Lifestyle and fertility-specific quality of life affect reproductive outcomes in couples undergoing in vitro fertilization.

Objective: A Mediterranean dietary pattern, sleeping habits, physical activity, and lifestyle appear to affect reproductive health. There are few reports about whether fertility-specific quality of life (QOL) is linked to infertility treatment outcomes. The aim of this study is to investigate when lifestyle factors and fertility-specific QOL are comprehensively considered, which factors influence assisted reproductive technology (ART) outcomes. Methods: This prospective cohort includes 291 women undergoing a first ART treatment at multiple centers in Japan and was designed to evaluate the influence of diet, physical activity, sleeping pattern, computer use duration, and fertility-specific quality of life tool (FertiQoL) score on ART treatment outcomes using a questionnaire. The primary endpoint was the good-quality blastocyst rate per oocyte retrieval and the secondary endpoints were a positive pregnancy test and gestational sac (GS) detection. Results: The good-quality blastocyst rate per oocyte retrieval tended to be negatively associated with frequent fish consumption. After all embryo transfer (ET) cycles, a positive pregnancy test tended to be positively associated with longer sleep and longer computer use (OR = 1.6, 95% CI = 0.9-2.7 and OR = 1.7, CI = 1.0-2.8, respectively) and negatively associated with a smoking partner (OR = 0.6, CI = 0.3-1.0). GS detection was positively and significantly associated with frequent olive oil intake and longer computer use (OR = 1.7, CI = 1.0-3.0 and OR = 1.7, CI = 1.0-3.0, respectively). After ET cycles with a single blastocyst, a positive pregnancy test was positively and significantly associated with longer computer use (OR = 2.0, CI = 1.1-3.7), while GS detection was significantly more likely in women with longer computer use (OR = 2.1, CI = 1.1-3.8) and tended to be more likely in women with a higher FertiQoL Total scaled treatment score (OR = 1.8, CI = 1.0-3.3). p < 0.05 was considered statistically significant and 0.05 ≤ p <0.01 as tendency. Conclusions: Olive oil may be an important factor in dietary habits. Fertility-specific QOL and smoking cessation guidance for partners are important for infertile couples.

Cellular senescence of granulosa cells in the pathogenesis of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, but its pathology has not been fully characterized and the optimal treatment strategy remains unclear. Cellular senescence is a permanent state of cell-cycle arrest that can be induced by multiple stresses. Senescent cells contribute to the pathogenesis of various diseases, owing to an alteration in secretory profile, termed 'senescence-associated secretory phenotype' (SASP), including with respect to pro-inflammatory cytokines. Senolytics, a class of drugs that selectively eliminate senescent cells, are now being used clinically, and a combination of dasatinib and quercetin (DQ) has been extensively used as a senolytic. We aimed to investigate whether cellular senescence is involved in the pathology of PCOS and whether DQ treatment has beneficial effects in patients with PCOS. We obtained ovaries from patients with or without PCOS, and established a mouse model of PCOS by injecting dehydroepiandrosterone. The expression of the senescence markers p16INK4a, p21, p53, γH2AX, and senescence-associated ß-galactosidase and the SASP-related factor interleukin-6 was significantly higher in the ovaries of patients with PCOS and PCOS mice than in controls. To evaluate the effects of hyperandrogenism and DQ on cellular senescence in vitro, we stimulated cultured human granulosa cells (GCs) with testosterone and treated them with DQ. The expression of markers of senescence and a SASP-related factor was increased by testosterone, and DQ reduced this increase. DQ reduced the expression of markers of senescence and a SASP-related factor in the ovaries of PCOS mice and improved their morphology. These results indicate that cellular senescence occurs in PCOS. Hyperandrogenism causes cellular senescence in GCs in PCOS, and senolytic treatment reduces the accumulation of senescent GCs and improves ovarian morphology under hyperandrogenism. Thus, DQ might represent a novel therapy for PCOS.

Ulipristal (UPA) effects on rat ovaries: Unraveling follicle dynamics, ovulation inhibition, and safety implications for prolonged use.

Ulipristal (UPA), a selective progesterone receptor modulator, has both agonistic and antagonistic effects on progesterone receptors. UPA suppresses ovulation by inhibiting the luteinizing hormone (LH) surge from the pituitary gland; however, the direct effect of UPA on ovarian tissue remains poorly studied. In the present study, we examined the effects of UPA on the ovaries of rats. Rats were treated for 28 days with UPA, and the effects of UPA on ovarian tissue were examined histologically and the expression of antioxidant genes and cell death markers were also investigated. UPA treatment increased the number of primordial follicles at each treatment group, primordial follicles increased at all dose levels, but the size/magnitude of the effect decreased with the increasing dose. The number of primary and antral follicles tended to increase with increasing UPA levels. Furthermore, the decrease in primary follicle number could be attributed to the exhaustion of follicles, but the examination of proliferation markers, oxidative stress markers, and cell death markers revealed no remarkable toxic effects on ovarian tissues. These results suggest that UPA treatment promotes follicle development at each stage but inhibits ovulation by suppressing the LH surge, resulting in an increase in atretic follicles or unruptured luteinized cysts. These results suggest that UPA may not have both toxic effects on the ovary and a direct local effect on ovarian follicles, but we should be careful about the effects of prolonged UPA treatment in patients with uterine fibroids on their future fecundity.

The Association between Endometriosis and Obstructive Müllerian Anomalies.

It is unclear whether clinical background differs between endometriosis in adolescent patients with obstructive Müllerian anomalies and those without anomalies. The aim of the study is to identify the difference in clinical characteristics of endometriosis in patients with or without obstructive Müllerian anomalies. The study involved 12 patients aged under 24 years old who underwent primary surgery for obstructive Müllerian anomalies and 31 patients aged under 24 years old who underwent surgery for ovarian endometrioma. A total of 6 out of 12 cases with obstructive Müllerian anomalies developed endometriosis (4 Herlyn-Werner-Wunderlich syndrome, 2 non-communicating functional uterine horn, 2 cervical aplasia). The age at surgery was significantly younger in endometriosis with obstructive Müllerian anomalies, compared with those without obstructive Müllerian anomalies (17.8 ± 4.4 vs. 23.1 ± 1.3, p = 0.0007). The rate of endometrioma was 50.0% and the rate of hydrosalpinx was significantly higher (66.7% vs. 0%, p = 0.0002) in the group of obstructive Müllerian anomalies. The recurrence rate of endometriosis was 20.0% in the group of anomalies and 25.9% in the group of those without anomalies. Adolescent patients with obstructive Müllerian anomalies more easily developed endometriosis and co-occurred with higher rate of hematosalipinx.

Inhibition of protein arginine methyltransferase 6 activates interferon signaling and induces the apoptosis of endometrial cancer cells via histone modification.

Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multi­omics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIP­seq) and RNA sequencing (RNA­seq). The expression of PRMT6 in EC was analyzed using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6­knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIP­seq of H3K27ac antibodies and RNA­seq. Finally, the downstream targets identified by multi­omics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6­KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIP­seq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNA­seq data demonstrated altered interferon­related pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide­3­kinase regulatory subunit 1, following PRMT6­KD. RT­qPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6­KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.

Altered release of thrombomodulin and HMGB1 in the placenta complicated with preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a severe pregnancy complication due to placental dysfunction. Thrombomodulin (TM), a glycoprotein expressed on the trophoblast cell membrane, plays an organ-protective role in the placenta by regulating coagulation and inflammation. TM-mediated regulation of High Mobility Group Box1(HMGB1) is an essential mechanism that contributes to placental homeostasis and prevents pregnancy complications in mice. Here, we aimed to clarify the role of placental TM and HMGB1 in the pathophysiology of human PE. METHODS AND RESULTS: In this study, maternal blood serum and placental tissue were obtained from 72 PE patients and 110 normal controls. Soluble TM(sTM) and HMGB1 levels in the maternal serum were assessed. The placental TM and HMGB1 expression levels were evaluated using immunohistochemistry and qPCR. Serum sTM and HMGB1 levels gradually increased with gestational age in normal pregnancies; however, both circulating sTM and HMGB1 levels were significantly higher in the PE group. Serum HMGB1/sTM ratio was elevated in PE patients compared to that in normal controls, which correlated positively with the clinical severity of PE. The immunohistochemistry analysis revealed the loss of TM and the increase in extranuclear HMGB1. TM mRNA expression was diminished in PE placentas, which negatively correlated with soluble fms-like tyrosine kinase-1 (sFlt-1) expression. DISCUSSION: The increase in circulating sTM and HMGB1 could be attributed to the enhanced placental TM shedding in PE patients. The molecular events mediated by the imbalance in the placental TM and HMGB1 levels could be an underlying feature of PE; maternal serum HMGB1/sTM ratio could reflect this status.

Characteristic hysteroscopy appearance considerations for detecting uterine endometrial malignancies.

AIM: The effectiveness of hysteroscopy in diagnosing endometrial lesions has been demonstrated, showing high diagnostic accuracy for malignant endometrial lesions. Although the characteristic appearances of atypical and malignant endometria have been reported, they are not definitive and sometimes complicated. This study aimed to identify a small number of characteristic features to detect endometrial abnormalities using a simple judgment system and analyze the diagnostic characteristics and their accuracy in endometrial malignancy diagnosis. METHODS: We performed a retrospective analysis of hysteroscopy video data of 250 patients, of which we selected for analysis based on pathology examination 152 cases with benign changes, 16 with atypical endometrium, and 18 with carcinoma in situ or endometrial cancer. Endometrial characteristics assessed included protrusion, desquamation, extended vessel, atypical vessel, and white/yellow lesion. RESULTS: Multivariable analysis revealed that desquamation (p = 0.001, odds ratio [OR] 5.28), atypical vessels (p < 0.001, OR 8.50), and white/yellow lesions (p = 0.011, OR 1.37) were significant predictors for endometrial malignancy. From their contribution status, scoring points of 4, 6, and 1 were settled according to the odds ratio proportions. When scores ≥5 (at least both desquamation and white/yellow lesions or only atypical vessels) were used to define endometrial malignancy, sensitivity and specificity were 100% and 92%, respectively. When detecting cancer, atypical, and benign cases, sensitivity and specificity were 88% and 90%, respectively. CONCLUSION: Our characteristics hysteroscopic findings showed a higher predictive ability in detecting endometrial malignancies. However, further examination with more cases would be needed to accurately diagnose endometrial malignancy by hysteroscopy.

Survey on the implementation status and reproductive outcomes of oocyte and ovarian tissue cryopreservation in Japan: Historical comparison with nationwide surveys.

PURPOSE: To clarify the reproductive outcomes of fertility preservation (FP) treatment. METHODS: We conducted a mailed-in questionnaire survey at institutions certified by the Japan Society of Obstetrics and Gynecology to investigate the number of oocyte cryopreservations (OC) and ovarian tissue cryopreservations (OTC) performed from December 2016 to the end of 2020. And, we conducted a detailed investigation of cases in which frozen specimens were used during the investigation period, and made historical comparisons with previous nationwide studies. RESULTS: Responses were received from 114 out of 150 facilities (response rate: 76.0%) for OC and 43 out of 51 for OTC (response rate: 84.3%). Breast cancer was the most common disease among patients whose FP specimens were used. During the study period, 1237 OCs and 198 OTCs were performed. In addition, 57 cycles of embryo transfer (ET) using cryopreserved oocytes and 12 cases of ovarian tissue transplantation (OTT) were performed. The mean age of patients who underwent ET using cryopreserved oocytes was 34.8 (±5.8) years, with a median age of 36 years. The pregnancy rate per ET using cryopreserved oocytes was 26.3% and the live birth rate (LBR) was 17.5%. Further, the LBR per patient was 43.3%, and the pregnancy rate following OTTs was 33.3%. Also, controlled ovarian stimulation using the random start method or the combination of aromatase inhibitors had no effect on pregnancy outcome. CONCLUSION: Implementation of both OCs and OTCs have markedly increased over time in Japan, with comparable reproductive outcomes as other reports.

Efficacy and safety of a novel pain management device, AT-04, for endometriosis-related pain: study protocol for a phase III randomized controlled trial.

BACKGROUND: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia. METHODS: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications. DISCUSSION: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278).

Endometriosis is a chronic inflammatory disorder that negatively impacts reproductive health via endometriosis-related pain, infertility, and endometriosis-associated ovarian cancer. Although current therapeutic options for endometriosis are effective for the endometriosis-related pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. This is the first randomized controlled trial to investigate the efficacy and safety of a novel portable pain management device, AT-04, that incorporates a combination of mixed alternating magnetic fields, for endometriosis-related pain. This is a multicenter, prospective, sham device-controlled, double-blind, parallel study. Enrolled women will have undergone standard hormonal treatment for endometriosis at baseline, and this allows for assessing whether the device remains effective when used in conjunction with existing treatment methods. The study also will explore the impact of AT-04 on reducing the size of ovarian endometriotic cysts that reflect the activity of endometriosis. The study reflects the strong desire by physicians to liberate women from the unbearable pain associated with endometriosis. The sole efficacy of AT-04 in treating endometriosis-related pain is difficult to evaluate as there is a possibility that menstrual cycles may influence the assessment of pain and quality of life. However, the study findings regarding the effectiveness of AT-04 for the treatment of endometriosis-related pain may benefit women with endometriosis who have pain that is not effectively relieved by other treatments. Consequently, it may contribute to the improvement of reproductive health within society.

The automatic diagnosis artificial intelligence system for preoperative magnetic resonance imaging of uterine sarcoma.

OBJECTIVE: Magnetic resonance imaging (MRI) is efficient for the diagnosis of preoperative uterine sarcoma; however, misdiagnoses may occur. In this study, we developed a new artificial intelligence (AI) system to overcome the limitations of requiring specialists to manually process datasets and a large amount of computer resources. METHODS: The AI system comprises a tumor image filter, which extracts MRI slices containing tumors, and sarcoma evaluator, which diagnoses uterine sarcomas. We used 15 types of MRI patient sequences to train deep neural network (DNN) models used by tumor filter and sarcoma evaluator with 8 cross-validation sets. We implemented tumor filter and sarcoma evaluator using ensemble prediction technique with 9 DNN models. Ten tumor filters and sarcoma evaluator sets were developed to evaluate fluctuation accuracy. Finally, AutoDiag-AI was used to evaluate the new validation dataset, including 8 cases of sarcomas and 24 leiomyomas. RESULTS: Tumor image filter and sarcoma evaluator accuracies were 92.68% and 90.50%, respectively. AutoDiag-AI with the original dataset accuracy was 89.32%, with 90.47% sensitivity and 88.95% specificity, whereas AutoDiag-AI with the new validation dataset accuracy was 92.44%, with 92.25% sensitivity and 92.50% specificity. CONCLUSION: Our newly established AI system automatically extracts tumor sites from MRI images and diagnoses them as uterine sarcomas without human intervention. Its accuracy is comparable to that of a radiologist. With further validation, the system could be applied for diagnosis of other diseases. Further improvement of the system's accuracy may enable its clinical application in the future.

Increased risk of placenta previa and preterm birth in pregnant women with endometriosis/adenomyosis: A propensity-score matching analysis of a nationwide perinatal database in Japan.

AIM: We aimed to investigate the associations of endometriosis and adenomyosis with pregnancy complications by using a large-scale Japanese database. METHODS: We retrospectively analyzed 145 590 singleton pregnancies from the Japan Perinatal Registry Network Database. Pregnant women registered as having endometriosis or adenomyosis were designated as the case group (EA), whereas the control group (non-EA) was selected using propensity-score matching adjusted for variables such as age, parity, BMI, smoking history, and the use of assisted reproductive technology. The main outcomes included placental malposition, preterm birth, and hypertensive disorders of pregnancy (HDP). RESULTS: In total, 1203 patients from both the EA and non-EA groups were matched and evaluated. The EA group showed significantly higher rates of placenta previa (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.84-4.92), low-lying placenta (OR, 2.02; 95% CI, 1.06-3.86), and preterm birth (OR, 1.44; 95% CI, 1.13-1.84) than the non-EA group. However, no significant difference was observed in the incidence of HDP (OR, 1.22; 95% CI, 0.90-1.66). CONCLUSION: The use of propensity-score matching to analyze a nationwide perinatal database in Japan clarified that EA was associated with increased pregnancy complications, specifically placental malposition, including placenta previa and low-lying placenta, and preterm birth, but not with HDP.

Identification of target cells of human papillomavirus 18 using squamocolumnar junction organoids.

Human papillomavirus 18 (HPV18) is a highly malignant HPV genotype among high-risk HPVs, characterized by the difficulty of detecting it in precancerous lesions and its high prevalence in adenocarcinomas. The cellular targets and molecular mechanisms underlying its infection remain unclear. In this study, we aimed to identify the cells targeted by HPV18 and elucidate the molecular mechanisms underlying HPV18 replication. Initially, we established a lentiviral vector (HPV18LCR-GFP vector) containing the HPV18 long control region promoter located upstream of EGFP. Subsequently, HPV18LCR-GFP vectors were transduced into patient-derived squamocolumnar junction organoids, and the presence of GFP-positive cells was evaluated. Single-cell RNA sequencing of GFP-positive and GFP-negative cells was conducted. Differentially expressed gene analysis revealed that 169 and 484 genes were significantly upregulated in GFP-positive and GFP-negative cells, respectively. Pathway analysis showed that pathways associated with cell cycle and viral carcinogenesis were upregulated in GFP-positive cells, whereas keratinization and mitophagy/autophagy-related pathways were upregulated in GFP-negative cells. siRNA-mediated luciferase reporter assay and HPV18 genome replication assay validated that, among the upregulated genes, ADNP, FHL2, and NPM3 were significantly associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. Among them, NPM3 showed substantially higher expression in HPV-related cervical adenocarcinomas than in squamous cell carcinomas, and NPM3 knockdown of HPV18-infected cells downregulated stem cell-related genes. Our new experimental model allows us to identify novel genes involved in HPV18 early promoter activities. These molecules might serve as therapeutic targets in HPV18-infected cervical lesions.

Clinical characteristics and outcomes of women with adenomyosis pain during pregnancy: a retrospective study.

OBJECTIVES: Adenomyosis is associated with unfavorable perinatal outcomes, and recent case reports show that some women with adenomyosis experience pain at the adenomyosis lesion during pregnancy and have detrimental perinatal outcomes. This study aimed to clarify the clinical characteristics of this pain and perinatal outcomes associated with this phenomenon. METHODS: This was a single-center retrospective analysis of pregnant women with adenomyosis. The incidence of pain onset at adenomyosis lesions, defined as persistent pain at the adenomyosis site with administration of analgesics for pain relief, and its association with perinatal outcomes were analyzed. RESULTS: Among 91 singleton pregnancies with adenomyosis, 12 pregnancies (13.2 %) presented with pain. One pregnancy resulted in second-trimester miscarriage, and 5 of the 11 pregnancies (45 %) developed preeclampsia, which resulted in preterm delivery, and 3 of the 12 pregnancies (25 %) achieved term delivery. The incidence of preeclampsia and preterm delivery was higher in those who experienced pain than in those without (45 % [5/11] vs. 15 % [11/74]; p<0.05, and 73 % [8/11] vs. 34 % [25/74]; p<0.05, respectively). Among women with pain, the maximum C-reactive protein level was significantly higher in women who developed preeclampsia than in those who did not (5.45 vs. 0.12 mg/dL, p<0.05). CONCLUSIONS: Our study revealed that adenomyosis can cause pain in over one of eight pregnancies with adenomyosis, which may be associated with the increased incidence of preeclampsia resulting in preterm delivery. Women with pain, especially those with high C-reactive protein levels, may be at high risk for future development of preeclampsia and consequent preterm delivery.

The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency.

Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by permanent cell growth arrest, in the pathologies of various diseases. Moreover, several promising senolytics, including dasatinib and quercetin (DQ), which remove senescent cells, are being developed. In the present study, we investigated whether cellular senescence is involved in Cy-induced POI and whether DQ treatment rescues Cy-induced ovarian damage. Expression of the cellular senescence markers p16, p21, p53, and γH2AX was upregulated in granulosa cells of POI mice and in human granulosa cells treated with Cy, which was abrogated by DQ treatment. The administration of Cy decreased the numbers of primordial and primary follicles, with a concomitant increase in the ratio of growing to dormant follicles, which was partially rescued by DQ. Moreover, DQ treatment significantly improved the response to ovulation induction and fertility in POI mice by extending reproductive life. Thus, cellular senescence plays critical roles in Cy-induced POI, and targeting senescent cells with senolytics, such as DQ, might be a promising strategy to protect against Cy-induced ovarian damage.

Clinical outcomes of personalized blastocyst embryo transfer after endometrial receptivity analysis: A multicenter, retrospective cohort study.

Purpose: To evaluate clinical outcomes after endometrial receptivity analysis (ERA). Methods: This was a multicenter, retrospective cohort study involving 861 women who underwent ERA testing at certified fertility clinics in Japan, and who received subsequent personalized blastocyst embryo transfers (ET) between 2018 and 2020. Clinical outcomes, including pregnancies, miscarriages, and live births, were evaluated according to receptivity status for ERA. Results: Mean patient age was 37.7 years (SD = 4.0), and the median number of previous ETs was 2 (interquartile range, 2-3). 41.0% (353/861) of patients were non-receptive for ERA testing. Clinical pregnancy, miscarriage, and live birth rates for personalized blastocyst ET were 44.5% (226/508), 26.1% (59/226), and 26.8% (136/508) for receptive patients, and 43.1% (152/353), 28.3% (43/152), and 28.9% (102/353) for non-receptive patients, all statistically nonsignificant. Multiple logistic regression demonstrated similar nonsignificant associations between receptivity and clinical outcomes. Greater patient age, smoking, and longer duration of infertility were significantly and negatively associated with receptivity, whereas a history of delivery was positively associated and statistically significant. Conclusions: Clinical outcomes after ERA testing were similar between receptive and non-receptive patients. Further prospective study including an appropriate comparison group are warranted to evaluate the efficacy of ERA testing.

Characterization of a fluorescence imaging probe that exploits metabolic dependency of ovarian clear cell carcinoma.

The purpose of this study is to clarify the metabolic dependence of ovarian clear cell carcinoma (CCC) by comparing normal tissues and to examine the applicability of fluorescence imaging probe to exploit these metabolic differences. Enhanced glutathione synthesis was supported by the increased uptake of related metabolites and elevated expression levels of genes. Accumulation of intracellular iron and lipid peroxide, induction of cell death by inhibition of the glutathione synthesis pathway indicated that ferroptosis was induced. The activation of γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent imaging probe that recognizes γ-glutamyl transferase, which is essential for the synthesis of glutathione, was investigated in fresh-frozen surgical specimens. gGlu-HMRG detected extremely strong fluorescent signals in the tumor lesions of CCC patients, compared to normal ovaries or endometrium. These results revealed that CCC occurs in the stressful and unique environment of free radical-rich endometrioma, and that glutathione metabolism is enhanced as an adaptation to oxidative stress. Furthermore, a modality that exploits these metabolic differences would be useful for distinguishing between CCC and normal tissues.

Cancer of unknown primary histologically, genetically and spatially diagnosed as left ovary­derived cancer: A case report.

Cancer of unknown primary (CUP) is a heterogeneous syndrome of metastatic cancer in which the primary site cannot be determined even after a standard and comprehensive search. The present report describes a case in which the spatial distribution of the lymph node metastases contributed to the identification of the primary site. While the standard workup did not identify the primary tumor, genomic profiling analysis was useful in therapeutic management. A 68-year-old woman presented with a cancerous pleural effusion (adenocarcinoma). The primary site could not be identified, and the pleural effusion resolved spontaneously. After 11 months, the patient had elevated Krebs von den Lungen-6 and cancer antigen 125 levels, and multiple enlarged lymph nodes. Pathological diagnosis based on a biopsy sample of the para-aortic lymph nodes indicated that the tumor was a high-grade serous carcinoma of possible gynecological organ origin. The patient underwent surgery, including hysterectomy, bisalpingo-oophorectomy and lymph node dissection. Although there were no primary sites in the gynecological organs, marked lymphovascular invasion was found around the left ovary, suggesting a left ovary-derived tumor. Genetic testing revealed a high loss of heterozygosity score and high tumor mutational burden (TMB). The patient received paclitaxel and carboplatin therapy followed by a poly ADP-ribose polymerase inhibitor as regimens for ovarian cancer and achieved complete remission. The unique course of the disappearance of the effusion and the absence of tumor in the adnexa might be associated with the high immunogenicity of the tumor characterized by the high TMB. This case may provide insights into the pathogenesis of CUP.

Differences in the incidence of obstetric complications depending on the extent and location of adenomyosis lesions.

OBJECTIVES: Although adenomyosis is reportedly associated with adverse pregnancy outcomes, clinical factors related to the high risk of obstetric complications are unclear. This study aimed to elucidate the characteristics of adenomyosis lesions associated with the increased incidence of obstetric complications based on imaging findings. METHODS: This was a retrospective, observational cohort study conducted in a tertiary perinatal care center. Eighty-eight singleton pregnant women with adenomyosis were included in the study. Based on magnetic resonance imaging or ultrasonography before and/or during pregnancy, patients were classified according to three types of image characteristics: the extent of adenomyosis lesion (focal type or diffuse type), location of the lesion (extrinsic type, intrinsic type, or indeterminate type), the positional relationship between the lesion and the placenta (placenta distant from adenomyosis or placenta over adenomyosis), and the incidence of obstetric complications were examined. RESULTS: Patients with diffuse type adenomyosis are significantly more likely to have spontaneous second-trimester miscarriage (diffuse type vs. focal type: 16.7 vs. 0%, p < .01), preterm premature rupture of membranes (19.4 vs. 1.9%, p < .01), and preeclampsia (25.0 vs. 7.7%, p = .02), as compared to those with focal type adenomyosis. In a comparison of the three location types, the incidence of placental malposition was higher in patients with the extrinsic type adenomyosis (extrinsic type vs. intrinsic type vs. indeterminate type: 20.0 vs. 6.7 vs. 2.3%, p = .03). Comparisons between the types of the placenta over or distant from adenomyosis lesion displayed no significant differences in the frequencies of obstetric complications. CONCLUSIONS: We demonstrated that the frequency of obstetric complications related to adenomyosis varies depending on the extent and location of the lesion; patients with diffuse type adenomyosis have an increased risk of spontaneous second-trimester miscarriage, preterm premature rupture of membranes, and preeclampsia, while patients with extrinsic type adenomyosis have an increased risk of placental malposition. Imaging evaluation of adenomyosis prior to conception or early in pregnancy may be useful for the obstetrical risk assessment among patients with adenomyosis.

The sFlt-1/PlGF Ratio Trend Is Useful in Predicting Preeclampsia Severity in Hyperreactio Luteinalis Complicated with Preeclampsia.

Hyperreactio luteinalis (HL) is a rare condition that presents as bilateral ovarian enlargement during pregnancy. Typically, it is thought to be caused by increased production of human chorionic gonadotropin (hCG) associated with gestational trophoblastic diseases or multiple pregnancies. The prognosis is relatively good, with many cases resulting in term birth. However, some obstetric complications, such as preeclampsia (PE) and preterm births, have been reported. We present a serious case of HL with subsequent PE that resulted in preterm delivery at 31 weeks of gestation. The soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio was very high at the onset of PE at 24 weeks of gestation, followed by a modest decline, which then increased in proportion to the exacerbation of symptoms. Since HL cases have also been reported to be associated with PE, repeated measurement of the sFlt-1/PlGF ratio proved useful for better pregnancy management.

Possible risks and benefits of adenomyomectomy on pregnancy outcomes: a retrospective analysis.

BACKGROUND: Adenomyosis is associated with unfavorable perinatal outcomes; however, the effect of an adenomyomectomy on pregnancy outcomes remains unclear. Pregnancy following an adenomyomectomy has been reported to be associated with a high risk for uterine rupture; however, the actual incidence remains unknown. OBJECTIVE: This study aimed to evaluate the effect of an adenomyomectomy on pregnancy outcomes by retrospectively comparing the pregnancy outcomes of women who underwent an adenomyomectomy with those of women with adenomyosis. STUDY DESIGN: This was a single-center retrospective study in which the pregnancy outcomes of women who underwent an adenomyomectomy and for whom complete resection of the affected tissue under laparotomy was achieved were compared with those of women with adenomyosis. The following pregnancy outcomes were examined: second-trimester miscarriage, preterm prelabor rupture of membranes, preterm delivery, spontaneous preterm delivery, preeclampsia, rate of cesarean delivery, blood loss during cesarean delivery, incidence of placenta accreta spectrum, neonatal body weight, and small for gestational age infants. RESULTS: A total of 18 pregnant women who underwent an adenomyomectomy and 105 pregnant women with adenomyosis were included in this study. All women who underwent an adenomyomectomy delivered via cesarean delivery, and among them, 1 had a uterine rupture at 30 weeks of gestation. Although there was no significant difference between pregnant women who underwent an adenomyomectomy and those with adenomyosis in the incidence of second-trimester miscarriage (0% [0/18] vs 7.6% [8/105], respectively; P=.22), preterm delivery (50% [9/18] vs 32% [34/105], respectively; P=.15), and spontaneous preterm delivery (6% [1/18] vs 15% [16/105], respectively; P=.26), a significant decrease in preterm prelabor rupture of membrane (0% [0/18] vs 12% [13/105], respectively; P<.05), preeclampsia (0% [0/18] vs 12% [13/105], respectively; P<.05), and small for gestational infants (0% [0/18] vs 15% [16/105], respectively; P<.05), as well as a significant increase in the incidence of placenta accreta spectrum (50% [9/18] vs 0% [0/105], respectively; P<.01) and blood loss during cesarean delivery (1748 mL vs 1330 mL, respectively; P<.05) were observed. CONCLUSION: Uterine rupture following an adenomyomectomy may occur because of the high incidence of placenta accreta spectrum. However, an adenomyomectomy may reduce adverse pregnancy outcomes associated with adenomyosis, such as preterm prelabor rupture of membranes, preeclampsia, and small for gestational age infants. An adenomyomectomy may be a viable option for women among whom the procedure is inevitable before conception.