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Presents both cases of bilateral multicystic dysplastic kidney (MCDK) and unilateral MCDK in fetuses. Sonographic findings; Development of Potter's syndrome with Potter IIA type kidneys in the case of bilateral MCDK; Importance of ascertaining if the MCDK is unilateral or bilateral to avoid an unnecessary caesarean section and unavoidable neonatal death.

Abstract Background Theca cells play an important role in controlling ovarian steroidogenesis by providing aromatizable androgens for granulosa cell estrogen biosynthesis. Although it is well established that the steroidogenic activity of theca cells is mainly regulated by LH, the intracellular signal transduction mechanisms that regulate thecal proliferation and/or steroidogenesis remain obscure. In this study, we examined whether and how LH controls the PI3K/Akt signaling pathway and androgen production in bovine theca cells. We also explored whether this LH-induced PI3K/Akt activation is modulated with other signaling pathways (i.e. PKA and MAPK). Methods Ovarian theca cells were isolated from bovine small antral follicles and were incubated with LH for various durations. Phospho-Akt and total-Akt content in the cultured theca cells were examined using Western blotting. Androstenedione levels in the spent media were determined using EIA. Semi-quantitative RT-PCR analyses were conducted to analyze the mRNA levels of CYP17A1 and StAR in the theca cells. To examine whether Akt activity is involved in theca cell androgen production, the PI3K inhibitors wortmannin and LY294002 were also added to the cells. Results Akt is constitutively expressed, but is gradually phosphorylated in cultured bovine theca cells through exposure to LH. LH significantly increased androstenedione production in bovine theca cells, whereas addition of the wortmannin and LY294002 significantly decreased LH-induced androstenedione production. LH significantly increased CYP17A1 mRNA level in theca cells, whereas addition of LY294002 significantly decreased LH-induced CYP17A1 expression. Neither LH nor PI3K inhibitors alter the mRNA levels of StAR in theca cells. Although H89 (a selective inhibitor of PKA) does not affect LH-mediated changes in Akt, U0126 (a potent MEK inhibitor) suppressed LH-induced Akt phosphorylation, CYP17A1 expression, and androgen production in theca cells. Conclusion These results indicate that LH stimulates CYP17 mRNA expression and androgen production in theca cells via activation of the PI3K/Akt pathway. The LH-induced Akt phosphorylation and androgen production are modulated by the MAPK signaling in bovine theca cells.

Abstract The preantral-early antral follicle transition is the penultimate stage of follicular development in terms of gonadotropin dependence and follicle destiny (growth versus atresia). Follicular growth during this period is tightly regulated by oocyte-granulosa-theca cell interactions. Formation of the theca cell layer is a key event that occurs during this transitional stage. Granulosal factor(s) stimulates the recruitment of theca cells from cortical stromal cells, while oocyte-derived growth differentiation factor-9 (GDF-9) is involved in the differentiation of theca cells during this early stage of follicular development. The preantral to early antral transition is most susceptible to follicular atresia. GDF-9 promotes follicular survival and growth during transition from preantral stage to early antral stage by suppressing granulosa cell apoptosis and follicular atresia. GDF-9 also enhances preantral follicle growth by up-regulating theca cell androgen production. Thecal factor(s) promotes granulosa cell proliferation and suppress granulosa cell apoptosis. Understanding the intraovarian mechanisms in the regulation of follicular growth and atresia during this stage may be of clinical significance in the selection of the best quality germ cells for assisted reproduction. In addition, since certain ovarian dysfunctions, such as polycystic ovarian syndrome and gonadotropin poor-responsiveness, are consequences of dysregulated follicle growth at this transitional stage, understanding the molecular and cellular mechanisms in the control of follicular development during the preantral-early antral transition may provide important insight into the pathophysiology and rational treatment of these conditions.

The article presents a case study of a 45-year-old woman with a vaginal hysterectomy for multiple leiomyomas of the uterus which were found in the form of a pelvic mass. The tumor was being fed from the peritoneal vessels and was removed without any traces of cancerous growth. Leiomyomas usually grow in the lungs, lymph nodes and heart. However, when a parasitic leiomyoma detaches itself from its original location, it attaches itself to the pelvic organs.

Background: The increasing trend of cervical cancer in women in their 20s in Japan is largely attributable to the low rate of cervical cancer screening. This study aimed to assess the usefulness of human papillomavirus (HPV) self-sampling among 24-year-old Japanese women who had never previously been screened for cervical cancer during the coronavirus disease (COVID-19) pandemic., Methods: In August 2021, consenting eligible women received HPV self-sampling kits. An Evalyn brush was used for self-sampling, and a Cobas 4800 PCR-based HPV DNA test was used to detect high-risk HPV genotypes. We analyzed the return rates of self-sampling kits and conducted a survey on the acceptability of the self-sampling method., Results: Of the total 1997 eligible women, 13.4% (268/1997) agreed to participate. The return rate of the kits was 72.4% (194/268), corresponding to 9.7% of the eligible population. Among the participants who returned the kits, 14.9% (29/194) tested positive for HPV, and 41.4% (12/29) of these underwent subsequent cytological testing. The questionnaire results indicated that 57.8% of participants reported no pain during self-sampling, and 72.9% expressed a willingness to continue using the self-sampling method in the future., Conclusion: This study demonstrated that opt-in HPV self-sampling among 24-year-old women who had never been screened for cervical cancer had a favorable kit return rate and was well accepted by the participants, especially during the COVID-19 pandemic. However, the follow-up cytology test rates were low, highlighting the need for improved post-screening management.

Background: Nutritional status is an important factor influencing toxicity of treatment. Nutritional assessment indicators such as the Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT) score and modified Glasgow Prognostic Score (mGPS) have been reported to be associated with treatment-related adverse events (AEs) for various malignancies. However, there are no reports investigating the relationship between nutritional status and AEs from poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which are widely used in recent years as maintenance therapy for ovarian cancer., Objective: The primary objective was to investigate the usefulness of nutritional assessment indicators in predicting treatment discontinuation due to AEs from PARPi., Methods: This multicenter retrospective study included patients diagnosed with ovarian cancer who received maintenance therapy with PARPi from January 2018 to December 2023. PNI, CONUT score, and mGPS were calculated based on hematological parameters measured within 7 days before the start of PARPi therapy., Results: A total of 272 patients received maintenance therapy with PARPi during the period, but due to the absence of the blood collection of albumin levels within one week or other exclusion criteria, 71 patients were finally included in this analysis. AEs were seen in 59 patients (83.1%), including 25 (35.2%) severe events (grade ≥3 in Common Terminology Criteria for Adverse Events v5.0). Eighteen patients (25.4%) discontinued treatment due to PARPi-related AEs. Low PNI (<48.44) and high mGPS (≥1) were predictors of treatment discontinuation in both univariate and multivariate analyses. CONUT was not a significant predictor in this study., Conclusions: Our study suggested that PNI and mGPS can predict the risk of treatment discontinuation due to PARPi-related AEs before starting maintenance therapy. This insight opens avenues for more personalized treatment plans, potentially improving patient outcomes.

Introduction: Uterine adenosarcoma (UA) is a rare malignant mesenchymal neoplasm characterized by benign epithelial and malignant stromal components. Comprehensive genomic profiling has identified a high frequency of murine double-minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) amplification in UA. However, the significance of these genetic alterations in tumor biology remains poorly understood. This report presents a case of UA with immunohistochemically positive MDM2 and CDK4 expression., Case Presentation: The patient was a 72-year-old woman with a history of genital bleeding. Magnetic resonance imaging revealed an 11 × 5 × 7 cm mass in the endometrial cavity, extending into the uterine cervix. Biopsy of the tumor showed no malignant findings. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Microscopically, the tumor consisted of benign glandular epithelial components and low-grade sarcoma. The diagnosis was UA stage IA, pT1aNxM0. No sarcomatous overgrowth and no myometrial or lymphovascular invasions were observed. Immunohistochemistry confirmed MDM2 and CDK4 expression in the mesenchymal tissue. No recurrence was observed 12 months post-surgery., Conclusion: The pathological diagnosis of UA was based on histomorphological features. This study demonstrates that immunohistochemistry for MDM2 and CDK4 can help elucidate the molecular genetic features of UA. Further studies are needed to correlate the expression of these genes with the biological behavior of UA., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Sex steroid hormones, primarily synthesized by gonadal somatic cells, are pivotal for sexual development and reproduction. Mice studies have shown that two transcription factors, steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1), are involved in gonadal development. However, their role in human gonadal somatic differentiation remains unclear. We therefore aimed to investigate the roles of SF-1 and WT1 in human gonadal steroidogenic cell differentiation., Methods: Using a transient lentivirus-mediated gene expression system, we assessed the effects of SF-1 and WT1 expression on the steroidogenic potential of human amniotic membrane-derived mesenchymal stem cells (hAmMSCs)., Results: SF-1 and WT1-KTS, a splice variant of WT1, played distinct roles in human steroidogenic differentiation of hAmMSCs. SF-1 induced hAmMSC differentiation into progesterone- and androgen-producing cell lineages, whereas WT1-KTS promoted hAmMSC differentiation into estrogen-producing cell lineages., Conclusion: Our findings revealed that SF-1 and WT1-KTS play important roles in human gonadal steroidogenic cell differentiation, especially during ovarian development. These findings may pave the way for future studies on human ovarian differentiation and development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Miyazaki, Orisaka, Fujita, Mizutani, Yazawa and Yoshida.)

Recent studies show increased expression of human epidermal growth factor receptor 2 (HER2) in cervical cancer, but the efficacy of anti-HER2 therapy remains under-researched. Here, we present a case of recurrent HER2-positive serous carcinoma, presumably arising in the cervix, diagnosed by comprehensive genomic profiling, which responded to trastuzumab. The patient underwent a radical hysterectomy with concurrent adjuvant chemoradiotherapy. One year after surgery, the patient experienced recurrence (multiple lymph node metastases). She underwent chemotherapy and subsequent comprehensive genomic profiling, which revealed HER2 positivity. Despite treatment, the lymph node and peritoneal metastases progressed. Therefore, combination chemotherapy with paclitaxel and trastuzumab was initiated. Subsequently, the patient's clinical symptoms improved considerably, and good health was maintained for 8 months. This report highlights the importance of comprehensive genomic profiling and targeted therapies when standard treatments fail., (© 2024 The Author(s). Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Endometrial cancer (EC) in women is increasing globally, necessitating improved diagnostic methods and prognosis prediction. While endometrial histology is the conventional approach, liquid-based endometrial cytology may benefit from novel analytical techniques for cell clusters. A clinical study was conducted at the University of Fukui Hospital from 2012 to 2018, involving 210 patients with endometrial cytology. The liquid-based cytology images were analyzed using cell cluster analysis with Image J software. Logistic regression, ROC analysis, and survival analysis were employed to assess the diagnostic accuracy and prognosis between cell cluster analysis and EC/atypical endometrial hyperplasia (AEH). Circularity and fractal dimension demonstrated significant associations with EC and AEH, regardless of age and cytology results. The ROC analysis revealed improved diagnostic accuracy when combining fractal dimension with cytology, particularly in menopausal age groups. Lower circularity and solidity were independently associated with poor overall survival, while higher fractal dimension values correlated with poorer overall survival in Grades 2 and 3 endometrial cancers. The combination of circularity and fractal dimension with cytology improved diagnostic accuracy for both EC and AEH. Moreover, circularity, solidity, and fractal dimension may serve as prognostic indicators for endometrial cancer, contributing to the development of more refined screening and diagnostic strategies.

Background: Placenta accreta spectrum (PAS) cesarean hysterectomy is performed under conditions of shock and can result in serious complications. This study aimed to evaluate the usefulness of the "Holding-up uterus" surgical technique with a shock index (S.I.) > 1.5., Methods: Twelve patients who underwent PAS cesarean hysterectomy were included in the study., Results: Group I had S.I. > 1.5, and group II had S.I. ≤ 1.5. Group I had more complications, but none were above Grade 3 or fatal. Preoperative scheduled uterine artery embolization did not result in serious complications, but three patients who had emergency common iliac artery balloon occlusion (CIABO) and a primary total hysterectomy with S.I. > 1.5 had postoperative Grade 2 thrombosis. Two patients underwent manual ablation of the placenta under CIABO to preserve the uterus, both with S.I. > 1.5., Conclusions: The study found that the "Holding-up uterus" technique was safe, even in critical situations with S.I. > 1.5. CIABO had no intervention effect. The study also identified assisted reproductive technology pregnancies with a uterine cavity length of less than 5 cm before conception as a critical factor., (© 2024. The Author(s).)

The ovarian microenvironment is critical for follicular development and oocyte maturation. Maternal conditions, including polycystic ovary syndrome (PCOS), endometriosis, and aging, may compromise the ovarian microenvironment, follicular development, and oocyte quality. Chronic low-grade inflammation can induce oxidative stress and tissue fibrosis in the ovary. In PCOS, endometriosis, and aging, pro-inflammatory cytokine levels are often elevated in follicular fluids. In women with obesity and PCOS, hyperandrogenemia and insulin resistance induce ovarian chronic low-grade inflammation, thereby disrupting follicular development by increasing oxidative stress. In endometriosis, ovarian endometrioma-derived iron overload can induce chronic inflammation and oxidative stress, leading to ovarian ferroptosis and fibrosis. In inflammatory aging (inflammaging), senescent cells may secrete senescence-associated secretory phenotype factors, causing chronic inflammation and oxidative stress in the ovary. Therefore, controlling chronic low-grade inflammation and fibrosis in the ovary would present a novel therapeutic strategy for improving the follicular microenvironment and minimizing ovarian dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Orisaka, Mizutani, Miyazaki, Shirafuji, Tamamura, Fujita, Tsuyoshi and Yoshida.)

The effect on survival of radiographic lymph node metastasis in uterine cervical cancer patients is more important than before, even though its prognostic value not been well investigated. The aim of our study is to evaluate the prognostic potential of 18 F-fluorodeoxyglucose Positron Emission Tomography ( 18 F-FDG PET) compared with Computed Tomography (CT) in uterine cervical cancer patients with stage IIICr allocated by imaging. Fifty-five patients with biopsy-proven primary cervical cancer underwent definitive radiation therapy for stages IIB-IVB of The International Federation of Gynecology and Obstetrics (FIGO) 2018 classifications. The prognostic performance of pretreatment 18 F-FDG PET and CT for assessing lymph node metastasis was evaluated by two experienced readers. The PET and CT findings were correlated with the risk of progression-free survival (PFS) and overall survival (OS). Kaplan-Meier survival curves showed that PFS was significantly worse in patients with positive lymph nodes on 18 F-FDG PET than in those patients with negative lymph nodes on 18 F-FDG PET (p = 0.003), whereas there was no significant difference in PFS between patients with lymph nodes sized ≥ 1 cm and those sized < 1 cm (p = 0.140). Univariate analysis showed that positive lymph nodes on 18 F-FDG PET was significantly associated with poor PFS (p = 0.006), whereas lymph node size was not significantly associated with poor PFS (p = 0.145). In multivariate analysis, positive lymph nodes on 18 F-FDG PET was significantly associated with poor PFS (p = 0.006) and was an independent prognostic factor for PFS. 18 F-FDG PET offers high prognostic value for patients with stage IIICr allocated by imaging compared with CT, suggesting that 18 F-FDG PET might be useful in clinical staging decisions and thus promote optimal diagnostic and therapeutic strategies., (© 2023. The Author(s).)

The coronavirus disease (COVID-19) pandemic has raised concerns about the impact of delayed health check-ups and cancer screenings on cancer diagnosis and treatment. This study aimed to investigate the awareness of cancer patients on future screening measures during the pandemic in rural Japan. An anonymized open-data survey was undertaken in Fukui Prefecture, a rural region of Japan, in 2021. Participants were asked about their cancer screening history, screening frequency during the pandemic, and reasons for not undergoing screening. Among the 1262 respondents, the proportion of patients who underwent cancer screening in 2020 during the pandemic was similar to the proportion who underwent regular (annual or biannual) screening in 2019 before the pandemic. Of those who underwent regular screening, 82% still underwent screening in 2020, while only 21% of those who had irregular screenings. The number of respondents who believed they were healthy and did not require screening increased over time, possibly due to restrictions on going out and refraining from activities during the pandemic. This study in rural Japan found that regular cancer screening prior to the pandemic was associated with a more positive attitude toward screening during the pandemic. Raising awareness about the importance of cancer screening and encouraging participation is crucial for promoting positive attitudes in the future. The findings highlight the need for continued efforts to ensure access to screening services during the pandemic and future public health emergencies., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Infant stimuli attract caregiver attention and motivate parenting behavior. Studies have confirmed the existence of attentional bias toward infant face stimuli; however, relatively little is known about whether attentional bias exists for infant cry stimuli, which are as important as faces in child-rearing situations. Furthermore, scarce longitudinal evidence exists on how attentional bias toward infant crying changes through the postpartum period., Methods: In the present study, we conducted an experiment to assess bias toward infant crying at two postpartum time points: at Time 1 (Mean = 75.24 days), 45 first-time mothers participated and at Time 2 (Mean = 274.33 days), 30 mothers participated. At both time points, the mothers participated in a Stroop task with infant crying and white noise as the stimuli. They were instructed to answer the color out loud as quickly and accurately as possible, while ignoring the sound. Four types of audio stimuli were used in this task (the cry of the mother's own infant, the cry of an unfamiliar infant, white noise matched to the cry of the mother's own infant, and white noise matched to the cry of an unfamiliar infant), one of which was presented randomly before each trial. Response time and the correct response rate for each condition were the dependent variables., Results: For response time, the main effect of familiarity was significant, with longer response times when the participant's infant's cry was presented. In addition, response times were lower at Time 2 than at Time 1 in some conditions in which crying was presented., Discussion: The results suggest that mothers may be less disturbed by infant crying as they gain more experience. Elucidating the characteristics of postpartum mothers' changes in cognitive performance related to infants' cries would be useful in fundamental and applied research to understand the process of parents' adaptation to parenting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hiraoka, Makita, Sakakibara, Morioka, Orisaka, Yoshida and Tomoda.)

Background: This study aimed to evaluate whether "visiting restrictions" implemented due to the coronavirus disease 2019 (COVID-19) pandemic are a risk factor for postpartum depression using the Edinburgh Postnatal Depression Scale (EPDS)., Methods: This case-control study participants who gave birth during the spread of COVID-19 (COVID-19 study group) and before the spread of COVID-19 (control group). Participants completed the EPDS at 2 weeks and 1 month after childbirth., Results: A total of 400 cases (200 in each group) were included in this study. The EPDS positivity rate was significantly lower with visiting restrictions than without (8.5% vs.18.5%, p = 0.002). Multivariate analysis of positive EPDS screening at the 1st month checkup as the objective variable revealed that visiting restrictions (odds ratio (OR): 0.35, 95% confidence interval (CI): 0.18-0.68), neonatal hospitalization (OR: 2.17, 95% CI: 1.08-4.35), and prolonged delivery (OR: 2.87, 95% CI: 1.20-6.85) were factors associated with an increased risk of positive EPDS screening., Conclusion: Visiting restrictions on family during the hospitalization period for delivery during the spread of COVID-19 pandemic did not worsen EPDS screening scores 1 month postpartum, but stabilized the mental state of some mothers., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Mature and immature teratomas are differentiated based on tumor markers and calcification or fat distribution. However, no study has objectively quantified the differences in calcification and fat distributions between these tumors. This study aimed to evaluate the diagnostic potential of CT-based textural analysis in differentiating between mature and immature teratomas in patients aged < 20 years., Materials and Methods: Thirty-two patients with pathologically proven mature cystic (n = 28) and immature teratomas (n = 4) underwent transabdominal ultrasound and/or abdominal and pelvic CT before surgery. The diagnostic performance of CT for assessing imaging features, including subjective manual measurement and objective textural analysis of fat and calcification distributions in the tumors, was evaluated by two experienced readers. The histopathological results were used as the gold standard. The Mann-Whitney U test was used for statistical analysis., Results: We evaluated 32 patients (mean age, 14.5 years; age range, 6-19 years). The mean maximum diameter and number of calcifications of immature teratomas were significantly larger than those of mature cystic teratomas (p < 0.01). The mean number of fats of immature teratomas was significantly larger than that of mature cystic teratomas (p < 0.01); however, no significant difference in the maximum diameter of fats was observed. CT textural features for calcification distribution in the tumors showed that mature cystic teratomas had higher homogeneity and energy than immature teratomas. However, immature teratomas showed higher correlation, entropy, and dissimilarity than mature cystic teratomas among features derived from the gray-level co-occurrence matrix (GLCM) (p < 0.05). No significant differences were observed in the CT features of fats derived from GLCM., Conclusion: Our results demonstrate that calcification distribution on CT is a potential diagnostic biomarker to discriminate mature from immature teratomas, thus enabling optimal therapeutic selection for patients aged < 20 years., (© 2023. BioMed Central Ltd., part of Springer Nature.)

BACKGROUND Spontaneous hemoperitoneum in pregnancy (SHiP), defined as nontraumatic, acute intra-abdominal bleeding during pregnancy or the postpartum period, is a serious life-threatening complication to mother and child. Endometriosis is a major risk factor for SHiP. This study presents the case of a 41-year-old woman with adenomyosis who developed hemoperitoneum due to endometriosis at 28 weeks of pregnancy. CASE REPORT The patient was a 41-year-old woman (gravida 1, para 0) who conceived via artificial insemination. She had diffuse adenomyosis in the posterior uterine wall and was admitted to our hospital at 12 weeks of gestation with persistent lower abdominal pain. She had started treatment with hydroxyprogesterone caproate to reduce the focal inflammation of adenomyosis. At 28 weeks of gestation, she developed severe lower abdominal pain, and ultrasonography revealed prolonged fetal heart rate deceleration. An emergency cesarean delivery was performed, and a 907 g female infant with an Apgar score of 2/3 was delivered. Umbilical artery blood pH was 7.15. Bleeding from the veins surrounding an endometriotic lesion on the posterior wall of the uterus was observed, and SHiP was diagnosed. CONCLUSIONS Pregnancies complicated by endometriosis or adenomyosis require perinatal management, considering the possibility of SHiP complication. If acute abdominal pain and fetal heart rate deceleration occur during pregnancy, a search for intra-abdominal bleeding should be performed and emergent open hemostasis or cesarean delivery should be considered.

Aims: To elucidate the influence of the time-intervals between the onset and arrival (TIME 1), onset and delivery (TIME 2), and the decision to deliver and delivery (TIME 3) on severe adverse outcomes of offspring born to mothers complicated by placental abruption outside the hospital., Methods: This is a multicenter nested case-control study about placental abruption at Fukui Prefecture, a regional area in Japan, through 2013 to 2017. Multiple pregnancy, fetal or neonatal congenital abnormality, and unknown detailed information at onset of placental abruption were excluded. A composite of perinatal death and cerebral palsy or death at 18-36 months of corrected age was defined as the adverse outcome. The relationship between time-intervals and the adverse outcome was analyzed., Results: The 45 subjects for analysis were divided into two groups, including a group with and without adverse outcome (poor, n = 8; and good, n = 37). TIME 1 was longer in the poor group (150 vs. 45 min, p < 0.001). A subgroup analysis targeted to 29 cases with preterm birth at the third trimester indicates that TIME 1 and TIME 2 were longer in the poor group (185 vs. 55 min, p = 0.02; and 211 vs. 125 min, p = 0.03), while TIME 3 was shorter in the poor group (21 vs. 53 min, p = 0.01)., Conclusions: Long time-intervals between onset and arrival or onset and delivery may be correlated with perinatal death or cerebral palsy in surviving infants affected by placental abruption., (© 2023 Japan Society of Obstetrics and Gynecology.)

Steroidogenesis in ovarian granulosa cells is regulated by the follicle-stimulating hormone (FSH) via transcriptional regulation of its related genes. We herein showed the involvement of the Hippo pathway in this regulation. In KGN granulosa cell, repression of YAP/TAZ activity induced the expression of CYP11A1, HSD3B2, and CYP19A1 in a TEAD-dependent manner without cAMP stimulation. A selective inhibitor of p38 MAP kinase, suppressed YAP/TAZ knockdown-indued the expression of these genes, suggesting this signal could be involved. The expression of these genes was induced by 8Br-cAMP, whereas that of CYR61 and ADATS1, typical YAP/TAZ-TEAD target genes, was suppressed, suggesting that the cellular signaling of cAMP reduced YAP/TAZ-TEAD activity. The constitutively active mutant YAP canceled the FSH- and 8Br-cAMP-mediated induction of these genes in primary rat granulosa and KGN cells, respectively. Moreover, regulation of steroidogenesis-related genes by YAP/TAZ-TEAD was independent of steroidogenic factor 1, a master gene regulator of steroidogenesis. These results suggest that YAP/TAZ-TEAD is a negative regulator of steroidogenesis and that suppression of YAP/TAZ-TEAD activity by FSH is involved in ovarian steroidogenesis., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

During placentation, placental cytotrophoblast (CT) cells differentiate into syncytiotrophoblast (ST) cells and extravillous trophoblast (EVT) cells. In the placenta, the expression of various genes is regulated by the Hippo pathway through a transcription complex, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ)-TEA domain transcription factor (TEAD) (YAP/TAZ-TEAD) activity. YAP/TAZ-TEAD activity is controlled by multiple factors and signaling, such as cAMP signaling. cAMP signaling is believed to be involved in the regulation of trophoblast function but is not yet fully understood. Here we showed that YAP/TAZ-TEAD expressions and their activities were altered by cAMP stimulation in BeWo cells, a human choriocarcinoma cell line. The repression of YAP/TAZ-TEAD activity induced the expression of ST-specific genes without cAMP stimulation, and transduction of constitutively active YAP, i.e. YAP-5SA, resulted in the repression of 8Br-cAMP-induced expressions of ST-specific genes in a TEAD-dependent manner. We also investigated the role of YAP/TAZ-TEAD in maintaining CT cells and their differentiation into ST and EVT cells using human trophoblast stem (TS) cells. YAP/TAZ-TEAD activity was involved in maintaining the stemness of TS cells. Induction or repression of YAP/TAZ-TEAD activity resulted in marked changes in the expression of ST-specific genes. Using primary CT cells, which spontaneously differentiate into ST-like cells, the effects of YAP-5SA transduction were investigated, and the expression of ST-specific genes was found to be repressed. These results indicate that the inhibition of YAP/TAZ-TEAD activity, with or without cAMP stimulation, is essential for the differentiation of CT cells into ST cells., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Problem: Pre-ovulatory mature follicles are not readily induced from gonadotropin (Gn)-independent early follicles in the poor ovarian response (POR) state, characterized by reduced number of retrieved oocytes. Bone morphogenetic protein (BMP), which is expressed in the ovary, contributes to early folliculogenesis, but its precise underlying mechanism remains unknown. The purpose of this study was to examine the effects of BMP-2 on granulosa cells (GCs) of Gn-independent early follicles., Method of Study: Sphingosine kinase 1 (SPHK1) localization, which produces sphingosine 1-phosphate (S1P), was examined in human early follicles by immunohistochemistry. SPHK1 mRNA levels were examined in Gn-independent bovine GCs (bGCs) and human nonluteinized granulosa cell line (HGrC1) cells. Phosphorylated Yes-associated protein (YAP) expression was evaluated by Western blot, and its localization was evaluated immunocytochemically in bGCs. Verteporfin, a selective YAP inhibitor, was used to explore the influence of YAP on BMP-2-induced bGCs proliferation., Results: The expression of SPHK1 was observed in human GCs of primary and secondary follicles. BMP-2 significantly induced SPHK1 mRNA expression in bGCs and HGrC1 cells. Both BMP-2 and S1P decreased phosphorylated YAP protein levels and induced the nuclear translocation of YAP significantly, thereby increasing the number of bGCs by suppressing the Hippo pathway. This BMP-2-induced cell proliferation was completely blocked by verteporfin., Conclusion: This is a first report showing that BMP-2 up-regulated SPHK1 mRNA expression in GCs and promoted GCs proliferation through Hippo pathway suppression. Thus, BMP-2 contributes to Gn-independent folliculogenesis via SPHK1, suggesting a potential therapeutic strategy for the POR patients with follicular dysgenesis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To clarify the mentality of pregnant women and obstetric healthcare workers about prenatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening testing., Methods: A multicenter questionnaire survey about prenatal SARS-CoV-2 screening testing was conducted among pregnant women, midwives and nurses (M&Ns), and obstetricians at all delivery facilities in Fukui Prefecture between June 30, 2020 and July 22, 2020., Results: Of 297 pregnant women, 150 (50.5%) underwent prenatal polymerase chain reaction (PCR) testing, and 107 of them (71.3%) answered that because of prenatal PCR tests, they could give birth with relief. One hundred forty-five (48.8%) were concerned about the disadvantages of receiving positive prenatal PCR results. Of 287 M&Ns, 151 (52.6%) answered that prenatal PCR screening testing could reduce anxiety about infection to themselves; this belief was more common among M&Ns working at the nonreception facility than among those at COVID-19 reception facilities (60.7% vs. 47.1%, P = 0.02). Of 57 obstetricians, 31 (54.4%) agreed to prenatal SARS-CoV-2 PCR screening testing, the rate of which was significantly higher among obstetricians at nonreception facilities than those at reception facilities (70.3% vs. 25.0%, P < 0.01). Fourteen obstetricians (24.6%) were concerned about excessive medical treatment for asymptomatic pregnant women with false-positive PCR results., Conclusions: Pregnant women experience anxieties during the COVID-19 pandemic, and prenatal SARS-CoV-2 screening may reduce their anxiety to some extent. However, obstetrics staff at COVID-19 reception facilities are aware of the limits of prenatal screening and are concerned about excessive medical intervention due to false-positive results., (© 2021 Japan Society of Obstetrics and Gynecology.)

Although 11-ketotestosterone (11KT) and testosterone (T) are major androgens in both teleosts and humans, their 5α-reduced derivatives produced by steroid 5α-reductase (SRD5A/srd5a), i.e., 11-ketodihydrotestosterone (11KDHT) and 5α-dihydrotestosterone (DHT), remains poorly characterized, especially in teleosts. In this study, we compared the presence and production of DHT and 11KDHT in Japanese eels and humans. Plasma 11KT concentrations were similar in both male and female eels, whereas T levels were much higher in females. In accordance with the levels of their precursors, 11KDHT levels did not show sexual dimorphism, whereas DHT levels were much higher in females. It is noteworthy that plasma DHT levels in female eels were higher than those in men. In addition, plasma 11KDHT was undetectable in both sexes in humans, despite the presence of 11KT. Three srd5a genes ( srd5a1 , srd5a2a and srd5a2b ) were cloned from eel gonads. All three srd5a genes were expressed in the ovary, whereas only both srd5a2 genes were expressed in the testis. Human SRD5A1 was expressed in testis, ovary and adrenal, whereas SRD5A2 was expressed only in testis. Human SRD5A1, SRD5A2 and both eel srd5a2 isoforms catalyzed the conversion of T and 11KT into DHT and 11KDHT, respectively, whereas only eel srd5a1 converted T into DHT. DHT and 11KDHT activated eel androgen receptor (ar)α-mediated transactivation as similar fashion to T and 11KT. In contrast, human AR and eel arβ were activated by DHT and11KDHT more strongly than T and 11KT. These results indicate that in teleosts, DHT and 11KDHT may be important 5α-reduced androgens produced in the gonads. In contrast, DHT is the only major 5α-reduced androgens in healthy humans., Competing Interests: Author YM was employed by the company ASKA Pharmaceutical Medical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yazawa, Inaba, Imamichi, Sekiguchi, Uwada, Islam, Orisaka, Mikami, Ida, Sato, Miyashiro, Takahashi, Khan, Suzuki, Umezawa and Kitano.)

Background: The process of follicle development is tightly regulated by pituitary gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) and intraovarian regulators (eg, steroids, growth factors, and cytokines)., Methods: This review outlines recent findings on the mechanisms of human follicle development, based on the research on animal models such as mice, rats, cows, and sheep., Main Findings: Phosphatidylinositol 3-kinase/protein kinase B signaling pathway and anti-Müllerian hormone are involved in primordial follicle activation during the gonadotropin-independent phase. The intraovarian regulators, such as androgen, insulin-like growth factor system, activin, oocyte-derived factors (growth differentiation factor-9 and bone morphogenetic protein 15), and gap junction membrane channel protein (connexin), play a central role in the acquisition of FSH dependence in preantral follicles during the gonadotropin-responsive phase. Antral follicle development can be divided into FSH-dependent growth and LH-dependent maturation. The indispensable tetralogy for follicle selection and final maturation of antral follicles involves (a) acquisition of LH dependence, (b) greater capacity for E2 production, (c) activation of the IGF system, and (d) an antiapoptotic follicular microenvironment., Conclusion: We reproductive endocrinologists should accumulate further knowledge from animal model studies to develop methods that promote early folliculogenesis and connect to subsequent gonadotropin therapy in infertile women., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Background: The mitochondrial fission protein, Dynamin related protein 1 (Drp1), and its upstream protein calcium/calmodulin-dependent protein kinase I (CaMKI) play a critical role in chemoresistance in ovarian cancer (OVCA). Thus, we examined the expression of Drp1, CaMKI and their phosphorylated forms and their prognostic impact in epithelial OVCA patients., Methods: Expression analysis was performed by immunohistochemistry (IHC) of paraffin-embedded tumor samples from 49 patients with epithelial OVCA. Staining intensity and the percentage of positively stained tumor cells were used to calculate an immunoreactive score (IRS) of 0-12. The expression scores calculated were correlated with clinicopathological parameters and patient survival., Results: High immunoreactivity of phospho-Drp1 Ser637 was significantly correlated with high-grade serous carcinoma (HGSC) (p = 0.034), residual postoperative tumor of > 1 cm (p = 0.006), and non-responders to adjuvant chemotherapy (p = 0.007), whereas high expression of CaMKI was significantly correlated with stage III/IV [International Federation of Gynecologists and Obstetricians (FIGO)] (p = 0.011) and platinum-resistant recurrence (p = 0.030). ROC curve analysis showed that Drp1, phospho-Drp1 Ser637 and CaMKI could significantly detect tumor progression with 0.710, 0.779, and 0.686 of area under the curve (AUC), respectively. The Kaplan-Meier survival curve showed that patients with high Drp1, phospho-Drp1 Ser637 and CaMKI levels had significantly poorer progression free survival (PFS) (p = 0.003, p < 0.001 and p = 0.017, respectively). Using multivariate analyses, phospho-Drp1 Ser637 was significantly associated with PFS [p = 0.043, hazard ratio (HR) 3.151, 95% confidence interval (CI) 1.039-9.561]., Conclusions: Drp1 and CaMKI are novel potential candidates for the detection and prognosis of epithelial OVCA and as such further studies should be performed to exploit their therapeutic significance.

Polycystic ovary syndrome (PCOS) is a clinical syndrome characterized by hyperandrogenism, oligo/anovulation, and polycystic ovary. Autophagy is an intracellular system that degrades cytosolic proteins and organelles. The relationship between autophagy and PCOS has not been clarified. We found that p62 and ubiquitin were significantly increased in theca cells of women with PCOS using immunohistochemistry. Autophagy inhibition by palmitic acid and chloroquine in bovine theca cells increased p62 and ubiquitin and induced the expression of cytochrome P450 17A1 (CYP17A1) and plasminogen activator inhibitor-1 (PAI-1) mRNA. Furthermore, palmitic acid and chloroquine exposure significantly increased reactive oxygen species (ROS) and activated p38 and c-Jun N-terminal kinase (JNK). Inhibition of p38 and JNK significantly reduced CYP17A1 and PAI-1 mRNA expression. We showed that inhibition of autophagy in theca cells may have contributed to the pathogenesis of PCOS, based on CYP17A1 and PAI-1 mRNA expression via the ROS/p38 and JNK signalling pathways., (Copyright © 2020 Elsevier B.V. All rights reserved.)

LH supplementation in assisted reproductive technology cycles improves the ongoing pregnancy rate in women with poor ovarian response (POR). However, our knowledge of the precise role of LH during the follicular phase of the menstrual cycle is incomplete. To explore the role of LH in the maturation of small antral follicles, we used an in vitro two-cell system that involved coculturing bovine granulosa cells (GCs) and theca cells (TCs) on a collagen membrane. Treatment of TCs with LH stimulated androgen production in TCs by inducing the expression of androgenic factors, subsequently increasing estrogen biosynthesis in GCs by providing androgen substrates, and inducing aromatase expression. LH stimulation of TCs induced functional LH receptor expression in GCs, a response modulated by the synthesis and action of estrogen. In the presence of TCs, LH stimulation of TCs and FSH stimulation of GCs increased the expression of IGF-1, IGF-2, and IGF-1 receptor in GCs. LH-induced expression of thecal IGF-1 protected GCs from apoptosis and promoted GC survival. Furthermore, LH stimulation of TCs increased FSH sensitivity in GCs. Thus, the LH-TC axis may be involved in the acquisition of LH dependence and the survival of small antral follicles by upregulating androgen/estrogen biosynthesis and activating the IGF system. The use of LH supplementation in ovarian stimulation may increase gonadotropin sensitivity in small antral follicles and promote follicular growth and survival by suppressing GC apoptosis and follicular atresia, resulting in multiple follicular development, even in patients with POR.

Introduction: Primary spinal cord tumours can lead to severe neurological complications and even death. Pregnant women often complain of discomfort of the lower limbs, which is usually caused by sciatica. Here we present the case of a pregnant woman, who was initially considered to have sciatica, but was finally diagnosed with a primary intramedullary spinal cord tumour., Case Presentation: A 28-year-old pregnant woman presented to our hospital with inexplicable numbness in her lower limbs. She was initially considered to have sciatica, but acute deterioration of neurological symptoms and plain magnetic resonance imaging (MRI) findings suggested malignancy. The patient was finally diagnosed with a primary intramedullary spinal cord tumour at the C3-Th5 region. An emergency caesarean section was performed, after which the spinal cord lesion was evaluated using contrast-enhanced MRI, positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-d-glucose integrated with computed tomography, and spinal angiography, and further treatment was initiated. However, while the patient's spinal cord tumour surgery was performed in early postpartum, her paraplegia and bladder and rectal disturbances remained unchanged even 1 year after surgery., Discussion: Because of the low incidence of spinal cord tumours during pregnancy, no definite reports have been published on the treatment of pregnant patients with spinal cord tumours. Although safe imaging tests during pregnancy are limited, intervention in such patients should be performed as early as possible to avoid irreversible neurological deterioration., Competing Interests: Compliance with ethical standardsThe authors declare that they have no conflict of interest.

Cisplatin (CDDP) and its derivatives are first line anti-cancer drugs for ovarian cancer (OVCA). However, chemoresistance due to high incidence of p53 mutations leads to poor clinical prognosis. Saikosaponin-d (Ssd), a saponin from a herbal plant extract, has been shown to induce cell death and sensitize chemoresistant cells to chemotherapeutic agents. Here, we demonstrated that Ssd sensitized chemoresistant OVCA cells with either p53-wt, -mutant and -null to CDDP. The action of Ssd appears to be through induction of mitochondrial fragmentation and G2/M arrest. Ssd is mediated via calcium signaling, up-regulation of the mitochondrial fission proteins Dynamin-related protein 1 (Drp1) and optic atrophy 1 (Opa1), and loss in mitochondrial membrane potential (MMP). Moreover, in the presence of CDDP, Ssd also down-regulates protein phosphatase magnesium-dependent 1 D (PPM1D) and increases the phosphorylation of checkpoint protein kinases (Chk) 1, cell division cycle 25c (Cdc25c) and Cyclin dependent kinase 1 (Cdk1). Our findings suggest that Ssd could sensitize OVCA to CDDP independent of the p53 status through multiple signaling pathways. They support the notion that Ssd may be a novel adjuvant for the treatment of chemoresistant OVCA., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Context: 11-ketotestosterone (11-KT) is a novel class of active androgen. However, the detail of its synthesis remains unknown for humans., Objective: The objective of this study was to clarify the production and properties of 11-KT in human. Design, Participants, and Methods: Expression of cytochrome P450 and 11β-hydroxysteroid dehydrogenase types 1 and 2 (key enzymes involved in the synthesis of 11-KT) were investigated in human gonads. The production of 11-KT was investigated in Leydig cells. Plasma concentrations of testosterone and 11-KT were measured in 10 women and 10 men of reproductive age. Investigation of its properties was performed using breast cancer-derived MCF-7 cells., Results: Cytochrome P450 and 11β-hydroxysteroid dehydrogenase types 1 and 2 were detected in Leydig cells and theca cells. Leydig cells produced 11-KT, and relatively high levels of plasma 11-KT were measured in both men and women. There was no sexual dimorphism in the plasma levels of 11-KT, even though testosterone levels were more than 20 times higher in men than in women. It is noteworthy that the levels of testosterone and 11-KT were similar in women. In a luciferase reporter system, 11-KT activated human androgen receptor-mediated transactivation. Conversely, 11-KT did not activate estrogen receptor-mediated transactivation in aromatase-expressed MCF-7 cells, whereas testosterone did following conversion to estrogen. 11-KT did not affect the estrogen/estrogen receptor -mediated cell proliferation of MCF-7 cells. Furthermore, it significantly inhibited cell proliferation when androgen receptor was transfected into MCF-7 cells., Conclusions: The current study indicates that 11-KT is produced in the gonads and represents a major androgen in human. It can potentially serve as a nonaromatizable androgen.

Background: A high serum estradiol (E2) level is occasionally detected in postmenopausal women with common epithelial ovarian tumors with functioning stroma. It has been proven that functioning stroma has the capacity to convert androgens to estrogens. However, the mechanism of the initiation and development of functioning stroma remains unclear., Case Presentation: We present two cases of elevated E2 levels in elderly women with ovarian mucinous adenocarcinomas that contained functioning stroma. Immunohistochemical evaluation revealed high expression levels of aromatase and steroidogenic factor-1 (SF-1), which is considered to be a master regulator of steroidogenesis, in their ovarian stroma., Conclusions: These cases suggest that overexpression of SF-1 may promote estrogen biosynthesis through regulation of P450 aromatase expression in ovarian tumors with functioning stroma; this in turn induces high serum E2 levels in postmenopausal women with common epithelial ovarian tumors.

Chemoresistance enables cancer cells to evade apoptotic stimuli and leads to poor clinical prognosis. It arises from dysregulation of signaling factors responsible for inducing cell proliferation and death and for modulating the microenvironment. In gynecologic cancers, p53 is a pivotal determinant of cisplatin sensitivity, while BCL-2 family members are associated with taxane sensitivity. Mitochondria fusion and fission dynamics are required for many mitochondrial functions and are also involved in mitochondria-mediated apoptosis, which is closely associated with chemosensitivity. Mitochondrial dynamics are controlled by a number of intracellular proteins, including fusion (Opa1 and mitofusion 1 and 2) and fission proteins (Drp1 and Fis1), which can be proapoptotic or antiapoptotic, depending on the cell types, status, and stimuli from the microenvironment. This paper describes the role of mitochondrial dynamics in the mechanism of chemoresistance and the evidence supporting a significant contribution of a hyperfusion state to chemoresistance in gynecological cancers. Moreover, we discuss our findings showing that enforced fission induces apoptosis of cancer cells and sensitizes them to chemotherapeutic agents. Understanding the regulation of mitochondrial dynamics in chemoresistance may provide insight into new biomarkers that better predict cancer chemosensitivity and may aid the development of effective therapeutic strategies for clinical management of gynecologic cancers., (© 2015 New York Academy of Sciences.)

Reduced fertility is one of the main long-term consequences of chemotherapy given for lymphoma, leukemia, and other malignancies in young women. We examined with a female rat model whether and how dienogest, a fourth-generation progestin, modulates reduced fertility following exposure to gonadotoxic chemotherapy. Female rats were administered cyclophosphamide with or without GnRH agonist and different concentrations of dienogest for 20 days. Animals were sacrificed on Day 29, and the numbers of follicle at primordial, preantral and antral stage in the ovaries were counted histologically. Rats treated with sterile saline solution (as control), cyclophosphamide, cyclophosphamide plus GnRH agonist, and cyclophosphamide plus dienogest were also mated with male rats to evaluate their fertility and pregnancy outcomes. Cyclophosphamide significantly reduced the number of primordial follicles, whereas dienogest suppressed depletion of primordial follicle pool induced by chemotherapy. Although the rats exposed to cyclophosphamide alone failed to deliver live births, co-treatment with dienogest improved the pregnancy outcomes of treated rats. The protective effect of dienogest on chemotherapy-induced ovarian damage and reduced fertility was comparable to that of GnRH agonist. The present results suggest that the co-administration of dienogest and chemotherapy may be a useful strategy in preserving ovarian function and fertility in premenopausal women facing gonadotoxic chemotherapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)