Gynecological Diseases Research Articles

Endometriosis, a prevalent disease, is associated with significant cardiac disease

Abstract Background Endometriosis, a chronic systemic gynecological disease affecting 10% of women in the reproductive age, shares pathophysiological characteristics with cardiovascular disease. However, data on the relationship between endometriosis and cardiac outcomes are scarce. Further research is needed to address this gap in knowledge as highlighted by recent calls from the European Heart Journal. Purpose To examine the incidence of the following outcomes both as a composite and individually: 1) ischemic events, 2) arrhythmias, and 3) heart failure among women with endometriosis compared with the background population. Methods Using Danish nationwide registries, all women with a diagnosis of endometriosis (1977-2021) were identified and matched with women from the background population in a 1:4 ratio based on year of birth. The incidence of 1) ischemic heart disease and ischemic stroke, 2) arrhythmias (including atrial flutter/fibrillation), and 3) heart failure were examined and compared between women with and without endometriosis. Results After exclusion of women with ischemic events/arrhythmias/heart failure prior to index, 59,194 women with endometriosis and 238,352 matched controls were included (median age 37.1 years [IQR 29.8-44.4 years]). The women were followed for a median of 17 years and a maximum of 45 years. Overall, women with endometriosis were more comorbid and used more medications than their matched controls. The 40-year cumulative incidences of the composite outcome were 36.2% (95%CI 35.4-37.1%) and 30.2% (95%CI 29.8-30.7%) among women with and without endometriosis, whereas it were 23.8% (95%CI 23.0%-24.5%) and 18.8% (95%CI 18.5%-19.1%) for ischemic events, 20.1% (95%CI 19.4%-20.9%) and 17.2% (95%CI 16.8%-17.5%) for arrhythmias, and 7.5% (95%CI 7.0-8.0%) and 6.6% (95%CI 6.3-6.8%) for heart failure, respectively (Figure 1). The most common arrhythmia was atrial fibrillation/flutter constituting more than half of the events in both groups. In both unadjusted and adjusted analyses, women with endometriosis compared with controls had a significantly higher associated risks of the composite outcome (unadjusted HR 1.30 [95%CI 1.27-1.34], adjusted HR 1.29 [95%CI 1.25-1.32]), ischemic events (unadjusted HR 1.32 [95%CI 1.28-1.37], adjusted HR 1.31 [95%CI 1.26-1.35]), arrhythmias (unadjusted HR 1.25 [95%CI 1.20-1.30], adjusted HR 1.24 [95%CI 1.19-1.29]), and heart failure (unadjusted HR 1.07 [95%CI 1.01-1.14]), adjusted analysis (HR 1.05 [95%CI 0.98-1.12]). Conclusions Women with endometriosis have a higher associated long-term risk of significant cardiac outcomes compared with the background population. Despite the small relative differences, the high prevalence of endometriosis underscores the importance of these findings and emphasizes the need for enhanced understanding and prevention of its long-term cardiac outcomes.

Effectiveness of psychological interventions in endometriosis: a systematic review with meta-analysis

IntroductionEndometriosis is a chronic gynecological disease associated with chronic debilitating pain, poor mental health and quality of life. The objective of this paper is to evaluate the effectiveness of psychological interventions aimed at improving the pain, quality of life and mental health of women with endometriosis.MethodsA systematic review (SR) of the literature with meta-analysis (MA) was carried out. MEDLINE, Embase, PsycINFO and CENTRAL were searched to locate Randomized Controlled Trials (RCTs). The risk of bias assessment of each study was conducted using the Cochrane Collaboration’s RoB 2.0 tool.ResultsSeven RCTs were included (N = 757). The data obtained suggest that psychological interventions reduce dyspareunia [standardized mean difference (SMD): -0.54, 95% CI: −0.86, −0.22] and dyschezia [mean difference (MD): -2.90, 95% CI: −4.55, −1.26] and increase mental health levels (SMD: 0.70, 95% CI: 0. 42, 0.99); they also point to a large reduction in levels of trait anxiety (MD: -6.63, 95% CI: −8.27, −4.99) and depression (MD: -2.49, 95% CI: −3.20, −1.79), and a likely reduction in state anxiety (MD: -9.72, 95% CI: −13.11, −6.33) experienced by women with endometriosis. It was also identified that psychological interventions probably slightly reduce pelvic pain and may increase physical health. However, most of the included studies have a high overall risk of bias or have certain concerns, which limit conclusions about the certainty of the evidence.DiscussionThe available evidence indicates that psychological interventions are effective in improving the pain, quality of life and mental health variables of women with endometriosis.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, CRD42024516100.

How can healthcare providers reduce the adverse effects of endometriosis on women’s life course?

Abstract Background Endometriosis is a chronic gynecological disease that affects about 10% of women of reproductive age. Its symptoms vary in severity and manifestation. Diagnosis is often delayed by an average of 10 years, which may significantly affect women’s lives. This study explores how endometriosis morbidity affects women’s relationships, intimacy, and employment over their lifetime. Methods An online survey was conducted in February 2024 among Jewish Israeli women aged 18 to 50. Out of the 573 women, 270 were diagnosed with endometriosis. The survey collected information on the women’s diagnostic status, pain severity, social support, negative interactions, life-course impact, and distance from the doctor’s clinic. Results Women with endometriosis experience a negative impact on their life course compared to women without the disease, particularly in relationships and intimacy (39.41 vs. 18.44, p<.001) and employment (19.39 vs. 19.11, p<.001). A multivariate regression model was used to predict the effect of endometriosis on the women’s life course and revealed that a negative impact on relationships and intimacy (R2=.385, n = 505) might be predicted by longer travel distance to the doctor’s clinic, higher reported pain level, less reported social support level, and higher reported negative interactions. Furthermore, a negative effect on employment (R2 = .270, n = 513) was predicted by a longer distance to the clinic, a higher reported pain level, less reported social support level, and higher reported negative interactions. Conclusions Enencing supportive environments and increasing accessibility to health services is vital to improving the negative impact of endometriosis on women’s lives. Key messages • Endometriosis treatment requires a multi-faceted approach, including supportive frameworks, reducing negative interactions, and addressing gaps in health service accessibility. • Awareness must be raised among employers regarding endometriosis, creating a supportive environment and making necessary adjustments for employees to openly communicate their needs and struggles.

Cross-Tissue Regulatory Network Analyses Reveal Novel Susceptibility Genes and Potential Mechanisms for Endometriosis

Endometriosis (EMT) is a common gynecological disease with a strong genetic component, while its precise etiology remains elusive. This study aims to integrate transcriptome-wide association study (TWAS), Mendelian randomization (MR), and bioinformatics analyses to reveal novel putatively causal genes and potential mechanisms. We obtained summary-level data of the Genotype-Tissue Expression Project (GTEx), v8 expression quantitative loci (eQTL) data, and the genome-wide association study (GWAS) data of EMT and its subtypes from the R11 release results of the FinnGen consortium for analysis. GWAS data of modifiable risk factors were collected from IEU Open GWAS. Cross-tissue TWAS analyses were performed using the unified test for molecular signature (UTMOST), while functional summary-based imputation (FUSION) was employed for single-tissue TWAS analyses. Furthermore, we also conducted multi-marker analysis of genomic annotation (MAGMA) analyses to validate the significant associations. Subsequent Mendelian randomization (MR) and colocalization analysis elucidated the causal associations between the identified genes across various tissues and EMT. To further delve into mechanisms, two-sample network MR analyses were conducted. At last, bioinformatics analyses were employed to enhance our understanding of the functional implications and expression patterns of these identified genes. For EMT, 22 significant gene signals were identified by UTMOST, 615 by FUSION, and 354 by MAGMA. Ultimately, six genes, including CISD2, EFRB, GREB1, IMMT, SULT1E1, and UBE2D3, were identified as candidate susceptibility genes for EMT. Through similar procedures, we identified GREB1, IL1A, and SULT1E1 for EMT of the ovary, and we identified GREB1 for EMT of the pelvic peritoneum, EMT of rectovaginal septum and vagina, and deep EMT. In MR analyses, the expression of IMMT in 21 tissues, EFR3B in the adrenal gland, CISD2 in 17 tissues, and UBE2D3 in 7 tissues demonstrated causal relationships with EMT risk. In addition, CISD2, IMMT, and UBE2D3, across different tissues, exhibited strong colocalization with EMT (PPH4 > 0.7). Two-sample network MR analyses revealed that CISD2, EFR3B, and UBE2D3 could potentially regulate the levels of blood lipids and hip circumference so as to influence the risk of EMT. Furthermore, bioinformatics analyses confirmed our findings and delved into the biological functions of the identified genes. Our study unveiled seven novel candidate genes whose predicted expression was associated with the risk of EMT, providing new insights into the underlying genetic framework of EMT. These findings will facilitate a deeper comprehension of the tissue-specific transcriptional regulatory mechanisms associated with EMT, paving the way for optimizing the management and treatment of EMT.

Intrauterine adhesions repair with menstrual blood-derived mesenchymal stem cells via CXCL13-CXCR5 signal axis and its mechanism

BackgroudIntrauterine Adhesions (IUA) is a common gynecological disease which is seriously endangers the reproductive function of women without any ideal treatment. Some researchers found Menstrual Blood-derived Mesenchymal Stem Cells (MenSCs) can repair of damaged endometrium, however, has not been fully clarified. This study aims to evaluate the therapeutic effects of MenSCs in IUA and the repair mechanism in vivo.MethodsThis study is Laboratory-based study. To evaluate the therapeutic effects of MenSCs in IUA, We cultivated MenSCs, established mouse endometrial injury model, observed the uterine morphology and degree of endometrial fibrosis and compared the expression of CXC chemokine ligand-13 (CXCL13)、CXC chemokine receptor-5 (CXCR5)、Plasmin Activating Inhibitor-1(Pai-1), Transforming Growth Faction-β1(TGF- β1) and Matrix Metalloproteinase-9 (Mmp-9) among each groups. GraphPad Prism 8.0 was used for statistical processing. Data were expressed as mean ± SD. Statistical comparisons among groups were performed with one-way ANOVA. P < 0.05 were considered statistically significant.ResultsWe successfully cultured and identified MenSCs and established mice model of uterine adhesion. After treatment with MenSCs, endometrial morphology of mice was partially restored, endometrial thickness was increased, and glands were multipiled. The concentrations of CXCL13 and CXCR5 were significantly increased by immunofluorescence detection compared with the control group. The results of RT-qPCR showed that the expressions of Pai-1 and Mmp-9 were significantly lower than those of the control group.ConclusionsMenSCs may reduce endometrial fibrosis and the down-regulating expression of Pai-1、Mmp-9 and CXCL13-CXCR5 axis were involved in the process of MenSCs repaired IUA.

Disorders in cytokine synthesis in women with uterine fibroids

In the structure of gynecological diseases, uterine fibroids occupy an “honorable” second place after inflammatory processes of the genital organs, and its share reaches 40%. Uterine fibroids are a benign monoclonal tumor that develops from one abnormal smooth muscle cell of the myometrium, which, as a result of mutation, has the ability to grow unregulated. Common symptoms of the disease include pelvic discomfort or pain, excessive uterine bleeding, secondary anemia, infertility, and bowel and bladder dysfunction. Uterine fibroids can negatively affect the general condition of a woman, causing hormonal, vegetative-vascular and psycho-emotional disorders. Moreover, about 80% of patients with uterine fibroids undergo radical surgical treatment. The mechanisms of development and growth of this benign tumor have not been fully established and remain controversial. The role of immune disorders in the pathogenesis of fibroids is currently being discussed. It has been proven that the growth of fibroids is accompanied by a weakening of immune defense against the background of an increase in the level of proinflammatory cytokines, which are regulators of the processes of proliferation and apoptosis, mediators of the action of sex steroids. The aim of the study was to study the level of some pro-inflammatory cytokines (IL-1β, IL-2, TGF-β2 and MCP-1) in the blood serum of women of reproductive age with uterine fibroids, depending on the size and nature of tumor growth. A comparative analysis of the results of examination of 123 women with uterine fibroids, who made up 2 groups: 1st group of 65 women with simple uterine fibroids and 2nd group of 58 women with rapidly growing uterine fibroids, is presented. The examination included a comprehensive clinical and laboratory study. The level of cytokines (IL-1β, IL- 2, TGF-β2, MCP-1) in the blood serum was assessed by ELISA. It was found that in patients of reproductive age with uterine fibroids, there is an increase in the levels of IL-1β, TGF-β2 and MCP-1. In women with rapidly growing uterine fibroids, these changes are more pronounced. The concentration of IL-2 is reduced in all women with uterine fibroids, regardless of the size and nature of tumor growth. It has been established that an increase in the size of myomatous nodes is accompanied by an increase in immune imbalance: there is an increase in the levels of pro-inflammatory cytokines (IL-1β, TGF-β2, MCP-1) against the background of a reduced content of the lymphokine IL-2, which we regard as possible links in the pathogenesis of uterine fibroids. A pronounced deficiency of IL-2 in the blood serum against the background of a sharp increase in the concentration of TGF-β2 and MCP-1 in the blood of women with uterine fibroids can be considered as a negative criterion for predicting disease progression and used as an additional prognostic marker of tumor growth

Characterization of E-Cadherin, SSEA-1, MSI-1, and SOX-2 Expression and Their Association with Pale Cells in Adenomyosis

Adenomyosis (AM) is a gynecological disease characterized by the invasion of endometrial glands and stroma within the myometrium. The etiology and pathogenesis of AM remain inadequately understood. Pale cells were identified as a novel cell type characterized by the absence of desmosomal contacts and light-colored cytoplasm. These cells were observed to migrate individually through ultra-micro ruptures in the basal membrane of the endometrial glands, translocating into the stroma and then further into the myometrium. Our study aimed to explore the possible stem cell properties of these pale cells. Forty hysterectomy specimens were analyzed using immunohistochemistry and immunofluorescence to assess negative E-cadherin expression and the positive expression of stem cell markers SSEA-1, MSI-1, and SOX-2. Immunohistochemical analysis revealed the presence of pale cells and occasionally rounded, enlarged E-cadherin-negative cells predominantly in the basal endometrial epithelium. The stem cell marker SSEA-1 was significantly elevated in the basalis epithelium, as well as in the ectopic epithelium. SSEA-1 positive cells were also identified in the stroma and myometrium. Sporadic colocalization of SSEA-1+/E-cadherin– cells was confirmed through immunofluorescence. The positive staining of pale cells for SSEA-1 and MSI-1 was also confirmed at the ultrastructural level by immunoelectron microscopy. These findings indicate that pale cells may possess stem cell characteristics, particularly a positive SSEA-1 profile, warranting further in vitro investigation into their role in the pathogenesis of adenomyosis.

Endometrial Dysbiosis: A Possible Association with Estrobolome Alteration

Background/Objectives: Microbiota modification at the endometrial level can favor gynecological diseases and impair women’s fertility. The overgrowth of pathogen microorganisms is related to the contemporary alteration of estrogen-metabolizing bacteria, including β-glucuronidase, thereby enhancing estrogen-related inflammatory states and decreasing anti-inflammatory cells. The possible connection between estrobolome impairment and gynecological diseases has been suggested in animal models. Nevertheless, in humans, coherent evidence on the estrobolome alteration and functionality of the female reproductive tract is still lacking. The objective of this study was to explore alterations in estrogen-related signaling and the putative link with endometrial dysbiosis. Methods: Women with infertility and repeated implantation failure (RIF, N = 40) were enrolled in order to explore the putative link between estrogen metabolism and endometrial dysbiosis. Endometrial biopsies were used to measure inflammatory and growth factor molecules. β-glucuronidase enzyme activity and estrogen receptor (ER) expression were also assessed. Results: Herein, increased levels of inflammatory molecules (i.e., IL-1β and HIF-1α) and decreased levels of the growth factor IGF-1 were found in the endometrial biopsies of patients presenting dysbiosis compared to eubiotic ones. β-glucuronidase activity and the expression of ERβ were significantly enhanced in patients in the dysbiosis group. Interestingly, Lactobacilli abundance was inversely related to β-glucuronidase activity and to ERβ expression, thus suggesting that an alteration of the estrogen-activating enzyme may affect the expression of ERs as well. Conclusions. Overall, these preliminary data suggested a link between endometrial dysbiosis and estrobolome impairment as possible synergistic contributing factors to women infertility and RIF.

Comparison of Abdominal and Vaginal Hysterectomy: A Comparative Clinical Study at A Tertiary Hospital of Southern Part of Bangladesh

Background: Hysterectomy is indicated in several common gynecologic problems and is one of the commonly performed operations in many hospitals of Bangladesh. Though Hysterectomy is a reasonably safe operative procedure but at times minor to major complications may occur. Current study was undertaken to compare the feasibility and safety of abdominal hysterectomy (AH) and vaginal hysterectomy (VH) procedures in the treatment of benign uterine diseases, and to determine the outcomes of both procedures. Objectives: To compare outcomes of vaginal and abdominal hysterectomy procedures in women with benign gynaecological diseases. Materials and Methods: This was a prospective study of outcomes of consecutive patients who underwent AH or VH for benign gynaecological diseases. Patient characteristics before, during, and after the operations were reviewed. Patients were followed up for three months to evaluate postoperative complications. Results: This study included a total of 305 patients. 199 patients underwent AH and 106 patients underwent VH. Baseline characteristics were similar between the two groups. Mean operative time was 95.78±18.46 minutes for AH group and 76.26±19.24 minutes for VH group (p&lt;0.006). Mean hospital stay was 5.32±0.67 days for AH group and 4.08±0.19 days for VH group with p-value &lt;0.047. There was a significant lesser total operation cost in VH group than AH group (VH: 12058±386 BDT, AH: 14275±276 BDT; P &lt; 0.05). Furthermore there was no wound infection; paralytic ileus and no need to reopening any patient in case of VH group compared to AH group. Conclusion: This study showed that vaginal hysterectomy was associated with less intraoperative complications and postoperative morbidities and complications as compared to abdominal hysterectomy. KYAMC Journal Volume: 15, No: 01, April 2024: 40-45.

Limited utility of subendometrial enhancement in assessing the interface between the endometrium and myometrium

This study was conducted to re-evaluate the utility of subendometrial enhancement (SEE) in assessing the interface between the endometrium and myometrium. In total, 110 women who underwent pelvic magnetic resonance imaging (MRI) for non-endometrial gynecologic diseases were enrolled in this prospective study. Two radiologists independently assessed the presence or absence of subendometrial enhancement (SEE) on dynamic contrast-enhanced (CE) MRI. A subgroup analysis was performed to evaluate the impact of menstrual status on the detection of SEE. Identified areas of SEE were rated using a 4-point Likert scale to determine their reliability in assessing the interface between the endometrium and myometrium. SEE was identified in 44.5% (49/110) of cases by radiologist 1 and in 39.1% (43/110) by radiologist 2. A subgroup analysis indicated no significant differences in the detection of SEE based on menstrual status. The identified areas of SEE were deemed reliable for assessing the interface between the endometrium and myometrium in 24.5% (12/49) of the cases evaluated by radiologist 1 and in 32.6% (14/43) of those evaluated by radiologist 2. Among the 110 women studied, reliable areas of SEE for assessing the interface between the endometrium and myometrium were observed in 10.9% (n = 12) by radiologist 1 and 12.7% (n = 14) by radiologist 2. The evaluation of SEE using dynamic CE MRI may be limited in its ability to assess the interface between the endometrium and myometrium.

Network pharmacology-based strategy to reveal the mechanism of pinocembrin against ovarian cancer.

Ovarian cancer stands as the foremost cause of mortality among gynaecological diseases globally, characterized by high morbidity and mortality. Pinocembrin, a flavonoid from natural plant sources, exhibits diverse pharmacological properties. Despite its known pharmacological activities, its specific role in ovarian cancer treatment remains scarcely reported, and its precise molecular mechanism remains elusive. This study integrates network pharmacology and molecular docking techniques to explore pinocembrin's potential mechanism in ovarian cancer treatment. The targets of pinocembrin were compiled from the several online databases. Ovarian cancer targets were identified using the GeneCards database, with common target genes determined by data aggregation. Protein-protein interactions were analysed using the STRING platform. Subsequent Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed. Molecular docking assessed the binding affinity between potential targets and active compounds. Finally, target validity was verified through in vitro experiments. We identified 163 potential pinocembrin targets for ovarian cancer treatment. GO and KEGG analyses revealed pinocembrin's involvement in protein kinase activity, protein phosphorylation, protein kinase complexes and cancer pathways in ovarian cancer treatment. Molecular docking demonstrated strong binding affinity between pinocembrin and most potential target active sites. In vitro experiments suggested pinocembrin's potential to induce apoptosis in ovarian cancer cells through the AKT1-mTOR signalling pathway. This study comprehensively elucidates pinocembrin's potential targets and mechanisms against ovarian cancer, aiming to provide promising candidates for developing novel and effective alternative and/or complementary nutritional supplements for the clinical treatment of ovarian cancer.

Cross-disciplinary working between gynaecologists and mental healthcare professionals: a mixed-methods systematic review protocol

IntroductionReproductive hormone transitions (menstrual cycle, post partum and menopause) can trigger mental disorders in a subset of women. Gynaecological diseases, such as endometriosis and polycystic ovary syndrome, can also elevate...

Determining key residues of engineered scFv antibody variants with improved MMP-9 binding using deep sequencing and machine learning

Given the crucial role of specific matrix metalloproteinases (MMPs) in the extracellular matrix, an imbalance in the regulation of activation of matrix metalloproteinase-9 (MMP-9) zymogen and inhibition of the enzyme can result in various diseases, such as cancer, neurodegenerative, and gynecological diseases. Thus, developing novel therapeutics that target MMP-9 with single-chain antibody fragments (scFvs) is a promising approach. We used fluorescent-activated cell sorting (FACS) to screen a synthetic scFv antibody library displayed on yeast for enhanced binding to MMP-9. The screened scFv mutants demonstrated improved binding to MMP-9 compared to the natural inhibitor of MMPs, tissue inhibitor of metalloproteinases (TIMPs). To identify the molecular determinants of these engineered scFv variants that affect binding to MMP-9, we used next-generation DNA sequencing and computational protein structure analysis. Additionally, a deep-learning language model was trained on the screened scFv library of variants to predict the binding affinities of scFv variants based on their CDR-H3 sequences.

Ethnobotanical study of medicinal and aromatic plants commonly used in the daily life of the populations of the Moroccan Middle Atlas: results of pharmacy surveys

Abstract This in-depth ethnobotanical study was conducted specifically in the Middle Atlas region of Morocco to document and analyze the use of medicinal and aromatic plants (MAPs) among local populations suffering from various chronic conditions. This survey involved 99 participants with gastrointestinal, cardiovascular, endocrine, urinary, gynecological, or similar diseases. The main objective was to draw up a complete inventory of the MAPs used, detailing their therapeutic indications and identifying any adverse effects associated with their use, whether through misapplication, overdosing, or interaction with other drugs taken by the patients. In the present, twenty MAPs species belonging to twelve distinct botanical families were identified. Among these plants, oregano (Origanum compactum) from the Lamiaceae family is the most widely used species, with a frequency of over 30%. Leaves were the most commonly used plant organ in traditional recipes (60.6%), whereas decoction was the most predominant preparation method (51.5%). This survey was conducted using questionnaires distributed in some pharmacies, and provided valuable data on MAP use practices, highlighting the predominance of certain plant species, their main therapeutic indications, and the preparation methods preferred by the Middle Atlas inhabitants to treat their ailments.

Progesterone receptor status predicts aggressiveness of human endometriotic lesions in murine avatars

To utilize murine avatars for studying human endometriotic lesion response to two different hormonal regimens to determine if PR can prospectively predict response to progestin-based therapy. Endometriosis is a chronic gynecologic disease afflicting 1-in-10 reproductive-aged women; however response to medical therapy is highly variable as endometriotic lesions do not consistently respond to first-line, progestin-based therapy. We have previously demonstrated in a retrospective study that progesterone receptor (PR) status in lesions correlated with response to progestins. Here, we hypothesize that a prospective approach utilizing PR status to predict response to medical will allow clinicians to individualize effective, timely treatment for this debilitating disease. Patient-Derived Xenograft Murine Model SUBJECTS: Eight-week old NOD/SCID mice undergoing transplantation of endometrioma lesions collected from women undergoing surgery for endometriosis. Daily subcutaneous injections with vehicle (DMSO), Medroxyprogesterone acetate (MPA) or GnRH antagonist, Cetrorelix for 1 month. Lesion size 1 month post-treatment RESULTS: Lesions with high PR demonstrated a robust response to MPA compared to lesions with low PR. Average post-MPA treatment size in high PR lesions was 6-fold smaller than low PR lesions. Low PR lesions respond far more completely to GnRH antagonist than to MPA. Surprisingly, there were differences in response to GnRH antagonist between low and high PR lesions. High PR lesions responded almost completely to GnRH antagonist with a 21-fold smaller post-treatment size on average compared to low PR lesions. Use of murine avatars to test clinical response is a novel approach in endometriosis. Hormonal suppression of disease is a cornerstone of therapy, however response is not fully predictable. We have previously shown that women with low PR lesions respond poorly to progestin-based therapy. Here, we prospectively validate our prior work using a mouse xenograft model, demonstrating that lesions with low PR expression do not respond to progestin-based therapy; PR status predicted response to progestin-based therapy. Moreover, PR status identifies a more aggressive form of endometriosis that is not only progesterone resistant, however is also less dependent on estradiol for growth. Our findings highlight the need to develop novel, nonhormonal therapies aimed at targeting the more aggressive forms of endometriosis that do not rely on the usual hormonal signals.

Effects of Shaofu Zhuyu decoction on intestinal flora and fibrosis in a mouse model of endometriosis

Shaofu Zhuyu decoction has been widely used to treat gynecological diseases; however, its mechanism of action in endometriosis remains unclear. We analyzed Shaofu Zhuyu decoction’s chemical composition using ultra-high performance liquid chromatography-mass spectrometry. In an endometriosis mouse model, ectopic lesions weight measurements and hematoxylin and eosin staining were used to assess the therapeutic efficacy of Shaofu Zhuyu decoction. Effects on intestinal microflora were analyzed using 16S ribosomal ribonucleic acid sequencing, and impacts on focal fibrosis were analyzed using Masson’s trichrome staining. Moreover, fibrosis- and metabolism-related proteins were assessed using immunohistochemistry and enzyme-linked immunosorbent assay. The study identified 157 chemical constituents within Shaofu Zhuyu decoction. Shaofu Zhuyu decoction treatment in mice with endometriosis resulted in a reduction in ectopic lesions weight (P<0.05) and delayed disease progression. Moreover, it improved the diversity and abundance of intestinal flora, and decreased the expression of Lachnospiraceae (P<0.05), Rikenellaceae (P<0.01), Ruminococcaceae (P<0.01), Lachnoclostridium (P<0.05), and unclassified_f__Ruminococcaceae (P<0.05). Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment in carbohydrate, amino acid, and lipid metabolism pathways. Masson’s trichrome staining revealed that compared to the untreated group, the Shaofu Zhuyu decoction group exhibited significantly reduced collagen deposition areas (P<0.001), lower TGF-β1 (P<0.001), COL1A1 (P<0.05), and α-SMA (P<0.01) expression in ectopic lesions, along with increased serum adiponectin (P<0.05), decreased serum leptin (P<0.05), TGF-β1 (P<0.001), and CTGF (P<0.05). Shaofu Zhuyu decoction regulates the intestinal flora of mice with endometriosis while also reducing fibrosis at the lesion site. These findings highlight novel mechanisms for its efficacy in alleviating endometriosis.

Association of mixed exposure to microplastics with sperm dysfunction: a multi-site study in China

Microplastics are environmental pollutants detected in various human organs and tissues. These particles originate from multiple sources including the degradation of larger plastic items and the intentional inclusion in consumer goods. Potential risks for human health resulting from microplastics exposure have also been reported. However, the distribution in the male reproductive system and its effect remains largely unknown. This study aims to investigate the presence of multiple microplastics in human semen and urine and their association with sperm quality in a multi-site study across China. We conducted a cross-sectional study involving 113 male participants from three regions in China. Semen and urine samples were collected and analysed using Raman microscopy to detect eight types of microplastics: polystyrene (PS), polypropylene (PP), polycarbonate (PC), polyethylene (PE), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), polyethylene terephthalate (PET), and acrylonitrile butadiene styrene (ABS). Semen quality parameters, including total sperm count, concentration, motility, and morphology, were assessed. Statistical analyses, including single and multi-variable models, were used to evaluate the relationship between microplastic exposure and semen quality, with a focus on PTFE, after adjusting confounding factors of age, body mass index (BMI), smoking, alcohol drinking, and sites. Microplastics were detected in all semen and urine samples, with participants typically exposed to 3-5 different types. The detection rates of PS, PP and PE were the highest. Notably, PTFE exposure was significantly associated with decreased semen quality. Participants exposed to PTFE showed reductions in total sperm count [188.90±163.71 vs. 207.67±132.36 million, p=0.091], sperm concentration [52.13±47.47 vs. 58.32±37.26 million/mL, p=0.041], and progressive motility [40.29%±19.06 vs. 34.11%±17.02, p=0.083]. The multi-linear regression analysis indicated that each additional type of microplastic exposure was associated with a significant decrease in total sperm number [β=-15.4 (95% CI:-25.6,-5.2)], sperm concentration [β=-7.2 (95% CI:-12.4,-2.0)], and progressive motility [β=-8.3 (95% CI:-13.5,-3.1)]. Latent category analysis further refined these groups by types of microplastic exposure, highlighting specific types more strongly associated with decreased semen quality (OR=3.5, 95% CI: 1.8, 6.9, p<0.001). The nomogram can be used to assess the risk of sperm damage by combining the type of microplastic exposure in urine with age and BMI. Our findings highlight the potential reproductive health risks posed by microplastic contamination, particularly PTFE, a non-stick pan coating material, and raise concerns about the potential of urine testing as an indicator of male reproductive microplastic exposure. Future research is warranted to further elucidate the mechanisms underlying the adverse effects of microplastics on male fertility and cross-generational effects. This study was funded by the Clinical Research Project of Shanghai Municipal Commission of Health and Family planning (20224Y0085), Open Fund Project of Guangdong Academy of Medical Sciences (YKY-KF202202), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-064), Shanghai Clinical Research Center for Gynecological Diseases (22MC1940200), Shanghai Urogenital System Diseases Research Centre (2022ZZ01012), Key Discipline Construction Project (2023-2025) of Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai (GWVI-11.1-35, GWVI-11.2-YQ29) and Shanghai Frontiers Science Research Base of Reproduction and Development.

Incidence and risk factors of parasitic myoma after laparoscopic myomectomy using uncontained power morcellation: Retrospective analysis of 87 patients who had a subsequent second laparoscopic surgery.

Studies on parasitic myomas after laparoscopic morcellation are mainly limited to case reports, and the incidence and risk factors have not yet been well-understood. We aimed to clarify the actual incidence and risk factors of parasitic myoma after laparoscopic myomectomy using uncontained power morcellation by reviewing cases with subsequent laparoscopic surgery. This retrospective study included 87 patients who had laparoscopic myomectomy using uncontained power morcellation, followed by subsequent second laparoscopic surgery for gynecological disease between 2008 and 2021. First, the incidence and characteristics of parasitic myomas detected at the second laparoscopic surgery were reviewed. Second, patients were stratified according to the presence of parasitic myoma (PM+ and PM- groups), and risk factors were analyzed by comparing the background, intraoperative findings, and clinical course after laparoscopic myomectomy. Of the 87 patients, parasitic myomas were detected in 16 (18.4%). Twelve patients (75.0%) were asymptomatic and diagnosed incidentally during surgery. Two patients presented with acute abdomen requiring emergency surgery. Comparing the PM+ and PM- groups, the total weight of the enucleated myomas and the diameter of the largest myoma at the initial laparoscopic myomectomy were significantly greater in the PM+ group. Other factors, including age and number of enucleated myomas did not differ between the groups. The actual incidence of parasitic myoma after laparoscopic myomectomy using uncontained power morcellation is higher than that previously reported. In laparoscopic power morcellation, large myomas increase the risk of developing parasitic myoma, and a containment bag system is expected to minimize this complication.

Coumarins with Different Substituents from Leonurus japonicus Have Opposite Effects on Uterine Smooth Muscle.

Leonurus japonicus Houtt is an exceptional medicinal herb used to treat obstetrical and gynecological diseases in traditional Chinese medicine, and it has significant effects on the treatment of dysmenorrhea and postpartum hemorrhage. This study investigated the effects of coumarins with diverse substituent groups from L. japonicus on isolated uterine smooth muscle and the preliminary mechanism of the most effective compound. Eight coumarins isolated from L. japonicus were assessed for their effects on the isolated uterine smooth muscle of nonpregnant rats in vitro. Coumarins 1 and 2 significantly promoted the contraction of rat uterine smooth muscle strips, whereas coumarins 3-5 showed remarkable relaxing effects against oxytocin (OT)-induced rat uterine smooth muscle contraction. Further mechanism investigations revealed that bergapten (coumarin 1) significantly increased the level of Ca2+ in uterine tissues by promoting extracellular Ca2+ influx and intracellular Ca2+ release, which were related to the activation of L-type Ca2+ channels and α-receptors. By contrast, osthole (coumarin 5), an α receptor antagonist, inhibited OT-induced uterine smooth muscle contraction by decreasing the level of Ca2+ in uterine tissues via inhibition of extracellular Ca2+ influx and intracellular Ca2+ release. This study demonstrates that the coumarins from L. japonicus are effective substances for regulating uterine smooth muscle contraction, but different coumarins with diverse substituent groups have different, even opposite effects. It can be inferred that coumarins are closely related to the efficacy of L. japonicus in the treatment of dysmenorrhea and postpartum hemorrhage.

Integrated bioinformatic analysis reveals the gene signatures, epigenetic roles, and regulatory networks in endometriosis

ObjectivesEndometriosis is a common gynecological disease with a significant economic burden. Growing evidence has suggested the role of aberrant gene expression and epigenetic mechanisms in the pathogenesis of endometriosis. This study aims to identify potential key genes, epigenetic features, and regulatory networks in endometriosis using an integrated bioinformatic approach. MethodsSix microarray and RNA-sequencing datasets (GSE23339, GSE7305, GSE25628, GSE51981, GSE120103, GSE87809) were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) of each dataset were analyzed using the GEO2R tool, and their mRNA, miRNA, and lncRNA components were identified subsequently. The common DEGs between datasets were combined, and the Gene ontology (GO) and pathway enrichment were analyzed using the ShinyGo. The protein–protein interaction (PPI) network of DEGs, miRNA, and lncRNA was constructed using STRING and Cytoscape, and then the top 15 hub genes in the PPI network were identified using CytoHubba. ResultsA total of 551 common DEGs were identified from four or more studies, including 292 upregulated and 259 downregulated genes. Besides alterations in protein-coding genes (mRNA), 16 miRNA (5 upregulated and 11 downregulated) were identified from all studies, along with 12 lncRNA (10 upregulated and 2 downregulated) that were common in at least three studies. Enriched DEGs were mainly associated with extracellular matrix (ECM) interaction, P53 signaling pathway, and focal adhesion, which are suggested to play vital roles in the pathogenesis of endometriosis. Through PPI network construction of common DEGs, 178 nodes and 683 edges were obtained, from which 15 hub genes were identified, including CDK1, CCNB1, KIF11, CCNA2, BUB1B, DLGAP5, BUB1, TOP2A, ASPM, CEP55, CENPF, TPX2, CCNB2, KIFC, NCAPG. ConclusionsOur in-depth bioinformatics analysis reveals the critical molecular basis underlying endometriosis. The role of identified hub genes, miRNA, and lncRNA may also have an opportunity to be explored as potential biomarkers for endometriosis diagnosis and prognosis.