Association between post-COVID-19 conditions and male semen quality in Japan: A descriptive investigation.

Some reports suggest that coronavirus disease 2019 (COVID-19) may affect male reproductive function. There is also concern in Japan that COVID-19 may contribute to the pre-existing decline in male fertility; however, no studies have investigated the effects of COVID-19 on male reproductive function. In this study, we aimed to analyze the semen quality of men who had recovered from COVID-19. Male patients who had recovered from COVID-19 between February 2020 and September 2021 were recruited for this study. Participants were sent a semen collection kit; they were asked to collect semen at home and deliver it to a laboratory at Osaka University. We used these samples to analyze sperm concentration, total sperm count, and semen volume. In total, 125 participants were included in this study. The median age of all patients was 46 years (interquartile range (IQR): 38-52 years). The severity of COVID-19 was mild in 80 patients; 19 were moderate I, 22 were moderate II, and four were severe. The median semen volume was 2.5 mL (IQR: 1.8-3.1), the median sperm concentration was 98.9 million/mL (IQR: 43.8-162.2), and the median total sperm count was 212.1 million (IQR: 89.7-368.2). In a previous study in Japan, the median sperm count in adult men was reported to be 201 million. Participants in our study did not have lower sperm counts than this, despite their older age. Our results suggest that the long-term effects of COVID-19 on spermatogenesis are minimal.

Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function.

Autophagy degrades unnecessary proteins or damaged organelles to maintain cellular function. Therefore, autophagy has a preventive role against various diseases including hepatic disorders, neurodegenerative diseases, and cancer. Although autophagy in germ cells or Sertoli cells is known to be required for spermatogenesis and male fertility, it remains poorly understood how autophagy participates in spermatogenesis. We found that systemic knockout mice of Rubicon, a negative regulator of autophagy, exhibited a substantial reduction in testicular weight, spermatogenesis, and male fertility, associated with upregulation of autophagy. Rubicon-null mice also had lower levels of mRNAs of Sertoli cell-related genes in testis. Importantly, Rubicon knockout in Sertoli cells, but not in germ cells, caused a defect in spermatogenesis and germline stem cell maintenance in mice, indicating a critical role of Rubicon in Sertoli cells. In mechanistic terms, genetic loss of Rubicon promoted autophagic degradation of GATA4, a transcription factor that is essential for Sertoli cell function. Furthermore, androgen antagonists caused a significant decrease in the levels of Rubicon and GATA4 in testis, accompanied by elevated autophagy. Collectively, we propose that Rubicon promotes Sertoli cell function by preventing autophagic degradation of GATA4, and that this mechanism could be regulated by androgens.

Association between nocturnal polyuria and 24-h blood pressure fluctuations in males with lower urinary tract symptoms: A multicenter prospective study.

OBJECTIVES: Nocturnal polyuria (NP) is one of the causes of nocturia that impairs quality of life. It is necessary to consider that NP is latent when the initial treatment for nocturia is unsatisfactory. Therefore, it is important to establish a treatment for NP based on the pathophysiology. We have previously reported the relationship between NP and fluctuation in blood pressure. The present study aimed to investigate the association between NP and 24-h blood pressure fluctuations in a multicenter prospective study. METHODS: This study included male patients with lower urinary tract symptoms. We categorized the patients into the nonnocturnal polyuria (non-NP) group (≤0.33) and the NP group (>0.33) based on the nocturnal polyuria index from the frequency volume chart. We measured the 24-h diurnal blood pressure and compared the two groups. RESULTS: Among 90 patients, 46 in the non-NP group and 44 in the NP group were included. There was no significant difference in the systolic and diastolic blood pressure during waking time between the two groups; however, the degree of systolic blood pressure reduction during sleep time in the NP group was significantly less than that in the non-NP group (p = 0.039). In the multivariate analysis, systolic BP during sleep was significantly associated with NP (OR 0.970, p = 0.028). CONCLUSION: NP is associated with inadequate nocturnal blood pressure reduction in males, suggesting that reduction in nocturnal blood pressure may lead to improvement in nocturia.

KEAP1-NRF2 system regulates age-related spermatogenesis dysfunction.

Purpose: The average fatherhood age has been consistently increasing in developed countries. Aging has been identified as a risk factor for male infertility. However, its impact on various mechanisms remains unclear. This study focused on the KEAP1-NRF2 oxidative stress response system, by investigating the relationship between the KEAP1-NRF2 system and age-related changes in spermatogenesis. Methods: For examination of age-related changes, we used 10-, 30-, 60-, and 90-week-old mice to compare sperm count, sperm motility, and protein expression. For assessment of Keap1 inhibition, 85-week-old C57BL/6J mice were randomly assigned to the following groups: control and bardoxolone methyl (KEAP1 inhibitor). Whole-exome sequencing of a Japanese cohort of patients with non-obstructive azoospermia was performed for evaluating. Results: Sperm count decreased significantly with aging. Oxidative stress and KEAP1 expression in the testes were elevated. Inhibition of KEAP1 in aging mice significantly increased sperm count compared with that in the control group. In the human study, the frequency of a missense-type SNP (rs181294188) causing changes in NFE2L2 (NRF2) activity was significantly higher in patients with non-obstructive azoospermia than in healthy control group. Conclusions: The KEAP1-NRF2 system, an oxidative stress response system, is associated with age-related spermatogenesis dysfunction.

Therapeutic efficacy and safety of a free-standing motorized ejaculation aid for patients with intravaginal ejaculatory dysfunction.

Purpose: There are no approved drugs or devices for the treatment of intravaginal ejaculation disorders, and treatment is often difficult. This study aimed to evaluate the efficacy and safety of the A10 Cyclone SA + PLUS® ejaculation aid (Rends Co., Ltd., Chiba, Japan), which allows the user to adjust the intensity of stimulation, for intravaginal ejaculation disorders. Methods: Each participant was instructed to perform practice masturbation with the A10 Cyclone SA + PLUS to simulate vaginal ejaculation. After 8 weeks of training, the participants were asked about their intravaginal ejaculation status. Sexual function was also evaluated before and after the training using several specific questionnaires, including the numerical rating scale for ejaculatory satisfaction. Results: Among the 10 participants (41.5 ± 3.21 years) who completed the training and questionnaire evaluation, four (40%) became capable of intravaginal ejaculation. The questionnaire evaluation showed predominant improvement after training in the ejaculation-capable group according to the numerical rating scale, which expresses satisfaction with ejaculation. The participants experienced no significant adverse events. Conclusion: As no effective treatment currently exists for intravaginal ejaculation disorders, we conclude that the A10 Cyclone SA + PLUS may be one treatment tool for intravaginal ejaculation disorders with good efficacy and no adverse events.

Evaluation of the efficacy of creatine chemical exchange saturation transfer imaging in assessing testicular maturity.

Purpose: Microscopic testicular sperm extraction is the most effective treatment for NOA, but the sperm retrieval rate is low and depends on testicular maturity. However, there are limited useful tests to assess testicular maturity. Chemical exchange saturation transfer (CEST) imaging is a new magnetic resonance imaging (MRI) technique that can image the distribution of trace substances in vivo. We focused on the potential role of creatine (Cr) in testes and hypothesized that Cr-CEST could indicate intratesticular spermatogenesis. Methods: We performed Cr-CEST by using 7T MRI on wild-type C57B6/J mice and several types of male infertility models such as Sertoli-cell only (SCO) (Kitw/Kitwv), maturation arrest (MA) (Zfp541 knockout mouse and Kctd19 knockout mouse), and teratozoospermia (Tbc1d21 knockout mouse). After performing Cr-CEST, histological analysis was performed. Results: The SCO and MA models showed decreased CEST signal intensity (p < 0.05), while no reduction was observed in the teratozoospermia model (p = 1.0). CEST signal intensity increased as the spermatogenesis stage progressed from the SCO model to the MA and teratozoospermia models. Furthermore, CEST signal intensity was reduced in 4-week-old wild-type mice with immature testes (p < 0.05). Conclusions: This study suggests that Cr-CEST evaluates intratesticular spermatogenesis noninvasively and provides a new therapeutic strategy for treating male infertility.

The Firmicutes/Bacteroidetes ratio of the human gut microbiota is associated with prostate enlargement.

BACKGROUND: The pathophysiology of the prostate enlargement underlying lower urinary tract symptoms is unknown. Meanwhile, the gut microbiota can contribute to various host conditions. We hypothesized that the gut microbiota plays a role in prostate enlargement. METHODS: We included 128 patients who underwent prostate biopsies at our hospitals between December 2018 and March 2020, excluding those who had used antibiotics within the past 6 months and those who were diagnosed with prostate cancer of cT3 or higher. Patients with prostate volumes ≥30 ml were defined as the prostate-enlargement (PE) group; those with prostate volumes <30 ml were defined as the non-PE group. Their gut microbiotas were analyzed via 16S rRNA metagenomic analyses of rectal swab samples and were compared between the groups. RESULTS: The PE group included 66 patients; the non-PE group included 62 patients. Age, body mass index, and prostate-specific antigen levels did not significantly differ between the groups. Linear discriminant analysis effect size analysis indicated a higher proportion of Firmicutes and Actinobacteria in the PE group and a higher proportion of Bacteroidetes in the non-PE group. The Firmicutes/Bacteroidetes (F/B) ratio was significantly higher in the PE group than in the non-PE group (2.21 ± 0.39 vs. 1.61 ± 0.40, p = 0.015). CONCLUSION: The F/B ratio of the gut microbiota was associated with prostate enlargement. Although the detailed mechanisms are unclear, the gut microbiota might affect prostate enlargement.

The expression of human testis-specific actin capping protein predicts in vitro fertilization outcomes: A novel biomarker of sperm function for assisted reproductive technology.

PURPOSE: Sperm function tests do not adequately assess fertilization potential, and new indices are required. We have previously reported that human testis-specific actin capping proteins may be involved in both sperm morphology and function. This study aimed to determine whether testis-specific actin capping proteins can be a predictive marker of IVF success. METHODS: Ninety-seven infertile couples who underwent IVF at an infertility clinic were included. Sperm were immunohistochemically stained to evaluate capping protein expression, and the percentage of sperms with normal staining was calculated. The relationship between actin capping protein expression and IVF outcomes was examined. RESULTS: The couples were divided into four groups according to the percentage of normally expressing actin capping protein as follows: ≥90% Group Ⅰ, 80%-90% Group Ⅱ, 70%-80% Group Ⅲ, and <70% Group Ⅳ. Multiple regression analysis showed a significant trend in fertilization rates across the 4 groups (p for trend =0.008).There was no significant trend in pregnancy rates (p for trend =0.276). CONCLUSION: The human testis-specific actin capping protein may be a marker of male contributing factors that predict IVF outcomes.

[A Case of Presacral Paraganglioma Resected by Laparoscopic Surgery].

A 25-year-old woman, with chief complaints of palpitation and vomiting, was suspected of having acute myocarditis and was taken to our critical care center. She was diagnosed with Takotsubo syndrome based on the results of echocardiography, coronary angiography, and myocardial biopsy. The 24-hour urine test showed high levels of normetanephrine and noradrenaline. The abdominal computed tomographic scan showed a presacral tumor (26 mm) just below the aortic bifurcation, and ¹³¹I-meta-iodobenzylguanidine scintigraphy showed abnormal accumulation in the tumor. Finally, she was diagnosed with Takotsubo syndrome associated with presacral paraganglioma. The hemodynamics became stable with conservative treatment. Then she underwent elective laparoscopic surgery. The histopathological analysis revealed paraganglioma. The immunohistochemistry for succinate dehydrogenase was negative in the tumor cells. There has been no recurrence as of 15 months after surgery.

[A Case of Spermatic Cord Liposarcoma Difficult to Distinguish from Inguinal Hernia].

A 53-year-old man visited a doctor due to left inguinal enlargement. He was diagnosed with left inguinal hernia with omentum as the content by a computed tomography (CT)scan. He underwent open inguinal hernia repair ; however, an inguinal tumor was diagnosed intraoperatively and was resected as much as possible. Although the tumor resection was macroscopically incomplete, he was followed up without any treatment because the tumor was histologically diagnosed as lipoma. Sixteen months after surgery, a 15 cm inguinal mass and a 7 cm left intrascrotal mass were detected by follow-up CT, and he was referred to our hospital. He underwent open surgery for wide excision of the tumor with a diagnosis of spermatic cord liposarcoma and left hydrocele of testis. The spermatic cord tumor was histologically diagnosed as well differentiated liposarcoma. He has been alive without recurrence for more than 10 months after surgery. It is sometimes difficult to distinguish a spermatic cord liposarcoma from inguinal hernia by imaging examinations.

Intravesical ATP instillation induces urinary frequency because of activation of bladder afferent nerves without inflammatory changes in mice: A promising model for overactive bladder.

ATP in the suburothelial layer is released from the bladder urothelium by mechanical stimuli. ATP directly activates purinergic receptors that are expressed on primary bladder afferent neurons and induces the micturition reflex. Although ATP is also released to the bladder lumen from the bladder urothelium, the role of ATP in the bladder lumen is unknown. Recently, clinical studies have reported that urinary ATP levels are much higher in patients with an overactive bladder than healthy controls. These results suggest that ATP in the bladder lumen is also involved in the micturition reflex. In this study, we performed intravesical ATP instillation in the mouse bladder. We evaluated urinary function with novel reliable methods using improved cystometry and ultrasonography, which we previously established. We found that intravesical ATP instillation induced urinary frequency because of activation of bladder afferent nerves without inflammatory changes in the bladder or an increase in post-void residual urine. These results suggest that not only ATP in the suburothelial layer, but also ATP in the bladder lumen, are involved in enhancement of the micturition reflex.

[Two Cases of Clear Cell Adenocarcinoma Arising in Urethral Diverticulum].

We report two cases of clear cell adenocarcinoma arising in the urethral diverticulum. Case 1 occurred in a 79-year-old woman presenting with complaints of frequent micturition. Magnetic resonance imaging (MRI) revealed a localized urethral diverticular tumor. Transurethral resection of the tumor was performed, and the final histopathological diagnosis was clear cell adenocarcinoma. Anterior pelvic exenteration was performed. She had no recurrence 15 months after surgery. Case 2 occurred in a 79-year-old woman presenting with urinary incontinence. As in Case 1, MRI and histopathological findings of transurethral resection of the tumor revealed clear cell adenocarcinoma in the urethral diverticulum. Anterior pelvic exenteration and ileal conduit formation were performed. She had no recurrence 16 months after surgery. Clear cell adenocarcinoma in the urethral diverticulum is very rare. We review 17 cases of clear cell adenocarcinoma arising in the urethral diverticulum in Japan.

Urothelial ATP signaling: what is its role in bladder sensation?

AIM: Bladder functional disorders are common health problems; however, their pathologies are poorly understood. Adenosine triphosphate (ATP) released from the urothelium has been suggested to have an essential role in the micturition reflex, and its involvement in bladder functional disorders has been intensively investigated. Here, we review the latest advances in research on urothelial ATP signaling. METHODS: We reviewed research articles on the role of the urothelium and urothelial ATP release in bladder function. RESULTS: Mice lacking purinergic receptors have been reported to exhibit marked bladder hyporeflexia. Based on this observation, it was commonly believed, according to the widely held ATP urothelial signaling theory, that stretch-induced urothelial ATP release mediates the sensation of bladder filling via purinergic receptors. However, recent studies employing novel experimental methods and approaches have demonstrated that there are no significant differences in bladder function between wild-type and purinergic receptor knockout mice under physiological conditions. Nonetheless, under pathological conditions, inhibition of purinergic receptors has been shown to improve bladder hyperactivity. Moreover, enhanced urothelial ATP release has been reported in patients with bladder functional disorders. CONCLUSIONS: Recently, conflicting evidence has led us to question the role of urothelial ATP signaling in normal micturition reflex. In contrast, under pathological conditions, it seems likely that enhanced urothelial ATP signaling mediates bladder hyperactivity. These recent findings suggest that the urothelial ATP signaling pathway is a potential therapeutic target for bladder functional disorders.

[Seminal Vesicle Abscess Associated with Zinner Syndrome].

We report a case of seminal vesicle abscess associated with Zinner syndrome. A 26-year-old male was admitted to our hospital because of fever and right scrotal swelling. Ultrasound showed an enlarged epididymis and color Doppler ultrasound showed increased vascularity in the epididymis. We diagnosed the case as acute epididymitis and started intravenous antibiotic therapy. Four days after admission, remittent fever persisted and blood culture was positive for Staphylococcus aureus. We performed computed tomography, which showed a right seminal vesicle cyst abscess and right renal agenesis. Our diagnosis was an abscess associated with Zinner syndrome. Transrectal ultrasound-guided transperineal drainage was performed 30 days after admission because seminal vesicle abscess could not be controlled by conservative treatment. Eight days after the procedure, the patient was discharged. One year after the procedure, recurrence of seminal vesicle abscess has not been observed.

[A CASE OF ABO INCOMPATIBLE LIVING KIDNEY TRANSPLANTATION IN A PATIENT WITH SELECTIVE IgA DEFICIENCY].

We report a case of ABO incompatible living kidney transplantation in a 45-year-old man with selective IgA deficiency. He has been on hemodialysis for 1 year due to chronic renal failure. Although the serum anti-IgA antibody was negative, he has experienced anaphylactic reaction to red blood cell product in the past. Before the transplantation, we performed double filtration plasmapheresis for two times, but didn't performed plasma exchange, considering the possibility of producing anti-IgA antibody and anaphylactic reaction. He underwent kidney transplantation from his mother without anaphylactic reaction, following to the recirculation of renal blood flow. He was discharged on the 29th postoperative day when the serum creatinine level was 1.2 mg/dL. The graft function was stable at 8 months after transplantation with no evidence of rejection and infection.

Combination of bladder ultrasonography and novel cystometry method in mice reveals rapid decrease in bladder capacity and compliance in LPS-induced cystitis.

Various animal models have been used in research into bladder dysfunction, and in vivo cystometry is a common method to analyze bladder function in animals. However, it is rather difficult to perform reliably in small animals. Transabdominal bladder ultrasonography combined with cystometry in urethane-anesthetized mice have revealed physical inhibition of bladder wall movement by a bladder catheter conventionally placed in the bladder apex. For reliable evaluation of mouse lower urinary tract function, we established a novel cystometry method in which a catheter was placed in the bladder anterior wall, in combination with bladder ultrasonography. This new method allowed the bladder to be well distended (i.e., larger maximum bladder capacity, lower pressure threshold, higher voided volume, and higher bladder compliance compared with conventional methods), which reflected more spontaneous voiding than conventional cystometry methods. We also demonstrated the usefulness of bladder ultrasonography for analysis of mouse bladder function, especially bladder dynamics, maximum bladder capacity, and post-voiding residual volume. We analyzed bladder functional changes in lipopolysaccharide (LPS)-induced cystitis by combining bladder ultrasonography and this new cystometry method. Bladder ultrasonography revealed a rapid decrease in bladder capacity, and cystometry showed a rapid decrease in voided volume due to intravesical LPS instillation. This new cystometry method also revealed a rapid decrease in bladder compliance caused by LPS instillation, which was not detectable by conventional methods. The combination of ultrasonography and the new cystometry method may become a powerful tool for analysis of mouse bladder function and could contribute to the development of new treatments for bladder dysfunction.

Sexual life of Japanese patients with erectile dysfunction taking phosphodiesterase type 5 inhibitors: an Internet survey using the Psychological and Interpersonal Relationship Scales-Short Form questionnaire.

OBJECTIVES: To investigate details of sexual function of erectile dysfunction in Japanese patients taking phosphodiesterase type 5 inhibitors. METHODS: A Japanese version of the Psychological and Interpersonal Relationship Scales-Short Form was used to carry out a nationwide survey using the Internet. A total of 556 erectile dysfunction patients (age 30-70 years) who had been prescribed a phosphodiesterase type 5 inhibitor and had attempted sexual intercourse within the past 6 months were included in this survey. Scores were compared in relation to the phosphodiesterase type 5 inhibitors most frequently taken within the past 6 months. RESULTS: In the subdomains of self-confidence and spontaneity of the Psychological and Interpersonal Relationship Scales-Short Form, scores for vardenafil and tadalafil were significantly higher than those for sildenafil. In the subdomain of time concern of the Psychological and Interpersonal Relationship Scales-Short Form, the score for tadalafil was significantly lower than that for others. CONCLUSIONS: Our findings support the hypothesis that Japanese patients with erectile dysfunction have high sexual self-confidence, spontaneity and low time concerns when taking tadalafil. These characteristics of tadalafil could be associated with high patient satisfaction and high preference.

Efficacy and Safety of Anti-angiogenic Agents for Cancer Patients With Proteinuria or a History of Proteinuria: A Systematic Review.

BACKGROUND/AIM: The safety and efficacy of anti-angiogenic agents in patients with cancer with proteinuria and a history of proteinuria are not well established. This systematic review aimed to answer these questions. MATERIALS AND METHODS: We searched three electronic databases for articles published until June 18, 2021. The main outcomes used were "death", "renal impairment", and "proteinuria impairment". RESULTS: After screening 303 references in the PubMed, Cochrane Library, and ICHUSHI-web databases, this review included five studies on renal cell carcinoma (RCC). In patients with metastatic RCC, the hazard ratio of the presence of (or having) proteinuria (1+ or higher) at baseline was 0.82 (0.23-2.97); thus, proteinuria was not significantly associated with the outcome of death. No significant deterioration in kidney function was observed in patients with proteinuria. Although proteinuria at baseline was a significant risk factor for proteinuria progression during and after treatment, most patients maintained grade 1 or 2 proteinuria and continued treatment without dose reduction or discontinuation. CONCLUSION: While weak evidence suggests that proteinuria at the start of treatment with anti-angiogenic agents might be a risk factor for worsening proteinuria, it was not significantly associated with death or renal impairment.

[Successful treatment of spontaneous rupture of pheochromocytoma with laparoscopic adrenalectomy: a case report].

A 46-year-old man had sudden onset of severe left hypochondrial pain and went into shock following hospitalization. Computed tomography, echocardiography, and endocrinological tests revealed spontaneous rupture of a pheochromocytoma associated with catecholamine cardiomyopathy. After he underwent conservative management with fluid replacement, his blood pressure stabilized and cardiac function improved. Twenty-two days later, he was referred to our hospital. After admission, as his circulatory dynamics was stable, we performed elective laparoscopic left adrenalectomy. He was discharged on the tenth postoperative day. Spontaneous rupture of a pheochromocytoma is very rare : laparoscopic surgery for this condition has been reported only on 2 previous occasions worldwide.