Frontiers in Endocrinology

Role of gonadotropin-releasing hormone 2 and its receptor in human reproductive cancers

Gonadotropin-releasing hormone (GnRH1) and its receptor (GnRHR1) drive reproduction by regulating gonadotropins. Another form, GnRH2, and its receptor (GnRHR2), also exist in mammals. In humans, GnRH2 and GnRHR2 genes are present, but coding errors in the GnRHR2 gene are predicted to hinder full-length protein production. Nonetheless, mounting evidence supports the presence of a functional GnRHR2 in humans. GnRH2 and its receptor have been identified throughout the body, including peripheral reproductive tissues like the ovary, uterus, breast, and prostate. In addition, GnRH2 and its receptor have been detected in a wide number of reproductive cancer cells in humans. Notably, GnRH2 analogues have potent anti-proliferative, pro-apoptotic, and/or anti-metastatic effects on various reproductive cancers, including endometrial, breast, placental, ovarian, and prostate. Thus, GnRH2 is an emerging target to treat human reproductive cancers.

Comprehensive identification of a disulfidptosis-associated long non-coding RNA signature to predict the prognosis and treatment options in ovarian cancer

PurposeDistinguished from cuproptosis and ferroptosis, disulfidptosis has been described as a newly discovered form of non-programmed cell death tightly associated with glucose metabolism. However, the prognostic profile of disulfidptosis-related lncRNAs (DRLRs) in ovarian cancer (OC) and their biological mechanisms need to be further elucidated.Materials and methodsFirst, we downloaded the profiles of RNA transcriptome, clinical information for OC patients from the TCGA database. Generated from Cox regression analysis, prognostic lncRNAs were utilized to identify the risk signature by least absolute shrinkage and selection operator analysis. Then, we explored the intimate correlations between disulfidptosis and lncRNAs. What’s more, we performed a series of systemic analyses to assess the robustness of the model and unravel its relationship with the immune microenvironment comprehensively.ResultsWe identified two DRLR clusters, in which OC patients with low-risk scores exhibited a favorable prognosis, up-regulated immune cell infiltrations and enhanced sensitivity to immunotherapy. Furthermore, validation of the signature by clinical features and Cox analysis demonstrated remarkable consistency, suggesting the universal applicability of our model. It’s worth noting that high-risk patients showed more positive responses to immune checkpoint inhibitors and potential chemotherapeutic drugs.ConclusionOur findings provided valuable insights into DRLRs in OC for the first time, which indicated an excellent clinical value in the selection of management strategies, spreading brilliant horizons into individualized therapy.

Estrogen Receptor Function: Impact on the Human Endometrium

The physiological role of estrogen in the female endometrium is well established. On the basis of responses to steroid hormones (progesterone, androgen, and estrogen), the endometrium is considered to have proliferative and secretory phases. Estrogen can act in the endometrium by interacting with estrogen receptors (ERs) to induce mucosal proliferation during the proliferative phase and progesterone receptor (PR) synthesis, which prepare the endometrium for the secretory phase. Mouse knockout studies have shown that ER expression, including ERα, ERβ, and G-protein-coupled estrogen receptor (GPER) in the endometrium is critical for normal menstrual cycles and subsequent pregnancy. Incorrect expression of ERs can produce many diseases that can cause endometriosis, endometrial hyperplasia (EH), and endometrial cancer (EC), which affect numerous women of reproductive age. ERα promotes uterine cell proliferation and is strongly associated with an increased risk of EC, while ERβ has the opposite effects on ERα function. GPER is highly expressed in abnormal EH, but its expression in EC patients is paradoxical. Effective treatments for endometrium-related diseases depend on understanding the physiological function of ERs; however, much less is known about the signaling pathways through which ERs functions in the normal endometrium or in endometrial diseases. Given the important roles of ERs in the endometrium, we reviewed the published literature to elaborate the regulatory role of estrogen and its nuclear and membrane-associated receptors in maintaining the function of endometrium and to provide references for protecting female reproduction. Additionally, the role of drugs such as tamoxifen, raloxifene, fulvestrant and G-15 in the endometrium are also described. Future studies should focus on evaluating new therapeutic strategies that precisely target specific ERs and their related growth factor signaling pathways.

Targeting the FSH/FSHR axis in ovarian cancer: advanced treatment using nanotechnology and immunotherapy

Ovarian cancer (OC) is the gynecological malignancy with the poorest prognosis. Surgery and chemotherapy are the primary therapies for OC; however, patients often experience recurrence. Given the intimate interaction between OC cells and the tumor microenvironment (TME), it is imperative to devise treatments that target both tumor cells and TME components. Recently, follicle-stimulating hormone (FSH) levels in the blood have been shown to correlate with poorer prognosis in individuals with OC. Ovarian carcinoma cells express FSH receptors (FSHRs). Thus, FSH is an important target in the development of novel therapeutic agents. Here, we review the effects of FSH on normal physiology, including the reproductive, skeletal, cardiac, and fat metabolic systems. Importantly, this review outlines the role and mechanism of the FSH/FSHR axis in the proliferation, survival, and metastasis of OC, providing theoretical support for the targeted FSHR treatment of OC. Current progress in targeting FSHR for OC, including the recent application of nanotechnology and immunotherapy, is presented. Finally, we discuss prospects and future directions of targeted FSHR therapy in OC.

Body mass index and glioma risk: A prospective multicenter study

BackgroundThe association between glioma risk and body mass index (BMI) remains obscure.MethodsThis study aimed to assess the association between glioma risk and BMI in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsThe onset of a total of 269 gliomas was observed during a median follow-up period of 12.04 years. Compared with the normal weight, overweight (HR: 1.05; 95% CI: 0.80, 1.39) and obesity (HR: 0.91; 95% CI: 0.56, 1.39) were not significantly associated with glioma risk. Further analysis showed a nonlinear relationship between glioma risk and BMI in men but not women. The multivariable-adjusted HRs per unit increase in BMI were 0.94 (95% CI: 0.89, 1.00; P = 0.037) in men with BMI >25 kg/m2 and 1.16 (95% CI: 0.98, 1.38; P = 0.075) in men with BMI <25 kg/m2.ConclusionThe present data provide evidence that there may be a nonlinear association between BMI and glioma risk in men. The risk of glioma decreased with increasing BMI among men with BMI >25 kg/m2. Future studies are needed to validate our observation.

The Emerging Roles and Therapeutic Implications of Epigenetic Modifications in Ovarian Cancer

Ovarian cancer (OC) is one of the most lethal gynecologic malignancies globally. In spite of positive responses to initial therapy, the overall survival rates of OC patients remain poor due to the development of drug resistance and consequent cancer recurrence. Indeed, intensive studies have been conducted to unravel the molecular mechanisms underlying OC therapeutic resistance. Besides, emerging evidence suggests a crucial role for epigenetic modifications, namely, DNA methylation, histone modifications, and non-coding RNA regulation, in the drug resistance of OC. These epigenetic modifications contribute to chemoresistance through various mechanisms, namely, upregulating the expression of multidrug resistance proteins (MRPs), remodeling of the tumor microenvironment, and deregulated immune response. Therefore, an in-depth understanding of the role of epigenetic mechanisms in clinical therapeutic resistance may improve the outcome of OC patients. In this review, we will discuss the epigenetic regulation of OC drug resistance and propose the potential clinical implications of epigenetic therapies to prevent or reverse OC drug resistance, which may inspire novel treatment options by targeting resistance mechanisms for drug-resistant OC patients.

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

Epithelial ovarian cancer (EOC) is considered the deadliest gynecological disease and is normally diagnosed at late stages, at which point metastasis has already occurred. Throughout disease progression, EOC will encounter various ecosystems and the communication between cancer cells and these microenvironments will promote the survival and dissemination of EOC. The primary tumor is thought to develop within the ovaries or the fallopian tubes, both of which provide a microenvironment with high risk of causing DNA damage and enhanced proliferation. EOC disseminates by direct extension from the primary tumors, as single cells or multicellular aggregates. Under the influence of cellular and non-cellular factors, EOC spheroids use the natural flow of peritoneal fluid to reach distant organs within the peritoneal cavity. These cells can then implant and seed distant organs or tissues, which develop rapidly into secondary tumor nodules. The peritoneal tissue and the omentum are two common sites of EOC metastasis, providing a microenvironment that supports EOC invasion and survival. Current treatment for EOC involves debulking surgery followed by platinum-taxane combination chemotherapy; however, most patients will relapse with a chemoresistant disease with tumors developed within the peritoneum. Therefore, understanding the role of the unique microenvironments that promote EOC transcoelomic dissemination is important in improving patient outcomes from this disease. In this review article, we address the process of ovarian cancer cellular fate at the site of its origin in the secretory cells of the fallopian tube or in the ovarian surface epithelial cells, their detachment process, how the cells survive in the peritoneal fluid avoiding cell death triggers, and how cancer- associated cells help them in the process. Finally, we report the mechanisms used by the ovarian cancer cells to adhere and migrate through the mesothelial monolayer lining the peritoneum. We also discuss the involvement of the transcoelomic ecosystem on the development of chemoresistance of EOC.

Ovarian Strumal Carcinoid: Case Report, Systematic Literature Review and Pooled Analysis

BackgroundOvarian strumal carcinoid is a rare tumor in which thyroid (struma) and carcinoid components coexist. The disease is generally considered to be a borderline malignancy, however, cases with metastatic disease have been described. No data in the literature are available to guide diagnosis and therapy.MethodsWe performed a pooled analysis and a systematic review of histopathological-confirmed strumal carcinoid cases published in the literature using the following keywords: “strumal carcinoid of the ovary”, “strumal carcinoid case report”. A case of strumal carcinoid tumor diagnosed and followed-up at the Medical Oncology Unit of Spedali Civili (Brescia, Italy) was also described and included.ResultsSixty-six eligible publications were identified, providing data from one hundred and seventeen patients, plus a case diagnosed at our institution. At presentation, among the eighty-eight patients with symptomatic disease, 37% of patients suffered from abdominal distention and 49% from pain due to a growing abdominal tumor mass, 37% from constipation (peptide YY was analyzed in only nine of them, resulting above the physiologic range). Surgery was the primary therapy in 99% of the patients. Three patients had metastatic disease at diagnosis and five patients underwent recurrence after radical surgery. Histology at disease recurrence concerned the thyroid component in two patients, the carcinoid component in two patients, both histologies in one patient. Median disease-free survival and overall survival in this series were not attained.ConclusionStrumal carcinoid of the ovary generally presents a benign behavior and surgery is curative in most cases. However, a small group of patients with this disease can undergo disease recurrence due to both the thyroid and the neuroendocrine (carcinoid) components. A follow-up in radically operated patients is therefore needed, particularly in those with a voluminous disease at diagnosis.

BRCA1: An Endocrine and Metabolic Regulator

The breast and ovarian cancer susceptibility gene (BRCA1) is a tumor suppressor whose mutation has been associated with the development of breast, ovarian and, probably, other malignancies at young ages. The BRCA1 gene product participates in multiple biological pathways including the DNA damage response, transcriptional control, cell growth and apoptosis. Inactivating germline mutations of the BRCA1 gene can be detected in a substantial portion of families with inherited breast and/or ovarian cancer. While the genomic and cancer-related actions of BRCA1 have been extensively investigated, not much information exists regarding the cellular and circulating factors involved in regulation of BRCA1 expression and action. The present review article dissects the emerging role of BRCA1 as an important regulator of various endocrine and metabolic axes. Experimental and clinical evidence links BRCA1 with a number of peptide and steroid hormones. Furthermore, comprehensive analyses identified complex interactions between the insulin/insulin-like growth factor-1 (IGF1) signaling axis and BRCA1. The correlation between metabolic disorders, including diabetes and the metabolic syndrome, and BRCA1 mutations, are discussed in this article.

Preclinical In Silico Evidence Indicates the Pharmacological Targets and Mechanisms of Mogroside V in Patients With Ovarian Cancer and Coronavirus Disease 2019

The borderless transmission of coronavirus remains uncontrolled globally. The uncharted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant reduces the therapeutic efficacy of vaccines against coronavirus disease 2019 (COVID-19). Clinical observations suggest that tumour cases are highly infected with coronavirus, possibly due to immunologic injury, causing a higher COVID-19-related death toll. Presently, screening of candidate medication against coronavirus is in progress. Mogroside V, a bioactive ingredient of Siraitia grosvenorii, has been reported in China to have lung-protective and anticancer effects. The current study used network pharmacology and molecular docking to unlock the potential drug targets and remedial mechanisms of mogroside V against patients with ovarian cancer with COVID-19. We identified 24 related targets of mogroside V in patients with ovarian cancer and COVID-19 and characterised another 10 core targets of mogroside V against COVID-19 ovarian cancer, including Jun, IL2, HSP90AA1, AR, PRKCB, VEGFA, TLR9, TLR7, STAT3, and PRKCA. The core targets’ biological processes and signalling pathways were revealed by enrichment analysis. Molecular docking suggested favourable docking between core target protein and mogroside V, including vascular endothelial growth factor A (VEGFA). These findings indicated that mogroside V might be a potential therapeutic agent in the mitigation of COVID-19 ovarian cancer.

Causal relationship between genetically predicted uterine leiomyoma and cancer risk: a two-sample Mendelian randomization

PurposeStudies have demonstrated that hormonal imbalance, such as elevated level of estrogen or reduced level of progesterone, was the main inducing factor of uterine leiomyoma (UL) development and some cancers. UL has been reported to be associated with several cancers in observational studies. However, the causal associations between UL and cancers remain unclear.MethodsA two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal associations between UL and 16 site-specific cancers using the public databases. Four methods, namely, the inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode, were applied in our MR analysis. Sensitivity tests were also performed to evaluate the robustness of these causal associations.ResultsThe IVW analysis indicated that genetically predicted UL increased the risk of low malignant potential ovarian cancer [odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.06–1.40, p = 0.004], serous ovarian cancer (OR = 1.29, 95% CI: 1.10–1.52, p = 0.002), invasive mucinous ovarian cancer (OR = 1.24, 95% CI: 1.08–1.44, p = 0.003), clear cell ovarian cancer (OR = 1.25, 95% CI: 1.03–1.51, p = 0.023), breast cancer (OR = 1.07, 95% CI: 1.02–1.11, p = 0.002), and brain tumor (OR = 1.23, 95% CI: 1.06–1.42, p = 0.007). Conversely, genetically predicted UL reduced the risk of gastric cancer (OR = 0.91, 95% CI: 0.85–0.98, p = 0.008). The causal effects were consistent in the sensitivity analysis.ConclusionsOur results demonstrated that UL exhibits a causal relationship with high risk of several cancers. We suggest reinforcing the cancer screening in UL patients to enable the early detection of cancers.

The risk of ovarian cancer in hormone replacement therapy users: a systematic review and meta-analysis

BackgroundWith the increasing use of hormone replacement therapy (HRT), there is a need to understand its impact on the occurrence of female malignant tumors. This systematic review and meta-analysis aimed to assess the risk of ovarian cancer associated with HRT and its related risk factors.MethodsPUBMED, OVID, Embase, Cochrane, and Web of Science were searched from 1980 to April 2022 to identify studies on the risk of ovarian cancer and hormone replacement therapy. The random-effects model was used to estimate the pooled risk of HRT in ovarian cancer, both in cohort studies and case-control studies. Additionally, the analysis examined the outcomes associated with different types of estrogen plus progesterone regimens. Meta-regression and sensitive analysis were performed to evaluate the heterogeneity.Results21 cohort studies (involving 15,313 cases and 4,564,785 participants) and 30 case-control studies (including 18,738 cases and 57,747 controls) were analyzed. The pooled risks of ovarian cancer for HRT users were 1.20 (95% confidence interval [CI] 1.01–1.44) from cohort studies and 1.13 (95%CI 1.04–1.22) from case-control studies. However, after restricting the study period to recent decades, the significant results indicating a higher risk disappeared in cohort studies conducted after 2010 and in case-control studies conducted after 2006. Furthermore, the continuous use of estrogen-progesterone replacement therapy (EPRT) was associated with a risk comparable to that of sequential use. Subgroup analysis showed that both estrogen replacement treatment (ERT) and EPRT had minor risks; The risk further increased with prolonged exposure time, particularly for durations exceeding 10 years. Additionally, serous ovarian cancer appeared to be more susceptible than other pathological types.ConclusionThe risk of ovarian cancer associated with HRT has been decreasing over time. However, ERT may increase this risk, particularly when used for an extended period. It is recommended that long-time users consider continuous EPRT as a safer alternative.Systematic review registrationwww.crd.york.ac.uk/prospero/, identifier CRD42022321279.

Unveiling the causal link between metabolic factors and ovarian cancer risk using Mendelian randomization analysis

BackgroundMetabolic abnormalities are closely tied to the development of ovarian cancer (OC), yet the relationship between anthropometric indicators as risk indicators for metabolic abnormalities and OC lacks consistency.MethodThe Mendelian randomization (MR) approach is a widely used methodology for determining causal relationships. Our study employed summary statistics from the genome-wide association studies (GWAS), and we used inverse variance weighting (IVW) together with MR-Egger and weighted median (WM) supplementary analyses to assess causal relationships between exposure and outcome. Furthermore, additional sensitivity studies, such as leave-one-out analyses and MR-PRESSO were used to assess the stability of the associations.ResultThe IVW findings demonstrated a causal associations between 10 metabolic factors and an increased risk of OC. Including “Basal metabolic rate” (OR= 1.24, P= 6.86×10-4); “Body fat percentage” (OR= 1.22, P= 8.20×10-3); “Hip circumference” (OR= 1.20, P= 5.92×10-4); “Trunk fat mass” (OR= 1.15, P= 1.03×10-2); “Trunk fat percentage” (OR= 1.25, P= 8.55×10-4); “Waist circumference” (OR= 1.23, P= 3.28×10-3); “Weight” (OR= 1.21, P= 9.82×10-4); “Whole body fat mass” (OR= 1.21, P= 4.90×10-4); “Whole body fat-free mass” (OR= 1.19, P= 4.11×10-3) and “Whole body water mass” (OR= 1.21, P= 1.85×10-3).ConclusionSeveral metabolic markers linked to altered fat accumulation and distribution are significantly associated with an increased risk of OC.

A lactate metabolism-related signature predicting patient prognosis and immune microenvironment in ovarian cancer

IntroductionOvarian cancer (OV) is a highly lethal gynecological malignancy with a poor prognosis. Lactate metabolism is crucial for tumor cell survival, proliferation, and immune evasion. Our study aims to investigate the role of lactate metabolism-related genes (LMRGs) in OV and their potential as biomarkers for prognosis, immune microenvironment, and immunotherapy response.MethodsOvarian samples were collected from the TCGA cohort. And 12 lactate-related pathways were identified from the MsigDB database. Differentially expressed genes within these pathways were designated as LMRGs, which undergo unsupervised clustering to identify distinct clusters based on LMRGs. Subsequently, we assessed survival outcomes, immune cell infiltration levels, Hallmaker pathway activation patterns, and chemotaxis among different subtypes. After conducting additional unsupervised clustering based on differentially expressed genes (DEGs), significant differences in the expression of LMRGs between the two clusters were observed. The differentially expressed genes were subjected to subsequent functional enrichment analysis. Furthermore, we construct a model incorporating LMRGs. Subsequently, the lactate score for each tumor sample was calculated based on this model, facilitating the classification of samples into high and low groups according to their respective lactate scores. Distinct groups examined disparities in survival prognosis, copy number variation (CNV), single nucleotide variation (SNV), and immune infiltration. The lactate score served as a quantitative measure of OV's lactate metabolism pattern and an independent prognostic factor.ResultsThis study investigated the potential role of LMRGs in tumor microenvironment diversity and prognosis in OV, suggesting that LMRGs play a crucial role in OV progression and the tumor microenvironment, thus serving as novel indicators for prognosis, immune microenvironment status, and response to immunotherapy.

Case Report: Life-threatening hypercalcemia associated with MMR-deficient endometrial carcinoma secreting parathyroid hormone

Ectopic secretion of parathyroid hormone (PTH) is a rare cause of hypercalcemia in malignancy patients. A 56-year-old woman with life-threatening hypercalcemia was caused by poorly-differentiated endometrial carcinoma secreting PTH with concomitant nodular goiter mimic parathyroid tumors. The elevated level of PTH and calcium decreased immediately after cytoreductive surgery (CRS). The pathology confirmed mismatch repair (MMR)-deficient endometrial carcinoma with PTH expression. The patient received four-course chemotherapy and one-course immunotherapy after CRS. The disease progression led to multiple organ failure and death about five months after CRS. To our knowledge, this is the first case of hypercalcemia caused by MMR-deficient endometrial carcinoma with ectopic PTH secreting and the first report of malignancy associated hypercalcemia complicated with nodular goiter.

Alpha-fetoprotein level in fetuses, infants, and children with ovarian masses: a literature review

Alpha-fetoprotein (AFP) is a serum protein highly produced during the fetal period. It is also known as a biomarker of various pathologies. Commonly, tumors requiring diagnosis and monitoring through AFP determination appear during the first year of life, with poorer outcomes when presenting in fetal life. Due to advancements in imaging technology, the detectability of ovarian masses in infants is higher. However, the use of AFP as a biomarker could improve diagnosis in cases when imaging and histological examinations are not sensitive enough to detect tumors. From the outcome of our investigation, it is possible to conclude that there is evidence of an association between increased AFP levels and ovarian masses. However, previous studies have presented contradictory and unverified results, with the authors emphasizing that future research is needed. In this article, an analysis of the available literature on AFP as a biomarker of ovarian masses in children was performed. Two types of literature were reviewed: guidance and published studies (clinical trials, reviews, and systematic reviews). We searched the Embase, PubMed, ScienceDirect, and Web of Science databases to collect essential data.

Impacts of ovarian reserve on conservative treatment for endometrial cancer and atypical hyperplasia

ObjectivesReal-world data indicated that some endometrial atypical hyperplasia (EAH) and early endometrial carcinoma (EEC) patients of fertility preservation had a normal ovarian reserve, while some had a decreased ovarian reserve (DOR). This study was designed to investigate the effect of baseline ovarian reserve on the treatment of EAH and EEC patients who ask for preservation of fertility.MethodsThis was a prospective cohort study conducted at a single university-affiliated fertility center. A total of 102 EAH and EEC patients who received fertility-preserving treatment between March 2019 and August 2020 were included and divided into a DOR group (n=22) and a non-DOR group (n=80).ResultsThe 32-week CR rate of the non-DOR group was significantly higher than that of the DOR group (60.3% vs. 33.3%, P =0.028). The DOR group had a longer treatment duration to achieve CR than the non-DOR group (40.07 vs. 29.71 weeks, P=0.008, HR: 0.54, 95% CI: 0.36–0.86). Multivariate logistic regression analyses demonstrated that DOR (OR: 0.35, 95% CI: 0.13–0.99, P=0.049) and BMI ≥25 kg/m2 (OR: 0.40, 95% CI: 0.17–0.92, P=0.031) were negatively associated with 32-week CR.ConclusionsDecreased baseline ovarian reserve is negatively correlated with the efficacy of fertility-preserving treatment in EAH and EEC patients, as this group has a lower CR rate and a longer treatment duration to achieve CR than those without DOR.

Chinese Expert Consensus on ovarian function and fertility preservation of cervical cancer in pregnancy (2023)

Cervical cancer in pregnancy (CCIP) refers to cervical cancer diagnosed during pregnancy, the most common gynecological malignant tumor. Because of the special physiological changes of CCIP, although preserving ovarian function and fertility is very important, the methods are very limited. There is no guideline or consensus on the preservation methods of ovarian function and fertility in this special period. Therefore, the Committee of Fertility Protection and Preservation of China Association for the Promotion of Health Science and Technology, combined with the Chinese Society of Gynecological Endocrinology affiliated to the International Society of Gynecological Endocrinology, Society Endocrinology Branch of Beijing Institute of Obstetrics & Gynecology, combined with Society on Fertility Preservation affiliated with the Chinese Preventive Medicine Association, organized relevant experts from different disciplines to formulate this consensus, in order to guide ovarian function and fertility preservation of CCIP patients.

Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer

Ovarian cancer is a highly malignant gynecological cancer influenced by the immune microenvironment, metabolic reprogramming, and cellular senescence. This review provides a comprehensive overview of these characteristics. Metabolic reprogramming affects immune cell function and tumor growth signals. Cellular senescence in immune and tumor cells impacts anti-tumor responses and therapy resistance. Targeting immune cell metabolism and inducing tumor cell senescence offer potential therapeutic strategies. However, challenges remain in identifying specific targets and biomarkers. Understanding the interplay of these characteristics can lead to innovative therapeutic approaches. Further research is needed to elucidate mechanisms, validate strategies, and improve patient outcomes in ovarian cancer.

Genetically predicted serum testosterone and risk of gynecological disorders: a Mendelian randomization study

BackgroundTestosterone plays a key role in women, but the associations of serum testosterone level with gynecological disorders risk are inconclusive in observational studies.MethodsWe leveraged public genome-wide association studies to analyze the effects of four testosterone related exposure factors on nine gynecological diseases. Causal estimates were calculated by inverse variance–weighted (IVW), MR–Egger and weighted median methods. The heterogeneity test was performed on the obtained data through Cochrane’s Q value, and the horizontal pleiotropy test was performed on the data through MR–Egger intercept and MR-PRESSO methods. “mRnd” online analysis tool was used to evaluate the statistical power of MR estimates.ResultsThe results showed that total testosterone and bioavailable testosterone were protective factors for ovarian cancer (odds ratio (OR) = 0.885, P = 0.012; OR = 0.871, P = 0.005) and endometriosis (OR = 0.805, P = 0.020; OR = 0.842, P = 0.028) but were risk factors for endometrial cancer (OR = 1.549, P < 0.001; OR = 1.499, P < 0.001) and polycystic ovary syndrome (PCOS) (OR = 1.606, P = 0.019; OR = 1.637, P = 0.017). dehydroepiandrosterone sulfate (DHEAS) is a protective factor against endometriosis (OR = 0.840, P = 0.016) and premature ovarian failure (POF) (OR = 0.461, P = 0.046) and a risk factor for endometrial cancer (OR= 1.788, P < 0.001) and PCOS (OR= 1.970, P = 0.014). sex hormone-binding globulin (SHBG) is a protective factor against endometrial cancer (OR = 0.823, P < 0.001) and PCOS (OR = 0.715, P = 0.031).ConclusionOur analysis suggested causal associations between serum testosterone level and ovarian cancer, endometrial cancer, endometriosis, PCOS, POF.

Evaluation of adipokines concentrations in plasma, peritoneal, and endometrioma fluids in women operated on for ovarian endometriosis

IntroductionSome studies indicate the role of selected adipokines in the development of endometriosis. However, a comprehensive assessment of plasma, peritoneal, and endometrioma fluids adipokines concentrations in women with ovarian endometriosis has not yet been performed. Therefore, this study aimed to analyze plasma, peritoneal, and endometrioma fluids selected adipokines concentrations in women operated on for ovarian endometriosis.Materials and methodsA cross-sectional cohort study involved 56 women operated on for ovarian endometriosis. Body mass, height, and waist circumference were measured, and BMI was calculated. Plasma, peritoneal, and endometrioma fluids adiponectin, leptin, omentin resistin, RBP4, and visfatin/NAMPT were determined by ELISA.ResultsThe highest plasma levels of adiponectin, leptin, omentin, and RBP4 than in the endometrioma and peritoneal fluids were found, while levels of resistin and visfatin/NAMPT were significantly higher in endometrioma fluid than in plasma and peritoneal fluid. In addition, levels of visfatin/NAMPT were significantly higher in peritoneal fluid than in plasma. There were also positive correlations between leptin, RBP4, and adiponectin levels in endometrioma and peritoneal fluids (ρ = 0.28; p < 0.05; ρ = 0.31; p < 0.05; ρ= 0.32; p < 0.05, respectively). There were no associations between adipokines levels in plasma, endometrioma, and peritoneal fluids and endometriosis stage.ConclusionOur results show that visfatin/NAMPT and resistin may be locally secreted in endometrioma related to inflammation regardless of the stage of endometriosis.

Analysis of risk factors for recurrence in infertile endometrial cancer patients after in vitro fertilization treatment

PurposeTo investigate the oncologic outcomes of patients with early-stage endometrioid endometrial cancer (EEC) treated with in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) following fertility-sparing treatment (FST).MethodsA total of 62 patients who underwent IVF/ICSI treatment in a single fertility center between June 2010 and December 2021 after conservative treatment for early-stage EEC were assigned to a recurrence group and a non-recurrence group. Their clinical characteristics and disease outcomes were retrospectively evaluated.ResultsThe 62 women with complete remission (CR) after FST for EEC underwent 103 IVF cycles, resulting in 41 fresh embryo transfers (ETs) and 70 frozen–thawed transfers; 27 (43.55%) achieved clinical pregnancies, and 20 (32.26%) gave birth to a total of 23 live neonates. Additionally, nine patients had live births from natural pregnancies after IVF failure, bringing the cumulative live birth rate to 46.77% (29/62). After a median follow-up period of 53.88 months (range 20.2–127.5 months), 17 patients (27.42%) experienced recurrence within 2.8 to 57.9 months after the first controlled ovarian stimulation (COS). The probability of relapse at 1, 2, and 3 years after the initiation of COS was 14.52% (9/62), 21% (13/62), and 25.81% (16/62), respectively. Factors such as the time to CR, the time to IVF, the frequency of COS, maintenance treatment before IVF, and histology type were not found to significantly affect recurrence (p = 0.079, 0.182, 0.093, 0.267, and 0.41, respectively). Live births (hazard ratio (HR): 0.28, 95% CI: 0.082–0.962, p = 0.043) and the protocol of letrozole plus gonadotropin-releasing hormone (GnRH) antagonist/agonist used during IVF (HR: 0.1, 95% CI: 0.011–0.882, p = 0.038) were identified as independent favorable factors for recurrence.ConclusionsLive birth was associated with decreased recurrence of EEC. Reducing estrogen levels during COS may serve to mitigate the risk of endometrial cancer recurrence.

Age at menopause is inversely related to the prevalence of common gynecologic cancers: a study based on NHANES

BackgroundThe fluctuation or even loss of estrogen level caused by menopause in women, and most gynecological cancers often occur before and after menopause, so the age of menopause may be related to the occurrence of gynecological cancer.AimTo investigate whether the age at menopause is independently associated with the incidence of gynecological cancers and to analyze the possible influencing factors.MethodsWe selected the NHANES public database to conduct the study, and by excluding relevant influencing factors, we finally included 5706 NHANES participants who had full data on age at menopause and the occurrence of gynecologic cancers to analyze the relationship between the amount of age at menopause and gynecologic cancers based on univariate or multifactorial logistic regression analysis. Further, the relationship between age at menopause and the prevalence of different gynecologic cancers was investigated, and changes in the prevalence of different gynecologic cancers by age at menopause subgroups were observed. Finally, other relevant factors affecting the prevalence of gynecologic cancers were further investigated by subgroup analysis as well as subcluster analysis.ResultsUnivariate logistic regression analysis between age at menopause and gynecologic tumor prevalence revealed a negative association between age at menopause and the prevalence of common gynecologic cancers ovarian and cervical cancer, and after adjusting for the effects of covariates, a higher risk of gynecologic tumors was found with statistically significant differences at earlier age at menopause. The regression results showed a negative association between age at menopause and gynecologic cancer prevalence in cervical and ovarian cancer patients (P<0.01,P<0.01). Cervical cancer (OR: 0.91, 95% CI: 0.87,0.94) and ovarian cancer (OR: 0.90, 95% CI: 0.86, 0.95) were more prevalent among those with younger age at menopause.ConclusionAge at menopause is negatively associated with the prevalence of cervical and ovarian cancers, and the earlier the age at menopause, the greater the risk of developing gynecological cancers.

Modulatory effect of pomegranate peel extract on key regulators of ovarian cellular processes in vitro

In this study, response of ovarian cells (human granulosa cell line HGL5, and human adenocarcinoma cell line OVCAR-3) to short-term pomegranate peel extract (PPE) treatment (for 24 hours in cell culture) was evaluated in vitro. Quantitative and qualitative screening of polyphenols revealed punicalagins α and β as major polyphenolic components. Total phenolic content (TPC) was 93.76 mg GAE/g d.w. with a high antioxidant activity of 95.30 mg TEAC/g d.w. In OVCAR-3, PPE treatment inhibited the metabolic activity, and increased cyclin-dependent kinase 1 (CDKN1A, p21) level at the highest dose, but not in HGL5. Flow cytometry analysis could not detect any significant difference between proportions of live, dead, and apoptotic cells in both cell lines. Reactive oxygen species (ROS) revealed an antioxidant effect on HGL5, and a prooxidant effect by stimulating ROS generation in OVCAR-3 cells at the higher doses of PPE. However, in contrast to HGL5, PPE treatment decreased release of growth factors – TGF-β2 and EGF at the highest dose, as well as their receptors TGFBR2 and EGFR in OVCAR-3 cells. PPE also influenced steroidogenesis in granulosa cells HGL5 by stimulating 17β-estradiol secretion at higher doses. In conclusion, the present study highlighted the bioactive compounds in pomegranate peels and the possible mechanisms of action of PPE, shedding light on its promising role in ovarian cancer (chemo)prevention and/or management.

The present status of metformin in fertility-preserving treatment in atypical endometrial hyperplasia and endometrioid endometrial cancer

Progestin therapy is the main fertility-sparing treatment for women with endometrial cancer (EC) and atypical endometrial hyperplasia (AEH). However, still 15-25% of these women failed to achieve complete response (CR) and then lost their fertility after definitive surgery. Metformin has been demonstrated to play an anti-cancer role in multiple cancers including EC. Several studies also suggested metformin had potential benefit in improving the therapeutic outcome of fertility-preserving treatment alongside with progestin. This review has discussed existed evidence regarding the effect of metformin combined with progestin for women with AEH and EC who desire childbearing. Nevertheless, the therapeutic effect of metformin varied in different studies due to the high heterogeneity in the patient’s characteristics, the inconsistency in dose and treatment duration of metformin, the combined use of hysteroscopy, the insufficient sample size and underpowered study-design. Therefore, care should be taken when interpreting the current results on this issue. Till now, there is still no strong evidence supporting the use of metformin in fertility-preserving treatment in AEH and EEC patients. Further research is needed to provide high-quality data to validate the role of metformin as adjunctive therapy alongside with progestin to preserve fertility for AEH and EEC patients.

Current research of Assisted Reproductive Technology for women with early endometrial cancer and atypical endometrial hyperplasia after conservative treatment

As the incidence of endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) has been increasing, and has shown young trend. It is crucial to study the fertility-preserving treatment of endometrial lesions and fertility-promoting protocols. Age, obesity, and irregular ovulation are not only high-risk factors for endometrial lesions but also key factors affecting female fertility. Assisted reproductive technology (ART) can significantly improve pregnancy outcomes in patients with AEH and EC after conservative treatment. Based on the existing studies, this article reviews the progress of research on pregnancy outcomes of ART and its influencing factors in such patients. It helps physicians in providing optimal fertility guidance.

Assessment of bidirectional relationships between hypothyroidism and endometrial cancer: a two-sample Mendelian randomization study

ObjectiveHypothyroidism, characterized by reduced thyroid hormone levels, and endometrial cancer, a prevalent gynecological malignancy, have been suggested to have a potential association in previous observational studies. However, the causal relationship between them remains uncertain. This study aimed to investigate the causal relationship between hypothyroidism and endometrial cancer using a bilateral Mendelian randomization approach.MethodsA bidirectional two-sample Mendelian randomization study was conducted using summary statistics from genome-wide association studies to identify genetic variants associated with hypothyroidism and endometrial cancer. The inverse variance weighting method was used as the main analysis, and sensitivity analyses were conducted to validate the MR results.ResultsThe results of our analysis did not support a causal effect of hypothyroidism (OR: 0.93, p=0.08) or autoimmune hypothyroidism (OR: 0.98, p=0.39) on endometrial cancer risk. In the reverse MR analysis, we did not find a significant causal effect of endometrial cancer on hypothyroidism (OR: 0.96, p=0.75) or autoimmune hypothyroidism (OR: 0.92, p=0.50). Based on subgroup analysis by pathological subtypes of endometrial cancer, the above findings were further substantiated (all p-value >0.05).ConclusionsOur Mendelian randomization analysis suggests a lack of causal association between hypothyroidism and endometrial cancer. To gain a deeper understanding of this association, it is essential to conduct large-scale randomized controlled trials in the future to validate our findings.

Identification of CAPG as a potential prognostic biomarker associated with immune cell infiltration and ferroptosis in uterine corpus endometrial carcinoma

IntroductionCapping actin protein, gelsolin-like (CAPG) is a potential therapeutic target in various cancers. However, the potential immunotherapeutic effects and prognostic value of CAPG in uterine corpus endometrial carcinoma (UCEC) remain unclear.MethodsThe characterization, methylation effects, prognostic value, targeted miRNAs of CAPG, and the correlation of CAPG with immune cell infiltration and ferroptosis in UCEC were investigated using multiple public databases and online tools. Furtherly, we explored the potential physiological function of CAPG using EdU and Transwell migration assays, identified the cell localization and expression of CAPG and GPX4 by immunofluorescence, and detected the intracellular Fe2+ levels using a FerroOrange fluorescent probe in Ishikawa cells. Additionally, the OncoPredict package was used to analyze the potential chemotherapeutic drugs for UCEC.ResultsCAPG showed generally high expression in tumor group. The overall survival rate of the high-risk group was significantly lower than that of the low-risk group. Enrichment analysis indicated that CAPG is involved in immune-related pathways and is closely associated with the tumor microenvironment. CAPG expression levels were affected by abnormal DNA methylation and/or targeted miRNAs, infiltration levels and marker genes of various immune cells, thereby impacting immune response, ferroptosis, and patient prognosis. Ferroptosis analysis indicated that ALOX5 and VLDLR were the top CAPG-related ferroptosis markers; glutathione metabolism levels in tumor group were generally high, and decitabine was a ferroptosis inducer. CAPG-siRNA suppressed the cell proliferation and invasion, and markedly elevated the expression levels of immune-related genes IL8, TNF, TLR4 and the intracellular Fe2+ levels. CAPG co-located with GPX4 in nucleus and co-regulated ferroptosis and metabolism in Ishikawa cells. Moreover, four chemotherapy drugs showed better sensitivity to UCEC patients in the low-risk cohort.ConclusionsCAPG may serve as a potential biomarker of UCEC owing to its role in modulating the immune response and ferroptosis, providing novel perspectives for combined immunotherapy of UCEC.

Neuroendocrine neoplasms as a lynch syndrome manifestation: a case report and comprehensive literature review

Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by pathogenic variants in DNA mismatch repair (MMR) genes, most commonly MLH1 and MSH2. LS significantly increases the risk of various cancers, including colorectal, endometrial, gastric, and ovarian malignancies. Neuroendocrine neoplasms (NENs) are rare tumors that arise from neuroendocrine cells, predominantly in the gastrointestinal tract, and are frequently associated with hereditary cancer syndromes such as multiple endocrine neoplasia types 1 and 2. While a definitive association between LS and NENs has not been established, isolated cases have been reported. We present the case of a 63-year-old woman with a history of colorectal cancer and a confirmed LS diagnosis, identified through genetic testing that revealed a pathogenic MLH1 variant. Years later, she developed a grade 2 non-functional neuroendocrine tumor (NET), likely of gastrointestinal origin. The patient underwent surgical resection, followed by treatment with somatostatin analogs. Due to this uncommon presentation, we conducted a literature review to explore the potential relationship between LS and NENs. Our analysis identified 13 additional cases of NENs in LS patients, encompassing NETs, neuroendocrine carcinomas (NECs), and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). This growing body of evidence suggests that NENs may be part of the LS tumor spectrum. Further research is needed to elucidate the underlying mechanisms and determine whether LS predisposes individuals to NENs. Enhanced surveillance in LS patients could improve early detection of rare malignancies such as NENs, ultimately expanding our understanding of LS-associated cancer risks and guiding more effective clinical management.

Environmental endocrine disruptors and endometrial cancer: a systematic review of epidemiological studies

Endometrial cancer (EC) is a hormone-dependent malignancy whose global incidence is steadily rising. Increasing evidence suggests that exposure to endocrine-disrupting chemicals (EDCs) may contribute to EC development through interference with hormonal signaling mediated by estrogen receptors (ER). This systematic review aimed to synthesize the available epidemiological evidence on the association between exposure to EDCs and the risk of EC. A comprehensive search of MEDLINE, EMBASE, Scopus, the Cochrane Library, and ClinicalTrials.gov was conducted up to April 2025, following PRISMA 2020 recommendations. Eligible studies included observational or interventional designs assessing quantified exposure to EDCs and EC incidence or risk. Eight studies met the inclusion criteria (five case-control, two cohort, and one randomized controlled trial), comprising 2, 609 EC cases and 1, 577 controls. Cadmium emerged as the EDC most frequently associated with EC, reported in five studies, four of which demonstrated a significant positive association, particularly among lean postmenopausal women. In contrast, evidence regarding bisphenol A (BPA) and its metabolites was inconsistent: only mono-n-butyl phthalate (MnBP) showed a positive correlation with EC in one study, while BPA and dibutyl phthalate (DBP) did not. Nonylphenol and octylphenol were also found to be positively associated with EC risk in a single study. Conversely, neither lead exposure nor dietary intake of isoflavones was associated with EC incidence. Overall, available epidemiological evidence supports a potential association between cadmium exposure and increased EC risk, while data for other EDCs remain limited and inconclusive. Substantial heterogeneity in exposure assessment, study design, and confounder adjustment limits comparability across studies and precludes definitive conclusions. Further well-designed longitudinal studies with standardized and repeated exposure measurements are needed to clarify causal relationships between EDC exposure and endometrial carcinogenesis. Systematic Review Registration https://inplasy.com/inplasy-2025-6-0030/ , identifier INPLASY202560030.

Association between endometrial cancer and subsequent risk of fracture: a national cohort study

AimsMost endometrial cancer (EC) cases are estrogen-dependent, and some are associated with diabetes mellitus (DM). We aimed to estimate the risk of fracture among patients with EC and those with DM.Materials and methodsA total of 20814 patients with EC were identified from the Taiwan National Cancer Registry from 2007 to 2018, with the outcome ascertainment using the National Health Insurance Research Database from 2004 to 2019. This observational study investigated the hazard ratios (HRs) for fracture and mortality events using Cox proportional hazards regression, with 95% confidence intervals (CIs). We adjusted baseline comorbidities, cancer therapy, cancer staging and grade, and pathological status of estrogen receptor and progesterone receptor. Considering the competing death events, we estimated the subdistribution hazard model to predict the probability of the fracture risk in the competing risks context.ResultsAmong 15,505 EC patients, there were 3,044 patients with and 12,461 patients without DM. Patients with EC exhibited a no significant association of fracture when compared to the matched general population. EC patients with DM, compared to those without DM, had a significantly increased odds of osteoporotic fracture (HR 1.29 [95% CI 1.08–1.55]), hip fracture (HR 2.37 [95% CI 1.44–3.92]), and vertebral fracture (HR 1.71 [95% CI 1.06–2.74]). Patients with DM had a no significant association of upper extremity fracture (HR 1.33 [95% CI 0.95–1.87]) compared with those with EC but without DM.ConclusionsEC patients had a no significant association of fracture, while DM increased the fracture risk in EC patients.

Progress of estrogen receptor and spliceosome in endometrial carcinoma

Endometrial cancer (EC) is one of the most common gynecological cancers in developed countries. Like EC, most female reproductive tract malignancies are thought to be hormonally driven, with estrogen signaling acting as an oncogenic signal. The actions of estrogen are mediated through the classical nuclear estrogen receptors α (ER-α) and β (ER-β) as well as transmembrane G protein-coupled estrogen receptors (GPR30 and GPER). Ligand-bound estrogen receptor (ER) and GPER trigger multiple downstream signaling pathways that regulate the cell cycle, differentiation, migration, and apoptosis in various tissues, including the endometrium. Additionally, growing evidence suggests that selective splicing events at the receptor result in multiple ERα proteins with different molecular weights and functional structural domains. Examples include ER-α66, ER-α46, and ER-α36. In addition, various post-translational modifications (PTMs) further affect ER-α cellular localization and ligand affinity, resulting in a change in the cellular function. These splice isoforms and PTMs are differentially expressed in a tissue-specific manner. They mediate some aspects of ER-α signaling and may even antagonize full-length ER-α. Therefore, both ER-α and its splice isoforms may play a role in the development of EC. In this review, we examine the influential roles of ER-α and ER-β, as well as the GPER estrogen signaling pathway, in EC. Our goal is to provide theoretical support for further research on the molecular mechanisms between ER and EC and to generate new ideas for the early diagnosis of EC and the development of new drugs.

The impact of altered gut microbiota and lipid metabolism on the progression of endometrial cancer in overweight populations

Background Endometrial cancer (EC) is one of the common malignant tumors among women, and in recent years, the role of gut microbiota in tumorigenesis has been increasingly gaining attention.Existing research has shown that the gut microbiome, establishes axis connections with multiple extra-intestinal organs. However, whether gut microbes affect the process of endometrial carcinogenesis through metabolic pathways and the specific mechanisms by which they promote the development of EC remain unclear. This study aims to explore the impact of overweight-mediated gut microbiota on the initiation or progression of EC and to assess its relationship with metabolites, thereby providing new insights for early diagnosis and treatment. Methods In this study, we analyzed gut microbiota differences among normal-weight, overweight EC patients, and healthy controls using 16S rRNA sequencing. Liquid chromatography-mass spectrometry (LC-MS) and KEGG analysis identified group-specific metabolites and pathways, while Spearman correlation analysis revealed associations between microbiota and metabolites. Results This study revealed that in the ECMO group, the genus Megamonas exhibited the highest abundance and significant intergroup differences (H=13.46, P<0.05). Additionally, the Bacillota/Bacteroidota ratio (B/B ratio) gradually increased in the CN, ECMN, ECMO group. LEfSe analysis identified Megamonas and Amedibacillus as potential biomarkers for the ECMO group. Serum metabolomics of overweight EC patients highlighted lipid metabolism-related metabolites with the most specific expression. KEGG enrichment analysis of differential metabolites highlighted that the Glycerophospholipid metabolism and Purine metabolism pathways were notably significant in both the ECMN and ECMO groups. Conclusion The study found significantly elevated abundance of Megamonas in the gut microbiota of overweight EC patients, which may promote EC progression by degrading inositol to enhance lipid absorption. This reveals the role of gut microbiota in EC pathogenesis through lipid metabolism regulation, providing a theoretical basis for microbiota-based diagnostic and therapeutic strategies.

Interacting and joint effects of triglyceride-glucose index and body mass index on future endometrial cancer risk and the mediating role of body mass index: a cross-sectional study

BackgroundThe triglyceride-glucose (TyG) index, a promising biomarker for insulin resistance, is linked to the risk of various metabolic-related cancers. However, to date, data on the association of TyG index with different subtypes of endometrial cancers and the potential mediating role of clinical factors remain limited.MethodologyData was collected from the Beijing Obstetrics and Gynecology Hospital, Capital Medical University spanning from 2014 to 2024. Female participants with complete data on the TyG index were included in the analysis. Multivariate logistic regression analyses were used to assess the association of TyG index with endometrial cancer risk, adjusted by series of confounders. Mediation effects were evaluated using Valeri and VanderWeele’s method.ResultsA total of 1,194 eligible participants were enrolled, with 597 (50%) women diagnosed with endometrial cancer. The fully adjusted multivariate logistic regression model revealed a significant association between the TyG index and the risk of endometrial cancer (odds ratio [OR]Tertile 3 versus Tertile 1: 1.93, 95% confidence interval [CI]: 1.37–2.73; P for trend=0.028). Notably, BMI exhibited significant mediation effects on this association, even after adjusted by potential confounders (P for trend<0.001). The proportion of the effect mediated by BMI was 25% in the crude analysis (95% CI: 0.15, 0.37; P<0.001) and increased to 41% in the adjusted analysis (95% CI: 0.24, 0.76; P<0.001). However, no correlation was found between TyG index and the clinical characteristics of endometrial cancer (P>0.05). Moreover, BMI is associated with the risk of different endometrial cancers.ConclusionThis cross-sectional study demonstrated that a higher TyG index, representing higher level of insulin resistance, was associated with a higher risk of endometrial cancer. Importantly, we found that BMI acted as a significant mediator in this relationship. Prospective studies are needed to further validate these findings.

The mechanisms crosstalk and therapeutic opportunities between ferroptosis and ovary diseases

Ferroptosis, a form of regulated cell death, was first defined in 2012. Ferroptosis mainly involves iron-driven lipid peroxidation damage of cells. This process is regulated by iron homeostasis, redox balance, lipid metabolism, glutathione metabolism, and various disease signaling pathways. Iron is one of the key mineral elements that regulate the physiological function of women and the development of ovarian tumors. Occurrence of Ferroptosis has some hidden dangers and advantages in ovary diseases. Some scholars have shown that ferroptosis of ovarian granulosa cells (GC) promotes the development of ovarian dysfunction and polycystic ovary syndrome (PCOS). Interestingly, drug-resistant ovarian cancer cells are very sensitive to ferroptosis, suggesting that pharmacological positive and negative regulation of ferroptosis has great potential in the treatment of benign ovarian diseases and ovarian cancer. This article aimed to assess how ferroptosis occurs and the factors controlling ferroptosis. Moreover, we summarize how ferroptosis can be used to predict, diagnose and target treatment ovary disease. Meanwhile, we also evaluated the different phenomena of Ferroptosis in ovarian diseases. It aims to provide new directions for the research and prevention of female reproductive diseases.

Progestin plus metformin improves outcomes in patients with endometrial hyperplasia and early endometrial cancer more than progestin alone: a meta-analysis

ObjectiveProgestin based therapy is the preferred option for fertility-sparing treatment of reproductive-age women with preserved fertility in endometrial hyperplasia (EH) or early endometrial cancer (EEC). Our objective was to investigate whether metformin could enhance the efficacy of progestin-based therapies by meta-analysis.MethodsWe conducted a meta-analysis of randomized or non-randomized controlled trials by searching of PubMed, Embase, Web of science, and Cochrane database from inception to November 8, 2022. The results of enrolled studies were pooled using meta-analysis to estimate the effect of progestin plus metformin on remission, recurrence, pregnancy rate and live birth rate.ResultsIn the analysis of progestin administered systemically or locally, complete response (CR) was significantly higher in progestin plus metformin versus progestin alone in the EH group (pooled OR 2.08, 95% CI 1.29 to 3.34, P=0.003), in the EEC group (pooled OR 1.86, 95% CI 1.13 to 3.05, P=0.01), but not in EEC and EH group (pooled OR 1.46, 95% CI 0.97 to 2.21, P=0.07). In the analysis of progestin administered systemically, complete response was improved in progestin plus metformin versus progestin alone, in the EH group (pooled OR 2.47, 95% CI 1.45 to 4.21, P=0.0009), in the EEC group (pooled OR 2.09, 95% CI 1.18 to 3.71, P=0.01), and in the EEC and EH group (pooled OR 2.03, 95% CI 1.16 to 3.54, P=0.01). The relapse rates of patients with EEC and EH were not different (pooled OR 0.54, 95% CI 0.24 to 1.20, P=0.13). For obstetric outcomes, the addition of metformin improved pregnancy rate (pooled OR 1.55, 95% CI 0.99 to 2.42, P=0.05), but not live birth rate (pooled OR 0.95, 95% CI 0.45 to 2.01, P=0.89).ConclusionFor fertility-sparing management, compared to progestin alone, the outcomes of patients with endometrial hyperplasia and early endometrial cancer were more improved with progestin plus metformin because progestin plus metformin increases the rate of remission and pregnancy.

A nomogram for predicting recurrence in endometrial cancer patients: a population-based analysis

ObjectiveEndometrial cancer recurrence is one of the main factors leading to increased mortality, and there is a lack of predictive models. Our study aimed to establish a nomogram predictive model to predict recurrence in endometrial cancer patients.MethodScreen 517 endometrial cancer patients who came to Nanjing Drum Tower Hospital from 2008 to 2018. All these data are listed as the training group, and then 70% and 60% are randomly divided into verification groups 1 and 2. Univariate, Multivariate logistic regression, stepwise regression were used to select variables for nomogram. Nomogram identification and calibration were evaluated by concordance index (c-index), area under receiver operating characteristic curve (AUC) over time and calibration plot Function. By decision curve analysis (DCA), net reclassification index (NRI), integrated discrimination improvement (IDI), we compared and quantified the net benefit of nomogram and ESMO-ESGO-ESTRO model-based prediction of tumor recurrence.ResultsA nomogram predictive model of endometrial cancer recurrence was established with the eight variables screened. The c-index (for the training cohort and for the validation cohort) and the time-dependent AUC showed good discriminative power of the nomogram. Calibration plots showed good agreement between nomogram predictions and actual observations in both the training and validation sets.ConclusionsWe developed and validated a predictive model of endometrial cancer recurrence to assist clinicians in assessing recurrence in endometrial cancer patients.

Exploring the role of macrophages in the progression from atypical hyperplasia to endometrial carcinoma through single-cell transcriptomics and bulk transcriptomics analysis

IntroductionIn this study, we aimed to identify key genes in endometrial cancer by conducting single-cell analysis of macrophages.MethodsWe sourced clinical data from the TCGA database as well as supplementary datasets GSE201926 and GSE173682. Using bulk-seq data of atypical endometrial hyperplasia and endometrial cancer, we pinpointed key differentially expressed genes. Single-cell RNA sequencing was utilized for further gene expression analysis. Cluster analysis was conducted on TCGA tumor data, identifying two distinct subtypes. Statistical methods employed included LASSO regression for diagnostic modeling and various clustering algorithms for subtype identification.ResultsWe found that subtype B was closely related to cellular metabolism. A diagnostic model was established using LASSO regression and was based on the genes CDH18, H19, PAGE2B, PXDN, and THRB. This model effectively differentiated the prognosis of cervical cancer. We also constructed a prognosis model and a column chart based on these key genes.DiscussionThrough CIBERSORT analysis, CDH18 and PAGE2B were found to be strongly associated with macrophage M0. We propose that these genes influence the transformation from atypical endometrial hyperplasia to endometrial cancer by affecting macrophage M0. In conclusion, these key genes may serve as therapeutic targets for endometrial cancer. A new endometrial cancer risk prognosis model and column chart have been constructed based on these genes, offering a reliable direction for future cervical cancer treatment.

Association between metabolic disorders and clinicopathologic features in endometrial cancer

BackgroundIn recent years, the incidence of Endometrial cancer (EC) has been on the rise due to high-fat, high-calorie diets and low-exercise lifestyles. However, the relationships between metabolic disorders and the progression of EC remain uncertain. The purpose of our study was to explore the potential association between obesity, hypertension, hyperglycemia and clinicopathologic characteristics in EC patients.MethodsIn categorical variables, Chi-square tests were used to calculate P values. Univariate logistic regression and multivariate logistic regression were used to identify the risk factors of myometrial invasion>1/2 and lymph node metastasis. Overall survival (OS) was estimated using the Kaplan-Meier method.ResultsThe study included 406 individuals with EC, 62.6% had type I and 37.4% had type II. Hypertension was seen in 132 (32.5%), hyperglycemia in 75 (18.5%), and overweight or obesity in 217 (53.4%). Hypertension, hyperglycemia, and obesity are strongly associated with the clinicopathologic features of EC. Multivariate logistic regression revealed that hyperglycemia (OR=2.439,95% CI: 1.025-5.804, P = 0.044) was a risk factor for myometrial invasion depth >1/2 in patients with type I EC, and hypertension (OR=32.124,95% CI: 3.287-313.992, P = 0.003) was a risk factor for lymph node metastasis in patients with type I EC. Survival analysis found that hyperglycemia (P < 0.001) and hypertension (P = 0.002) were associated with OS in type I EC. Neither hyperglycemia, hypertension, nor obesity were associated with the prognosis in type II EC.ConclusionHyperglycemia was a risk factor for myometrial invasion depth >1/2 in patients with type I EC and hypertension was a risk factor for lymph node metastasis in patients with type I EC. Hypertension and hyperglycemia were associated with poor prognosis in patients with type I EC.

Pre-receptor regulation of 11-oxyandrogens differs between normal and cancerous endometrium and across endometrial cancer grades and molecular subtypes

BackgroundEndometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time.MethodsWe performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets.ResultsWe discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low- and high-grade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression correlated with lower recurrence in TP53-wt tumors.ConclusionsThe intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC.

Serum protein N-glycome patterns reveal alterations associated with endometrial cancer and its phenotypes of differentiation

Background Aberrant N-glycosylation and its involvement in pathogenesis have been reported in endometrial cancer (EC). Nevertheless, the serum N-glycomic signature of EC remains unknown. Here, we investigated serum N-glycome patterns of EC to identify candidate biomarkers. Methods This study enrolled 34 untreated EC patients and 34 matched healthy controls (HC) from Peking Union Medical College Hospital. State-of-the-art MS-based methods were employed for N-glycans profiling. Multivariate and univariate statistical analyses were used to identify discriminative N-glycans driving classification. Receiver operating characteristic analyses were performed to evaluate classification accuracy. Results EC patients displayed distinct differences in serum N-glycome and had abnormal high-mannose and hybrid-type N-glycans, fucosylation, galactosylation, and linkage‐specific sialylation compared with HC. The glycan panel built with the four most discriminative and biologically important derived N-glycan traits could accurately identify EC (random forest model, the area under the curve [AUC]=0.993 [95%CI 0.955-1]). The performance was validated by two other models. Total hybrid-type N-glycans significantly associated with the differentiation types of EC could effectively stratify EC into well- or poorly-differentiated subgroups (AUC>0.8). Conclusion This study provides the initial evidence supporting the utility of serum N-glycomic signature as potential markers for the diagnosis and phenotyping of EC.

Circulating adrenal 11-oxygenated androgens are associated with clinical outcome in endometrial cancer

ContextRecent evidence support that androgens play an important role in the etiology of endometrial cancer (EC). Adrenal-derived 11-oxygenated androgens are highly potent agonists of the androgen receptor (AR), comparable to testosterone (T) and dihydrotestosterone (DHT) that have not been studied in the context of EC.MethodologyWe studied a cohort of 272 newly diagnosed postmenopausal EC cases undergoing surgical treatment. Circulating concentrations of seven 11-oxygenated androgens including precursors, potent androgens and their metabolites were established in serum samples collected before and 1 month after surgery using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). Free (unconjugated) and total (free + sulfate and glucuronide conjugates following enzymatic hydrolysis) were analyzed in relation to clinicopathological features, recurrence and disease-free survival (DFS).ResultsLevels of 11-oxygenated androgens were weakly correlated to those of canonical androgens such as testosterone (T) and dihydrotestosterone (DHT), with no evidence of their association with clinicopathological features. Levels of 11-oxygenated androgens declined after surgery but remained higher in overweight and obese compared to normal weight cases. Higher levels of preoperative free 11-ketoandrosterone (11KAST) were associated with an increased risk of recurrence (Hazard ratio (HR) of 2.99 (95%CI=1.09-8.18); P=0.03). Postoperative free 11β-hydroxyandrosterone (11OHAST) levels were adversely associated with recurrence and DFS (HR = 3.23 (1.11-9.40); P=0.03 and 3.27 (1.34-8.00); P=0.009, respectively).Conclusion11-oxygenated androgen metabolites emerge as potential prognostic markers of EC.

The interplay of sex steroid hormones and microRNAs in endometrial cancer: current understanding and future directions

IntroductionEndometrial cancer is a hormone-dependent malignancy, and sex steroid hormones play a crucial role in its pathogenesis. Recent studies have demonstrated that microRNAs (miRNAs) can regulate the expression of sex steroid hormone receptors and modulate hormone signaling pathways. Our aim is to provide an overview of the current understanding of the role of miRNAs in endometrial cancer regulated by sex steroid hormone pathways.MethodsA thorough literature search was carried out in the PubMed database. The articles published from 2018 to the present were included. Keywords related to miRNAs, endometrial cancer, and sex steroid hormones were used in the search.ResultsDysregulation of miRNAs has been linked to abnormal sex steroid hormone signaling and the development of endometrial cancer. Various miRNAs have been identified as modulators of estrogen and progesterone receptor expression, and the miRNA expression profile has been shown to be a predictor of response to hormone therapy. Additionally, specific miRNAs have been implicated in the regulation of genes involved in hormone-related signaling pathways, such as the PI3K/Akt/mTOR and MAPK/ERK pathways.ConclusionThe regulation of sex steroid hormones by miRNAs is a promising area of research in endometrial cancer. Future studies should focus on elucidating the functional roles of specific miRNAs in sex steroid hormone signaling and identifying novel miRNA targets for hormone therapy in endometrial cancer management.

The role of GnRH metabolite, GnRH-(1-5), in endometrial cancer

From the time of its discovery and isolation in the mammalian hypothalamus, the decapeptide, gonadotropin-releasing hormone (GnRH), has also been found to be expressed in non-hypothalamic tissues and can elicit a diverse array of functions both in the brain and periphery. In cancer, past studies have targeted the gonadotropin-releasing hormone receptors (GnRHR) as a way to treat reproductive cancers due to its anti-tumorigenic effects. On the contrary, its metabolite, GnRH-(1-5), behaves divergently from its parental peptide through putative orphan G-protein coupled receptor (oGPCR), GPR101. In this review, we will focus on the potential roles of GnRH-(1-5) in the periphery with an emphasis on its effects on endometrial cancer progression.

Prognostic model for the exemption of adjuvant chemotherapy in stage IIIC endometrial cancer patients

BackgroundThis study aimed to develop a nomogram to predict the survival for stage IIIC endometrial cancer (EC) patients with adjuvant radiotherapy (ART) alone and personalize recommendations for the following adjuvant chemotherapy (ACT).MethodsIn total, 746 stage IIIC EC patients with ART alone were selected from the Surveillance, Epidemiology, and End Results (SEER) registry. Cox regression analysis was performed to identify independent risk factors. A nomogram was developed accordingly, and the area under the receiver operating characteristic curve (AUC) and C-index were implemented to assess the predictive power. The patients were divided into different risk strata based on the total points derived from the nomogram, and survival probability was compared between each risk stratus and another SEER-based cohort of stage IIIC EC patients receiving ART+ACT (cohort ART+ACT).ResultsFive independent predictors were included in the model, which had favorable discriminative power both in the training (C-index: 0.732; 95% CI: 0.704–0.760) and validation cohorts (C-index: 0.731; 95% CI: 0.709–0.753). The patients were divided into three risk strata (low risk <135, 135 ≤ middle risk ≤205, and high risk >205), where low-risk patients had survival advantages over patients from cohort ART+ACT (HR: 0.45, 95% CI: 0.33–0.61, P < 0.001). However, the middle- and high-risk patients were inferior to patients from cohort ART+ACT in survival (P < 0.001).ConclusionA nomogram was developed to exclusively predict the survival for stage IIIC EC patients with ART alone, based on which the low-risk patients might be perfect candidates to omit the following ACT. However, the middle- and high-risk patients would benefit from the following ACT.

Shared sex hormone metabolism-related gene prognostic index between breast and endometrial cancers

AimsAs sex hormone-dependent tumors, it remains to be clarified whether there is a common genetic signature and its value between breast and endometrial cancers. The aim of this study was to establish the shared sex hormone metabolism-related gene prognostic index (SHMRGPI) between breast and endometrial cancers and to analyze its potential role in the therapeutic and prognostic assessment of endometrial cancers.MethodsUsing transcriptome data from TCGA, tumor-associated gene modules were identified by weighted gene co-expression network analysis, and the intersection of module genes with female sex hormone synthesis and metabolism genes was defined as sex hormone metabolism-related gene. SHMRGPI was established by the least absolute shrinkage and selection operator and Cox regression. Its prognostic value of patients with endometrial cancer was validated, and a nomogram was constructed. We further investigated the relationship between SHMRGPI groups and clinicopathological features, immune infiltration, tumor mutation burden, and drug sensitivity.ResultsA total of 8 sex hormone metabolism-related gene were identified as key genes for the construction of prognostic models. Based on SHMRGPI, endometrial cancer patients were divided into high and low SHMRGPI groups. Patients in the low SHMRGPI group had longer overall survival (OS) compared with the high group (P< 0.05). Furthermore, we revealed significant differences between SHMRGPI groups as regards tumor immune cell infiltration, somatic mutation, microsatellite instability and drug sensitivity. Patients with low SHMRGPI may be the beneficiaries of immunotherapy and targeted therapy.ConclusionsThe SHMRGPI established in this study has prognostic power and may be used to screen patients with endometrial cancer who may benefit from immunotherapy or targeted therapy.

Review of Mendelian Randomization Studies on Endometrial Cancer

Endometrial cancer (EC) is a common gynecological cancer. In some parts of the world, the incidence and mortality of EC are on the rise. Understanding the risk factors of EC is necessary to prevent the occurrence of this disease. Observational studies have revealed the association between certain modifiable environmental risk factors and EC risk. However, due to unmeasured confounding, measurement errors, and reverse causality, observational studies sometimes have limited ability to judge robust causal inferences. In recent years, Mendelian randomization (MR) analysis has received extensive attention, providing valuable insights for cancer-related research, and is expected to identify potential therapeutic interventions. In MR analysis, genetic variation (alleles are randomly assigned during meiosis and are usually independent of environmental or lifestyle factors) is used instead of modifiable exposure to study the relationship between risk factors and disease. Therefore, MR analysis can make causal inference about exposure and disease risk. This review briefly describes the key principles and assumptions of MR analysis; summarizes published MR studies on EC; focuses on the correlation between different risk factors and EC risks; and discusses the application of MR methods in EC research. The results of MR studies on EC showed that type 2 diabetes, uterine fibroids, higher body mass index, higher plasminogen activator inhibitor-1 (PAI-1), higher fasting insulin, early insulin secretion, longer telomere length, higher testosterone and higher plasma cortisol levels are associated with increased risk of EC. In contrast, later age of menarche, higher circulatory tumor necrosis factor, higher low-density lipoprotein cholesterol, and higher sex hormone-binding globulin levels are associated with reduced risk of EC. In general, despite some limitations, MR analysis still provides an effective way to explore the causal relationship between different risk factors and EC.

Follicle-Stimulating Hormone Induces Lipid Droplets via Gαi/o and β-Arrestin in an Endometrial Cancer Cell Line

Follicle-stimulating hormone (FSH) and its G protein-coupled receptor, FSHR, represents a paradigm for receptor signaling systems that activate multiple and complex pathways. Classically, FSHR activates Gαs to increase intracellular levels of cAMP, but its ability to activate other G proteins, and β-arrestin-mediated signaling is well documented in many different cell systems. The pleiotropic signal capacity of FSHR offers a mechanism for how FSH drives multiple and dynamic downstream functions in both gonadal and non-gonadal cell types, including distinct diseases, and how signal bias may be achieved at a pharmacological and cell system-specific manner. In this study, we identify an additional mechanism of FSH-mediated signaling and downstream function in the endometrial adenocarcinoma Ishikawa cell line. While FSH did not induce increases in cAMP levels, this hormone potently activated pertussis toxin sensitive Gαi/o signaling. A selective allosteric FSHR ligand, B3, also activated Gαi/o signaling in these cells, supporting a role for receptor-mediated activation despite the low levels of FSHR mRNA. The low expression levels may attribute to the lack of Gαs/cAMP signaling as increasing FSHR expression resulted in FSH-mediated activation of the Gαs pathway. Unlike prior reports for FSH-mediated Gαs/cAMP signaling, FSH-mediated Gαi/o signaling was not affected by inhibition of dynamin-dependent receptor internalization. While chronic FSH did not alter cell viability, FSH was able to increase lipid droplet size. The β-arrestins are key adaptor proteins known to regulate FSHR signaling. Indeed, a rapid, FSH-dependent increase in interactions between β-arrestin1 and Gαi1 was observed via NanoBiT complementation in Ishikawa cells. Furthermore, both inhibition of Gαi/o signaling and siRNA knockdown of β-arrestin 1/2 significantly reduced FSH-induced lipid droplet accumulation, implying a role for a Gαi/o/β-arrestin complex in FSH functions in this cell type. As FSH/FSHR has been implicated in distinct hormone-dependent cancers, including endometrial cancer, analysis of the cancer genome database from 575 human endometrial adenocarcinoma tumors revealed that a subpopulation of samples expressed FSHR. Overall, this study highlights a novel mechanism for FSHR signal pleiotropy that may be exploited for future personalized therapeutic approaches.

Effects of Metabolic Syndrome and Its Components on the Prognosis of Endometrial Cancer

ObjectiveTo explore the effects of metabolic syndrome (MetS) on the prognosis of endometrial cancer (EC) and to identify key components of MetS associated with EC.MethodsA total of 506 patients surgically diagnosed with EC were analyzed in this study. These patients were diagnosed with EC in the Department of Obstetrics and Gynecology at the People’s Hospital of Peking University between 2010 and 2016. The follow-up time was cut off at December 2019. MetS was characterized based on standards provided by the Chinese Diabetes Society in 2004.ResultsAmong the 506 EC patients analyzed, 153 patients were diagnosed with MetS. MetS patients were more likely to be older and postmenopausal. MetS was positively related to tumor grade, stage, LNM, LVSI, and MI. The univariate analysis showed that MetS was closely related to the OS (HR = 2.14; P = 0.032) and RFS (HR = 1.80; P = 0.045) of EC patients. K–M analysis also indicated that EC patients with MetS had shorter OS and RFS than EC patients without MetS. More specifically, patients that had ≥3 components showed a worse outcome compared with patients only having 0 or 1–2 components (P <0.05). In the multivariate-adjust model, after adjusting for age, histotype, tumor grade, and stage, HDL-C was found to be associated with increased risk of death related to EC (HR = 2.2, P = 0.034). However, MetS did not significantly correlate with this. ROC analysis revealed that the area under the ROC curve of combined factors (HDL-C + grade + stage) was better than traditional stage or grade at 1-, 3-, and 5-year survival rates. From this, a nomogram based on HDL-C, grade, and stage was constructed to predict survival of EC patients. Calibration curve analysis and decision curve analysis (DCA) showed the nomogram we constructed could better predict the survival of EC patients.ConclusionMetS is closely related to poor prognosis in EC patients. The prevalence of individual MetS components increase with worse outcomes in EC patients. A nomogram based on HDL-C, grade, and stage has good ability to predict survival of EC patients.

Complications of Pregnancy and the Risk of Developing Endometrial or Ovarian Cancer: A Case-Control Study

BackgroundThe association of complications of pregnancy and the risk of developing gynecological cancer is controversial with the limited study. In this study, we investigated the association of preeclampsia, or gestational diabetes mellitus (GDM), or large for gestational age (LGA), or intrauterine growth restriction (IUGR) and the risk of endometrial or ovarian cancer.MethodsIn this case-control study, 189 women with endometrial cancer and 119 women with ovarian cancer were included. 342 women without gynecological cancers were randomly selected as a control group. Data on the history of pregnancy and age at diagnosis of gynecological cancer as well as the use of intrauterine devices (IUDs) were collected.ResultsWomen with a history of preeclampsia or IUGR did not have an increased risk of developing endometrial or ovarian cancer. While women with a history of GDM or with the delivery of LGA infant increased the risk of developing endometrial cancer but not ovarian cancer. The odds of women with a history of GDM or with the delivery of LGA infant developing endometrial cancer was 2.691 (95% CI: 1.548, 4.3635, p=0.0003), or 6.383 (95% CI: 2.812, 13.68, p<0.0001) respectively, compared to the controls. The odds ratio of women who did not use IUDs developing ovarian cancer was 1.606 (95% CI: 1.057, 2.434), compared to the controls. There was no association of age at first birth and developing endometrial or ovarian cancer.ConclusionOur observational data suggested that GDM and delivery of an LGA infant are associated with an increased risk of endometrial cancer.

Synergistic impact of dysglycemia and HPV on cervical cancer risk: a potential mediating role of Ki-67

BackgroundCervical cancer, linked to HPV and dysglycemia, lacks clarity on their combined impact. This study explores Ki-67’s role in mediating HPV and dysglycemia effects on cervical cancer risk.MethodsThis study enrolled patients with abnormal cervical cancer screening results, undergoing colposcopy and conization at Fujian Maternity and Child Health Hospital’s Cervical Disease Center from June 2018 to June 2023. Statistical analyses compared baseline characteristics across cervical lesion categories. Multinomial logistic regression examined HPV and dysglycemia associations with LSIL (low-grade squamous intraepithelial lesions), HSIL(high-grade squamous intraepithelial lesions), and cervical cancer, highlighting interaction and mediation analyses involving Ki-67.ResultsA total of 4,115 participants were included: 573 with hyperglycemia, 1,479 with HPV only, and 548 with both HPV and hyperglycemia. Prediabetes and diabetes significantly increased cancer risk (OR: 2.47, 95% CI: 1.75-3.47 and OR: 3.67, 95% CI: 2.41-5.6, respectively). Coexisting hyperglycemia further elevated cervical cancer risk by over three-fold (OR: 3.12, 95% CI: 2.34-4.16) compared to HPV-positive normoglycemics. A significant interaction between hyperglycemia and HPV infection was observed (AP (attributable proportion): 0.69, 95% CI: 0.61-0.77, p<0.001; SI (synergy index): 3.27, 95% CI: 2.5-4.27, p<0.001). Ki-67+ expression accounted for 39.84%, 37.35%, and 55.18% of the total effect of hyperglycemia, HPV, and their combined impact, respectively. Additionally, the combination of dysglycemia and HPV had a significant indirect effect on Ki-67 levels (estimate: 0.08, 95% CI: 0.06- 0.09, p<0.001).ConclusionsDysglycemia and HPV infection synergistically elevate cervical cancer risk, possibly influenced by Ki-67. Effective screening and management for both are vital in prevention. Further research is required to validate findings and elucidate molecular mechanisms.

Integrated analysis of genome-wide gene expression and DNA methylation profiles reveals candidate genes in ovary endometriosis

BackgroundThe incidence of endometriosis (EMs), a common disease in gynecology, has increased over the years. Women suffer from the symptoms caused by EMs, such as chronic pelvic pain, dysmenorrhea, and infertility. However, the etiology and pathophysiology of EMs remain unclear. This study aimed to identify candidate genes of endometriosis through integrated analysis of genome-wide gene expression and DNA methylation profiles.ResultsEutopic and ectopic endometrial tissues were collected from patients who were diagnosed as ovarian EMs. Genome-wide methylation profiling identified 17551 differentially methylated loci, with 9777 hypermethylated and 7774 hypomethylated loci. Differentially methylated loci were mainly concentrated in the gene body and intergenic regions. Genome-wide gene expression profiling identified 1837 differentially expressed genes (DEGs), with 1079 genes upregulated and 758 downregulated in ectopic groups. Integrated analysis revealed that DNA methylation was negatively correlated to gene expression in most genomic regions, such as exon, 3’UTR, 5’UTR, and promoter. We also identified promoter-related (53 downregulated and 113 upregulated) and enhancer-related DMGs (212 downregulated and 232 upregulated), which were significantly correlated to the gene expression. Further validation of the top-ranked genes belonging to differentially methylated genes (DMGs) and DEGs revealed that TMEM184A, GREM2, SFN, KIR3DX1, HPGD, ESR1, BST2, PIK3CG and RNASE1 were significant candidate genes in ovarian endometriosis.ConclusionOur study revealed the significance of DNA methylation in the gene expression in ovary endometriosis, which provides new insights and a molecular foundation for understanding the underlying mechanisms of endometriosis.

An unyielding challenge for refractory hyponatremia in neuroendocrine cervix carcinoma: a case report

Neuroendocrine neoplasms (NENs) originate from peptidergic neurons and neuroendocrine cells, possessing endocrine functions, and are commonly found in the gastrointestinal tract, pancreas, and lungs. Neuroendocrine cervix carcinoma (NECC) is infrequent, prone to early dissemination and distant metastasis, and generally has a poor prognosis. The presence of electrolyte imbalance in such cases is even rarer. Here, we present a case of advanced NECC patient who developed refractory hyponatremia, accompanied by severe clinical symptoms such as palpitations, chest tightness, hematemesis, and delirium. Despite extensive investigations, all efforts to elucidate the underlying causes of hyponatremia were negative, suggesting a multifactorial etiology. Next-generation sequencing was also employed to explore the underlying mechanisms at the genetic level. Managing this case posed significant challenges for gynecologic oncologists, as the patient showed minimal response to various treatments, including sodium supplementation, fluid restriction or replenishment, chemotherapy modification, and the use of vasopressin-2 receptor antagonist. This case underscores the importance of monitoring and managing electrolytes in patients with gynecologic NENs, even though the exact mechanisms of such imbalances may remain elusive.

Identification of oxidative stress-related biomarkers in uterine leiomyoma: a transcriptome-combined Mendelian randomization analysis

BackgroundOxidative stress has been implicated in the pathogenesis of uterine leiomyoma (ULM) with an increasing incidence. This study aimed to identify potential oxidative stress-related biomarkers in ULM using transcriptome data integrated with Mendelian randomization (MR) analysis.MethodsData from GSE64763 and GSE31699 in the Gene Expression Omnibus (GEO) were included in the analysis. Oxidative stress-related genes (OSRGs) were identified, and the intersection of differentially expressed genes (DEGs), Weighted Gene Co-expression Network Analysis (WGCNA) genes, and OSRGs was used to derive differentially expressed oxidative stress-related genes (DE-OSRGs). Biomarkers were subsequently identified via MR analysis, followed by Gene Set Enrichment Analysis (GSEA) and immune infiltration analysis. Nomograms, regulatory networks, and gene-drug interaction networks were constructed based on the identified biomarkers.ResultsA total of 883 DEGs were identified between ULM and control samples, from which 42 DE-OSRGs were screened. MR analysis revealed four biomarkers: ANXA1, CD36, MICB, and PRDX6. Predictive nomograms were generated based on these biomarkers. ANXA1, CD36, and MICB were significantly enriched in chemokine signaling and other pathways. Notably, ANXA1 showed strong associations with follicular helper T cells, resting mast cells, and M0 macrophages. CD36 was positively correlated with resting mast cells, while MICB was negatively correlated with macrophages. Additionally, ANXA1 displayed strong binding energy with amcinonide, and MICB with ribavirin.ConclusionThis study identified oxidative stress-related biomarkers (ANXA1, CD36, MICB, and PRDX6) in ULM through transcriptomic and MR analysis, providing valuable insights for ULM therapeutic research.

Anti-Müllerian hormone: biology and role in endocrinology and cancers

Anti-Müllerian hormone (AMH) is a peptide belonging to the transforming growth factor beta superfamily and acts exclusively through its receptor type 2 (AMHR2). From the 8th week of pregnancy, AMH is produced by Sertoli cells, and from the 23rd week of gestation, it is produced by granulosa cells of the ovary. AMH plays a critical role in regulating gonadotropin secretion, ovarian tissue responsiveness to pituitary hormones, and the pathogenesis of polycystic ovarian syndrome. It inhibits the transition from primordial to primary follicles and is considered the best marker of ovarian reserve. Therefore, measuring AMH concentration of the hormone is valuable in managing assisted reproductive technologies. AMH was initially discovered through its role in the degeneration of Müllerian ducts in male fetuses. However, due to its ability to inhibit the cell cycle and induce apoptosis, it has also garnered interest in oncology. For example, antibodies targeting AMHR2 are being investigated for their potential in diagnosing and treating various cancers. Additionally, AMH is present in motor neurons and functions as a protective and growth factor. Consequently, it is involved in learning and memory processes and may support the treatment of Alzheimer’s disease. This review aims to provide a comprehensive overview of the biology of AMH and its role in both endocrinology and oncology.

Uterine leiomyoma causes an increase in systolic blood pressure: a two-sample Mendelian randomization study

ObjectivesHypertension and hypertensive disorders of pregnancy (HDP) are common diseases in women at different stages, which affect women’s physical and mental health, and the impact of the latter on the offspring cannot not be ignored. Observational studies have investigated the correlation between uterine leiomyoma (UL) and the above conditions, but the relationship remains unclear. In this study, we employed two-sample Mendelian randomization (MR) analysis to assess the association between UL and hypertension, HDP, as well as blood pressure.MethodsWe collected genetic association data of UL (35,474 cases), hypertension (129,909 cases), HDP (gestational hypertension with 8,502 cases, pre-eclampsia with 6,663 cases and eclampsia with 452cases), systolic blood pressure (SBP) and diastolic blood pressure (DBP) (both 757,601 participants) from published available genome-wide association studies (GWAS). The single nucleotide polymorphisms (SNPs) associated with UL phenotype were used as instrumental variables, and hypertension, three sub-types of HDP, SBP and DBP were used as outcomes. The inverse-variance weighted (IVW) method was employed as the primary method of causal inference. Heterogeneity was assessed using Cochran’s Q test, and sensitivity analyses were conducted using MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) tests to evaluate the pleiotropy of instrumental variables. PhenoScanner search was used to remove confounding SNP. Robustness and reliability of the results were assessed using methods such as the weighted median and weighted mode.ResultsThe IVW analysis revealed a positive correlation between genetically predicted UL and SBP [odds ratio (OR)= 1.67, 95% confidence interval (CI):1.24~2.25, P = 0.0007], and no statistical association was found between UL and hypertension, HDP, or DBP. The MR-Egger regression suggested that the above causal relationships were not affected by horizontal pleiotropy. The weighted median method and weighted model produced similar results to the IVW.ConclusionBased on large-scale population GWAS data, our MR analysis suggested a causal relationship between UL and SBP. Therefore, women with UL, especially pregnant women, should pay attention to monitoring their blood pressure levels. For patients with hypertension who already have UL, interventions for UL may serve as potential therapeutic methods for managing blood pressure.

The Genetic Association of Polycystic Ovary Syndrome and the Risk of Endometrial Cancer: A Mendelian Randomization Study

The association between polycystic ovary syndrome (PCOS) and endometrial cancer remains unclear. We aimed to investigate the causal association between genetically predicted PCOS and endometrial cancer risk in two ethnic groups through a two-sample Mendelian randomization (MR) approach. Our study includes 13 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for PCOS in Europeans, and another 13 SNPs are used as IVs for PCOS in Asians. Outcome data were obtained from the largest published meta-GWAS of European ancestry to date, as well as from the BioBank Japan Project of Asian ancestry. Our study demonstrates that genetically predicted PCOS is not causally associated with the risk of overall endometrial cancer in either Europeans or Asians (odds ratio (OR) = 0.93, 95% confidence interval (CI) = 0.85–1.01, p = 0.09 and OR = 0.98, 95% CI 0.84–1.13, p = 0.75, respectively). Subgroup analyses according to histotype further illustrate that PCOS might not be associated with the risk of either endometrioid endometrial cancer or non-endometrioid endometrial cancer in European ancestry. No pleiotropy is found in our study, and a sensitivity analysis shows similar results. Our results indicate that genetically predicted PCOS might not be associated with the risk of endometrial cancer.

Review of mendelian randomization studies on age at natural menopause

Menopause marks the end of the reproductive phase of life. Based on epidemiological studies, abnormal age at natural menopause (ANM) is thought to contribute to a number of adverse outcomes, such as osteoporosis, cardiovascular disease, and cancer. However, the causality of these associations remains unclear. A powerful epidemiological method known as Mendelian randomization (MR) can be used to clarify the causality between ANM and other diseases or traits. The present review describes MR studies that included ANM as an exposure, outcome and mediator. The findings of MR analyses on ANM have revealed that higher body mass index, poor educational level, early age at menarche, early age at first live birth, early age at first sexual intercourse, and autoimmune thyroid disease appear to be involved in early ANM etiology. The etiology of late ANM appears to be influenced by higher free thyroxine 4 and methylene tetrahydrofolate reductase gene mutations. Furthermore, early ANM has been found to be causally associated with an increased risk of osteoporosis, fracture, type 2 diabetes mellitus, glycosylated hemoglobin, and the homeostasis model of insulin resistance level. In addition, late ANM has been found to be causally associated with an increased systolic blood pressure, higher risk of breast cancer, endometrial cancer, endometrioid ovarian carcinoma, lung cancer, longevity, airflow obstruction, and lower risk of Parkinson’s disease. ANM is also a mediator for breast cancer caused by birth weight and childhood body size. However, due to the different instrumental variables used, some results of studies are inconsistent. Future studies with more valid genetic variants are needed for traits with discrepancies between MRs or between MR and other types of epidemiological studies.

Metabolic syndrome and risk of ovarian cancer: a systematic review and meta-analysis

BackgroundMetS is associated with greater morbidity and mortality in relation to a number of malignancies, but its association with ovarian cancer remains contested. The present study was a systematic review and meta-analysis of case-control and cohort studies examining the association between MetS and ovarian cancer risk.MethodsThe study was registered on the PROSPERO platform in January 2023 (CRD42023391830). Up until February 13, 2023, a complete search was undertaken in PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials. On the basis of inclusion and exclusion criteria, eligible studies for meta-analysis were screened to determine the association between MetS and ovarian cancer risk.ResultsFive studies were included in total, including three cohort studies and two case-control studies. Meta-analysis showed no significant correlation between metabolic syndrome and ovarian cancer (OR=1.29, 95% CI: 0.90-1.84). Significant heterogeneity (I2 = 92.6, P<0.05) existed between the included studies. We performed a subgroup analysis of the risk of bias and showed that only unadjusted stratification of risk of bias for smoking (OR= 3.19, 95% CI: 2.14-4.76) and hysterectomy (OR= 3.19, 95% CI: 2.14-4.76) demonstrated a relationship between metabolic syndrome and ovarian cancer risk. The meta-regression analysis revealed that smoking and hysterectomy excision were substantially linked with heterogeneity (p < 0.05).ConclusionOur research revealed no statistically significant association between MetS and ovarian cancer risk. The prevalence of metabolic syndrome has highlighted the need of enhancing and controlling women’s metabolic health. However, the evaluation of metabolic syndrome as a cancer risk factor may be deceptive and etiologically uninformative.

A signature based on anoikis-related genes for the evaluation of prognosis, immunoinfiltration, mutation, and therapeutic response in ovarian cancer

BackgroundOvarian cancer (OC) is a highly lethal and aggressive gynecologic cancer, with an overall survival rate that has shown little improvement over the decades. Robust models are urgently needed to distinguish high-risk cases and predict reliable treatment options for OC. Although anoikis-related genes (ARGs) have been reported to contribute to tumor growth and metastasis, their prognostic value in OC remains unknown. The purpose of this study was to construct an ARG pair (ARGP)-based prognostic signature for patients with OC and elucidate the potential mechanism underlying the involvement of ARGs in OC progression.MethodsThe RNA-sequencing and clinical information data of OC patients were obtained from The Center Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A novel algorithm based on pairwise comparison was utilized to select ARGPs, followed by the Least Absolute Shrinkage and Selection Operator Cox analysis to construct a prognostic signature. The predictive ability of the model was validated using an external dataset, a receiver operating characteristic curve, and stratification analysis. The immune microenvironment and the proportion of immune cells were analyzed in high- and low-risk OC cases using seven algorithms. Gene set enrichment analysis and weighted gene co-expression network analysis were performed to investigate the potential mechanisms of ARGs in OC occurrence and prognosis.ResultsThe 19-ARGP signature was identified as an important prognostic predictor for 1-, 2-, and 3-year overall survival of patients with OC. Gene function enrichment analysis showed that the high-risk group was characterized by the infiltration of immunosuppressive cells and the enrichment of adherence-related signaling pathway, suggesting that ARGs were involved in OC progression by mediating immune escape and tumor metastasis.ConclusionWe constructed a reliable ARGP prognostic signature of OC, and our findings suggested that ARGs exerted a vital interplay in OC immune microenvironment and therapeutic response. These insights provided valuable information regarding the molecular mechanisms underlying this disease and potential targeted therapies.

Machine learning-assisted analysis of epithelial mesenchymal transition pathway for prognostic stratification and immune infiltration assessment in ovarian cancer

BackgroundOvarian cancer is the most lethal gynaecological malignancy, and serous ovarian cancer (SOC) is one of the more important pathological subtypes. Previous studies have reported a significant association of epithelial tomesenchymal transition (EMT) with invasive metastasis and immune modulation of SOC, however, there is a lack of prognostic and immune infiltration biomarkers reported for SOC based on EMT.MethodsGene expression data for ovarian cancer and corresponding patient clinical data were collected from the TCGA database and the GEO database, and cell type annotation and spatial expression analysis were performed on single cell sequencing data from the GEO database. To understand the cell type distribution of EMT-related genes in SOC single-cell data and the enrichment relationships of biological pathways and tumour functions. In addition, GO functional annotation analysis and KEGG pathway enrichment analysis were performed on mRNAs predominantly expressed with EMT to predict the biological function of EMT in ovarian cancer. The major differential genes of EMT were screened to construct a prognostic risk prediction model for SOC patients. Data from 173 SOC patient samples obtained from the GSE53963 database were used to validate the prognostic risk prediction model for ovarian cancer. Here we also analysed the direct association between SOC immune infiltration and immune cell modulation and EMT risk score. and calculate drug sensitivity scores in the GDSC database.In addition, we assessed the specific relationship between GAS1 gene and SOC cell lines.ResultsSingle cell transcriptome analysis in the GEO database annotated the major cell types of SOC samples, including: T cell, Myeloid, Epithelial cell, Fibroblast, Endothelial cell, and Bcell. cellchat revealed several cell type interactions that were shown to be associated with EMT-mediated SOC invasion and metastasis. A prognostic stratification model for SOC was constructed based on EMT-related differential genes, and the Kapan-Meier test showed that this biomarker had significant prognostic stratification value for several independent SOC databases. The EMT risk score has good stratification and identification properties for drug sensitivity in the GDSC database.ConclusionsThis study constructed a prognostic stratification biomarker based on EMT-related risk genes for immune infiltration mechanisms and drug sensitivity analysis studies in SOC. This lays the foundation for in-depth clinical studies on the role of EMT in immune regulation and related pathway alterations in SOC. It is also hoped to provide effective potential solutions for early diagnosis and clinical treatment of ovarian cancer.

Ovarian juvenile granulosa cell tumors with Ollier’s disease in children with IDH1 gene somatic mutation

ObjectiveThe aim of this study was to explore the symptoms, treatment, and pathogenesis of ovarian juvenile granulosa cell tumors with Ollier’s disease in children.MethodsFrom October 2019 to October 2020, clinical data were retrospectively analyzed for one case of ovarian juvenile granulosa cell tumors with Ollier’s disease. Whole-exome sequencing and Sanger sequencing were used to detect gene mutation in ovarian tumor and chondroma tissue. NADP-dependent isocitrate dehydrogenase-1 (IDH1) and S6 ribosomal protein expression levels in cells transfected with wild-type or mutant plasmid were analyzed by Western blot.ResultsThe 4-year-old female showed multiple skeletal deformities, bilateral breast development with chromatosis, and vulvar discharge. Sex hormone assay suggested that estradiol and prolactin were elevated, and the x-ray of limbs suggested enchondroma. Pelvic ultrasound and abdominal CT revealed a right ovarian solid mass. Pathologic examination of the right ovarian solid mass showed a juvenile granulosa cell type. A c.394C>T (p. Arg132Cys) mutation of the IDH1 gene was detected in both the ovarian juvenile granulosa cell tumors and enchondroma. Transfection of HeLa cells with either WT or Mut plasmid caused 4.46- or 3.77-fold overexpression of IDH1 gene compared to non-transfected control cells, respectively. R132C mutation inhibited the phosphorylation of S6 ribosomal protein, which is central to the mTOR pathway. Postoperatively, estradiol and prolactin levels fell to values normal for her age and bilateral breast gradual retraction.ConclusionThe incidence of ovarian juvenile granulosa cell tumors with Ollier’s disease in children may be caused by generalized mesodermal dysplasia; IDH1 gene mutation may play a facilitated role in this process. Surgical operation is the main treatment. We suggest that patients with ovarian juvenile granulosa cell tumors and Ollier’s disease should undergo regular investigation.

Exploring a novel seven-gene marker and mitochondrial gene TMEM38A for predicting cervical cancer radiotherapy sensitivity using machine learning algorithms

BackgroundRadiotherapy plays a crucial role in the management of Cervical cancer (CC), as the development of resistance by cancer cells to radiotherapeutic interventions is a significant factor contributing to treatment failure in patients. However, the specific mechanisms that contribute to this resistance remain unclear. Currently, molecular targeted therapy, including mitochondrial genes, has emerged as a new approach in treating different types of cancers, gaining significant attention as an area of research in addressing the challenge of radiotherapy resistance in cancer.MethodsThe present study employed a rigorous screening methodology within the TCGA database to identify a cohort of patients diagnosed with CC who had received radiotherapy treatment. The control group consisted of individuals who demonstrated disease stability or progression after undergoing radiotherapy. In contrast, the treatment group consisted of patients who experienced complete or partial remission following radiotherapy. Following this, we identified and examined the differentially expressed genes (DEGs) in the two cohorts. Subsequently, we conducted additional analyses to refine the set of excluded DEGs by employing the least absolute shrinkage and selection operator regression and random forest techniques. Additionally, a comprehensive analysis was conducted in order to evaluate the potential correlation between the expression of core genes and the extent of immune cell infiltration in patients diagnosed with CC. The mitochondrial-associated genes were obtained from the MITOCARTA 3.0. Finally, the verification of increased expression of the mitochondrial gene TMEM38A in individuals with CC exhibiting sensitivity to radiotherapy was conducted using reverse transcription quantitative polymerase chain reaction and immunohistochemistry assays.ResultsThis process ultimately led to the identification of 7 crucial genes, viz., GJA3, TMEM38A, ID4, CDHR1, SLC10A4, KCNG1, and HMGCS2, which were strongly associated with radiotherapy sensitivity. The enrichment analysis has unveiled a significant association between these 7 crucial genes and prominent signaling pathways, such as the p53 signaling pathway, KRAS signaling pathway, and PI3K/AKT/MTOR pathway. By utilizing these 7 core genes, an unsupervised clustering analysis was conducted on patients with CC, resulting in the categorization of patients into three distinct molecular subtypes. In addition, a predictive model for the sensitivity of CC radiotherapy was developed using a neural network approach, utilizing the expression levels of these 7 core genes. Moreover, the CellMiner database was utilized to predict drugs that are closely linked to these 7 core genes, which could potentially act as crucial agents in overcoming radiotherapy resistance in CC.ConclusionTo summarize, the genes GJA3, TMEM38A, ID4, CDHR1, SLC10A4, KCNG1, and HMGCS2 were found to be closely correlated with the sensitivity of CC to radiotherapy. Notably, TMEM38A, a mitochondrial gene, exhibited the highest degree of correlation, indicating its potential as a crucial biomarker for the modulation of radiotherapy sensitivity in CC.

Ovarian cancer-associated immune exhaustion involves SPP1+ T cell and NKT cell, symbolizing more malignant progression

BackgroundOvarian cancer (OC) is highly heterogeneous and has a poor prognosis. A better understanding of OC biology could provide more effective therapeutic paradigms for different OC subtypes.MethodsTo reveal the heterogeneity of T cell-associated subclusters in OC, we performed an in-depth analysis of single-cell transcriptional profiles and clinical information of patients with OC. Then, the above analysis results were verified by qPCR and flow cytometry examine.ResultsAfter screening by threshold, a total of 85,699 cells in 16 ovarian cancer tissue samples were clustered into 25 major cell groups. By performing further clustering of T cell-associated clusters, we annotated a total of 14 T cell subclusters. Then, four distinct single-cell landscapes of exhausted T (Tex) cells were screened, and SPP1 + Tex significantly correlated with NKT cell strength. A large amount of RNA sequencing expression data combining the CIBERSORTx tool were labeled with cell types from our single-cell data. Calculating the relative abundance of cell types revealed that a greater proportion of SPP1 + Tex cells was associated with poor prognosis in a cohort of 371 patients with OC. In addition, we showed that the poor prognosis of patients in the high SPP1 + Tex expression group might be related to the suppression of immune checkpoints. Finally, we verified in vitro that SPP1 expression was significantly higher in ovarian cancer cells than in normal ovarian cells. By flow cytometry, knockdown of SPP1 in ovarian cancer cells could promote tumorigenic apoptosis.ConclusionThis is the first study to provide a more comprehensive understanding of the heterogeneity and clinical significance of Tex cells in OC, which will contribute to the development of more precise and effective therapies.

Bioinformatic analysis confirms differences in circular RNA expression profiles of cumulus cells between patients with ovarian and peritoneal endometriosis-associated infertility

Endometriosis has a detrimental effect on oocyte quality, and ovarian endometriosis (OEM) and peritoneal endometriosis (PEM) may have different effects on female fertility. Therefore, we conducted a study to explore the circular RNA (circRNA) expression profiles of cumulus cells (CCs) in patients with OEM (n = 3), PEM (n = 3), and tubal factor infertility (TFI, n = 3) using high-throughput sequencing techniques and attempted to identify common and unique circRNAs in the OEM and PEM groups. The CIRCexplorer2 program was used to identify circRNAs. Seven candidate circRNAs were validated in 30 samples using quantitative real-time polymerase chain reaction (qRT-PCR). Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to annotate the function of circRNA-targeted genes, which were verified by sequencing results and constructed circRNA–miRNA–mRNA networks. A total of 11833 circRNAs were identified in nine samples. The numbers of differentially expressed circRNAs between the OEM and TFI groups, PEM and TFI groups, and OEM and PEM groups were 130, 71, and 191, respectively. After taking intersections, 11 circRNAs were considered common circRNAs in the OEM and PEM groups; 39 circRNAs in the OEM group and 17 circRNAs in the PEM group were identified as unique key circRNAs. During qRT-PCR validation, hsa_circ_0003638 was significantly upregulated in the PEM group compared to that in the OEM and TFI groups. Functional analysis of circRNA-targeted genes revealed that apoptosis, PI3K-AKT, and p53 signaling pathways were enriched in the PEM–TFI comparison groups, whereas the functions of target genes involved in the JAK–STAT and TGF-β signaling pathways were enriched in the PEM–OEM comparison groups. Our findings confirmed differences in circRNA expression profiles of CCs between patients with OEM and PEM infertility and provide new insights into the different effects of various endometriosis phenotypes on oocytes.

Identification of copper metabolism-related subtypes and establishment of the prognostic model in ovarian cancer

BackgroundOvarian cancer (OC) is one of the most common and most malignant gynecological malignancies in gynecology. On the other hand, dysregulation of copper metabolism (CM) is closely associated with tumourigenesis and progression. Here, we investigated the impact of genes associated with copper metabolism (CMRGs) on the prognosis of OC, discovered various CM clusters, and built a risk model to evaluate patient prognosis, immunological features, and therapy response.Methods15 CMRGs affecting the prognosis of OC patients were identified in The Cancer Genome Atlas (TCGA). Consensus Clustering was used to identify two CM clusters. lasso-cox methods were used to establish the copper metabolism-related gene prognostic signature (CMRGPS) based on differentially expressed genes in the two clusters. The GSE63885 cohort was used as an external validation cohort. Expression of CM risk score-associated genes was verified by single-cell sequencing and quantitative real-time PCR (qRT-PCR). Nomograms were used to visually depict the clinical value of CMRGPS. Differences in clinical traits, immune cell infiltration, and tumor mutational load (TMB) between risk groups were also extensively examined. Tumour Immune Dysfunction and Rejection (TIDE) and Immune Phenotype Score (IPS) were used to validate whether CMRGPS could predict response to immunotherapy in OC patients.ResultsIn the TCGA and GSE63885 cohorts, we identified two CM clusters that differed significantly in terms of overall survival (OS) and tumor microenvironment. We then created a CMRGPS containing 11 genes to predict overall survival and confirmed its reliable predictive power for OC patients. The expression of CM risk score-related genes was validated by qRT-PCR. Patients with OC were divided into low-risk (LR) and high-risk (HR) groups based on the median CM risk score, with better survival in the LR group. The 5-year AUC value reached 0.74. Enrichment analysis showed that the LR group was associated with tumor immune-related pathways. The results of TIDE and IPS showed a better response to immunotherapy in the LR group.ConclusionOur study, therefore, provides a valuable tool to further guide clinical management and tailor the treatment of patients with OC, offering new insights into individualized treatment.

Bidirectional Mendelian randomization study of insulin-related traits and risk of ovarian cancer

BackgroundIt is well known that the occurrence and development of ovarian cancer are closely related to the patient’s weight and various endocrine factors in the body.AimMendelian randomization (MR) was used to analyze the bidirectional relationship between insulin related characteristics and ovarian cancer.MethodsThe data on insulin related characteristics are from up to 5567 diabetes free patients from 10 studies, mainly including fasting insulin level, insulin secretion rate, peak insulin response, etc. For ovarian cancer, UK Biobank data just updated in 2021 was selected, of which the relevant gene data was from 199741 Europeans. Mendelian randomization method was selected, with inverse variance weighting (IVW) as the main estimation, while MR Pleiotropy, MR Egger, weighted median and other methods were used to detect the heterogeneity of data and whether there was multi validity affecting conclusions.ResultsAmong all insulin related indicators (fasting insulin level, insulin secretion rate, peak insulin response), the insulin secretion rate was selected to have a causal relationship with the occurrence of ovarian cancer (IVW, P < 0.05), that is, the risk of ovarian cancer increased with the decrease of insulin secretion rate. At the same time, we tested the heterogeneity and polymorphism of this indicator, and the results were non-existent, which ensured the accuracy of the analysis results. Reverse causal analysis showed that there was no causal effect between the two (P>0.05).ConclusionThe impairment of the insulin secretion rate has a causal effect on the risk of ovarian cancer, which was confirmed by Mendel randomization. This suggests that the human glucose metabolism cycle represented by insulin secretion plays an important role in the pathogenesis of ovarian cancer, which provides a new idea for preventing the release of ovarian cancer.

Editorial: March 2022: Ovarian and prostate cancer awareness month

Prognosis comparison between small cell carcinoma of ovary and high-grade serous ovarian cancer: A retrospective observational cohort study

BackgroundSmall cell carcinoma of ovary (SCCO) is a rare and aggressive cancer primarily reported in the form of case reports. Due to limited epidemiological and prognostic analyses based on large populations, SCCO has varied considerably without prognostic models and a recognized first-line treatment strategy. The study aimed to compare the clinical characteristics, treatment methods, and prognosis of SCCO and high-grade serous ovarian cancer (HGSOC), the most prevalent subtype of ovarian cancer, in a large sample and develop a predictive model for these two subtypes.MethodsData from the Surveillance, Epidemiology, and End Results program were analyzed for patients with SCCO or HGSOC from 2000 to 2017. Clinical, demographic, and treatment characteristics were compared between the two groups. Propensity-score matching, Cox risk regression analysis, and Kaplan-Meier survival curves were used to assess the data. Finally, a nomogram was developed to predict the patient survival time.ResultsA total of 32,185 women, including 31,979 (99.4%) diagnosed with HGSOC and 206 (0.6%) diagnosed with SCCO, were identified. Age ≤ 51 years, single, median house income less than $70,000, early stage, and unilateral disease were more common characteristics of patients with SCCO than those with HGSOC. Patients with SCCO were more likely to receive radiotherapy (6.8% vs. 0.8%, p <0.001) and have tumors ≥ 141 mm (38.3% vs. 9.7%, p <0.001) than patients with HGSOC. The independent risk factors for SCCO patients included older age at diagnosis, advanced stage, surgery, radiotherapy, chemotherapy, larger tumor size, and bilateral tumor. Overall and cancer-specific survival rates were significantly lower for SCCO than more malignant HGSOC. Prognostic models and nomograms had been constructed to predict the individual survival rates of patients with SCCO and HGSOC.ConclusionPatients with SCCO presented with the early-stage disease more frequently than patients with HGSOC and had decreased overall and cancer-specific survival rates.

Elafin is related to immune infiltration and could predict the poor prognosis in ovarian cancer

BackgroundOvarian cancer (OC) is the most lethal gynecologic malignancy, yet the clinical results for OC patients are still variable. Therefore, we examined how elafin expression affects the patients’ prognoses and immunotherapy responses in OC, which may facilitate treatment selection and improve prognosis.MethodsThe elafin mRNA expression profile was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Elafin’s prognostic potential and its relationship with clinical variables were investigated using Kaplan–Meier survival curves, time-dependent receiver operating characteristic curves as well as univariate and multivariate Cox regression models. As validation, protein expression in the tumor and adjacent tissues of OC patients was investigated by using immunohistochemistry (IHC). Comprehensive analyses were then conducted to explore the correlation between immune infiltration and elafin expression.ResultsA higher mRNA expression of elafin was associated with an unfavorable prognosis in TCGA cohort and was validated in GSE31245 and IHC. Moreover, elafin was indicated as an independent risk factor for OC. A significantly higher protein expression of elafin was detected in the adjacent tissues of OC patients with shorter overall survival (OS). The immune-related pathways were mainly enriched in the high-elafin-mRNA-expression group. However, the mRNA expression of elafin was favorably correlated with indicators of the immune filtration and immunotherapy response, which also proved better immunotherapy outcomes.ConclusionThe high elafin expression was associated with an unfavorable OS, while it also indicated better immunotherapy responses. Thus, the detection of elafin is beneficial to diagnosis and treatment selection.

Hypertension and hyperglycaemia are positively correlated with local invasion of early cervical cancer

BackgroundMetabolic disorders are involved in the development of numerous cancers, but their association with the progression of cervical cancer is unclear. This study aims to investigate the association between metabolic disorders and the pathological risk factors and survival in patients with early cervical cancer.MethodsPatients with FIGO IB1 (2009) primary cervical cancer who underwent radical hysterectomy and systematic pelvic lymph node dissection at our institution from October 2014 to December 2017 were included retrospectively. Clinical data regarding the metabolic syndrome and surgical pathology of the patient were collected. The correlations between metabolic disorders (hypertension, hyperglycemia, and obesity) and clinicopathological characteristics as well as survival after surgery were analyzed.ResultsThe study included 246 patients with clinical IB1 cervical cancer, 111 (45.1%) of whom had at least one of the comorbidities of hypertension, obesity, or hyperglycemia. Hypertension was positively correlated with parametrial invasion and poorly differentiated histology; hyperglycemia was positively correlated with stromal invasion; obesity was negatively associated with lymph node metastasis; but arbitrary disorder did not show any correlation with pathologic features. Hypertension was an independent risk factor for parametrial invasion (OR=6.54, 95% CI: 1.60-26.69); hyperglycemia was an independent risk factor for stromal invasion (OR=2.05, 95% CI: 1.07-3.95); and obesity was an independent protective factor for lymph node metastasis (OR=0.07, 95% CI: 0.01-0.60). Moreover, the patients with hypertension had a significantly lower 5-year OS rate (70.0% vs. 95.3%, P<0.0001) and a significantly lower 5-year PFS rate than those without hypertension (70.0% vs. 91.2%, P=0.010).ConclusionHypertension and hyperglycemia are positively associated with local invasion of early cervical cancer, which need to be verified in multi-center, large scale studies.

Sea buckthorn, its bioactive constituents, and mechanism of action: potential application in female reproduction

Sea buckthorn (Hippophae rhamnoides L.) is a flowering shrub, and its berries have been utilized for decades as a raw ingredient in cuisines and herbal remedies. This evidence-based study focuses on its key bioactive constituents, and mechanism of protective effects with a focus on female reproductive processes. Parts of the plant contain phenols, carotenoids (lycopene, carotene, lutein, and zeaxanthin), flavonoids (isorhamnetin, quercetin, glycosides, and kaempferol), tocopherols, sterols, polyunsaturated fatty acids, minerals, vitamins, omega 3, 6, 9 and rare omega 7 fatty acids etc. Key polyphenolic flavonoids such as isorhamnetin and quercetin are believed to be mainly responsible behind its health benefits (against cardiovascular diseases, metabolic syndrome, obesity etc.) through properties including anti-cancer, antioxidant, and anti-inflammatory activities. These sea buckthorn constituents appear to mediate healthy ovarian cell proliferation, death, and hormone release, as well as decrease ovarian cancer possibly through apoptosis, and hormonal (estrogen) release. Thus, sea buckthorn and its bioactive ingredients may have potential in the management of gynecological problems such as uterine inflammation, endometriosis, and easing symptoms of vulvovaginal atrophy in postmenopausal women (by targeting inflammatory cytokines and vascular endothelial growth factor – VEGF). Apigenin, myricetin, and luteolin have also been recommended as prospective ovarian cancer preventative and adjuvant therapy options as they can inhibit ovarian cancerogenesis by triggering apoptosis and halting the cell cycle in ovarian tumors. Furthermore, its oil (containing carotenoid, sterol, and hypericin) has been speculated as an alternative to estrogen replacement therapy for postmenopausal women particularly to improve vaginal epithelial integrity. However, it is uncertain whether steroid hormone receptors, reactive oxygen species (ROS), and inflammatory regulators are actually behind sea buckhorn’s actions. Sea buckthorn, and its compounds’ health promoting potential warrants further validation not just in vitro and in animal research, but also in clinical trials to identify and/or standardize optimal methods of delivery of biologically active molecules.

Trace element zinc metabolism and its relation to tumors

Zinc is an essential trace element in the human body, playing a crucial role in cellular metabolism.Dysregulation of zinc homeostasis can lead to abnormal cellular metabolism, contributing to diseases and closely related to tumor development. Adequate zinc intake can maintain zinc homeostasis in the body and support normal cellular metabolism. This review discusses the metabolic processes of zinc in the human body and its close relationship with tumorigenesis. It briefly describes zinc absorption, transport, storage, and release, as well as its important role in gene expression, signal transduction, oxidative stress, immune response, and apoptosis. It focuses on the abnormal cellular metabolism caused by excessive or insufficient zinc, the relationship between zinc homeostasis disruption and metabolic syndrome, and the mechanisms involved in tumor development. It analyzes how changes in the expression and activity of zinc transporters may lead to disrupted zinc homeostasis in tumor tissues. It points out that zinc deficiency is associated with various cancers, including prostate cancer, hepatocellular carcinoma, pancreatic cancer, lung cancer, ovarian cancer, esophageal squamous cell carcinoma, and breast cancer. The summary emphasizes that zinc metalloproteins could serve as potential targets for cancer therapy, and regulating the expression and activity of zinc transport proteins may offer new methods and strategies for clinical cancer treatment.

Establishing patient-derived organoids from human endometrial cancer and normal endometrium

Endometrial cancer is the most common gynecologic malignancy in the United States and is one of the few malignancies that had an increasing incidence and mortality rate over the last 10 years. Current research models fail to recapitulate actual characteristics of the tumor that are necessary for the proper understanding and treatment of this heterogenous disease. Patient-derived organoids provide a durable and versatile culture system that can capture patient-specific characteristics such as the mutational profile and response to therapy of the primary tumor. Here we describe the methods for establishing, expansion and banking of endometrial cancer organoids to develop a living biobank. Samples of both endometrial tumor tissue and matched normal endometrium were collected from 10 patients. The tissue was digested into single cells and then cultured in optimized media to establish matched patient endometrial cancer and normal endometrial tissue organoids. Organoids were created from all major endometrial cancer histologic subtypes. These organoids are passaged long term, banked and can be utilized for downstream histological and genomic characterization as well as functional assays such as assessing the response to therapeutic drugs.

Medical Significance of Uterine Corpus Endometrial Carcinoma Patients Infected With SARS-CoV-2 and Pharmacological Characteristics of Plumbagin

BackgroundClinically, evidence shows that uterine corpus endometrial carcinoma (UCEC) patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have a higher death-rate. However, current anti-UCEC/coronavirus disease 2019 (COVID-19) treatment is lacking. Plumbagin (PLB), a pharmacologically active alkaloid, is an emerging anti-cancer inhibitor. Accordingly, the current report was designed to identify and characterize the anti-UCEC function and mechanism of PLB in the treatment of patients infected with SARS-CoV-2 via integrated in silico analysis.MethodsThe clinical analyses of UCEC and COVID-19 in patients were conducted using online-accessible tools. Meanwhile, in silico methods including network pharmacology and biological molecular docking aimed to screen and characterize the anti-UCEC/COVID-19 functions, bio targets, and mechanisms of the action of PLB.ResultsThe bioinformatics data uncovered the clinical characteristics of UCEC patients infected with SARS-CoV-2, including specific genes, health risk, survival rate, and prognostic index. Network pharmacology findings disclosed that PLB-exerted anti-UCEC/COVID-19 effects were achieved through anti-proliferation, inducing cytotoxicity and apoptosis, anti-inflammation, immunomodulation, and modulation of some of the key molecular pathways associated with anti-inflammatory and immunomodulating actions. Following molecular docking analysis, in silico investigation helped identify the anti-UCEC/COVID-19 pharmacological bio targets of PLB, including mitogen-activated protein kinase 3 (MAPK3), tumor necrosis factor (TNF), and urokinase-type plasminogen activator (PLAU).ConclusionsBased on the present bioinformatic and in silico findings, the clinical characterization of UCEC/COVID-19 patients was revealed. The candidate, core bio targets, and molecular pathways of PLB action in the potential treatment of UCEC/COVID-19 were identified accordingly.

The miR-33a-5p/CROT axis mediates ovarian cancer cell behaviors and chemoresistance via the regulation of the TGF-β signal pathway

Due to the lack of symptoms and detection biomarkers at the early stage, most patients with ovarian cancer (OC) are diagnosed at an advanced stage and often face chemoresistance and relapse. Hence, defining detection biomarkers and mechanisms of chemoresistance is imperative. A previous report of a cDNA microarray analysis shows a potential association of carnitine O-octanoyltransferase (CROT) with taxane resistance but the biological function of CROT in OC remains unknown. The current study explored the function and regulatory mechanism of CROT on cellular behavior and paclitaxel (PTX)-resistance in OC. We found that CROT was downregulated in OC tissues and PTX-resistant cells. Furthermore, CROT expression was negatively correlated with the prognosis of OC patients. Overexpression of CROT inhibited the OC cell proliferation, migration, invasion, and colony formation, arrested the cell cycle at the G2/M phase, and promoted cell apoptosis. In addition, miR-33a-5p bound directly to the 3’UTR of CROT to negatively regulate the expression of CROT and promoted OC cell growth. Finally, overexpression of CROT decreased the phosphorylation of Smad2, whereas knockdown of CROT increased the nuclear translocation of Smad2 and Smad4, two transducer proteins of TGF-β signaling, indicating that CROT is a tumor suppressor which mediates OC cell behaviors through the TGF-β signaling pathway. Thus, targeting the miR-33a-5p/CROT axis may have clinical potential for the treatment of patients with OC.

Ovarian gonadoblastoma with dysgerminoma in a girl with 46,XX karyotype 17a-hydroxylase/17, 20-lyase deficiency: A case report and literature review

17α−hydroxylase/17,20−lyase deficiency (17-OHD), caused by mutations in the gene of the cytochrome P450 family 17 subfamily A member 1 (CYP17A1), is a rare type of congenital adrenal hyperplasia (CAH), usually characterized by cortisol and sex steroid deficiency combined with excessive mineralocorticoid. Gonadoblastoma is a relatively rare ovarian tumor that is frequently seen among patients with 46,XY gonadal dysgenesis. Rarely have they been reported in female patients with normal 46,XX karyotype. Here, we report an interesting case of an 11-year-old Chinese girl who presented acute abdominal pain that was later attributed to tumor rupture of right ovarian gonadoblastoma with dysgerminoma. Further evaluations revealed hypertension and hypokalemia. Hormonal findings showed increased progesterone, hypergonadotropic hypogonadism, and low cortisol levels. Her chromosome karyotype was 46,XX without Y chromosome material detected. Genetic analysis revealed that the patient had a homozygous pathogenic variant c.985_987delTACinsAA (p.Y329Kfs*90) in exon 6 of the CYP17A1 gene and that her parents were all heterozygous carriers of this pathogenic variant. Due to the variable clinical manifestations of 17-OHD, meticulous assessment including genetic analysis is necessary. Further study is warranted to unravel the mechanism of gonadoblastoma in a patient with normal karyotypes.

β-arrestin 2 Is a Prognostic Factor for Survival of Ovarian Cancer Patients Upregulating Cell Proliferation

Establishing reliable prognostic factors as well as specific targets for new therapeutic approaches is an urgent requirement in advanced ovarian cancer. For several tumor entities, the ubiquitously spread scaffold protein β-arrestin 2, a multifunctional scaffold protein regulating signal transduction and internalization of activated G protein-coupled receptors (GPCRs), has been considered with rising interest for carcinogenesis. Therefore, we aimed to elucidate the prognostic impact of β-arrestin 2 and its functional role in ovarian cancer. β-arrestin 2 expression was analyzed in a subset of 156 samples of ovarian cancer patients by immunohistochemistry. Cytoplasmic expression levels were correlated with clinical as well as pathological characteristics and with prognosis. The biologic impact of β-arrestin 2 on cell proliferation and survival was evaluated,

Postmenopausal ovarian hyperandrogenism of surgically treated patients: a case report and scoping review with individual patient’s data analysis

IntroductionPostmenopausal hyperandrogenism (PH) is a rare clinical condition caused by relative or absolute androgen excess after menopause. Tumorous or non-tumorous ovarian diseases can cause PH.MethodsIn this two-section hybrid study, the first section describes the case of a patient with PH caused by an ovarian disease and surgically treated. The second section shows the results of a scoping review with individual patient data (IPD) analysis, which was performed to define the biochemical and clinical features of PH patients with tumorous or non-tumorous ovarian diseases surgically treated. All PH cases caused by anything but ovarian disease and/or without surgical indication and/or without histological diagnosis were excluded.ResultsDue to imaging suspicion, our PH patient underwent robotic hysterectomy with bilateral ovariectomy. A Leydig cell tumor stage 1A was diagnosed. At 6 months after surgery, the PH was resolved. Overall, the IPD analysis included 280 PH patients with ovarian diseases (oPH) surgically treated. Among them, histological examination showed 174 tumorous oPH and 106 non-tumorous oPH. Patients with tumorous oPH showed lower body mass index and lower levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as higher levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), 17-OH progesterone, and estradiol compared with non-tumorous oPH patients. We defined the levels of testosterone (≥9.8 nmol/L), LH (≤15 mUI/ml), FSH (≤35 mUI/ml), and DHEA-S (≥1.6 μmol/L) able to differentiate between tumorous and non-tumorous oPH patients with suitable sensitivity (≥68.6%) and specificity (≥72.7%). No PH recurrence was described after surgery.DiscussionThe study results provide useful biochemical parameters to support the diagnosis of ovarian tumor in patients with oPH.

Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer

Epithelial ovarian cancer is predominantly diagnosed at advanced stages which creates significant therapeutic challenges. As a result, the 5-year survival rate is low. Within ovarian cancer, significant tumor heterogeneity exists, and the tumor microenvironment is diverse. Tumor heterogeneity leads to diversity in therapy response within the tumor, which can lead to resistance or recurrence. Advancements in therapy development and tumor profiling have initiated a shift from a “one-size-fits-all” approach towards precision patient-based therapies. Here, we review aspects of ovarian tumor heterogeneity that facilitate tumorigenesis and contribute to treatment failure. These tumor characteristics should be considered when designing novel therapies or characterizing mechanisms of treatment resistance. Individual patients vary considerably in terms of age, fertility and contraceptive use which innately affects the endocrine milieu in the ovary. Similarly, individual tumors differ significantly in their immune profile, which can impact the efficacy of immunotherapies. Tumor size, presence of malignant ascites and vascular density further alters the tumor microenvironment, creating areas of significant hypoxia that is notorious for increasing tumorigenesis, resistance to standard of care therapies and promoting stemness and metastases. We further expand on strategies aimed at improving oxygenation status in tumors to dampen downstream effects of hypoxia and set the stage for better response to therapy.

Clinical Approach to Neuroendocrine Neoplasm Associated With Ovarian Teratoma

BackgroundNeuroendocrine neoplasms are a heterogeneous group of cancers that develop from enterochromaffin cells of the diffuse endocrine system, with an increase in incidents over the last years. Ovarian neuroendocrine tumors (NET) are rare neoplasms, comprising 0.1% of all ovarian neoplasms and less than 5% of all neuroendocrine tumors. They may arise alone (as monodermal, specialized teratoma – ovarian carcinoid) or as a part of other ovarian lesion: cystic mature or immature teratomas. Due to the rarity and limited amount of such cases reported in the literature, there is no consensus on diagnostic and therapeutic procedures in this group of patients.Materials and MethodsThe group of 10 patients at the age of 19 to 77 years (mean 42.8 ± 17.9), diagnosed with unilateral NET within ovarian teratoma were analyzed. The histopathological type of tumor, progression free survival after surgical treatment and presence of hormonally active syndrome were assessed.Results70% (n=7) of patients was diagnosed with mature cystic teratomas containing NET component and 30% (n=3) with monodermal teratoma (strumal carcinoid). All cases of monodermal teratomas were found in women at premenopausal age. Determined Ki67 ranged from 2% to 9%. Ninety percent of lesions (n=9) stained positive for synaptophysin and chromogranin, while markers: CK20, CK7, TTF-1 and CDX2 were negative in all cases, which ruled out their metastatic nature. None of the patients presented with carcinoid syndrome. All followed-up patients remain progression-free, which confirms surgical intervention being a crucial and sufficient method of treatment.ConclusionsThe prognosis and clinical behavior of NETs associated with ovarian teratomas are good with long progression-free survival.

ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease

The insulin-like growth factors (IGF) are important players in the development of gynecological malignancies, including epithelial ovarian cancer (EOC). The identification of biomarkers that can help in the diagnosis and scoring of EOC patients is of fundamental importance in clinical oncology. We have recently identified the ZYG11A gene as a new candidate target of IGF1 action. The aim of the present study was to evaluate the expression of ZYG11A in EOC patients and to correlate its pattern of expression with histological grade and pathological stage. Furthermore, and in view of previous analyses showing an interplay between ZYG11A, p53 and the IGF1 receptor (IGF1R), we assessed a potential coordinated expression of these proteins in EOC. In addition, zyg11a expression was assessed in ovaries and uteri of growth hormone receptor (GHR) knock-out mice. Tissue microarray analysis was conducted on 36 patients with EOC and expression of ZYG11A, IGF1R and p53 was assessed by immunohistochemistry. Expression levels were correlated with clinical parameters. qPCR was employed to assess zyg11a mRNA levels in mice tissues. Our analyses provide evidence of reduced ZYG11A expression in high grade tumors, consistent with a putative tumor suppressor role. In addition, an inverse correlation between ZYG11A and p53 levels in individual tumors was noticed. Taken together, our data justify further exploration of the role of ZYG11A as a novel biomarker in EOC.

Case Report: Ectopic Adrenocortical Carcinoma in the Ovary

Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7–2.0 cases/million habitants/year. ACCs are rare and usually endocrinologically functional. We present the case of a 59-year-old woman who experienced abdominal fullness for 6 months and increased abdominal circumference. A large pelvic tumor was observed. She underwent cytoreductive surgery and the pathological test results revealed local tumor necrosis and prominent lympho-vascular invasion. Neuroendocrine carcinoma was the first impression, but positivity for synaptophysin, alpha-inhibin, transcription factor enhancer 3 (TFE-3), calretinin (focal), and CD56 (focal) and high Ki-67-labeling proliferating index (>80%) confirmed the diagnosis of ectopic ACC. Ectopic primary aldosteronism could not be excluded. However, we did not perform saline infusion test or captopril test due to poor performance status. When pathological test reports reveal neuroendocrine features not typically found in the organ being examined, IHC staining should be performed to rule out ectopic ACC. Whether the ectopic ACC is functional or not requires complete survey.

G Protein-Coupled Estrogen Receptor Correlates With Dkk2 Expression and Has Prognostic Impact in Ovarian Cancer Patients

PurposeWnt pathway modulator Dickkopf 2 (Dkk2) and signaling of the G protein-coupled estrogen receptor (GPER) seem to have essential functions in numerous cancer types. For epithelial ovarian cancer (EOC), it has not been proven if either Dkk2 or the GPER on its own have an independent impact on overall survival (OS). So far, the correlation of both factors and their clinical significance has not systematically been investigated before.MethodsExpression levels of Dkk2 were immunohistochemically analyzed in 156 patient samples from different histologic subtypes of EOC applying the immune-reactivity score (IRS). Expression analyses were correlated with clinical and pathological parameters to assess for prognostic relevance. Data analysis was performed using Spearman’s correlations, Kruskal-Wallis-test and Kaplan-Meier estimates.ResultsHighest Dkk2 expression of all subtypes was observed in clear cell carcinoma. In addition, Dkk2 expression differed significantly (p<0.001) between low and high grade serous ovarian cancer. A significant correlation of Dkk2 with the cytoplasmic GPER expression was noted (p=0.001) but not for the nuclear estrogen receptor alpha (ERα) or beta (ERβ). Patients exhibiting both, high expression Dkk2 (IRS>4) and GPER (IRS>8), had a significantly better overall survival compared to patients with low expression (61 months vs. 33 months; p=0.024).ConclusionDkk2 and GPER expression correlates in EOC and combined expression of both is associated with improved OS. These findings underline the clinical significance of both pathways and indicate a possible prognostic impact as well as a potential for treatment strategies addressing interactions between estrogen and Wnt signaling in ovarian cancer.

Ovarian cancer subtypes based on the regulatory genes of RNA modifications: Novel prediction model of prognosis

BackgroundOvarian cancer (OC) is a female reproductive system tumor. RNA modifications play key roles in gene expression regulation. The growing evidence demonstrates that RNA methylation is critical for various biological functions, and that its dysregulation is related to the progression of cancer in human.MethodOC samples were classified into different subtypes (Clusters 1 and 2) based on various RNA-modification regulatory genes (RRGs) in the process of RNA modifications (m1A, m6A, m6Am, m5C, m7G, ac4C, m3C, and Ψ) by nonnegative matrix factorization method (NMF). Based on differently expressed RRGs (DERRGs) between clusters, a pathologically specific RNA-modification regulatory gene signature was constructed with Lasso regression. Kaplan-Meier analysis and receiver operating characteristic (ROC) curves were used to evaluate the prognostic ability of the identified model. The correlations of clinicopathological features, immune subtypes, immune scores, immune cells, and tumor mutation burden (TMB) were also estimated between different NMF clusters and riskscore groups.ResultsIn this study, 59 RRGs in the process of RNA modifications (m1A, m6A, m6Am, m5C, m7G, ac4C, m3C, and Ψ) were obtained from TCGA database. These RRGs were interactional, and sample clusters based on these regulators were significantly correlated with survival rate, clinical characteristics (involving survival status and pathologic stage), drug sensibility, and immune microenvironment. Furthermore, Lasso regression based on these 21 DERRGs between clusters 1 and 2 constructed a four-DERRG signature (ALYREF, ZC3H13, WTAP, and METTL1). Based on this signature, 307 OC patients were classified into high- and low-risk groups based on median value of riskscores from lasso regression. This identified signature was significantly associated with overall survival, radiation therapy, age, clinical stage, cancer status, and immune cells (involving CD4+ memory resting T cells, plasma cells, and Macrophages M1) of ovarian cancer patients. Further, GSEA revealed that multiple biological behaviors were significantly enriched in different groups.ConclusionsOC patients were classified into two subtypes per these RRGs. This study identified four-DERRG signature (ALYREF, ZC3H13, WTAP, and METTL1) in OC, which was an independent prognostic model for patient stratification, prognostic evaluation, and prediction of response to immunotherapy in ovarian cancer by classifying OC patients into high- and low-risk groups.

A nomogram model based on clinical markers for predicting malignancy of ovarian tumors

ObjectiveThe aim of this study was to build a nomogram based on clinical markers for predicting the malignancy of ovarian tumors (OTs).MethodA total of 1,268 patients diagnosed with OTs that were surgically removed between October 2017 and May 2019 were enrolled. Clinical markers such as post-menopausal status, body mass index (BMI), serum human epididymis protein 4 (HE4) value, cancer antigen 125 (CA125) value, Risk of Ovarian Malignancy Algorithm (ROMA) index, course of disease, patient-generated subjective global assessment (PG-SGA) score, ascites, and locations and features of masses were recorded and analyzed (p 0.05). Significant variables were further selected using multivariate logistic regression analysis and were included in the decision curve analysis (DCA) used to assess the value of the nomogram model for predicting OT malignancy.ResultThe significant variables included post-menopausal status, BMI, HE4 value, CA125 value, ROMA index, course of disease, PG-SGA score, ascites, and features and locations of masses (p 0.05). The ROMA index, BMI (≥ 26), unclear/blurred mass boundary (on magnetic resonance imaging [MRI]/computed tomography [CT]), mass detection (on MRI/CT), and mass size and features (on type B ultrasound [BUS]) were screened out for multivariate logistic regression analysis to assess the value of the nomogram model for predicting OT malignant risk (p 0.05). The DCA revealed that the net benefit of the nomogram’s calculation model was superior to that of the CA125 value, HE4 value, and ROMA index for predicting OT malignancy.ConclusionWe successfully tailored a nomogram model based on selected clinical markers which showed superior prognostic predictive accuracy compared with the use of the CA125, HE4, or ROMA index (that combines both HE and CA125 values) for predicting the malignancy of OT patients.

Adiponectin: A player in the pathogenesis of hormone-dependent cancers

Hormone-dependent cancers are a major cause of morbidity and mortality in both genders. Accumulating evidence suggest that adiponectin, an adipokine with multifaceted functions, is implicated in the pathogenesis of several malignancies. In the present review, we discuss the existing data regarding this relationship. Several observational studies showed that low adiponectin levels are associated with higher risk for breast, cervical, endometrial, ovarian and prostate cancer. A relationship between adiponectin and the aggressiveness of some of these tumors has also been reported. In vitro studies reported that adiponectin inhibits the proliferation and induces apoptosis of breast, cervical, endometrial, ovarian and prostate cancer cells. Given the high prevalence of these cancers and the substantial associated morbidity and mortality, the role of agents that increase adiponectin levels and/or stimulate its activity should be evaluated for the prevention and management of these common tumors.

Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation

ObjectiveObesity increases the risk of certain cancers, especially tumours that reside close to adipose tissue (breast and ovarian metastasis in the omentum). The obesogenic and tumour micro-environment share a common pathogenic feature, oxygen deprivation (hypoxia). Here we test how hypoxia changes the metabolome of adipocytes to assist cancer cell growth.MethodsHuman and mouse breast and ovarian cancer cell lines were co-cultured with human and mouse adipocytes respectively under normoxia or hypoxia. Proliferation and lipid uptake in cancer cells were measured by commercial assays. Metabolite changes under normoxia or hypoxia were measured in the media of human adipocytes by targeted LC/MS.ResultsHypoxic cancer-conditioned media increased lipolysis in both human and mouse adipocytes. This led to increased transfer of lipids to cancer cells and consequent increased proliferation under hypoxia. These effects were dependent on HIF1α expression in adipocytes, as mouse adipocytes lacking HIF1α showed blunted responses under hypoxic conditions. Targeted metabolomics of the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes media revealed that culture with hypoxic-conditioned media from non-malignant mammary epithelial cells (MCF10A) can alter the adipocyte metabolome and drive proliferation of the non-malignant cells.ConclusionHere, we show that hypoxia in the adipose-tumour microenvironment is the driving force of the lipid uptake in both mammary and ovarian cancer cells. Hypoxia can modify the adipocyte metabolome towards accelerated lipolysis, glucose deprivation and reduced ketosis. These metabolic shifts in adipocytes could assist both mammary epithelial and cancer cells to bypass the inhibitory effects of hypoxia on proliferation and thrive.

The expression of autophagy-related gene CXCL12 in endometriosis associated ovarian cancer and pan-cancer analysis

BackgroundEndometriosis-associated ovarian cancer (EAOC), an aggressive form of malignant ovarian neoplasm with origins in endometriosis (EM), has risen to prominence recently. Despite extensive investigation, the precise pathophysiology remains elusive.This article explores new autophagy-related DEG genes between EM and EAOC, and investigates CXCL12’s expression and prognostic relevance across pan-cancer.MethodsFrom Gene Expression Omnibus (GEO), we retrieved gene sequencing data to uncover DEGs. We carried out enrichment analysis, PPI network construction and explored CXCL12’s multi-database expression and prognostic significance employing the analytical tools of ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter. Subsequently, assessing the relationship between CXCL12 expression and immune presence in cancer utilizing GEPIA and TIMER. Lastly, CXCL12, IL17, STAT3, and FOXP3 protein expressions were determined through immunohistochemistry analysis in EAOC, EM, and normal endometrial tissues.ResultsTwo DEGs were discovered and enrichment analysis indicated virus-cytokine/receptor interactions, chemokine signaling, and cytokine-cytokine receptor interplay as pivotal in EAOC. Notably, cancerous tissues exhibited reduced CXCL12 levels compared with non-malignant tissues across cancers. CXCL12, IL17, STAT3, Th17/Treg ratio, and FOXP3 expressions were also lower in EAOC than EM and normal tissues. Additionally, CXCL12 expression was related to stage, survival, immune subtype, and molecular classification across cancers.ConclusionsIn conclusion, our study implicates CXCL12 and altered Th17/Treg balance in progression from EM to EAOC. CXCL12 emerges as a predictive marker for cancer progression across various tumors and is associated with inflammatory response.

Diabetes associated with cervical carcinoma among high-risk HPV-infected patients with cytologically diagnosed high grade squamous intraepithelial lesion

BackgroundDiabetes causes metabolic disorders and immune changes that may be potential triggers of cervical cancer. Therefore, diabetes is not a “bystander” to cervical cancer. However, the conclusion that diabetes promotes cervical cancer lacks clinical epidemiological evidence, and the reported potential association between diabetes and cervical cancer is controversial.MethodsWe conducted an explorative cross-sectional study of 791 women with cytological HGSIL and HR-HPV, who attended the cervical clinic of the largest academic women’s hospital in China from May 2019 to March 2022. After cervical screening, patients who were requiring colposcopy were tested for HbA1c. HbA1c level of 6.5% or higher defines diabetes and HbA1c level of 5.7%-6.4% was defined as prediabetes. The relationship between diabetes and cervical cancer was observed by a dose-response graph. Subgroup analysis and multivariate logistic regression analysis were conducted to estimate the associations between diabetes and cervical cancer.ResultsAmong HGSIL patients with high-risk HPV infection, compared with women with HbA1c <5.7%, the odds ratio for women with prediabetes was 1.72 (95% CI: 0.87-3.41) and the odds ratio for women with diabetes was 3.29 (95% CI: 1.10-9.80) for cervical cancer. Sensitivity analysis showed that diabetes was significantly associated with cervical cancer in different age groups and different HPV variant. E-value analysis showed robustness to unmeasured confounding.ConclusionsIn patients with HR-HPV combined with HGSIL, diabetes and prediabetes are associated with cervical cancer.

A prognostic model for cervical cancer based on ferroptosis-related genes

BackgroundFerroptosis is widely involved in the occurrence and development of various cancers, but a specific mechanism involving ferroptosis in cervical cancer is still unclear.MethodsBased on the expressions of ferroptosis-related genes, a prognostic model was constructed using lasso regression, and the overall predictive performance of this model was verified. An in-depth analysis of the prognostic model was then conducted.ResultsThe prognostic model showed good predictive performance in both the validation and test sets. Mechanism analysis indicated that differences in the tumor microenvironment were the basis of the predictive ability of the model. Notably, CA9 mRNA was significantly overexpressed in cervical carcinoma, tissues but not in normal cervix tissues. A pair of ceRNAs (CA9/ULBP2) could be involved in the carcinogenesis and development of cervical cancer, and the potential target might be hsa-miR-34a. In addition, predicted miRNAs and drugs for these DEGs were identified.ConclusionsWe constructed a prognostic model with good predictive performance, based on the expression of ferroptosis-related genes. Further research found that the ceRNA pairs of ULBP2/CA9 could regulate cervical cancer through hsa-miR-34a. These results identified the mechanism of ferroptosis in cervical cancer, and might provide novel therapeutics for cervical cancer patients.

Distant organ metastasis patterns and prognosis of neuroendocrine cervical carcinoma: a population-based retrospective study

BackgroundNeuroendocrine carcinoma of the cervix (NECC) is a rare pathological form of cervical cancer. The prognosis of NECC with distant organ metastases is unclear. In our study, the patterns and prognosis of distant organ metastasis of NECC were investigated.MethodsData were obtained from the surveillance epidemiology and end results (SEER) database from 2000 to 2018. Cox regression, Kaplan–Meier and log-rank analyses were conducted.ResultsNECC was prone to single and multi-site metastases. The median overall survival (OS) was greatly decreased in patients with distant metastasis (P < 0.0001). Other characteristics such as age ≥60 years, poorer grade, higher T stage, those without surgery, no radiotherapy, and no chemotherapy were predictors of poor prognosis.ConclusionsMetastasis is an independent prognostic factor for patients with NECC. Surgery, radiotherapy, and chemotherapy give an overall survival advantage for patients with distant organ metastases.

Genetic association of lipids and lipid-lowering drug target genes with Endometrial carcinoma: a drug target Mendelian randomization study

BackgroundAberrant lipid metabolism is intricately linked to the development of endometrial cancer, and statin lipid-lowering medications are regarded as promising adjunctive therapies for future management of this malignancy. This study employed Mendelian randomization (MR) to explore the causal association between lipid traits and endometrial cancer while assessing the potential impact of drug targets on lower lipids on endometrial cancer.MethodTwo-sample Mendelian randomization was employed to probe the causal association between lipid traits and endometrial carcinoma. Drug-target Mendelian randomization was also utilized to identify potential drug-target genes for managing endometrial carcinoma. In instances where lipid-mediated effects through particular drug targets were notable, the impacts of these drug targets on endometrial carcinoma risk factors were investigated to bolster the findings.ResultNo causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC was found in two-sample Mendelian randomization. In drug target Mendelian randomization, genetic modeling of apolipoprotein B (APOB) (OR [95%CI]=0.31, [0.16-0.60]; p=4.73e-04) and cholesteryl ester transfer protein (CETP) (OR [95%CI]=1.83, [1.38-2.43]; p=2.91e-05) genetic mimicry was associated with non-endometrioid carcinoma.ConclusionThe results of our MR study revealed no causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC. Among the six lipid-lowering drug targets, we observed a significant association between lower predicted APOB levels and higher CETP levels with an increased risk of endometrioid carcinoma. These findings provide novel insights into the importance of lipid regulation in individuals with endometrial carcinoma, warranting further clinical validation and mechanistic investigations.

Surgical approaches to fertility preservation in the cancer patient: current and future directions

Advances in oncologic therapies have markedly improved survival among reproductive-age female patients, making fertility preservation an essential component of comprehensive cancer care. Gonadotoxic treatments, including chemotherapy, radiotherapy, and surgery, can disrupt ovarian and uterine endocrine function, resulting in premature ovarian insufficiency and infertility. This narrative review summarizes current and emerging surgical approaches to fertility preservation, organized by anatomic focus on the ovary, uterus, and cervix. Ovarian transposition preserves ovarian endocrine function by relocating the ovaries outside the pelvic radiation field, while ovarian tissue cryopreservation preserves primordial follicles through surgical harvesting, cryostorage, and reimplantation to restore ovarian function and fertility. Emerging uterine-preserving strategies, such as uterine transposition and uterine transplantation, demonstrate growing feasibility for restoring reproductive and endocrine uterine function. Fertility-sparing cervical procedures, including radical and simple trachelectomy, maintain favorable oncologic outcomes while preserving reproductive potential in appropriately selected patients. Across all modalities, multidisciplinary collaboration and individualized counseling are critical to optimize both oncologic and reproductive outcomes. Continued research aimed at refining surgical techniques, improve graft viability, and expanding equitable access will be key to advancing fertility preservation as a standard component of comprehensive cancer care.

Association between body mass index and anti-Müllerian hormone in women with ovarian endometrioma and dermoid cyst

Background Adiposity influences reproductive function via endocrine and immune pathways. The association between body mass index (BMI) and anti−Müllerian hormone (AMH) in endometriosis is uncertain, and BMI may not fully capture adiposity−related biology relevant to ovarian reserve. We assessed whether BMI is associated with AMH in untreated ovarian endometrioma and whether this differs from dermoid cysts. Methods Retrospective single−center cohort of 951 newly diagnosed, reproductive−age women from January 1, 2020 to December 31, 2023 (717 endometrioma; 234 dermoid). AMH was measured on one platform; imaging included transvaginal ultrasonography with MRI or contrast−enhanced abdominopelvic CT as needed. Multivariable linear regression modeled log−AMH versus BMI, adjusting for age, diagnosis, cyst size and laterality, parity, smoking, alcohol use, cycle regularity, and cycle length. Nonlinearity was screened with restricted cubic splines; piecewise models explored age breakpoints. An interaction term tested whether the BMI effect differed by diagnosis. Effects are reported as percent change in AMH per 1 kg/m². Results Women with endometrioma were older (31.9 vs 29.9 years; P<.001) and had lower BMI (21.1 vs 22.4 kg/m²; P<.001) than those with dermoid. Median AMH was 2.52 vs 2.70 ng/mL; age−adjusted geometric means did not differ (P = .245). Piecewise modeling identified earlier age breakpoints in endometrioma (35.7 years) than dermoid (40.4 years). In fully adjusted models, each 1 kg/m² higher BMI was associated with 2.3% lower AMH (P = .003). Group−specific estimates were −1.9% per kg/m² in endometrioma (P = .060) and −2.8% per kg/m² in dermoid (P = .009); the BMI×diagnosis interaction was not significant (P = .538). Model fit was modest (adjusted R²=0.22), and BMI explained 1% of AMH variance (partial R²=0.01). Sensitivity analyses restricting the BMI range yielded consistent directions of effect with attenuation at lower BMI. Conclusions Across endometrioma and dermoid cysts, BMI shows a weak inverse association with AMH without evidence of between−group differences. Given BMI’s minimal explanatory value, local ovarian factors may more strongly determine ovarian reserve in endometrioma. Limited numbers of obese participants constrain inference at higher BMI; studies with broader BMI distributions and integrated metabolic profiling are warranted.

Purinergic signal transduction and metabolic regulation by ENTPD5 and ENTPD6

ENTPD5 and ENTPD6 are members of the CD39-ectonucleoside triphosphate diphosphohydrolase (CD39-ENTPD) family, which play an important role in modulating the purinergic signaling pathway. Most of the knowledge in this area has been obtained by studying CD39/ENTPD1, the prototype member of this family, and evaluating the translational potential by either treating inflammation directly with recombinant proteins or by using antagonists to elicit immune responses in cancer. ENTPD5 and ENTPD6, “orphan-type” ectonucleotidases, are understudied to date, although both are expressed at high levels in various tissues, where they appear involved in regulating signal transduction, cellular energy, and metabolism. ENTPD5 is abnormally overexpressed in several types of malignancies, including prostate, liver, lung, and ovarian cancers. ENTPD5 appears to promote protein glycosylation and folding in part by regulating UDP and UMP levels, thereby enhancing the survival and proliferation of somatic or cancer cells. As such, ENTPD5 has been considered a potential proto-oncogene and a therapeutic target in cancer treatment. In contrast, despite comparable functionality, the related ENTPD6 shows relatively stable expression across tissues in both normal and pathological conditions, with specific roles in cancer yet unclear. This review provides a comprehensive overview of these two understudied ectoenzymes, detailing their shared molecular structures and control of purinergic signal transduction. In addition, we explore different patterns of tissue and organelle expression of these ecto-enzymes and propose relevance to the modulation of cellular metabolism, as would be important in cancer. We review the sometimes conflicting evidence from experimental animal models and propose potential future clinical applications. This review offers insights into the roles of this distinct duo of ENTPD family members to support future basic and translational research in this field.

Fertility in early breast cancer patients: integrating reproductive planning into oncology care

Fertility preservation (FP) and adequate counseling are crucial for young breast cancer patients in the early setting. We provide a brief summary of FP in young breast cancer patients, including current international guidelines, available FP treatments, and the safety of pregnancy. This review explores embryo/oocyte cryopreservation, ovarian tissue cryopreservation (OTC), and gonadotropin-releasing hormone agonists (GnRHa), along with evidence on temporary endocrine therapy interruption to attempt pregnancy. Despite strong recommendations, FP uptake remains low, underscoring the need for timely multidisciplinary counseling. Literature data underline that pregnancy can be considered after treatment, even for hormone receptor-positive and BRCA mutation-positive patients. Reproductive planning should be integrated into the oncologic treatment, balancing oncologic priorities with patients’ reproductive desires.

Cathepsins and cancer risk: a Mendelian randomization study

BackgroundPrevious observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated the causal relationship between cathepsins and cancer using Mendelian randomization (MR) analysis.MethodsWe used publicly available genome-wide association study (GWAS) data for bidirectional MR analysis. Inverse variance weighting (IVW) was used as the primary MR method of MR analysis.ResultsAfter correction for the False Discovery Rate (FDR), two cathepsins were found to be significantly associated with cancer risk: cathepsin H (CTSH) levels increased the risk of lung cancer (OR = 1.070, 95% CI = 1.027–1.114, P = 0.001, PFDR= 0.009), and CTSH levels decreased the risk of basal cell carcinoma (OR = 0.947, 95% CI = 0.919–0.975, P = 0.0002, PFDR= 0.002). In addition, there was no statistically significant effect of the 20 cancers on the nine cathepsins. Some unadjusted low P-value phenotypes are worth mentioning, including a positive correlation between cathepsin O (CTSO) and breast cancer (OR = 1.012, 95% CI = 1.001–1.025, P = 0.041), cathepsin S (CTSS) and pharyngeal cancer (OR = 1.017, 95% CI = 1.001–1.034, P = 0.043), and CTSS and endometrial cancer (OR = 1.055, 95% CI = 1.012–1.101, P = 0.012); and there was a negative correlation between cathepsin Z and ovarian cancer (CTSZ) (OR = 0.970, 95% CI = 0.949–0.991, P = 0.006), CTSS and prostate cancer (OR = 0.947, 95% CI = 0.902–0.944, P = 0.028), and cathepsin E (CTSE) and pancreatic cancer (OR = 0.963, 95% CI = 0.938–0.990, P = 0.006).ConclusionOur MR analyses showed a causal relationship between cathepsins and cancers and may help provide new insights for further mechanistic and clinical studies of cathepsin-mediated cancer.

BCAA metabolism: the Achilles’ heel of ovarian cancer, polycystic ovary syndrome, and premature ovarian failure

Branched-chain amino acids (BCAAs), including valine, leucine and isoleucine, are essential nutrient signals that influence mammalian animal metabolism. Many enzymes are involved in the metabolism of BCAAs, such as branched-chain amino acid transaminases (BCATs), branched-chain α-keto acid dehydrogenase (BCKDH), and BCKDH kinase (BCKDK). The aberrant expression of enzymes involved in BCAA metabolism and an imbalance in BCAA amino acid intake can lead to disordered metabolism. Aberrant BCAA metabolism can lead to several diseases, such as human ovarian disease, including ovarian cancer (OC), polycystic ovary syndrome (PCOS), and premature ovarian failure (POF), which are common gynaecological diseases. The overexpression of BCATs is found in OC, which promotes BCAA catalysis to provide a large amount of energy for tumorigenesis. However, BCKDK is overexpressed in epithelial ovarian cancer (EOC), which promotes proliferation and migration via MEK–ERK. In addition, several studies have reported that high levels of BCAAs are increased in the plasma of PCOS and POF patients. This review focuses on the role of BCAA metabolism and potential management methods for OC, PCOS and POF.

Bilateral atypical ovarian masses: don’t overlook a functional gonadotropic pituitary adenoma

Functional gonadotroph adenoma (FGA) is a rare condition associated with secretion of biologically active gonadotropins which affect reproductive organs. In women of reproductive age, it has been reported as a cause of spontaneous ovarian hyperstimulation syndrome (OHSS) occurring outside the context of assisted reproductive technology (ART). In rare instances, FGA may present as suspicious ovarian masses, leading to an overlooked pituitary disorder. We report the case of a 34-year-old woman initially suspected of having a bilateral ovarian tumor with a borderline component due to thick-walled cystic masses. She underwent pelvic surgery, resulting in an oophorectomy. However, a few weeks postoperatively, the sudden onset of galactorrhea prompted further investigation, revealing hyperprolactinemia, FSH hypersecretion, and low LH levels. Ultimately, the diagnosis of FGA was established. A literature review was conducted to analyze similar cases where patients underwent ovarian surgery without prior hormonal assessment or suspicion of pituitary pathology, only to be diagnosed with FGA later. Thirteen additional cases were identified, including ovarian cysts and two cases of suspicious ovarian masses, with diagnostic delays ranging from 1.5 to 10 years. This case highlights the importance of considering FGA in the differential diagnosis of bilateral ovarian masses to avoid unnecessary surgical procedures.

Adrenal adenoma secreting 17-hydroxyprogesterone mimicking non-classical 21-hydroxylase deficiency

In adrenal steroidogenesis, 17-hydroxyprogesterone (17-OHP) is a substrate for 21-hydroxylase, one of the crucial enzymes of the cortisol and aldosterone biosynthesis pathway. Thus, measurement serum 17-OHP concentration is used when the diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is suspected. In the classic 21-hydroxylase deficiency, randomly timed measurements of 17-OHP are generally significantly elevated using different immunoassays. In the non-classic form of CAH (NC-CAH), the activity of 21-hydroxylase is less decreased, therefore the measurements of 17-OHP after ACTH stimulation test are usually required for diagnosis. Nonetheless, elevated 17-OHP concentration may also origin from adrenal tumors or ovarian neoplasms as a result of defects in steroidogenesis with an accumulation of steroids precursors. The presented cases and the literature review draw attention to the occurrence of rare causes of benign adrenal adenomas with steroidogenesis defects which may lead to a misdiagnosis of CAH.

Association between female infertility and stroke mortality: evidence from the PLCO cancer screening trial

ObjectiveWhile infertility affects about 15% of women during their reproductive years, its long-term impact on stroke mortality after this period remains unclear. This study aims to investigate the association between infertility and stroke mortality in women using data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial.MethodsWe analyzed data from 75,778 female participants aged 55–74 years with a median follow-up of 16.84 years. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for stroke mortality, adjusting for potential confounders.ResultsAmong participants, 14.53% reported infertility. During follow-up, 1,159 women died from stroke. Compared to women without infertility, those with infertility had a higher risk of stroke mortality (HR 1.21, 95% CI 1.04–1.41, p = 0.016). This association remained statistically significant after adjusting for age, race, education level, marital status, smoking status, body mass index, history of hypertension, history of heart attack, history of diabetes mellitus, birth control pill use, hormone replacement therapy, endometriosis, first menstrual period and pregnancy history (HR 1.20, 95% CI 1.02–1.42, p = 0.029). Sensitivity and subgroup analyses yielded consistent results.ConclusionThe findings of this study indicate that infertility is associated with an increased risk of stroke mortality in women. Further research is needed to confirm these findings and elucidate the underlying mechanisms.

Assessing of programmed cell death gene signature for predicting ovarian cancer prognosis and treatment response

BackgroundProgrammed cell death (PCD) is an overwhelming factor affecting tumor cell metastasis, but the mechanism of PCD in ovarian cancer (OV) is still uncertain.MethodsTo define the molecular subtypes of OV, we performed unsupervised clustering based on the expression level of prognosis related PCD genes in the Cancer Genome Atlas (TCGA)-OV. COX and least absolute shrinkage and selection operator (LASSO) COX analysis were used to identify the OV prognostic related PCD genes, and the genes identified according to the minimum Akaike information criterion (AIC) were the OV prognostic characteristic genes. According to the regression coefficient in the multivariate COX analysis and gene expression data, the Risk Score of OV prognosis was constructed. Kaplan-Meier analysis was conducted to assess the prognostic status of OV patients, and receiver operating characteristic (ROC) curves were conducted to assess the clinical value of Risk Score. Moreover, RNA-Seq date of OV patient derived from Gene Expression Omnibus (GEO, GSE32062) and the International Cancer Genome Consortium (ICGC) database (ICGC-AU), verifying the robustness of the Risk Score via Kaplan-Meier and ROC analysis.Pathway features were performed by gene set enrichment analysis and single sample gene set enrichment analysis. Finally, Risk Score in terms of chemotherapy drug sensitivity and immunotherapy suitability was also evaluated in different groups.Results9-gene composition Risk Score system was finally determined by COX and LASSO COX analysis. Patients in the low Risk Score group possessed improved prognostic status, immune activity. PI3K pathway activity was increased in the high Risk Score group. In the chemotherapy drug sensitivity analysis, we found that the high Risk Score group might be more suitable for treatment with PI3K inhibitors Taselisib and Pictilisib. In addition, we found that patients in the low-risk group responded better to immunotherapy.ConclusionRisk Score of 9-gene composition of PCD signature possesses promising clinical potential in OV prognosis, immunotherapy, immune microenvironment activity, and chemotherapeutic drug selection, and our study provides the basis for an in-depth investigation of the PCD mechanism in OV.

Construction of novel hypoxia-related gene model for prognosis and tumor microenvironment in endometrial carcinoma

IntroductionEndometrial cancer is currently one of the three most common female reproductive cancers, which seriously threatens women’s lives and health. Hypoxia disrupts the tumor microenvironment, thereby affecting tumor progression and drug resistance.MethodsWe established hypoxia-related gene model to predict patient prognosis and 1-, 3-, and 5-year overall survival rates. Then, the expression level of hypoxia-related genes and survival data were extracted for comprehensive analysis by Cox regression analysis, and the model was established.ResultsWe analyzed the survival and prognosis of patients in the high and low-risk groups. The Kaplan-Meier curve showed that the low-risk group is associated with a better survival rate. The 1-, 3-, and 5-year AUC values of the model were 0.680, 0.698, and 0.687, respectively. Finally, we found that LAG3 may be a potential immune checkpoint for endometrial cancer.ConclusionWe found four hypoxia-related genes (ANXA2, AKAP12, NR3C1, and GPI) associated with prognosis. The hypoxia-related gene model can also predict prognosis and tumor microenvironment in endometrial cancer.

Trends and outcomes of fertility preservation in patients presenting with cancer during pregnancy or postpartum—a longitudinal observational cohort study

Objective The aim of this study was to assess the trends and outcomes of fertility preservation (FP) in women referred for FP counseling and presenting with pregnancy-associated cancer (PAC). Method This is a prospective cohort study of all patients referred for FP counseling between 2001 and 2024 to the FP program of Karolinska University Hospital, Sweden. Baseline data, age, parity, disease stage, treatment characteristics, and FP methods were retrieved from clinical registries. Results A total of 50 women with cancer diagnosed coincidentally with pregnancy (79%) or up to 1 year after delivery (21%) were referred for FP counseling. Among them, 30 women chose to proceed with FP; 10 by either hormonal stimulation to freeze eggs/embryos or ovarian tissue cryopreservation (OTC) after abortion/miscarriage, 10 by OTC at delivery, and 9 were planned for FP postpartum. The most common cancers were breast cancer ( N = 31, 62%), cervical cancer ( N = 6, 12%), and lymphoma ( N = 5, 10%). Most women diagnosed with cancer in the first trimester either terminated the pregnancy or had a miscarriage (76%). All patients diagnosed in the second and third trimesters delivered through cesarian section ( N = 14), scheduled from week 31 and onwards. All patients diagnosed in the third trimester started cancer treatment postpartum. In the FP group, 57% cryopreserved ovarian tissue postpartum or post-abortion and 43% underwent ovarian stimulation for oocyte/embryo cryopreservation prior to chemotherapy initiation. Four women proceed to FP after chemotherapy, three by ovarian tissue freezing and one through attempted, unsuccessful, hormonal stimulation. After a mean follow-up of 9.9 years, 45 patients were alive. The proportion of women having previous children at diagnosis was the same among the FP and no-FP groups. At the end of follow-up, the percentage of nulliparous women was 20% in the no-FP group and 13% in the FP group. Conclusions Our observations underscore the need to ensure good multidisciplinary communication to inform patients presenting with PAC on the future risk for infertility and on the available FP procedures. As FP has to be applied when the patients are not pregnant, these measures can be planned in connection with a cesarean section, or after completion of cancer treatment. Current guidelines for FP lack specific recommendations for women with PAC, and specialized PAC guidelines also lack specific information on FP. Clinical Trial Registration: ClinicalTrials.gov, identifier NTC04602962.