Implantation and Decidualization in PCOS: Unraveling the Complexities of Pregnancy.

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, affecting 5-15% globally with a large proportion undiagnosed. This review explores the multifaceted nature of PCOS and its impact on pregnancy, including challenges in fertility due to hormonal imbalances and insulin resistance. Despite restoring ovulation pharmacologically, women with PCOS face lower pregnancy rates and higher risks of implantation failure and miscarriage. Our review focuses on the complexities of hormonal and metabolic imbalances that impair endometrial receptivity and decidualization in PCOS. Disrupted estrogen signaling, reduced integrity of endometrial epithelial tight junctions, and insulin resistance impair the window of endometrial receptivity. Furthermore, progesterone resistance adversely affects decidualization. Our review also examines the roles of various immune cells and inflammatory processes in the endometrium, contributing to the condition's reproductive challenges. Lastly, we discuss the use of rodent models in understanding PCOS, particularly those induced by hormonal interventions, offering insights into the syndrome's impact on pregnancy and potential treatments. This comprehensive review underscores the need for advanced understanding and treatment strategies to address the reproductive complications associated with PCOS, emphasizing its intricate interplay of hormonal, metabolic, and immune factors.

Association of Lower Urinary Tract Symptoms Based on the International Prostate Symptom Score and Cardiovascular Disease.

BACKGROUND: Because it is unclear whether lower urinary tract symptoms (LUTS) are associated with cardiovascular disease (CVD) in the Japanese population, we explored the association in general Japanese men aged 55-75 years.Methods and Results:The cross-sectional study included male participants who had both national health checkup data and the International Prostate Symptom Score (IPSS) in the same calendar year between 2009 and 2017. LUTS severity was evaluated by IPSS. A robust Poisson regression model was used to assess the association between LUTS severity and the composite CVD outcome [coronary artery disease (CAD), stroke, or atrial fibrillation (AF)] and each component of the composite outcome. Prevalence ratio (PR) was adjusted for conventional cardiovascular risk factors. Of 16,781 male participants (mean age, 67±5 years), mild LUTS were observed in 9,243 (55.1%); moderate, 6,445 (38.4%); and severe, 1,093 (6.5%). Compared with the mild LUTS group, moderate LUTS [PR 1.18, 95% confidence interval (CI) 1.10-1.25, P<0.001] and severe LUTS (PR 1.38, 95% CI 1.24-1.53, P<0.001) were significantly associated with a higher prevalence of CVD. LUTS severity was associated with higher prevalence of CAD and stroke, but not AF. CONCLUSIONS: The severity of LUTS was associated with a higher prevalence of CVD, especially CAD and stroke, independent of conventional CVD risk factors.

Optimal screening interval for men with low baseline prostate-specific antigen levels (≤1.0 ng/mL) in a prostate cancer screening program.

PURPOSE: To optimize the rescreening schedule for men with low baseline prostate-specific antigen (PSA) levels, we evaluated men with baseline PSA levels of ≤1.0 ng/mL in PSA-based population screening. METHODS: We enrolled 8086 men aged 55-69 years with baseline PSA levels of ≤1.0 ng/mL, who were screened annually. The relationships of baseline PSA and age with the cumulative risks and clinicopathological features of screening-detected cancer were investigated. RESULTS: Among the 8086 participants, 28 (0.35 %) and 18 (0.22 %) were diagnosed with prostate cancer and cancer with a Gleason score (GS) of ≥7 during the observation period, respectively. The cumulative probabilities of prostate cancer at 12 years were 0.42, 1.0, 3.4, and 4.3 % in men with baseline PSA levels of 0.0-0.4, 0.5-0.6, 0.7-0.8, and 0.9-1.0 ng/mL, respectively. Those with GS of ≥7 had cumulative probabilities of 0.42, 0.73, 2.8, and 1.9 %, respectively. The cumulative probabilities of prostate cancer were significantly lower when baseline PSA levels were 0.0-0.6 ng/mL compared with 0.7-1.0 ng/mL. Prostate cancer with a GS of ≥7 was not detected during the first 10 years of screening when baseline PSA levels were 0.0-0.6 ng/mL and was not detected during the first 2 years when baseline PSA levels were 0.7-1.0 ng/mL. CONCLUSIONS: Our study demonstrated that men with baseline PSA levels of 0.0-0.6 ng/mL might benefit from longer screening intervals than those recommended in the guidelines of the Japanese Urological Association. Further investigation is needed to confirm the optimal screening interval for men with low baseline PSA levels.

[A CASE OF PARATESTICULAR FIBROUS HAMARTOMA OF INFANCY].

Fibrous hamartoma of infancy (FHI) is a rare, benign soft tissue tumor arising from subcutaneous tissue in children during the first two years of life. The tumor is commonly found in the axilla, shoulder and upper arm. Paratesticular FHI is extremely rare. To date, only a case of paratesticular FHI has been reported in Japan. We present a case of paratesticular FHI in an 11-month-old boy who eventually needed orchiectomy due to local recurrence one month after the excision of the tumor. Ten months postoperatively, there was no sign of recurrence.

ROR2 expression predicts human induced pluripotent stem cell differentiation into neural stem/progenitor cells and GABAergic neurons.

Despite the development of various in vitro differentiation protocols for the efficient derivation of specific cell types, human induced pluripotent stem cell (hiPSC) lines have varing ability to differentiate into specific lineages. Therefore, surrogate markers for accurately predicting the differentiation propensity of hiPSC lines may facilitate cell-based therapeutic product development and manufacture. We attempted to identify marker genes that could predict the differentiation propensity of hiPSCs into neural stem/progenitor cells (NS/PCs). Using Spearman's rank correlation coefficients, we investigated genes in the undifferentiated state, the expression levels of which were significantly correlated with the neuronal differentiation propensity of several hiPSC lines. Among genes significantly correlated with NS/PC differentiation (P < 0.01), we identified ROR2 as a novel predictive marker. ROR2 expression in hiPSCs was negatively correlated with NS/PC differentiation tendency, regardless of the differentiation method, whereas its knockdown enhanced differentiation. ROR2 regulates NS/PC differentiation, suggesting that ROR2 is functionally essential for NS/PC differentiation. Selecting cell lines with relatively low ROR2 expression facilitated identification of hiPSCs that can differentiate into NS/PCs. Cells with ROR2 knockdown showed increased efficiency of differentiation into forebrain GABAergic neurons compared to controls. These findings suggest that ROR2 is a surrogate marker for selecting hiPSC lines appropriate for NS/PC and GABAergic neuronal differentiations.

Steroid hormone signaling: multifaceted support of testicular function.

Embryonic development and adult physiology are dependent on the action of steroid hormones. In particular, the reproductive system is reliant on hormonal signaling to promote gonadal function and to ensure fertility. Here we will describe hormone receptor functions and their impacts on testicular function, focusing on a specific group of essential hormones: androgens, estrogens, progesterone, cortisol, and aldosterone. In addition to focusing on hormone receptor function and localization within the testis, we will highlight the effects of altered receptor signaling, including the consequences of reduced and excess signaling activity. These hormones act through various cellular pathways and receptor types, emphasizing the need for a multifaceted research approach to understand their critical roles in testicular function. Hormones exhibit intricate interactions with each other, as evidenced, for example, by the antagonistic effects of progesterone on mineralocorticoid receptors and cortisol's impact on androgens. In light of research findings in the field demonstrating an intricate interplay between hormones, a systems biology approach is crucial for a nuanced understanding of this complex hormonal network. This review can serve as a resource for further investigation into hormonal support of male reproductive health.

A Case of Solitary Kidney and Single-system Ectopic Ureter Draining Into the Vestibule in an Infant With Müllerian Duct Defect: Was the Bladder Missing?

We report a case of a solitary kidney and a single-system ectopic ureter draining into the vestibule in an infant with a Müllerian duct defect. Due to the absence of the upper vagina and uterus, an extremely underdeveloped bladder masqueraded as the vagina, and bladder agenesis was suspected preoperatively. Urinary continence was achieved using staged bladder surgery without augmentation or urinary diversion.

Prenatally diagnosed giant umbilical cord resulted from patent urachus in a monochorionic diamniotic twin with selective intrauterine growth restriction.

A long diffuse giant umbilical cord (GUC), caused by umbilical cord edema associated with a patent urachus, is an extremely rare anomaly. While patients with diffuse GUC appear to experience no significant complications and a good prognosis, little is known about their etiology and prenatal course. Here, we report the first case of prenatally diagnosed diffuse GUC resulted from patent urachus in a monochorionic diamniotic twin with selective intrauterine growth restriction. This case indicates that GUC is epigenetic and unrelated to multiple births.

Unilateral renal agenesis and ipsilateral absence of the vas deferens in a cryptorchid infant with Klippel-Feil syndrome.

We report an exceedingly rare case of Klippel-Feil syndrome (KFS), compounded by ipsilateral absence of the vas deferens, renal agenesis, and diaphragmatic hernia. Unilateral absence of the vas deferens was found incidentally during orchidopexy. To the best of our knowledge, no case of unilateral absence of the kidney and vas deferens has been reported in children with KFS.

Single-Cell RNA-Seq Reveals LRRC75A-Expressing Cell Population Involved in VEGF Secretion of Multipotent Mesenchymal Stromal/Stem Cells Under Ischemia.

Human multipotent mesenchymal stromal/stem cells (MSCs) have been utilized in cell therapy for various diseases and their clinical applications are expected to increase in the future. However, the variation in MSC-based product quality due to the MSC heterogeneity has resulted in significant constraints in the clinical utility of MSCs. Therefore, we hypothesized that it might be important to identify and ensure/enrich suitable cell subpopulations for therapies using MSC-based products. In this study, we aimed to identify functional cell subpopulations to predict the efficacy of angiogenic therapy using bone marrow-derived MSCs (BM-MSCs). To assess its angiogenic potency, we observed various levels of vascular endothelial growth factor (VEGF) secretion among 11 donor-derived BM-MSC lines under in vitro ischemic culture conditions. Next, by clarifying the heterogeneity of BM-MSCs using single-cell RNA-sequencing analysis, we identified a functional cell subpopulation that contributed to the overall VEGF production in BM-MSC lines under ischemic conditions. We also found that leucine-rich repeat-containing 75A (LRRC75A) was more highly expressed in this cell subpopulation than in the others. Importantly, knockdown of LRRC75A using small interfering RNA resulted in significant inhibition of VEGF secretion in ischemic BM-MSCs, indicating that LRRC75A regulates VEGF secretion under ischemic conditions. Therefore, LRRC75A may be a useful biomarker to identify cell subpopulations that contribute to the angiogenic effects of BM-MSCs. Our work provides evidence that a strategy based on single-cell transcriptome profiles is effective for identifying functional cell subpopulations in heterogeneous MSC-based products.

Immune Cells as Critical Regulators of Steroidogenesis in the Testis and Beyond.

Steroidogenesis is an essential biological process for embryonic development, reproduction, and adult health. While specific glandular cells, such as Leydig cells in the testis, are traditionally known to be the principal players in steroid hormone production, there are other cell types that contribute to the process of steroidogenesis. In particular, immune cells are often an important component of the cellular niche that is required for the production of steroid hormones. For several decades, studies have reported that testicular macrophages and Leydig cells are intimately associated and exhibit a dependency on the other cell type for their proper development; however, the mechanisms that underlie the functional relationship between macrophages and Leydig cells are unclear. Beyond the testis, in certain instances immune cells themselves, such as certain types of lymphocytes, are capable of steroid hormone production, thus highlighting the complexity and diversity that underlie steroidogenesis. In this review we will describe how immune cells are critical regulators of steroidogenesis in the testis and in extra-glandular locations, as well as discuss how this area of research offers opportunities to uncover new insights into steroid hormone production.

Unilateral Fibrous Hyperplasia of the Labium Majus in Pre- and Early Pubertal Girls: A Report on 3 Cases.

BACKGROUND: In recent years, certain prepubertal cases of asymmetric enlargement of the labium majus came to be recognized as a physiological condition in response to hormonal stimulation. However, there exist only scattered case reports or a few case series on this entity, with different terminology. CASE: We present 3 cases of unilateral asymptomatic swelling of the labium majus in otherwise healthy pre- and early pubertal girls. Physical examination revealed painless, fluctuating, nontender bulging that was recognized for a few years on one side of the labium majus. Ultrasound and magnetic resonance imaging showed increased labial soft tissue without any masses. In all cases, surgical excision was performed for cosmetic request. Histopathological diagnosis was fibrous hyperplasia of the labium majus in all cases. Recurrence occurred in one of 3 cases a year after surgery. SUMMARY AND CONCLUSION: Due to the site- and age-specific non-neoplastic physiological condition, we recommend prepubertal unilateral fibrous hyperplasia of the labium majus (PUFHLM), as the terminology accurately reflects this entity. For the differential diagnosis of genital disorders in children, recognition of PUFHLM is important to avoid unnecessary biopsy or invasive procedures. Surgical excision for cosmetic reasons should not be considered because of the benign nature of this entity and a high recurrence rate in childhood and early adolescence.

[CLINICAL AND IMAGING FINDINGS OF ACUTE EPIDIDYMITIS IN CHILDREN].

(Objective) The etiology of acute epididymitis in children remains poorly understood. Several studies have demonstrated that urine tests are negative in the majority of children with acute epididymitis, and the condition is self-limiting. The need for radiological evaluation of the urinary tract in children with acute epididymitis is still debatable. The aim of this study was to describe clinical and imaging findings in children with acute epididymitis. (Methods) We identified 47 children with acute epididymitis at our institute between 2017 and 2021.We retrospectively reviewed their clinical features and radiological and laboratory data. All children underwent ultrasonography of the kidney and urinary tract. (Results) Median patient age was 9 years (range, 6 months-16 years) and 60% of the cases occurred between the ages of 7 and 12 years. Thirteen children (28%) had a past history of genitourinary malformations. The common malformations were hypospadias in eight children and bladder dysfunction in three. Ultrasound revealed no new urinary tract abnormalities in the remaining 34 children. Urinalysis were performed in 27 children, nine of whom (33%) had pyuria. Urine culture was positive in two children. Of the nine children with genitourinary malformations, eight had pyuria. All 18 children without genitourinary malformations had a negative urinalysis except for one patient (p< 0.0001). (Conclusions) Acute epididymitis is a common cause of acute scrotum in pediatric patients. In this study, one-third of acute epididymitis cases presented pyuria, and about 30% had a past history of genitourinary malformations. The presence of pyuria was associated with a past history of genitourinary malformations. For children with no previous genitourinary malformations, routine use of ultrasound for the detection of urinary tract abnormalities is questionable due to the low yield.

Congenital perineal urethrocutaneous fistula without rupture in a neonate.

Congenital anterior urethrocutaneous fistula (CAUF) is a rare anomaly, commonly observed in the mid-shaft or more distal position of the penis. It can be seen in the perineum in anorectal anomalies or in cases of duplicated urethra. However, isolated CAUF opening into the perineum has not been reported. Herein, we present a case of congenital anterior urethral diverticulum and possible perineal urethrocutaneous fistula of an otherwise healthy neonate.

A selective cytotoxic adenovirus vector for concentration of pluripotent stem cells in human pluripotent stem cell-derived neural progenitor cells.

Highly sensitive detection of residual undifferentiated pluripotent stem cells is essential for the quality and safety of cell-processed therapeutic products derived from human induced pluripotent stem cells (hiPSCs). We previously reported the generation of an adenovirus (Ad) vector and adeno-associated virus vectors that possess a suicide gene, inducible Caspase 9 (iCasp9), which makes it possible to sensitively detect undifferentiated hiPSCs in cultures of hiPSC-derived cardiomyocytes. In this study, we investigated whether these vectors also allow for detection of undifferentiated hiPSCs in preparations of hiPSC-derived neural progenitor cells (hiPSC-NPCs), which have been expected to treat neurological disorders. To detect undifferentiated hiPSCs, the expression of pluripotent stem cell markers was determined by immunostaining and flow cytometry. Using immortalized NPCs as a model, the Ad vector was identified to be the most efficient among the vectors tested in detecting undifferentiated hiPSCs. Moreover, we found that the Ad vector killed most hiPSC-NPCs in an iCasp9-dependent manner, enabling flow cytometry to detect undifferentiated hiPSCs intermingled at a lower concentration (0.002%) than reported previously (0.1%). These data indicate that the Ad vector selectively eliminates hiPSC-NPCs, thus allowing for sensitive detection of hiPSCs. This cytotoxic viral vector could contribute to ensuring the quality and safety of hiPSCs-NPCs for therapeutic use.

A feeder-free and efficient production of functional neutrophils from human embryonic stem cells.

A novel, feeder-free hematopoietic differentiation protocol was established for highly efficient production of neutrophils from human embryonic stem cells (hESCs). For the induction of differentiation, spheres were generated in the presence of serum and cytokine cocktail and subjected to attachment culture on gelatin-coated plates. After approximately 2 weeks, a sac-like structure filled with abundant round cells emerged at the center of flattened spheres. After cutting off this sac-like structure, round cells actively proliferated, either floating in the supernatant or associated weakly with the adherent cells. Almost all of these round cells were CD45-positive hematopoietic cells with myeloid phagocytic markers (CD33 and CD11b), and approximately 30%-50% of the round cells were mature neutrophils, as judged from morphology, cytochemical characteristics (myeloperoxidase and neutrophil alkaline phosphatase), and neutrophil-specific cell surface markers (CD66b, CD16b, and GPI-80). In addition, hESC-derived neutrophils had chemotactic capacity in response to the bacterial chemotactic peptide formyl-methionyl-leucyl-phenylalanine and neutrophil-specific chemokine interleukin (IL)-8. Using "semipurified" neutrophils migrated to IL-8, both phagocytic and respiratory burst activities were demonstrated. Finally, it was shown that hESC-derived neutrophils had chemotactic activity in vivo in a murine air-pouch inflammatory model. The present results indicate successful induction of functional mature neutrophils from hESCs via highly efficient feeder-free differentiation culture system of human hematopoietic cells.

[A CASE OF SPLENOGONADAL FUSION PRESENTING NON-PALPABLE TESTIS AND PROXIMAL HYPOSPADIAS].

A 9-month-old boy, having a history of cardiac surgery in neonatal period, was referred to our department for evaluation of genital anomalies. The antenatal course was uneventful, except for unknown gender. His family history was unremarkable. He was delivered at full term, and his birth weight was 3,510 g. Physical examination revealed proximal hypospadias and a non-palpable testis on the left side. Chromosome studies showed a normal male karyotype with positive SRY. At the age of 14 months, he underwent hypospadias repair. Three months later, left testicular exploration was performed along with orchidopexy of an ascending testis on the contralateral side. As nothing was found through an inguinal incision on the left side, laparoscopy was indicated. Laparoscopic observation revealed a small dark reddish mass cranially connected to the left hypoplastic testis that was located high in the left iliac fossa. The epididymis and vas deference looked abnormal, and detachment to the testis was apparent. Testicular vessels were undifferentiated from the mass. Therefore, the left testis was excised with the mass. Histopathological examination confirmed the testis and spleen tissue, and the diagnosis of splenogonadal fusion was made postoperatively.

Variation of Gonadal Dysgenesis and Tumor Risk in Patients With 45,X/46,XY Mosaicism.

OBJECTIVE: To describe the gonadal features of patients with 45,X/46,XY mosaicism, and to evaluate the prevalence of gonadal tumor in different phenotypes. MATERIALS AND METHODS: The medical records of consecutive patients with 45,X/46,XY karyotype or its variants who had undergone gonadal biopsy or gonadectomy at a single institute between 1996 and 2017 were retrospectively reviewed. RESULTS: Of 34 patients with 45,X/46,XY mosaicism, a unilateral dysgenetic testis and a contralateral streak gonad was detected in 20 patients (59%), bilateral streak gonads in 9 (26%), and bilateral dysgenetic testes in 5 (15%). A gonad composed of both streak and dysgenetic testicular portions was observed in 7 gonads of 6 patients. All streak gonads were removed, and bilateral gonadectomy was performed in 15 patients raised as girls. Pathologic examination revealed gonadal tumors in 6 of the 34 (18%) patients, including a gonadoblastoma in 7 gonads among 5 patients and an association of dysgerminoma with gonadoblastoma in 1 gonad. All 6 patients who developed gonadal tumor had female genitalia. Postoperative course was uneventful except 1 boy. A seminoma was developed in his soritaly scrotal testis at the age of 16 years. CONCLUSION: The prevalence of gonadal tumor in patients with 45,X/46,XY mosaicism may vary according to the phenotype, and high in patients with female phenotype. Considering the increased risk of gonadal tumors in such patients, early investigation and individual management, including prophylactic gonadectomy, are recommended. In male patients, a close follow-up of the preserved testes is mandatory until adulthood.

[LOCALIZED CYSTIC DISEASE OF THE KIDNEY IN A 6-YEAR-OLD GIRL].

Localized cystic disease of the kidney (LCDK) is a rare, non-hereditary, non-progressive benign cystic renal condition. It is found primarily in adults, and is rarely reported in children. To date, only 5 prepubertal cases of LCDK have been reported in the literature. In this report, we present a case of LCDK that was difficult to differentiate from malignant renal tumor in a 6-year-old girl. Nephron-sparing surgery could not be performed.A 6-year-old girl with no past medical history presented with gross hematuria and right-sided abdominal pain. An abdominal ultrasound at a local hospital showed multiple variable-sized cysts throughout the right kidney. She was referred to our hospital for further evaluation. Computed tomography demonstrated that the region between cysts was slightly enhanced in some part of the lower pole and was diagnosed III in the Bosniak classification. Nephrectomy was performed for possible cystic renal neoplasm. After surgery, a diagnosis of LCDK was made by histopathological examination.