1, and TNFRSF13C) and 5 signaling pathways (cytokine-cytokine receptor interaction, apoptosis, regulation of actin cytoskeleton, MAPK, and p53 signaling pathway) were predicted. CONCLUSION: This research clarified the effect and explored the mechanisms of EI-FFs on the apoptosis of TI-GCs and indicated the protein biomarkers and signaling pathways for further study.

Serum levels of alpha1-antitrypsin isoforms in patients with ovarian clear cell carcinoma: An exploratory study.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is frequently associated with endometriosis. Since serum levels of cancer antigen 125 (CA125) have limited diagnostic and prognostic value in this malignancy, there is an unmet need for reliable and specific biomarkers. Previous findings indicated that alpha 1-antitrypsin isoforms (isoAAT) are significantly increased in the peritoneal fluid of patients with endometriosis. This study was undertaken to examine whether serum isoAAT levels in patients with OCCC differ from those measured in women with endometriosis or benign ovarian tumors. We also investigated whether this biomarker may be useful for predicting survival in OCCC. METHODS: Paired serum samples before and after debulking surgery were collected from 27 patients with OCCC. All sera from patients with endometriosis (n = 44) and benign ovarian tumors (n = 32) were obtained in the pretreatment phase. Serum isoAAT levels were assayed using a proprietary ELISA kit. RESULTS: The highest levels of serum isoAAT (median, range) were identified in patients with OCCC (preoperative values: 160.9 ng/mL, range, 101.4-1098.8 ng/mL), followed by patients with endometriosis (125.0 and 83.4-473.2 ng/mL), and those with benign tumors (125.2 and 60.5-191.3 ng/mL). The differences in serum isoAAT levels between patients with OCCC and benign tumors were significant (p = 0.041). Debulking surgery of OCCC resulted in a significant decrease in serum isoAAT levels compared with the preoperative period (median, 160.9 versus 113.0 ng/mL, respectively, p = 0.012). As for prognostic prediction, we found that none of the nine patients with OCCC and serum isoAAT levels ≤130 ng/mL died of disease. CONCLUSION: Serum isoAAT levels may be diagnostically useful to distinguish OCCC from benign ovarian tumors and could also serve as a potential prognostic marker.

A review of the pathophysiology of recurrent implantation failure.

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition-something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.

Diet quality and perceived effects of dietary changes in Dutch endometriosis patients: an observational study.

RESEARCH QUESTION: What is the current diet of women with endometriosis, in terms of adherence to dietary guidelines and use of diets, and what are the perceived effects of dietary modifications? DESIGN: In this online explorative observational study, the Dutch Healthy Diet 2015 index (DHD-15) and quality of life (QoL) with the Endometriosis Health Profile-30 questionnaire (EHP-30) were used to assess diet quality. RESULTS: The questionnaires were completed by 157 participants. Many participants made one or more dietary adaptations for their endometriosis, in the form of a specific diet (46.5%), with the use of dietary supplements (56.1%), with other dietary adjustments (64.3%), or all. Endometriosis patients had a significantly lower DHD-15 score, indicating a lower diet quality than a healthy reference group (P = 0.004). In the endometriosis group, diet users had a significantly higher total DHD-15 score than non-diet users (P < 0.0001). Diet quality was not correlated with QoL (Pearson's r = -0.010, P = 0.904). Many specific dietary adjustments (71.3%), however, were reported to reduce endometriosis pain-related symptoms. The removal of gluten, dairy or soy, as well as the addition of vegetables, showed the greatest perceived reductions of symptoms in participants. CONCLUSIONS: Although no specific dietary adjustment was found to increase QoL, endometriosis patients do feel that dietary adjustments have a beneficial effect on their symptoms. Therefore, more research is needed to gain evidence about the specific effects of nutrients on endometriosis symptoms.

Molecular Basis of Endometriosis and Endometrial Cancer: Current Knowledge and Future Perspectives.

The human endometrium is a unique tissue undergoing important changes through the menstrual cycle. Under the exposure of different risk factors in a woman's lifetime, normal endometrial tissue can give rise to multiple pathologic conditions, including endometriosis and endometrial cancer. Etiology and pathophysiologic changes behind such conditions remain largely unclear. This review summarizes the current knowledge of the pathophysiology of endometriosis and its potential role in the development of endometrial cancer from a molecular perspective. A better understanding of the molecular basis of endometriosis and its role in the development of endometrial pathology will improve the approach to clinical management.

Mapping of endometriosis in patients with unilateral endometrioma.

ABSTRACT: To map the distribution of the sites most affected by endometriosis in patients with unilateral ovarian endometriomas.A descriptive case series of 84 patients with unilateral endometriomas undergoing laparoscopy for the treatment of endometriosis. To evaluate the distribution of the sites of endometriosis lesions, the peritoneal compartments were divided into 5 zones: zone 1/the anterior compartment, including the anterior uterine serosa, vesicouterine fold, round ligament, and bladder; zone 2/the lateral compartment, including the left and right ovary, ovarian fossa, tubes, mesosalpinx, uterosacral ligaments, parametrium, and the ureter; zone 3/the posterior compartment, including posterior uterine serosa, the pouch of Douglas, posterior vaginal fornix, and bowel; zone 4 consisting of the abdominal wall; and zone 5 consisting of the diaphragm.Of the 5 zones evaluated, the lateral compartment (zone 2) was the most affected, with 60.7% of the patients having dense adhesions around the left ovarian fossa and 57.1% around the right ovarian fossa. The ovarian endometriomas were more commonly found on the left side (54.8%) compared to the right (45.2%). In the posterior compartment (zone 3), the posterior cul-de-sac was obliterated in 51.2% of the patients. In the anterior compartment (zone 1), there were lesions in the vesicouterine fold in 30.9% of the patients and in the bladder in 19%. Lesions were found in the abdominal wall (zone 4) and diaphragm (zone 5) in 21.4% and 10.7% of patients, respectively.Unilateral endometriomas are important markers of the severity of endometriosis.

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

INTRODUCTION: Transvaginal 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 METHODS: It 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. RESULTS: The 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. DISCUSSION: Hydrosalpinx 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.