Search Results (119)

Follicle-stimulating hormone receptor (FSHR) is expressed on the plasma membrane of granulosa cells in the ovarian follicles. FSHR is involved in the development and maturation of Graafian follicles, along with granulosa proliferation and estrogen synthesis. There are two well-characterized non-synonymous single-nucleotide gene polymorphisms in the exon 10 of the human FSHR gene, namely rs6165 (c.919G>A, Ala307Thr) and rs6166 (c.2039A>G, Ser680Asn). Recent research clarifies the association of rs6165/rs6166 with susceptibility to infertility-associated ovarian diseases, ranging from polycystic ovarian syndrome, premature ovarian insufficiency, endometriosis, to ovarian cancer, along with response/resistance to ovulation induction/ovarian stimulation with clomiphene citrate, letrozole, metformin, FSH preparations, and adjunctive growth hormone in infertility treatment. This narrative review aims to update the knowledge on the relationship among rs6165/rs6166, infertility etiology, and differential responses to oral ovulation induction agents, FSH preparations, and adjunctive growth hormone. The re6165/rs6166 genotype-guided choice of individualized ovulation stimulation preparations has great potential to reduce unexpected poor or high ovarian responses in ovulation induction and ovarian stimulation and improve clinical outcomes in reproductive medicine. Current evidence is insufficient, and further studies are warranted to ascertain its potential for clinical implementation. Full article

Endometriosis, a chronic estrogen-dependent disease, is associated with a risk of developing gynecological cancers. The mechanisms of this association remain unclear, but emerging evidence implicates key signaling pathways, including PI3K/AKT/mTOR and ARID1A alterations, in malignant transformation. This article examines current reports on the association between endometriosis and cervical, ovarian, and endometrial cancers, with particular emphasis on diagnostic challenges and molecular mechanisms. Imaging methods such as ultrasound, magnetic resonance imaging, and computed tomography (CT) are used for diagnosis, as well as biomarkers such as Cancer Antigen-125 (CA-125) and Human Epididymal protein 4 (HE4), but their specificity is limited, motivating research into novel molecular and non-invasive diagnostics. Laparoscopy is an invasive diagnostic method, serving as the gold standard for confirming the diagnosis. We discuss personalized clinical strategies, including risk-based surveillance for patients with atypical lesions or ARID1A alterations, and implications for ovarian cancer management in endometriosis. Prospective cohort studies will be necessary to further understand the complex mechanisms of endometriosis’s malignant transformation. Optimizing therapy and improving quality of life require a holistic, individualized approach to patient care. This review provides an integrated synthesis of epidemiological and molecular evidence, highlighting both established and emerging targets for diagnosis and treatment in endometriosis-associated malignancies. Full article

Background: Endometriosis affects an estimated 10% of reproductive-aged women and is associated with increased ovarian cancer risk. While BRCA1/2 mutations are established risk factors for ovarian cancer, their association with endometriosis remains unclear. This study aimed to characterize the prevalence and clinical features of endometriosis within a large cohort of BRCA mutation carriers. Methods: A descriptive analysis was conducted using data from a multi-center longitudinal cohort of women with pathogenic BRCA variants. Reproductive history and related factors were collected through self-reported questionnaires and compared. Results: Among 16,950 BRCA carriers, the prevalence of endometriosis was 2.4%. Compared to BRCA carriers without endometriosis, those with endometriosis were more likely to carry a BRCA2 mutation, have post-secondary education, and experience earlier menarche. BRCA carriers with endometriosis had a lower ovarian cancer prevalence than those without (10% vs. 15%, p < 0.001). Conclusions: This is the first study of this scale to report the prevalence of endometriosis among BRCA mutation carriers, which was lower than previously reported in the general population. The association between endometriosis and ovarian cancer does not appear to be generalizable to this population. Further prospective studies are warranted to clarify this association among BRCA mutation carriers. Full article

Endometriosis is traditionally regarded as a condition predominantly affecting women of reproductive age, often associated with infertility and cyclical pelvic pain. As a result, a significant body of research and clinical attention has been directed toward the younger patient population. However, there is growing recognition that endometriosis can persist or even arise anew in peri-menopausal and post-menopausal women, yet the impact of the disease in this group remains underappreciated. Many women may have lived with undiagnosed or misdiagnosed endometriosis for decades, often being reassured that period pain and pelvic discomfort were normal aspects of menstruation, and therefore not subjected to appropriate investigation or intervention. This review aims to highlight the clinical significance of endometriosis in peri-menopausal and post-menopausal women. We will examine the common symptoms encountered in this population, discuss current strategies and challenges in diagnosis, and review evidence-based approaches to management. Special consideration will be given to the complex interface between endometriosis and HRT, as well as the potential risk of malignant transformation. Finally, drawing from existing guidelines and expert opinion, we propose recommendations for the diagnosis, treatment, and long-term follow-up of these patients, with the goal of improving outcomes and quality of life for this often overlooked cohort of women. Full article

Background and Objectives: Endometriosis has been shown to be associated with an increased cancer risk, and apoptosis may be important in the pathophysiology of endometriosis. To date, it remains unclear whether the tissue cell surface apoptosis marker (annexin V) is an important parameter in terms of cancer and endometriosis. This retrospective study aimed to compare endometriosis cases and ovarian cancer cases in terms of apoptosis and cell proliferation markers’ levels. Materials and Methods: In total, 65 (30 ovarian endometrioma, 35 ovarian carcinoma) paraffin blocks were taken for flow cytometric analysis. The flow cytometry analysis markers and annexin V staining levels were compared. Results: The G2/M stage cell ratio, S-phase fraction, proliferative index, aneuploidy cell ratio, and annexin V apoptotic index ratio were found to be statistically significantly lower in the endometrioma group compared to the carcinoma group. However, the G0/G1 phase cell ratio was found to be higher in the endometrioma group. According to the correlation analysis results, annexin V expression level showed a positive correlation with the G2/M cell ratio and S-phase fraction, while it showed a negative correlation with the G0/G1 level. In addition, as the apoptotic index increased, the cell aneuploidy rate also increased, which was statistically significant. When the apoptotic index was used to distinguish between endometrioma and ovarian cancer (cutoff value 16.05%), the sensitivity was found to be 94.3%, and the specificity was found to be 80%, which was statistically significant for cases below the cutoff value to be accepted as endometrioma. Conclusions: Apoptosis was reduced in endometriosis cases. The cell DNA activity was altered in endometriosis cases, as in cancer cases. Flow cytometric analysis can be used in the diagnosis of endometriosis even in paraffin-embedded tissues. The flow cytometric annexin V analysis provided results in an average of 30 min, making it a promising and highly sensitive differential diagnostic marker to distinguish between endometriosis and ovarian cancer. Full article

Nucleus accumbens-associated protein 1 (NAC1), a cancer-related transcriptional regulator, is overexpressed in several malignancies, including ovarian cancer. However, its role in ovarian carcinogenesis remains unclear. We aimed to investigate whether NAC1 contributes to metabolic adaptation in endometriosis-related ovarian neoplasms (ERONs) and elucidate its regulatory mechanisms. The clinical relationship between NAC1 and its potential downstream target, phosphoenolpyruvate carboxykinase isoform 2 (PCK2), was examined using immunohistochemical analysis of ovarian cancer specimens. A cell viability assay was performed to clarify the impact of PCK2 on ovarian cancer cell viability. Reporter and chromatin immunoprecipitation (ChIP) assays were conducted to evaluate transcriptional regulation by NAC1. Metabolomic profiling was performed to assess the functional impact of the NAC1–PCK2 axis. A positive correlation between NAC1 and PCK2 expression was observed, and co-expression was associated with poor long-term survival. Knockdown of PCK2 led to a significant reduction in cell viability, indicating that PCK2 is required for maintaining cell survival. Reporter and ChIP assays confirmed that NAC1 directly binds to the PCK2 promoter via the CATG motif. The metabolomic analysis demonstrated that NAC1 promotes truncated gluconeogenesis and de novo serine synthesis through PCK2 upregulation. These findings suggest that NAC1 contributes to ovarian cancer progression by promoting metabolic adaptation, highlighting the NAC1–PCK2 axis as a potential therapeutic target for ERONs. Full article

Objectives: The purpose of this retrospective cohort study was to ascertain the risk of abortion, ectopic pregnancy and hydatidiform mole development in women with polycystic ovary syndrome (PCOS) using data from Korea’s National Health Insurance Service. Method: The women aged 20–49 years who were diagnosed with PCOS between 1 January 2012 and 31 December 2020 were enrolled. The control group (non-PCOS group) was composed of women aged 20–49 years who visited medical institutions for health examinations during the same period. Women diagnosed with any cancer were excluded from both groups. Logistic regression analysis was used to evaluate the risks of abortion, ectopic pregnancy and hydatidiform mole in PCOS in the presence of certain pregnancy-related confounding factors. Results: A total of 724,307 women were extracted, 169,998 women without PCOS and 44,714 women with PCOS were enrolled in the study. The PCOS group had a higher incidence of GDM and endometriosis. Abortions, ectopic pregnancies and hydatidiform moles were higher in the PCOS group than in the control group (abortion: 14.7% vs. 7.3%, p < 0.001; ectopic pregnancy: 3.3% vs. 1.1%, p < 0.001; hydatidiform mole: 0.2% vs. 0.1%, p < 0.001). After adjusted logistic regression, PCOS was found to be a risk factor for abortion (RR = 1.473, 95% CI = 1.424–1.524; p < 0.001) and ectopic pregnancy (RR = 1.845, 95% CI = 1.716–1.984, p < 0.001) but not hydatidiform mole (RR = 1.225, 95% CI = 0.927–1.62, p = 0.154). Conclusions: A history of PCOS itself might increase the risk of abortion and ectopic pregnancy. These findings could be useful in prenatal counseling and the management of patients with PCOS-associated pregnancies. Full article

Background/Objectives: Rarely, primary (PriCs) or metastatic (metECs) carcinomas occur in the episiotomy site. Methods: A systematic literature review of metECs was carried out. We reviewed the PRISMA guidelines and the Scopus, Pubmed, and Web of Science databases. Results: We found 21 carcinomas; all of them were cervical carcinomas (11 squamous, SCC; 6 adenocarcinomas; 3 adenosquamous; 1 SCC or adenocarcinoma) diagnosed during pregnancy (38%) or 0.25–8 months postpartum (57%). SCCs were larger (mean size: 4.8 cm). At presentation, only two cases were pN+, and no distant metastases were found, excluding four episiotomy metastases (one anticipating the cervical cancer diagnosis); the remaining episiotomy metastases (mean size: 3 cm; one multifocal) were found at follow-up (these were first metastases in 86% of cases). The time range from the episiotomy/last delivery to first episiotomy metastasis was 1–66 (mean, 12.3) months. Treatment was variable: hysterectomy (71%) ± lymphadenectomy (67%) and/or adjuvant treatment (19%); chemoradiation/radiotherapy alone (24%). A total of 90% of cases recurred after 18 days to 66 months (mean, 12 months). At last follow-up, ten patients (48%) were disease-free after 12–120 (mean, 63.5) months, two patients (10%) were alive with disease, and nine (42%) patients died of disease after 6–36 (mean, 12.5) months (including two never-cleared/progressing cases). Conclusions: PriCs and metECs are rare. Iatrogenic/obstetric implantation or vascular dissemination of cervical cancer at the site of episiotomy may occur. For episiotomy lesions, accurate gynecological/perineal examination is required, and biopsy can be considered. Larger studies are required in order to determine treatment guidelines. Compared to PriCs, metECs occurred in younger (premenopausal) patients, were not associated with endometriosis, and demonstrated slightly smaller size and shorter mean time from episiotomy to episiotomy metastases, with a higher likelihood of a less favorable prognosis. Full article

Estrogen-dependent conditions, such as endometriosis, adenomyosis, lipedema, polycystic ovary syndrome, and breast cancer, are intimately involved with hormonal changes related to estrogen and their receptors. These conditions can be expressed mainly during hormonal changes such as pregnancy, puberty, and menopause. They are associated with alterations in estrogen function and inflammatory mechanisms, leading to significant discomfort and a marked decrease in self-esteem in women. Resveratrol has been studied in the treatment of inflammatory diseases like obesity, metabolic syndrome, and endometriosis. The research suggests potential pathways through which resveratrol may also be beneficial in treating metabolic and estrogen-dependent conditions. We reviewed 63 articles from 2000 to 2025, prioritizing systematic reviews, meta-analyses, and randomized controlled trials in the PubMed, ScienceDirect, and SciELO databases. Our results suggest that resveratrol may benefit metabolic and estrogen-dependent conditions by modulating anti-inflammatory factors that regulate estrogen receptor activity, increasing lipolysis, decreasing insulin resistance, and mitigating oxidative stress. Future research should evaluate the long-term safety and potential therapeutic effects of resveratrol in metabolic conditions. Full article

Orphan nuclear receptor 4A1 (NR4A1) is a member of the NR4A subfamily that was initially discovered as an intermediate early gene expressed in response to stressors, including inflammatory agents. This review addresses the hypothesis that NR4A1 is a key nutrient sensor that contributes to the anti-aging and health-protective effects of receptor ligands, dietary phenolics, and other diet-derived compounds. There is evidence in animal models including humans that NR4A1 serves as an important gene that decreases the rate of aging and its associated diseases. For example, in humans and mice, NR4A1 expression decreases with age and loss of NR4A1 enhances disease susceptibility, and survival curves show that NR4A1-deficient mice live 4 months less than wild-type animals. An extensive comparison of inflammatory diseases, immune dysfunction, and fibrosis in multiple tissues shows that in NR4A1^−/− mice and rats these diseases and injuries are enhanced compared to wild-type NR4A1^−/− animals. There is evidence showing that structurally diverse NR4A1 ligands reverse the induced adverse effects in NR4A1 wild-type mice. This raises an important question regarding the mechanisms of NR4A1-dependent inhibition of the aging process and the potential for this receptor as a nutrient sensor. It has been well established that polyphenolics, including flavonoids, resveratrol, and other compounds in the diet, are health-protective and decrease the aging process. Recent studies show that resveratrol and flavonoids such as quercetin and kaempferol bind NR4A1 and exhibit protective NR4A1-dependent inhibition of endometriosis and cancer. These limited studies support a role for NR4A1 as a potential dietary sensor of nutrients that are known to be health-protective and a potential nutrient target for improving health. Full article

Objectives: The objective of this study was to evaluate the safety of postoperative in vitro fertilization (IVF) for atypical endometriosis (AE) in terms of ovarian endometrioma recurrence and development of endometriosis-related ovarian cancer (EAOC). Methods: Premenopausal women with AE who had undergone ovarian surgery between 2008 and 2022 and had attended follow-up appointments for at least 3 months were included in this retrospective study. The recurrence of endometriosis, postoperative pregnancy rate, occurrence of postoperative EAOC in cases of AE, and independent risk factors of AE recurrence were analyzed. Results: A total of 105 patients were included in the study with a median age of 33 years (range, 16–50 years) and a median follow-up duration of 29.0 months (range, 3–143 months). Most of the patients were treated with cyst enucleation (96.2%). Recurrent ovarian endometrioma was detected in 19 patients (18.1%), 4 of whom (19.0%) underwent reoperation, and there were no cases of EAOC. The cumulative recurrence rate at 12, 24, and 50 months was 7.4, 15.8, and 26.3%, respectively. Among the 105 patients, 36 wanted to become pregnant; of these, 12 underwent IVF, which, according to a univariable analysis, did not increase their risk of recurrent ovarian endometrioma. According to a subsequent multivariable analysis, previous history of ovarian endometrioma operation was the sole significant risk factor for AE recurrence (HR, 4.246; 95% CI, 1.262–14.285; p = 0.020). Conclusions: IVF trials for pregnancy did not represent a risk factor for recurrence, as treated AE showed a low possibility of malignant transformation, and IVF was not a risk factor for recurrence. Full article

Background: Endometriosis is a chronic inflammatory condition affecting 10–15% of women of reproductive age. Genome-wide association studies (GWASs) have accounted for only a fraction of its high heritability, indicating the need for alternative approaches to identify rare genetic variants contributing to its etiology. To this end, we performed whole-exome sequencing (WES) in a multi-affected family. Methods: A multigenerational family was studied, comprising three sisters, their mother, grandmother, and a daughter, all diagnosed with endometriosis. WES was conducted on the three sisters and their mother. We used the enGenome-Evai and Varelect software to perform our analysis, which mainly focused on rare, missense, frameshift, and stop variants. Results: Bioinformatic analysis identified 36 co-segregating rare variants. Six missense variants in genes associated with cancer growth were prioritized. The top candidates were c.3319G>A (p.Gly1107Arg) in the LAMB4 gene and c.1414G>A (p.Gly472Arg) in the EGFL6 gene. Variants in NAV3, ADAMTS18, SLIT1, and MLH1 may also contribute to disease onset through a synergistic and additive model. Conclusions: We identified novel candidate genes for endometriosis in a multigenerational affected family, supporting a polygenic model of the disease. Our study is an exploratory family-based WES study, and replication and functional studies are warranted to confirm these preliminary findings. Full article

Backgroud. Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the ectopic presence of endometrial-like tissue. Although genome-wide association studies (GWAS) have identified susceptibility variants, their tissue-specific regulatory impact remains poorly understood. Objective. To functionally characterize endometriosis-associated variants by exploring their regulatory effects as expression quantitative trait loci (eQTLs) across six physiologically relevant tissues: peripheral blood, sigmoid colon, ileum, ovary, uterus, and vagina. Methods. GWAS-identified variants were cross-referenced with tissue-specific eQTL data from the GTEx v8 database. We prioritized genes either frequently regulated by eQTLs or showing the strongest regulatory effects (based on slope values, which indicate the direction and magnitude of the effect on gene expression). Functional interpretation was performed using MSigDB Hallmark gene sets and Cancer Hallmarks gene collections. Results. A tissue specificity was observed in the regulatory profiles of eQTL-associated genes. In the colon, ileum, and peripheral blood, immune and epithelial signaling genes predominated. In contrast, reproductive tissues showed the enrichment of genes involved in hormonal response, tissue remodeling, and adhesion. Key regulators such as MICB, CLDN23, and GATA4 were consistently linked to hallmark pathways, including immune evasion, angiogenesis, and proliferative signaling. Notably, a substantial subset of regulated genes was not associated with any known pathway, indicating potential novel regulatory mechanisms. Conclusions. This integrative approach highlights the com-plexity of tissue-specific gene regulation mediated by endometriosis-associated variants. Our findings provide a functional framework to prioritize candidate genes and support new mechanistic hypotheses for the molecular pathophysiology of endometriosis. Full article

Background/Objectives: Endometriosis and high-grade serous ovarian cancer (HGS-OC) share common features within the peritoneal immune microenvironment, yet they exhibit divergent clinical outcomes. This study aimed to dissect the immune–metabolic landscape of the peritoneal cavity in patients with endometriosis and ovarian cancer by evaluating macrophage polarization, intracellular signaling pathways, and iron-driven oxidative stress. Methods: A prospective cohort study enrolled 40 patients with endometriosis, 198 with ascitic ovarian cancer (178 HGS-OC), and 200 controls with benign gynecological conditions. Peritoneal and peripheral blood samples were analyzed via flow cytometry for macrophage (M1/M2) polarization markers, mTOR/AKT expression, and glucose uptake. Inflammatory markers (IL-6, CRP), oxidative stress (ROS), and iron metabolism parameters (hepcidin, ferritin, transferrin, serum/free iron) were quantified. Results: HGS-OC displayed a predominance of M1-polarized tumor-associated macrophages (TAMs) (CD14⁺/CD80⁺/Glut1⁺) and a high M1/M2 ratio (2.5 vs. 0.8 and 0.9; p = 0.019), correlating positively with IL-6 (p = 0.015), ROS (p = 0.023), hepcidin (p = 0.038), and ferritin (p = 0.043). Conversely, endometriosis showed a dominant M2 profile (CD14⁺/CD163⁺), elevated intracellular mTOR and AKT expression in both TAMs and epithelial cells (p < 0.01), and significantly higher ascitic ROS and free iron levels (p = 0.047 and p < 0.0001, respectively). In endometriosis, the M1/M2 ratio correlated inversely with free iron (p = 0.041), while ROS levels were directly associated with iron overload (p = 0.0034). Conclusions: Endometriosis exhibits a distinct immune–metabolic phenotype characterized by M2 macrophage predominance and iron-induced oxidative stress, contrasting with the inflammatory, M1-rich profile of HGS-OC. These findings suggest that iron metabolism and macrophage plasticity contribute to disease persistence in endometriosis and may inform future immunomodulatory strategies. Full article

(1) Background and Objectives: Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. It affects 5–15% of women of reproductive age. Ovarian cancer develops in approximately 1% of patients with endometriosis. Prediction of those with endometriosis who will develop ovarian cancer is among the current research topics. (2) Materials and Methods: With this study, we aimed to reveal the role of miRNA 200b and miRNA 21 in endometriosis-associated ovarian carcinoma (EAOC). Thirteen patients diagnosed as having EAOC between 2015 and 2023 were included, with their endometriosis and eutopic endometrium tissues (Group 3: 13 patients, 39 tissue samples). Two separate groups were then detected to compare with these cases: Group 2 composed of tuba-ovarian endometriosis with its eutopic endometrium (10 patients, 20 tissue samples) and Group 1 composed of eutopic endometrium only (10 patients, 10 tissue samples). The foci marked on H&E sections were determined from the area on the relevant paraffin blocks and small tissue samples were taken in tubes to be studied with real-time PCR. (3) Results: No significant difference was detected for miRNA 21 and miRNA 200b expression levels among eutopic endometrium, endometriosis, and cancer foci in Group 3. However, miRNA 21 and miRNA 200b expression levels in the eutopic endometrial tissue of cases with ovarian cancer were significantly higher than in the eutopic endometrial tissues of cases with (Group 2) and without endometriosis (Group 1). (4) Conclusions: This study suggests that increased miRNA 200b and miRNA 21 expression levels detected in eutopic endometrial tissue of patients with endometriosis may contribute to identifying cases that may develop EAOC. Full article