Relationship between Cyst Fluid Concentrations of Iron and Severity of Dysmenorrhea in Patients with Ovarian Endometrioma.

OBJECTIVES AND DESIGN: Endometriosis-related pain can be caused by anatomical distortions as well as environmental factors such as inflammation and oxidative stress. The aim of this study is to investigate the relationship between the severity of dysmenorrhea in patients with ovarian endometrioma (OMA) and cyst fluid (CF) concentrations of irons, including total iron, heme iron, and free iron. METHOD: Eighty-three patients who were histologically diagnosed with OMA were enrolled in the Department of Gynecology, Nara Medical University Hospital, between 2013 and 2019. The patients were divided into 4 groups according to the severity of dysmenorrhea: no pain, mild, moderate, and severe. Iron concentration was measured by the inductively coupled plasma optical emission spectrometry method. RESULTS: There were no significant differences among the 4 groups in variables such as age at diagnosis, preoperative CA125, preoperative CA19-9, cyst size, and tumor laterality (unilateral or bilateral). There was a positive correlation between the severity of dysmenorrhea and total iron (p < 0.001) and heme iron (p = 0.016) concentrations. Multiple regression analyses revealed that the CF concentration of total iron (hazard ratio 18.75, 95% confidence interval: 2.26-155.35, p = 0.007) was a significant independent variable associated with the severity of dysmenorrhea. A receiver operating characteristic curve analysis showed that a total iron exceeding 290.8 mg/L was associated with severe dysmenorrhea with a sensitivity of 90.9% and a specificity of 65.7%. LIMITATIONS: This study excluded patients with adenomyosis, superficial endometriosis, or deep endometriosis, resulting in a smaller number of cases. Iron levels could not be compared to the endometriosis stage using the r-ASRM score. CONCLUSIONS: There is no clear evidence that iron predicts the severity of endometriosis-related pain. However, iron may be closely associated with dysmenorrhea.

Revisiting estrogen-dependent signaling pathways in endometriosis: Potential targets for non-hormonal therapeutics.

Endometriosis is an estrogen-dependent gynecologic disease. Endometriotic cells survive in oxidative stress and hypoxic environments. The aim of this review is to reconsider new therapeutic strategies for endometriosis by focusing on estrogen signaling, ROS production and scavenging, and mitochondrial metabolism. Each keyword alone or in combination was used to search from PubMed and Embase by applying the filters of the title and the publication years between January 2000 and May 2020. Abnormal epigenetic marks of estrogen receptors (ERs) in endometriosis cause overexpression of ERß, progesterone resistance, inflammation, anti-apoptosis, and mitochondrial metabolic modification. In addition to hormonal action, estrogen is involved in various functions such as mitochondrial biosynthesis and energy metabolism. Estrogen works with its downstream target genes to modulate mitochondrial gene expression, regulate ROS production, and affect mitochondrial biology, including ATP production, antioxidant defenses, mitochondrial biosynthesis, quality control, and energy-transducing capacity. Endometriosis can shift mitochondrial metabolism from oxidative phosphorylation to aerobic glycolysis. This metabolic conversion suppresses ROS production and thus activates the survival signal of endometriotic cells. Therefore, molecules associated with aerobic glycolysis and mitochondrial metabolism are considered therapeutic targets for endometriosis. In conclusion, estrogen downstream target genes involved in mitochondrial metabolic biosynthesis may be potential targets for non-hormonal treatment of endometriosis.

Nonhormonal Treatment for Endometriosis Focusing on Redox Imbalance.

The aim of this review is to investigate the oxidant/antioxidant status and its regulatory mechanisms in patients with endometriosis and to summarize the antioxidant therapy as an alternative to hormonal therapy for endometriosis. Each keyword alone or in combination was used to search from PubMed and Embase by applying the filters of the title and the publication years between January 2000 and March 2020. Endometriosis is a chronic inflammatory disease characterized by repeated episodes of hemorrhage. Methemoglobin in repeated hemorrhage produces large amounts of superoxide anion via the autoxidation of hemoglobin. Excessive free-radical production causes redox imbalance, leading to inadequate antioxidant defenses and damage to endometrial cells, but may contribute to endometrial cell growth and survival through activation of various signaling pathways. In addition, to overcome excessive oxidative stress, estradiol participates in the induction of antioxidants such as superoxide dismutase in mitochondria. Several antioxidants that suppress free radicals may be effective in endometriosis-related pain. We searched for 23 compounds and natural substances that could reduce the pain caused by superoxide/reactive oxygen species in basic research and animal models. Next, we built a list of 16 drugs that were suggested to be effective against endometriosis other than hormone therapy in preclinical studies and clinical trials. Of the 23 and 16 drugs, 4 overlapping drugs could be potential candidates for clinically reducing endometriosis-related pain caused by superoxide anion/reactive oxygen species. These drugs include polyphenols (resveratrol and polydatin), dopamine agonists (cabergoline), and statins (simvastatin). However, no randomized controlled trials have evaluated the efficacy of these drugs. In conclusion, this review summarizes the following 2 points: superoxide anion generation by methemoglobin is enhanced in endometriosis, resulting in redox imbalance; and some compounds and natural substances that can suppress free radicals may be effective in endometriosis-related pain. Further randomized clinical trials based on larger series are mandatory to confirm the promising role of antioxidants in the nonhormonal management of endometriosis.

The Development of a New Uterine Manipulation Method during Minimally Invasive Radical Hysterectomy.

STUDY OBJECTIVE: The use of a vaginal uterine manipulator may compromise the oncological outcomes of patients with cervical cancer undergoing minimally invasive radical hysterectomy (MIS-RH). We aimed to describe the safety and efficacy of a novel uterine manipulation device during MIS-RH. DESIGN: Retrospective study. SETTING: A university hospital and a tertiary care hospital. PATIENTS: Patients with early-stage cervical cancer who were treated with MIS-RH. INTERVENTIONS: We developed the U-traction, a new device that consists of a 65-mm half-curved cutting needle with a 2.5-mm polyester tape (45-cm long), and investigated its utility to manipulate the uterus during MIS-RH. MEASUREMENTS AND MAIN RESULTS: This study describes the utility and safety of the U-traction for uterine manipulation during laparoscopic or robotic RH in 8 patients with cervical cancer. Uterine manipulation was successfully and safely performed using the U-traction during laparoscopic or robotic RH in patients with cervical cancer without any complications. The application time was less than 5 minutes. In all cases, the use of a vaginal manipulator, an additional incision for an extra port, or the need for assistant surgeons for uterine manipulation was avoided. CONCLUSION: The novel U-traction device allows for easy and reproducible uterine manipulation during MIS-RH. With this device, the use of a vaginal uterine manipulator can be avoided, and MIS-RH can be safely performed without the need for an assistant surgeon for uterine manipulation.

Relationship between adenomyosis and endometriosis; Different phenotypes of a single disease?

Adenomyosis and endometriosis are common gynecological disorders, but their pathophysiology is still under debate. The aim of this review is to discuss whether adenomyosis and endometriosis represent two different entities or different phenotypes of a single disease. We searched PubMed electronic databases published between January 2000 and April 2020. Endometriosis is classified into three phenotypes; superficial peritoneal disease (SUP), ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE) lesions. Adenomyosis presents several different subtypes, including intrinsic adenomyosis, extrinsic adenomyosis, adenomyosis externa and focal adenomyosis located in the outer myometrium (FAOM). Human uterus is embryologically composed of archimetra, originating from the Müllerian duct, and neometra, arising from the non-Müllerian duct, and adenomyosis and endometriosis are diseases of archimetra. The outer myometrial layer of the uterus is composed of highly differentiated smooth muscle cells (SMCs), while the inner myometrial cells are immature. Inappropriate uterine contractions can cause retrograde menstruation and chronic inflammation in the pelvic cavity, then influencing the development of pelvic endometriosis. Furthermore, hyperperistalsis results in physiological and pathological changes to the endometrial-myometrial junctional barrier, allowing invagination of the normal endometrial tissue into the inner myometrial layer. This can trigger the development of intrinsic adenomyosis. There are insufficient data available to draw conclusions, but extrinsic adenomyosis may result from pelvic endometriosis and FAOM from rectal and bladder DIE/adenomyosis externa. In conclusions, this paper contributes to the debate in the possibility that adenomyosis and endometriosis represent different phenotypes of a single disease.

Subtype I (intrinsic) adenomyosis is an independent risk factor for dienogest-related serious unpredictable bleeding in patients with symptomatic adenomyosis.

We aimed to retrospectively analyze the risk factors of a continuous dienogest (DNG) therapy for serious unpredictable bleeding in patients with symptomatic adenomyosis. This is a retrospective study based on data extracted from medical records of 84 women treated with 2 mg of DNG orally each day between 2008 and 2017. 47 subjects were excluded from the original analyses due to an inadequate subcategorization into subtype I and subtype II and a lack of hemoglobin levels. The influence of various independent variables on serious unpredictable bleeding was assessed. Of the 37 eligible patients who received the continuous DNG therapy, 14 patients experienced serious unpredictable bleeding. Univariate analysis revealed that the serious bleeding group had subtype I adenomyosis (P = 0.027). There was no correlation between age, parity, minimum hemoglobin level before treatment, previous endometrial curettage, and duration of DNG administration, or uterine or adenomyosis size and the serious bleeding. A DNG-related serious unpredictable bleeding is associated with the structural type of adenomyosis (subtype I) in patients with symptomatic adenomyosis.

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer.

Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies. We conducted a literature review for putative PARP sensitivity genes that are associated with the CCC pathophysiology. Previous studies identified a variety of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used as biomarkers or therapeutic targets for PARP inhibition. BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and PTEN were considered as candidate genes for synthetic lethality gene partners for PARP interactions. When considering the biological background underlying PARP inhibition, we hypothesized that PARP inhibitors would be a novel synthetic lethal therapeutic approach for CCC tumors harboring homologous recombination deficiency and activating oncogene mutations. The results showed that the majority of CCC tumors appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of CCC.