Molecular mechanism of autophagy and apoptosis in endometriosis: Current understanding and future research directions.

Background: Endometriosis is a common gynecological condition, with symptoms including pain and infertility. Regurgitated endometrial cells into the peritoneal cavity encounter hypoxia and nutrient starvation. Endometriotic cells have evolved various adaptive mechanisms to survive in this inevitable condition. These adaptations include escape from apoptosis. Autophagy, a self-degradation system, controls apoptosis during stress conditions. However, to date, the mechanisms regulating the interplay between autophagy and apoptosis are still poorly understood. In this review, we summarize the current understanding of the molecular characteristics of autophagy in endometriosis and discuss future therapeutic challenges. Methods: A search of PubMed and Google Scholar databases were used to identify relevant studies for this narrative literature review. Results: Autophagy may be dynamically regulated through various intrinsic (e.g., PI3K/AKT/mTOR signal transduction network) and extrinsic (e.g., hypoxia and iron-mediated oxidative stress) pathways, contributing to the development and progression of endometriosis. Upregulation of mTOR expression suppresses apoptosis via inhibiting the autophagy pathway, whereas hypoxia or excess iron often inhibits apoptosis via promoting autophagy. Conclusion: Endometriotic cells may have acquired antiapoptotic mechanisms through unique intrinsic and extrinsic autophagy pathways to survive in changing environments.

Current understanding of the pathogenesis of placenta accreta spectrum disorder with focus on mitochondrial function.

AIM: The refinement of assisted reproductive technology, including the development of cryopreservation techniques (vitrification) and ovarian stimulation protocols, makes frozen embryo transfer (FET) an alternative to fresh ET and has contributed to the success of assisted reproductive technology. Compared with fresh ET cycles, FET cycles were associated with better in vitro fertilization outcomes; however, the occurrence of pregnancy-induced hypertension, preeclampsia, and placenta accreta spectrum (PAS) was higher in FET cycles. PAS has been increasing steadily in incidence as a life-threatening condition along with cesarean rates worldwide. In this review, we summarize the current understanding of the pathogenesis of PAS and discuss future research directions. METHODS: A literature search was performed in the PubMed and Google Scholar databases. RESULTS: Risk factors associated with PAS incidence include a primary defect of the decidua basalis or scar dehiscence, aberrant vascular remodeling, and abnormally invasive trophoblasts, or a combination thereof. Freezing, thawing, and hormone replacement manipulations have been shown to affect multiple cellular pathways, including cell proliferation, invasion, epithelial-to-mesenchymal transition (EMT), and mitochondrial function. Molecules involved in abnormal migration and EMT of extravillous trophoblast cells are beginning to be identified in PAS placentas. Many of these molecules were also found to be involved in mitochondrial biogenesis and dynamics. CONCLUSION: The etiology of PAS may be a multifactorial genesis with intrinsic predisposition (e.g., placental abnormalities) and certain environmental factors (e.g., defective decidua) as triggers for its development. A distinctive feature of this review is its focus on the potential factors linking mitochondrial function to PAS development.

Role of the mitophagy-apoptosis axis in the pathogenesis of polycystic ovarian syndrome.

AIM: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by menstrual irregularities, androgen excess, and polycystic ovarian morphology, but its pathogenesis remains largely unknown. This review focuses on how androgen excess influences the molecular basis of energy metabolism, mitochondrial function, and mitophagy in granulosa cells and oocytes, summarizes our current understanding of the pathogenesis of PCOS, and discuss perspectives on future research directions. METHODS: A search of PubMed and Google Scholar databases were used to identify relevant studies for this narrative literature review. RESULTS: Female offspring born of pregnant animals exposed to androgens recapitulates the PCOS phenotype. Abnormal mitochondrial morphology, altered expression of genes related to glycolysis, mitochondrial biogenesis, fission/fusion dynamics, and mitophagy have been identified in PCOS patients and androgenic animal models. Androgen excess causes uncoupling of the electron transport chain and depletion of the cellular adenosine 5'-triphosphate pool, indicating further impairment of mitochondrial function. A shift toward mitochondrial fission restores mitochondrial quality control mechanisms. However, prolonged mitochondrial fission disrupts autophagy/mitophagy induction due to loss of compensatory reserve for mitochondrial biogenesis. Disruption of compensatory mechanisms that mediate the quality control switch from mitophagy to apoptosis may cause a disease phenotype. Furthermore, genetic predisposition, altered expression of genes related to glycolysis and oxidative phosphorylation, or a combination of these factors may also contribute to the development of PCOS. CONCLUSION: In conclusion, fetuses exposed to a hyperandrogenemic intrauterine environment may cause the PCOS phenotype possibly through disruption of the compensatory regulation of the mitophagy-apoptosis axis.

An integral role of mitochondrial function in the pathophysiology of preeclampsia.

Preeclampsia (PE) is associated with high maternal and perinatal morbidity and mortality. The development of effective treatment strategies remains a major challenge due to the limited understanding of the pathogenesis. In this review, we summarize the current understanding of PE research, focusing on the molecular basis of mitochondrial function in normal and PE placentas, and discuss perspectives on future research directions. Mitochondria integrate numerous physiological processes such as energy production, cellular redox homeostasis, mitochondrial dynamics, and mitophagy, a selective autophagic clearance of damaged or dysfunctional mitochondria. Normal placental mitochondria have evolved innovative survival strategies to cope with uncertain environments (e.g., hypoxia and nutrient starvation). Cytotrophoblasts, extravillous trophoblast cells, and syncytiotrophoblasts all have distinct mitochondrial morphology and function. Recent advances in molecular studies on the spatial and temporal changes in normal mitochondrial function are providing valuable insight into PE pathogenesis. In PE placentas, hypoxia-mediated mitochondrial fission may induce activation of mitophagy machinery, leading to increased mitochondrial fragmentation and placental tissue damage over time. Repair mechanisms in mitochondrial function restore placental function, but disruption of compensatory mechanisms can induce apoptotic death of trophoblast cells. Additionally, molecular markers associated with repair or compensatory mechanisms that may influence the development and progression of PE are beginning to be identified. However, contradictory results have been obtained regarding some of the molecules that control mitochondrial biogenesis, dynamics, and mitophagy in PE placentas. In conclusion, understanding how the mitochondrial morphology and function influence cell fate decisions of trophoblast cells is an important issue in normal as well as pathological placentation biology. Research focusing on mitochondrial function will become increasingly important for elucidating the pathogenesis and effective treatment strategies of PE.

Understanding Ultrasound Features that Predict Symptom Severity in Patients with Adenomyosis: a Systematic Review.

Adenomyosis is associated with pelvic pain, abnormal uterine bleeding, and infertility. Several ultrasound-based classifications have been reported, but it is not clear which criteria reflect the severity of symptoms. The aim of this review is to summarize the ultrasound features that correlate with clinical manifestations of adenomyosis and to discuss diagnostic methods for predicting disease severity. A literature search of PubMed and Google Scholar published up to March 2022 was performed. A consensus-based classification was determined primarily by defining the mapping or topography of the lesion. Ultrasound features can be classified into direct (i.e., the presence of ectopic endometrial tissue within the myometrium) and indirect findings (i.e., changes in the myometrial structure and translesional vascularity secondary to myometrial invasion). There are some reports that symptoms are positively correlated with the location and spread of the disease. Indeed, the lesion thickness, diffuse or internal adenomyosis, and focal adenomyosis may be associated with increased risks of dysmenorrhea, abnormal uterine bleeding, and infertility, respectively. Two ultrasound markers (i.e., the presence of heterogeneous myometrium and myometrial cysts) appear to be the criteria most clinicians focus on. However, decision-making on treatment necessity is determined by symptom severity rather than the topography of the lesions. There is currently no consensus that symptom severity can be predicted based on ultrasound features, but the ultrasound-based criteria may be helpful in diagnosing adenomyosis.

Altered Energy Metabolism, Mitochondrial Dysfunction, and Redox Imbalance Influencing Reproductive Performance in Granulosa Cells and Oocyte During Aging.

Female fertility decreases during aging. The development of effective therapeutic strategies to address the age-related decline in oocyte quality and quantity and its accurate diagnosis remain major challenges. In this review, we summarize our current understanding of the study of aging and infertility, focusing primarily on the molecular basis of energy metabolism, mitochondrial function, and redox homeostasis in granulosa cells and oocytes, and discuss perspectives on future research directions. Mitochondria serve as a central hub sensing a multitude of physiological processes, including energy production, cellular redox homeostasis, aging, and senescence. Young granulosa cells favor glycolysis and actively produce pyruvate, NADPH, and other metabolites. Oocytes rely on oxidative phosphorylation fueled by nutrients, metabolites, and antioxidants provided by the adjacent granulosa cells. A reduced cellular energy metabolism phenotype, including both aerobic glycolysis and mitochondrial respiration, is characteristic of older female granulosa cells compared with younger female granulosa cells. Aged oocytes become more susceptible to oxidative damage to cells and mitochondria because of further depletion of antioxidant-dependent ROS scavenging systems. Molecular perturbations of gene expression caused by a subtle change in the follicular fluid microenvironment adversely affect energy metabolism and mitochondrial dynamics in granulosa cells and oocytes, further causing redox imbalance and accelerating aging and senescence. Furthermore, recent advances in technology are beginning to identify biofluid molecular markers that may influence follicular development and oocyte quality. Accumulating evidence suggests that redox imbalance caused by abnormal energy metabolism and/or mitochondrial dysfunction is closely linked to the pathophysiology of age-related subfertility.

A comprehensive overview of recent developments on the mechanisms and pathways of ferroptosis in cancer: the potential implications for therapeutic strategies in ovarian cancer.

Cancer cells adapt to environmental changes and alter their metabolic pathways to promote survival and proliferation. Metabolic reprogramming not only allows tumor cells to maintain a reduction-oxidation balance by rewiring resources for survival, but also causes nutrient addiction or metabolic vulnerability. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides. Excess iron in ovarian cancer amplifies free oxidative radicals and drives the Fenton reaction, thereby inducing ferroptosis. However, ovarian cancer is characterized by ferroptosis resistance. Therefore, the induction of ferroptosis is an exciting new targeted therapy for ovarian cancer. In this review, potential metabolic pathways targeting ferroptosis were summarized to promote anticancer effects, and current knowledge and future perspectives on ferroptosis for ovarian cancer therapy were discussed. Two therapeutic strategies were highlighted in this review: directly inducing the ferroptosis pathway and targeting metabolic vulnerabilities that affect ferroptosis. The overexpression of SLC7A11, a cystine/glutamate antiporter SLC7A11 (also known as xCT), is involved in the suppression of ferroptosis. xCT inhibition by ferroptosis inducers (e.g., erastin) can promote cell death when carbon as an energy source of glucose, glutamine, or fatty acids is abundant. On the contrary, xCT regulation has been reported to be highly dependent on the metabolic vulnerability. Drugs that target intrinsic metabolic vulnerabilities (e.g., GLUT1 inhibitors, PDK4 inhibitors, or glutaminase inhibitors) predispose cancer cells to death, which is triggered by decreased nicotinamide adenine dinucleotide phosphate generation or increased reactive oxygen species accumulation. Therefore, therapeutic approaches that either directly inhibit the xCT pathway or target metabolic vulnerabilities may be effective in overcoming ferroptosis resistance. Real-time monitoring of changes in metabolic pathways may aid in selecting personalized treatment modalities. Despite the rapid development of ferroptosis-inducing agents, therapeutic strategies targeting metabolic vulnerability remain in their infancy. Thus, further studies must be conducted to comprehensively understand the precise mechanism linking metabolic rewiring with ferroptosis.

The role of mitochondrial dynamics in the pathophysiology of endometriosis.

AIM: Endometriosis is a chronic disease of reproductive age, associated with pelvic pain and infertility. Endometriotic cells adapt to changing environments such as oxidative stress and hypoxia in order to survive. However, the underlying mechanisms remain to be fully elucidated. In this review, we summarize our current understanding of the pathogenesis of endometriosis, focusing primarily on the molecular basis of energy metabolism, redox homeostasis, and mitochondrial function, and discuss perspectives on future research directions. METHODS: Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this narrative literature review. RESULTS: Mitochondria serve as a central hub sensing a multitude of physiological processes, including energy production and cellular redox homeostasis. Under hypoxia, endometriotic cells favor glycolysis and actively produce pyruvate, nicotinamide adenine dinucleotide phosphate (NADPH), and other metabolites for cell proliferation. Mitochondrial fission and fusion dynamics may regulate the phenotypic plasticity of cellular energy metabolism, that is, aerobic glycolysis or OXPHOS. Endometriotic cells have been reported to have reduced mitochondrial numbers, increased lamellar cristae, improved energy efficiency, and enhanced cell proliferation and survival. Increased mitochondrial fission and fusion turnover by hypoxic and normoxic conditions suggests an activation of mitochondrial quality control mechanisms. Recently, candidate molecules that influence mitochondrial dynamics have begun to be identified. CONCLUSION: This review suggests that unique energy metabolism and redox homeostasis driven by mitochondrial dynamics may be linked to the pathophysiology of endometriosis. However, further studies are needed to elucidate the regulatory mechanisms of mitochondrial dynamics in endometriosis.

Tissue factor pathway inhibitor 2: Current understanding, challenges, and future perspectives.

AIM: Tissue factor pathway inhibitor 2 (TFPI2) is a structural homolog of tissue factor pathway inhibitor 1 (TFPI1). Since TFPI2 is a placenta-derived protein, dynamic changes in TFPI2 levels may be related to pregnancy-related diseases. Furthermore, TFPI2 has been reported to be a novel serum biomarker for detecting ovarian cancer, especially clear cell carcinoma (CCC). This review aims to summarize the current knowledge on the biological function of TFPI2, highlight the major challenges that remain to be addressed, and discuss future research directions. METHODS: Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this review. We also provide novel complementary information to what is known about the action of TFPI2. RESULTS: Since TFPI2 concentrations in the blood of pregnant women, preeclampsia patients, and cancer patients vary greatly, its pathophysiological functions have attracted attention. Downregulation of TFPI2, a tumor-suppressor gene, by hypermethylation may contribute to the progression of several cancers. On the other hand, TFPI2 overexpressed in CCC is a risk factor for the development of thrombosis, possibly through inhibition of plasmin activity. However, agreement on the biological function of TFPI2 is still lacking and there are many scientific questions to be addressed. In particular, the lack of international standardization for the quantification of TFPI2 concentrations makes it difficult for researchers and clinicians to evaluate, pool, and compare data from different studies across countries. DISCUSSION: This review summarizes current understandings and challenges in TFPI2 research and discusses future perspectives.

Current Understanding of and Future Directions for Endometriosis-Related Infertility Research with a Focus on Ferroptosis.

BACKGROUND: To date, the development of therapy for endometriosis and disease-related infertility remains a major challenge. Iron overload caused by periodic bleeding is a hallmark of endometriosis. Ferroptosis is an iron- and lipid-reactive oxygen species-dependent type of programmed cell death that is distinct from apoptosis, necrosis, and autophagy. This review summarizes the current understanding of and future directions for the research and treatment of endometriosis and disease-related infertility, with the main focus on the molecular basis of ferroptosis in endometriotic and granulosa cells. METHODS: Papers published between 2000 and 2022 in the PubMed and Google Scholar databases were included in this review. RESULTS: Emerging evidence suggests that ferroptosis is closely linked to the pathophysiology of endometriosis. Endometriotic cells are characterized by ferroptosis resistance, whereas granulosa cells remain highly susceptible to ferroptosis, suggesting that the regulation of ferroptosis is utilized as an interventional target for research into the treatment of endometriosis and disease-related infertility. New therapeutic strategies are urgently needed to efficiently kill endometriotic cells while protecting granulosa cells. CONCLUSIONS: An analysis of the ferroptosis pathway in in vitro, in vivo, and animal research enhances our understanding of the pathogenesis of this disease. Here, we discuss the role of ferroptosis modulators as a research approach and potential novel treatment for endometriosis and disease-related infertility.

Tissue Factor Pathway Inhibitors as Potential Targets for Understanding the Pathophysiology of Preeclampsia.

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy that causes maternal and perinatal morbidity and mortality worldwide. Preeclampsia is associated with complex abnormalities of the coagulation and fibrinolytic system. Tissue factor (TF) is involved in the hemostatic system during pregnancy, while the Tissue Factor Pathway Inhibitor (TFPI) is a major physiological inhibitor of the TF-initiated coagulation cascade. The imbalance in hemostatic mechanisms may lead to a hypercoagulable state, but prior research has not comprehensively investigated the roles of TFPI1 and TFPI2 in preeclamptic patients. In this review, we summarize our current understanding of the biological functions of TFPI1 and TFPI2 and discuss future directions in preeclampsia research. METHODS: A literature search was performed from inception to 30 June 2022 in the PubMed and Google Scholar databases. RESULTS: TFPI1 and TFPI2 are homologues with different protease inhibitory activities in the coagulation and fibrinolysis system. TFPI1 is an essential physiological inhibitor of the TF-initiated extrinsic pathway of coagulation. On the other hand, TFPI2 inhibits plasmin-mediated fibrinolysis and exerts antifibrinolytic activity. It also inhibits plasmin-mediated inactivation of clotting factors and maintains a hypercoagulable state. Furthermore, in contrast to TFPI1, TFPI2 suppresses trophoblast cell proliferation and invasion and promotes cell apoptosis. TFPI1 and TFPI2 may play important roles in regulating the coagulation and fibrinolytic system and trophoblast invasion to establish and maintain successful pregnancies. Concentrations of TF, TFPI1, and TFPI2 in maternal blood and placental tissue are significantly altered in preeclamptic women compared to normal pregnancies. CONCLUSIONS: TFPI protein family may affect both the anticoagulant (i.e., TFPI1) and antifibrinolytic/procoagulant (i.e., TFPI2) systems. TFPI1 and TFPI2 may function as new predictive biomarkers for preeclampsia and navigate precision therapy.

The role of tissue factor pathway inhibitor 2 in the coagulation and fibrinolysis system.

AIM: Tissue factor (TF), the primary initiator of the extrinsic coagulation pathway, contributes to the generation of a hypercoagulable and prothrombotic state in cancer patients. TF pathway inhibitor (TFPI) is a major inhibitor of TF-mediated coagulation pathway. The two proteins, TFPI1 and TFPI2, are encoded by separate genes. Indeed, various cancer patients with venous thromboembolism (VTE) had significantly lower TFPI1 levels than those without VTE. In contrast, serum TFPI2 level was found to increase in ovarian cancer patients with VTE. It remains unclear why TFPI2, unlike TFPI1, is elevated in ovarian cancer patients with VTE. The aim of this review is to explore the pathophysiological role of TFPI2 on the coagulation and fibrinolysis system. METHODS: A literature search was performed from inception to April 30, 2022 in the PubMed and Google Scholar databases. RESULTS: TFPI1 and TFPI2 are homologs with different protease inhibitory activities in the coagulation and fibrinolysis system. TFPI1 inhibits TF/factor VIIa (FVIIa) catalyzed factor X (FX) activation. On the other hand, TFPI2 is unlikely to affect TF-initiated thrombin generation, but it has strong inhibitory activity against plasmin. Plasmin is involved in fibrin degradation, clot lysis, and inactivation of several coagulation factors (such as FV, FVIII, FIX, and FX). TFPI2 may increase the risk of VTE by inhibiting plasmin-dependent fibrinolysis. CONCLUSION: TFPI1 and TFPI2 may have different key functions in regulating the coagulation and fibrinolytic systems.

Understanding the molecular mechanisms of macrophage polarization and metabolic reprogramming in endometriosis: A narrative review.

Background: Endometriosis is an estrogen-dependent disease and causes pelvic pain and infertility. The limits of current pharmacotherapy in women who desire to become pregnant prompt the development of various targeted molecules for more effective treatment. A review article focused on the unique aspect of cellular metabolic reprogramming of endometriotic cells has been reported. The cellular metabolic pathways are reprogrammed to adapt to a variety of environmental stresses (e.g., nutrient starvation or glucose deprivation, hypoxic stress, excessive reactive oxygen species generation, and other environmental factors). This review aims to summarize macrophage polarization and metabolic reprogramming in endometriosis. Methods: A literature search was performed between January 2000 and March 2022 in the PubMed and Google Scholar databases using a combination of specific terms. Results: Macrophage cellular metabolism has a marked influence on its phenotype and function. Preclinical studies showed that metabolic conversion toward glycolysis or oxidative phosphorylation drives macrophage polarization to M1 or M2 phenotype, respectively. Such cellular metabolic rewiring can offer new therapeutic opportunities. Conclusion: A better understanding of metabolic reprogramming biology in endometriosis-associated macrophages is essential in considering novel therapeutic approach for endometriosis. However, there are currently no detailed studies on therapeutic strategies targeting the cellular metabolic properties of endometriosis-associated macrophages.

Revisiting therapeutic strategies for ovarian cancer by focusing on redox homeostasis.

Recent advances in molecular genetics have expanded our understanding of ovarian cancer. High levels of reactive oxygen species (ROS) and upregulation of antioxidant genes are common characteristic features of human cancers. This review reconsiders novel therapeutic strategies for ovarian cancer by focusing on redox homeostasis. A literature search was performed for preclinical and clinical studies published between January 1998 and October 2021 in the PubMed database using a combination of specific terms. ROS serves a central role in tumor suppression and progression by inducing DNA damage and mutations, genomic instability, and aberrant anti- and pro-tumorigenic signaling. Cancer cells increase their antioxidant capacity to neutralize the extra ROS. Additionally, antioxidants, such as CD44 variant isoform 9 (CD44v9) and nuclear factor erythroid 2-related factor 2 (Nrf2), mediate redox homeostasis in ovarian cancer. Furthermore, studies conducted on different cancer types revealed the dual role of antioxidants in tumor progression and inhibition. However, in animal models, genetic loss of antioxidant capacity in the host cannot block cancer initiation and progression. Host-derived antioxidant systems are essential to suppress carcinogenesis, suggesting that antioxidants serve a pivotal role in suppressing cancer development. By contrast, antioxidant activation in cancer cells confers aggressive phenotypes. Antioxidant inhibitors can promote cancer cell death by enhancing ROS levels. Concurrent inhibition of CD44v9 and Nrf2 may trigger apoptosis induction, potentiate chemosensitivity and enhance antitumor activities through the ROS-activated p38/p21 pathway. Antioxidants may have tumor-promoting and -suppressive functions. Therefore, an improved understanding of the role of antioxidants in redox homeostasis and developing antioxidant-specific inhibitors is necessary for treating ovarian cancer.

Reprogramming of glucose metabolism of cumulus cells and oocytes and its therapeutic significance.

The aim of this review is to summarize our current understanding of the molecular mechanism for the glucose metabolism, especially pyruvate dehydrogenase (PDH), during oocyte maturation, as well as future perspectives of therapeutic strategies for aging focusing on metabolic regulation between aerobic glycolysis and the tricarboxylic acid (TCA) cycle/oxidative phosphorylation (OXPHOS). Each keyword alone or in combination was used to search from PubMed. Glucose metabolism is a dynamic process involving "On" and "Off" switches by the pyruvate dehydrogenase kinase (PDK)-PDH axis, which is crucial for energy metabolism and mitochondrial efficiency in cumulus cell differentiation and oocyte maturation. Activation of PDK suppresses the conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA) through the inactivation of PDH, which allows the cumulus cells to supply sufficient amounts of pyruvate, lactate, and nicotinamide adenine dinucleotide phosphate (NADPH) to the oocytes. On the other hand, inactivation of PDK in oocytes can produce adenosine triphosphate (ATP) through a metabolic shift from aerobic glycolysis to the TCA cycle/OXPHOS. The metabolic balance between aerobic glycolysis and TCA cycle/OXPHOS presents us with a number of enzymes, ligands, receptors, and antioxidants that are potential therapeutic targets, some of which have already been successfully pursued to improve fertility outcomes. However, there are also many reports that question their efficacy. In conclusion, understanding the molecular mechanisms involved in the PDK-PDH axis is a crucial step to advance in novel therapeutic strategies to improve oocyte quality.

Effects of iron-related compounds and bilirubin on redox homeostasis in endometriosis and its malignant transformations.

OBJECTIVES: The balance between oxidative stress and antioxidant defense has been reported to differ between women with endometriosis and patients with its malignant transformation. The aim of this study is to investigate changes in redox balance in endometriosis and endometriosis-related ovarian cancer (EAOC) by simultaneously measuring iron-related compounds and bilirubin. METHODS: This study included 235 patients with a histopathologically confirmed diagnosis of endometriosis (n=178) and EAOC (n=57). Cyst fluid samples were collected in Nara Medical University hospital from January 2013 to May 2019. The levels of iron-related compounds (total iron, heme iron, free iron, oxyhemoglobin [oxyHb], methemoglobin [metHb], and metHb/oxyHb ratio) and bilirubin were measured. RESULTS: Total iron, heme iron, free iron, metHb/oxyHb ratio, and bilirubin were significantly elevated in endometriosis compared to EAOC. In both endometriosis and EAOC, iron-related compounds in the cyst were correlated with each other. There was no statistically significant difference in oxyHb and metHb levels between the two groups, but the metHb/oxyHb ratio was significantly higher in endometriosis than in EAOC. Bilirubin was positively correlated with total iron and free iron in EAOC, but there was no correlation between bilirubin and iron-related compounds in endometriosis. CONCLUSIONS: Iron-induced oxidative stress in endometriosis may exceed bilirubin-dependent antioxidant capability, while redox homeostasis in EAOC can be maintained by at least bilirubin.

Clinicopathological characteristics and imaging findings to identify adenomyosis-related symptoms.

PURPOSE: The study aims to identify the clinicopathological risk factors and magnetic resonance (MR) imaging findings for adenomyosis-related symptoms, including menorrhagia, dysmenorrhea, and infertility. METHODS: This was an observation-based cross-sectional study using data from the adenomyosis cohort study. The authors evaluated the clinicopathological variables and various MR imaging findings. RESULTS: Two hundred twenty patients with histologically confirmed adenomyosis were included in this study. Multivariate analysis showed that a middle/retroflexed uterus and adenomyosis lesions of 21 mm or more were significant independent predictors of dysmenorrhea. The history of dysmenorrhea and the maximum length from the cervix to the uterine fundus ≥103 mm were independent risk factors of menorrhagia. One of the key factors associated with non-infertility included the absence of deep infiltrating endometriosis (DIE) and/or superficial peritoneal disease (SUP). CONCLUSIONS: This study identified clinicopathological risk factors and imaging findings associated with adenomyosis-related symptoms. The maximum length from the cervix to the uterine fundus and adenomyosis lesion thickness are independent predictors for the presence of menorrhagia and dysmenorrhea, respectively. Infertility may be associated with the coexistence of endometriosis rather than adenomyosis itself. This result is from an analysis of a small number of infertility patients and requires further study.

Clinicopathological features of different subtypes in adenomyosis: Focus on early lesions.

BACKGROUND: The aim of this study is to investigate the clinicopathological features of intrinsic and extrinsic subtypes in adenomyosis. In particular, we focused on the early lesions of adenomyosis. METHODS: This is a single-center, prospective study of women who elected surgery for adenomyosis at the Department of Gynecology, Nara Medical University Hospital, Kashihara, Japan, from April 2008 to March 2018. Adenomyosis was histologically classified as intrinsic, extrinsic, and others, depending on the type of intramural growth. Adenomyosis that occurs at the inner and outer myometrium was defined as an intrinsic and extrinsic type, respectively. RESULTS: One hundred eighty-nine patients with histologically confirmed adenomyosis were classified into three different types, 74 intrinsic type, 78 extrinsic type, and 37 other type. Compared to the intrinsic type, the extrinsic type was more likely to have endometriosis, including ovarian endometrioma (OMA), superficial peritoneal endometriosis (SUP), or deep infiltrating endometriosis (DIE). To further identify the clinicopathological features of early-stage adenomyosis, we focused only on patients with intrinsic and extrinsic types of adenomyosis with less than one-third of muscular layer infiltration. Patients with early-stage intrinsic adenomyosis were more likely to experience induced abortions. Patients with early-stage extrinsic adenomyosis were more likely to have endometriosis. The coexistence of endometriosis and the lack of induced abortion were independent predictors of extrinsic adenomyosis. Multivariate logistic regression analysis identified coexistence of endometriosis as independent predictors of the early stage extrinsic adenomyosis. CONCLUSION: The study suggests that there are at least two types of adenomyosis, where the intrinsic type is closely associated with a history of induced abortion, while the extrinsic type is strongly associated with endometriosis. Adenomyosis might be a gynecological disorder with complex pathogenesis implicating both traumatic and endometriotic factors.

Toward an understanding of tissue factor pathway inhibitor-2 as a novel serodiagnostic marker for clear cell carcinoma of the ovary.

AIMS: Tissue factor pathway inhibitor (TFPI)-2 has recently emerged as a serodiagnostic marker for patients with epithelial ovarian cancer (EOC), especially clear cell carcinoma (CCC). This review discusses the biological properties of TFPI-2 and why serum levels are elevated in CCC patients. METHODS: A comprehensive literature search was conducted in PubMed up until March, 2021. RESULTS: TFPI-2 is a Kunitz-type protease inhibitor and negatively regulates the enzymatic activities, such as plasmin. TFPI-2 has been characterized as a tumor suppressor gene and was frequently downregulated through promoter hypermethylation in various human cancers. In contrast, TFPI-2 was overexpressed only in CCC. TFPI-2 may be involved in the pathophysiology of CCC, possibly through regulation of coagulation system, stabilization of extracellular matrix (ECM), and induction of intracellular signal transduction. TFPI-2 suppresses tissue factor-induced hypercoagulation in a hypoxic environment. TFPI-2, secreted by CCC cells, platelets, and adjacent vascular endothelial cells, may suppress tumor growth and invasion through ECM remodeling. Nuclear TFPI-2 may suppress matrix metalloproteinase production via transcription factors and modulate caspase-mediated cell apoptosis. CCC cells may upregulate the TFPI-2 expression to adapt to survival in the demanding environment. TFPI-2 is secreted by CCC cells and enters the systemic circulation, resulting in elevated blood levels. DISCUSSION: Serum TFPI-2 reflects the overexpression of TFPI-2 in CCC tissues and is a potential serodiagnostic marker. Further research is needed to explore the expression, clinical significance, biological function, and potential mechanism of TFPI-2 in CCC.

Proposal for developing treatment algorithms of women with symptomatic adenomyosis: A single-center experience.

AIMS: The most common symptoms of adenomyosis include heavy menstrual bleeding and dysmenorrhea. A variety of medical or surgical techniques are utilized for the treatment of adenomyosis, but there are currently no specific treatment guidelines and best practice recommendations for management. The aim of this study is to summarize current treatment strategies for women with symptomatic adenomyosis in a single-center university hospital in order to provide reliable information for developing treatment algorithms. METHODS: We conducted an observational cross-sectional study using data from the adenomyosis cohort study from January 2008 to December 2020. Detailed information, including demographic, clinicopathological, and imaging data, were collected from 220 pathologically confirmed patients with adenomyosis. RESULTS: First, we identified clinical and imaging characteristics in women who underwent surgery or hormone therapy, especially dienogest (DNG) treatment, as first-line treatment. Surgery was generally recommended for multiparous women over the age of 43, especially for patients with intrinsic adenomyosis. Next, we identified the parameters that allowed the continuation of DNG treatment. Oral DNG was given to certain patients with a myometrium thickness of 35 mm or greater and coexisting with endometriosis and/or uterine fibroids. To prevent serious bleeding, DNG treatment can be limited to women with extrinsic adenomyosis with a uterine length of 125 mm or less. DISCUSSION: Our findings may provide useful information in developing an evidence-based treatment guideline for patients with symptomatic adenomyosis, nevertheless, further investigation is needed for the validation of treatment algorithms.