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BACKGROUND: Surgical penile prosthesis implantation (PPI) procedures have only recently been introduced to mainland China, with the overall number of such procedures having been conducted to date remaining relatively low. Accordingly, relatively little remains known with respect to the annual trends in PPI. Accordingly, this study was developed with the goal of clarifying these trends across different hospitals in mainland China, while also providing a single-center overview of post-PPI patient outcomes. RESULTS: To identify males in mainland China who had undergone PPI, a retrospective review of data from January 2019 - October 2023 was conducted. This approach revealed an increase in the total PPI caseload from 120 in 2019 to 413 within the first 10 months of 2023. Over this same interval, the number of surgeons performing PPI rose from 33 to 74. A retrospective review of the 112 patients who had undergone PPI at Shanghai General Hospital from 2019-2023 revealed that these patients had a median age of 39 [27-63] years, and PPI treatment led to a significant increase in median International Index of Erectile Function-5 (IIEF-5) scores from a baseline value of 10.23 ± 1.26 to a post-treatment value of 22.6 ± 2.73. The underlying causes of erectile dysfunction for these patients included vasculogenic factors (58/112; 51.8%), diabetes mellitus (21/112; 18.8%), and injuries to the spinal cord or pelvis (14/112; 12.5%). The overall rates of satisfaction with the PPI reported by patients and their partners were 93.0% and 90.4%, respectively, and the 3-year PPI survival rate for this cohort was 87%. CONCLUSION: These data highlight a rising trend in the number of PPI being performed in China, with these steadily increasing rates since 2019 emphasizing the increasingly high levels of acceptance of this procedure by patients and clinicians as a means of treating erectile dysfunction. However, the expertise is restricted to a small number of surgeons. Even so, it is a safe and efficacious approach to managing severe erectile dysfunction for patients in China, and when performed by experienced surgeons based on standardized protocols, low complication rates can be achieved while providing patients and their sexual partners with high levels of satisfaction.
RéSUMé: CONTEXTE: Les procédures chirurgicales d'implantation de prothèses péniennes (IPP) n'ont été que récemment introduites en Chine continentale, le nombre total de procédures de ce type ayant été effectuées à ce jour restant relativement faible. On ne sait donc encore que relativement peu de choses sur les tendances annuelles de l'IPP. La présente étude a été développée dans le but de clarifier ces tendances dans différents hôpitaux de Chine continentale, tout en fournissant une vue d'ensemble des résultats des patients post-IPP dans un seul centre. RéSULTATS: Afin d'identifier les hommes de Chine continentale qui avaient subi un IPP, une recherche rétrospective des données a été effectuée de janvier 2019 à octobre 2023. Cette approche a révélé une augmentation du nombre total de cas d'IPP de 120 en 2019 à 413 au cours des 10 premiers mois de 2023. Au cours de cette même période, le nombre de chirurgiens pratiquant des IPP est passé de 33 à 74. L'étude rétrospective des 112 patients qui avaient subi un IPP à l'hôpital général de Shanghai de 2019 à 2023 a révélé qu' ils avaient un âge médian de 39 [2763] ans, et que le traitement par IPP a entraîné une augmentation significative des scores médians de l'indice international de la fonction érectile-5, qui sont passés d'une valeur de base de 10,2 ± 1,3 à une valeur post-traitement de 22,6 ± 2,7. Les causes sous-jacentes de la dysfonction érectile chez ces patients comprenaient des facteurs vasculogéniques (58/112; 51,8%), un diabète (21/112; 18,8%) et des lésions de la moelle épinière ou du bassin (14/112; 12,5%). Les taux globaux de satisfaction à l'égard de l'IPP, rapportés par les patients et leurs partenaires, étaient respectivement de 93,0% et 90,4%, et le taux de survie à 3 ans de l'IPP dans cette cohorte était de 87%. CONCLUSION: Ces données mettent en évidence une tendance à la hausse du nombre d'IPP pratiquées en Chine; ces taux en constante augmentation depuis 2019 soulignent les niveaux de plus en plus élevés d'acceptation de cette procédure par les patients et les cliniciens comme moyen de traitement de la dysfonction érectile. Cependant, l'expertise est limitée à un petit nombre de chirurgiens. Malgré cela, il s'agit d'une approche sûre et efficace pour gérer la dysfonction érectile sévère pour les patients en Chine, et lorsqu'elle est effectuée par des chirurgiens expérimentés sur la base de protocoles standardisés, de faibles taux de complications peuvent être atteints tout en offrant aux patients et à leurs partenaires sexuels des niveaux élevés de satisfaction.
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BACKGROUND: Pediatric inguinal hernia repair (IHR) is a common cause of obstructive azoospermia (OA). Yet, the surgical treatment for this kind of OA remains difficult with poor fertility outcome. OBJECTIVES: To evaluate the safety and effectiveness of totally extraperitoneal laparoscopy-assisted microsurgical vasovasostomy (VV) in the treatment of OA caused by pediatric bilateral IHR. MATERIALS AND METHODS: Totally, 37 patients with OA caused by pediatric bilateral IHR were enrolled in this study from March 2015 to December 2020 in Shanghai General Hospital. The clinical data and fertility outcomes were collected and analyzed. RESULTS: All patients enrolled had a history of bilateral IHR at the age of 1-10 years old. The mean age of patients was 27 ± 4.31 (range: 18-35) years. Totally extraperitoneal laparoscopy (TEP) was applied in 31 patients for the exploration and retrieval of pelvic vas deferens end, and 30 of them underwent microsurgical VV successfully. Among the six cases where TEP was not applied, five cases underwent microsurgical anastomosis. Intraoperative exploration revealed that the location of vas deferens injuries included scrotum (2.70%, 1/37), inguinal canal (5.41%, 2/37), pelvic cavity (78.37%, 29/37), and multiple sites (13.51%, 5/37). The mean operation time was 339 ± 96.73 min (range: 130-510 min). There were no surgical complications. Thirty-three cases were followed up for 5-48 months with four cases lost to follow-up. The overall patency rate, pregnancy rate, and natural pregnancy rate were 75.86% (22/29), 46.67% (14/30), and 36.84% (7/19, 3 patients without family planning), respectively. And seven couples conceived through the assisted reproductive technique, two of which using fresh sperm in the ejaculate. CONCLUSION: TEP laparoscopy-assisted microscopic VV is an effective treatment for patients with OA caused by pediatric bilateral IHR.
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Primate-specific DAZ (deleted in azoospermia) has evolved in the azoospermia factor c (AZFc) locus on the Y chromosome. Loss of DAZ is associated with azoospermia in patients with deletion of the AZFc region (AZFc_del). However, the molecular mechanisms of DAZ in spermatogenesis remain uncertain. In this study, the molecular mechanism of DAZ is identified, which is unknown since it is identified 40 years ago because of the lack of a suitable model. Using clinical samples and cell models, it is shown that DAZ plays an important role in spermatogenesis and that loss of DAZ is associated with defective proliferation of c-KIT-positive spermatogonia in patients with AZFc_del. Mechanistically, it is shown that knockdown of DAZ significantly downregulated global translation and subsequently decreased cell proliferation. Furthermore, DAZ interacted with PABPC1 via the DAZ repeat domain to regulate global translation. DAZ targeted mRNAs that are involved in cell proliferation and cell cycle phase transition. These findings indicate that DAZ is a master translational regulator and essential for the maintenance of spermatogonia. Loss of DAZ may result in defective proliferation of c-KIT-positive spermatogonia and spermatogenic failure.
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Proliferación Celular , Proteína 1 Delecionada en la Azoospermia , ARN Mensajero , Proteínas de Unión al ARN , Espermatogénesis , Espermatogonias , Masculino , Espermatogonias/metabolismo , Proliferación Celular/genética , Humanos , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Espermatogénesis/genética , Proteína 1 Delecionada en la Azoospermia/genética , Proteína 1 Delecionada en la Azoospermia/metabolismo , Animales , Azoospermia/genética , Azoospermia/metabolismo , AdultoRESUMEN
Age-related changes in testicular function can impact health and well-being. The mechanisms underlying age-related testicular dysfunction, such as late-onset hypogonadism (LOH), remain incompletely understood. Using single-cell RNA sequencing on human testes with LOH, we delineated Sertoli cells (SCs) as pivotal metabolic coordinators within the testicular microenvironment. In particular, lysosomal acidity probing revealed compromised degradative capacity in aged SCs, hindering autophagy and phagocytic flux. Consequently, SCs accumulated metabolites, including cholesterol, and have increased inflammatory gene expression; thus, we termed these cells as phago-/auto-lysosomal deregulated SCs. Exposure to a high-fat diet-induced phago-/auto-lysosomal dysregulated-like SCs, recapitulating LOH features in mice. Notably, efferent ductular injection and systemic TRPML1 agonist administration restored lysosomal function, normalizing testosterone deficiency and associated abnormalities in high-fat diet-induced LOH mice. Our findings underscore the central role of SCs in testis aging, presenting a promising therapeutic avenue for LOH.
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Dieta Alta en Grasa , Hipogonadismo , Lisosomas , Células de Sertoli , Masculino , Células de Sertoli/metabolismo , Animales , Lisosomas/metabolismo , Ratones , Hipogonadismo/metabolismo , Hipogonadismo/genética , Hipogonadismo/patología , Humanos , Dieta Alta en Grasa/efectos adversos , Testículo/metabolismo , Testículo/patología , Testosterona/metabolismo , Autofagia/efectos de los fármacos , Envejecimiento/metabolismoRESUMEN
Dynamic chromosome remodeling and nuclear compartmentalization take place during mammalian meiotic prophase I. We report here that the crucial roles of male pachynema-specific protein (MAPS) in pachynema progression might be mediated by its liquid-liquid phase separation in vitro and in cellulo. MAPS forms distinguishable liquid phases, and deletion or mutations of its N-terminal amino acids (aa) 2-9 disrupt its secondary structure and charge properties, impeding phase separation. Maps-/- pachytene spermatocytes exhibit defects in nucleus compartmentalization, including defects in forming sex bodies, altered nucleosome composition, and disordered chromatin accessibility. MapsΔ2-9/Δ2-9 male mice expressing MAPS protein lacking aa 2-9 phenocopy Maps-/- mice. Moreover, a frameshift mutation in C3orf62, the human counterpart of Maps, is correlated with nonobstructive azoospermia in a patient exhibiting pachynema arrest in spermatocyte development. Hence, the phase separation property of MAPS seems essential for pachynema progression in mouse and human spermatocytes.
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Cromatina , Meiosis , Humanos , Masculino , Ratones , Animales , Cromatina/metabolismo , Fase Paquiteno , Separación de Fases , Profase Meiótica I , Espermatocitos/metabolismo , Mamíferos/genéticaRESUMEN
Nonobstructive azoospermia (NOA), the most severe manifestation of male infertility, lacks a comprehensive understanding of its genetic etiology. Here, a bi-allelic loss-of-function variant in REC114 (c.568C > T: p.Gln190*) were identified through whole exome sequencing (WES) in a Chinese NOA patient. Testicular histopathological analysis and meiotic chromosomal spread analysis were conducted to assess the stage of spermatogenesis arrested. Co-immunoprecipitation (Co-IP) and Western blot (WB) were used to investigate the influence of variant in vitro. In addition, our results revealed that the variant resulted in truncated REC114 protein and impaired interaction with MEI4, which was essential for meiotic DNA double-strand break (DSB) formation. As far as we know, this study presents the first report that identifies REC114 as the causative gene for male infertility. Furthermore, our study demonstrated indispensability of the REC114-MEI4 complex in maintaining DSB homoeostasis, and highlighted that the disruption of the complex due to the REC114 variant may underline the mechanism of NOA.
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Azoospermia , Infertilidad Masculina , Humanos , Masculino , Azoospermia/genética , Azoospermia/patología , Pérdida de Heterocigocidad , Infertilidad Masculina/genética , Infertilidad Masculina/patología , Testículo/patología , Meiosis/genética , Proteínas de Ciclo Celular/genéticaRESUMEN
ABSTRACT: The regulation of spermatogonial proliferation and apoptosis is of great significance for maintaining spermatogenesis. The single-cell RNA sequencing (scRNA-seq) analysis of the testis was performed to identify genes upregulated in spermatogonia. Using scRNA-seq analysis, we identified the spermatogonia upregulated gene origin recognition complex subunit 6 (Orc6), which is involved in DNA replication and cell cycle regulation; its protein expression in the human and mouse testis was detected by western blot and immunofluorescence. To explore the potential function of Orc6 in spermatogonia, the C18-4 cell line was transfected with control or Orc6 siRNA. Subsequently, 5-ethynyl-2-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, flow cytometry, and western blot were used to evaluate its effects on proliferation and apoptosis. It was revealed that ORC6 could promote proliferation and inhibit apoptosis of C18-4 cells. Bulk RNA sequencing and bioinformatics analysis indicated that Orc6 was involved in the activation of wingless/integrated (Wnt)/ ß-catenin signaling. Western blot revealed that the expression of ß-catenin protein and its phosphorylation (Ser675) were significantly decreased when silencing the expression of ORC6. Our findings indicated that Orc6 was upregulated in spermatogonia, whereby it regulated proliferation and apoptosis by activating Wnt/ß-catenin signaling.
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BACKGROUND: Although the orchiopexy is recommended for cryptorchidism to preserve male fertility, non-obstructive azoospermia (NOA) may occur in adulthood. Fortunately, a great many of azoospermic men may obtain sperm by microdissection testicular sperm extraction (mTESE). Due to the potential injuries caused by testicular diagnostic biopsy and vascular damage at the time of orchidopexy, minimal invasiveness is particularly important during mTESE, aims to reduce the surgical damage and avoids secondary testicular failure. This comparative study aims to investigate the efficacy of stepwise mini-incision mTESE technique by comparison with standard mTESE in the treatment of NOA patients with a history of cryptorchidism. RESULTS: A total of 73 mTESE procedures were divided into two groups: Group 1 included 37 cases performed by stepwise mini-incision mTESE, while Group 2 included 36 cases with standard mTESE. The overall sperm retrieval rate (SRR) in the two groups was 68.5% (50/73), with no significant difference in SRR between Group 1 (78.4%, 29/37) and Group 2 (58.3%, 21/36) (P = 0.1). In addition, 46.0% of the patients (17/37) obtained sperm in the first mini-incision step in Group 1, which was also equal to an overall SRR in Group 2 (58.3%, 21/36) (P = 0.3). The operation time in Group 1 (72.6 ± 33.9 min) was significantly shorter than that in Group 2 (90.4 ± 36.4 min) (P = 0.04). Patients with an orchidopexy age no more than 10 years old had a higher SRR (79.5%, 31/39) than others (55.9%, 19/34) (P = 0.03). There were no postoperative complications including wound infection, scrotal hematoma, persistent pain, and testicular atrophy during a follow-up period of at least 6 months. CONCLUSIONS: In conclusion, our study suggests that the stepwise mini-incision mTESE could be a promising approach for sperm retrieval in NOA men with a history of cryptorchidism. While the technique may potentially reduce operation time and surgical invasiveness, further research is needed to validate these findings on a larger scale. The results also suggest that age at orchidopexy may affect SRR and have important implications for the management of cryptorchidism.
RéSUMé: CONTEXTE: Bien que l'orchidopexie soit recommandée en cas de cryptorchidie afin de préserver la fertilité masculine, une azoospermie non obstructive (NOA) peut survenir à l'âge adulte. Heureusement, un grand nombre d'hommes azoospermiques peuvent obtenir des spermatozoïdes lors d'une extraction de spermatozoïdes testiculaire par microdissection (mTESE). En raison des potentielles lésions causées par la biopsie diagnostique testiculaire et des lésions vasculaires survenant au moment de l'orchidopexie, une approche minimalement invasive est particulièrement importante pendant la mTESE; elle vise à réduire les dommages chirurgicaux et à éviter une insuffisance testiculaire secondaire. La présente étude comparative a pour but d' étudier l'efficacité de la mTESE par mini-incision par étapes en comparaison avec la mTESE standard dans le traitement des patients NOA qui ont des antécédents de cryptorchidie. RéSULTATS: Au total, 73 procédures de mTESE ont été divisées en deux groupes: le Groupe 1 comprenait 37 cas effectués avec la mTESE par mini-incision par étapes, tandis que le Groupe 2 comprenait 36 cas réalisés par la mTESE standard. Le taux global de récupération de spermatozoïdes (SRR) dans les deux groupes était de 68, 5% (50/73), sans différence significative de SRR entre le Groupe 1 (78, 4%, 29/37) et le Groupe 2 (58, 3%, 21/36) (P = 0,1). De plus, 46% des patients (17/37) ont obtenu des spermatozoïdes lors de la première étape de mini-incision dans le Groupe 1, ce qui était identique au SRR global dans le Groupe 2 (58%, 21/36) (P = 0,3). Le temps opératoire du Groupe 1 (72, 6 ± 34 min) était significativement plus court que celui du Groupe 2 (90, 4 ± 36 min) (P = 0,04). Les patients dont l'orchidopexie avait été réalisée au plus tard à l'âge de 10 ans avaient un SRR plus élevé (79, 5%, 31/39) que les autres (55, 9%, 19/34) (P = 0,03). Il n'y a pas eu de complications postopératoires, que ce soit infection de la plaie, hématome scrotal, douleur persistante, ou atrophie testiculaire pendant une période de suivi d'au moins 6 mois. CONCLUSIONS: Notre étude suggère que la mTESE par mini-incision par étapes pourrait être une approche prometteuse pour la récupération de spermatozoïdes chez les hommes NOA ayant des antécédents de cryptorchidie. Bien que la technique puisse potentiellement réduire le temps d'opération et le caractère invasif du geste chirurgical, des recherches supplémentaires sont nécessaires pour valider ces résultats à plus grande échelle. Les résultats suggèrent également que l'âge à l'orchidopexie peut affecter le SRR et avoir des implications importantes pour la prise en charge de la cryptorchidie.
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Meiotic arrest is a common pathologic phenotype of non-obstructive azoospermia (NOA), yet its genetic causes require further investigation. Meiotic nuclear divisions 1 (MND1) has been proved to be indispensable for meiotic recombination in many species. To date, only one variant of MND1 has been reported associated with primary ovarian insufficiency (POI), yet there has been no report of variants in MND1 associated with NOA. Herein, we identified a rare homozygous missense variant (NM_032117:c.G507C:p.W169C) of MND1 in two NOA-affected patients from one Chinese family. Histological analysis and immunohistochemistry demonstrated meiotic arrest at zygotene-like stage in prophase I and lack of spermatozoa in the proband's seminiferous tubules. In silico modeling demonstrated that this variant might cause possible conformational change in the leucine zippers 3 with capping helices (LZ3wCH) domain of MND1-HOP2 complex. Altogether, our study demonstrated that the MND1 variant (c.G507C) is likely responsible for human meiotic arrest and NOA. And our study provides new insights into the genetic etiology of NOA and mechanisms of homologous recombination repair in male meiosis.
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Genetic causation for the majority of non-obstructive azoospermia (NOA) remains unclear. Mutations in synaptonemal complex (SC)-associated genes could cause meiotic arrest and NOA. Previous studies showed that heterozygous truncating variants in SYCP2 encoding a protein essential for SC formation, are associated with non-obstructive azoospermia and severe oligozoospermia. Herein, we showed a homozygous loss-of-function variant in SYCP2 (c.2689_2690insT) in an NOA-affected patient. And this variant was inherited from heterozygous parental carriers by natural reproduction. HE, IF, and meiotic chromosomal spread analyses demonstrated that spermatogenesis was arrested at the zygotene stage in the proband with NOA. Thus, this study revealed that SYCP2 associated with NOA segregates in an autosomal recessive inheritance pattern, rather than an autosomal dominant pattern. Furthermore, our study expanded the knowledge of variants in SYCP2 and provided new insight into understanding the genetic etiology of NOA.
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Azoospermia , Masculino , Humanos , Azoospermia/genética , Mutación del Sistema de Lectura , Mutación , Espermatogénesis/genética , Proteínas de Unión al ADN/genética , Proteínas de Ciclo Celular/genéticaRESUMEN
Klinefelter syndrome (KS) is the most common genetic cause of human male infertility. However, the effect of the extra X chromosome on different testicular cell types remains poorly understood. Here, we profiled testicular single-cell transcriptomes from three KS patients and normal karyotype control individuals. Among the different somatic cells, Sertoli cells showed the greatest transcriptome changes in KS patients. Further analysis showed that X-inactive-specific transcript ( XIST ), a key factor that inactivates one X chromosome in female mammals, was widely expressed in each testicular somatic cell type but not in Sertoli cells. The loss of XIST in Sertoli cells leads to an increased level of X chromosome genes, and further disrupts their transcription pattern and cellular function. This phenomenon was not detected in other somatic cells such as Leydig cells and vascular endothelial cells. These results proposed a new mechanism to explain why testicular atrophy in KS patients is heterogeneous with loss of seminiferous tubules but interstitial hyperplasia. Our study provides a theoretical basis for subsequent research and related treatment of KS by identifying Sertoli cell-specific X chromosome inactivation failure.
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Síndrome de Klinefelter , Células de Sertoli , Animales , Humanos , Masculino , Femenino , Células de Sertoli/metabolismo , Síndrome de Klinefelter/genética , Células Endoteliales , Testículo/metabolismo , Cromosoma X/metabolismo , Mamíferos/genéticaRESUMEN
This study aimed to evaluate the ability of rete testis thickness (RTT) and testicular shear wave elastography (SWE) to differentiate obstructive azoospermia (OA) from nonobstructive azoospermia (NOA). We assessed 290 testes of 145 infertile males with azoospermia and 94 testes of 47 healthy volunteers at Shanghai General Hospital (Shanghai, China) between August 2019 and October 2021. The testicular volume (TV), SWE, and RTT were compared among patients with OA and NOA and healthy controls. The diagnostic performances of the three variables were evaluated using the receiver operating characteristic curve. The TV, SWE, and RTT in OA differed significantly from those in NOA (all P ≤ 0.001) but were similar to those in healthy controls. Males with OA and NOA were similar at TVs of 9-11 cm 3 ( P = 0.838), with sensitivity, specificity, Youden index, and area under the curve of 50.0%, 84.2%, 0.34, and 0.662 (95% confidence interval [CI]: 0.502-0.799), respectively, for SWE cut-off of 3.1 kPa; and 94.1%, 79.2%, 0.74, and 0.904 (95% CI: 0.811-0.996), respectively, for RTT cut-off of 1.6 mm. The results showed that RTT performed significantly better than SWE in differentiating OA from NOA in the TV overlap range. In conclusion, ultrasonographic RTT evaluation proved a promising diagnostic approach to differentiate OA from NOA, particularly in the TV overlap range.
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Azoospermia , Masculino , Humanos , Red Testicular , China , TestículoRESUMEN
Stepwise mini-incision microdissection testicular sperm extraction (mTESE) is a procedure that attempts to minimize testicular damage. However, the mini-incision approach may vary in patients with different etiologies. Here, we performed a retrospective analysis of 665 men with nonobstructive azoospermia (NOA) who underwent stepwise mini-incision mTESE (Group 1) and 365 men who underwent standard mTESE (Group 2). The results showed that the operation time (mean ± standard deviation) for patients with successful sperm retrieval in Group 1 (64.0 ± 26.6 min) was significantly shorter than that in Group 2 (80.2 ± 31.3 min), with P <0.001. The total sperm retrieval rate (SRR) was 23.1% in our study, and there was no significant difference between Group 1 and Group 2 ( P >0.05), even when the etiologies of NOA were taken into consideration. The results of consecutive multivariate logistic regression analysis (odds ratio [OR]: 0.57; 95% confidence interval [CI]: 0.38-0.87; P =0.009) and receiver operating characteristic (ROC) analysis (area under the ROC curve [AUC]=0.628) showed that preoperative anti-Müllerian hormone (AMH) level in idiopathic NOA patients was a potential predictor for surgical outcomes after initial three small incisions made in the equatorial region without sperm examined under an operating microscope (Steps 2-4). In conclusion, stepwise mini-incision mTESE is a useful technique for NOA patients, with comparable SRR, less surgical invasiveness, and shorter operation time compared with the standard approach. Low AMH levels may predict successful sperm retrieval in idiopathic patients even after a failed initial mini-incision procedure.
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Non-obstructive azoospermia (NOA) is characterized by the failure of sperm production due to testicular disorders and represents the most severe form of male infertility. Growing evidences have indicated that gene defects could be the potential cause of NOA via genome-wide sequencing approaches. Here, bi-allelic deleterious variants in meiosis inhibitor protein 1 (MEI1) were identified by whole-exome sequencing in four Chinese patients with NOA. Testicular pathologic analysis and immunohistochemical staining revealed that spermatogenesis is arrested at spermatocyte stage, with defective programmed DNA double-strand breaks (DSBs) homoeostasis and meiotic chromosome synapsis in patients carrying the variants. In addition, our results showed that one missense variant (c.G186C) reduced the expression of MEI1 and one frameshift variant (c.251delT) led to truncated proteins of MEI1 in in vitro. Furthermore, the missense variant (c.T1585A) was assumed to affect the interaction between MEI1 and its partners via bioinformatic analysis. Collectively, our findings provide direct genetic and functional evidences that bi-allelic variants in MEI1 could cause defective DSBs homoeostasis and meiotic chromosome synapsis, which subsequently lead to meiosis arrest and male infertility. Thus, our study deepens our knowledge of the role of MEI1 in male fertility and provides a novel insight to understand the genetic aetiology of NOA.
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Azoospermia , Infertilidad Masculina , Humanos , Masculino , Azoospermia/genética , Azoospermia/patología , Semen , Proteínas/genética , Infertilidad Masculina/genética , Meiosis/genética , Proteínas de Ciclo Celular/genéticaRESUMEN
Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory to the similarity of spermatogenesis among mammals. Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia. SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded independently in rodents and primates. As the mouse model could not be used for studying SSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression in the testes. Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology. Further, RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis. Collectively, our experimental observations in humans and cynomolgus monkey and tree shrew models highlight the crucial role of SSX1 in spermatogenesis. Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy. This study provides important guidance for genetic counseling and clinical diagnosis and, significantly, describes the approaches for elucidating the functions of testis-enriched PSGs in spermatogenesis.
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Astenozoospermia , Tupaia , Animales , Masculino , Macaca fascicularis , Primates , Semen , Motilidad Espermática , TupaiidaeRESUMEN
BACKGROUND: The development of single-cell sequencing technology has expanded the understanding of cell heterogeneity and disease progression in the male genitourinary system. However, complex processing and unprofessional analytical annotations limit the daily use and widely sharing of published datasets. OBJECTIVES: Single-cell sequencing data of male-specific tissues and organs. MATERIALS AND METHODS: The data were downloaded from published studies and were processed based on the Seurat R package, including quality control, cell clustering, reduction and graph generation, and cell type annotation were differentiated by referring to the related paper or recognized cell markers. Input and visual results output through the Shiny package, which was loaded into the remote server. RESULTS: The current version of the Male Health Atlas database includes two species (human and mouse), five male-specific tissues and organs (testis, epididymis, vas deferens, corpus cavernosum, and prostate), and eight major cell types, with a total of 57 samples and 258,428 single-cell profiles. The results were divided into two main parts: Cell Clustering and Gene Display. In Cell Clustering section, visitors are free to change cell dimensionality reduction (t-distributed stochastic neighbor embedding, or uniform manifold approximation and projection), color palette, and annotation (cell type or sample type). The Gene Display section includes a reduced dimension scatter plot, violin plot, and bubble plot. Visitors can easily view the expression characteristics of single or multiple genes, and compare the expression differences between different cell types or groups. DISCUSSION AND CONCLUSION: Male Health Atlas is the first single-cell database website in the field of andrology and male reproduction, providing researchers with single-cell sequencing resources and an accessible tool. Male Health Atlas is freely available at http://malehealthatlas.cn/.
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Análisis de la Célula Individual , Análisis de Expresión Génica de una Sola Célula , Masculino , Humanos , Animales , Ratones , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Análisis por Conglomerados , Bases de Datos Factuales , Perfilación de la Expresión Génica/métodosRESUMEN
Patients with congenital unilateral absence of the vas deferens (CUAVD) manifest diverse symptoms from normospermia to azoospermia. Treatment for CUAVD patients with obstructive azoospermia (OA) is complicated, and there is a lack of relevant reports. In this study, we describe the clinical features and evaluate the treatments and outcomes of CUAVD patients with OA. From December 2015 to December 2020, 33 patients were diagnosed as CUAVD with OA in Shanghai General Hospital (Shanghai, China). Patient information, ultrasound findings, semen analysis, hormone profiles, and treatment information were collected, and the clinical outcomes were evaluated. Of 33 patients, 29 patients were retrospectively analyzed. Vasoepididymostomy (VE) or cross VE was performed in 12 patients, the patency rate was 41.7% (5/12), and natural pregnancy was achieved in one of the patients. The other 17 patients underwent testicular sperm extraction as the distal vas deferens (contralateral side) was obstructed. These findings showed that VE or cross VE remains an alternative treatment for CUAVD patients with OA, even with a relatively low rate of patency and natural pregnancy.
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Azoospermia , Conducto Deferente , Embarazo , Femenino , Humanos , Masculino , Conducto Deferente/cirugía , Conducto Deferente/anomalías , Azoospermia/cirugía , Epidídimo/cirugía , Estudios Retrospectivos , Centros de Atención Terciaria , China , SemenRESUMEN
BACKGROUND: A recent sham-controlled clinical study has shown that low-intensity pulsed ultrasound twice per week can safely and effectively treat patients with mild-to-moderate erectile dysfunction (ED). However, large-scale clinical trials are needed to verify its efficacy and safety and determine a reasonable treatment interval. AIM: To study whether low-intensity pulsed ultrasound therapy thrice per week is non-inferior to twice per week in patients with mild-to-moderate ED. METHODS: A randomized, open-label, parallel-group, non-inferiority clinical trial was conducted in 7 hospitals in China. A total of 323 patients with mild-to-moderate ED were randomized (1:1) into thrice per week (3/W) and twice per week (2/W) groups. Low-intensity pulsed ultrasound was applied on each side of the penis for 16 sessions. OUTCOMES: The primary outcome was response rate using the minimal clinically important difference in the International Index of Erectile Function (IIEF-EF) score at week 12. Secondary outcomes included Erection Hardness Score (EHS), Sexual Encounter Profile, Global Assessment Question, and Self Esteem and Relationship Questionnaire. RESULTS: Response rates in 3/W and 2/W groups were 62.0% and 62.5%, respectively. Treatment effect in the 3/W group was noninferior to that of the 2/W group, with rate difference lower bound of -0.01% [95% confidence interval -0.11 to 0.10%] within the acceptable margin (-14.0%). No significant difference was found among secondary outcomes. IIEF-EF score showed a significant increase from baseline in the 3/W group (16.8 to 20.7) and 2/W group (17.8 to 21.7), and the percentage of patients with EHS ≥3 increased in the 3/W (54.9% to 84.0%) and 2/W (59.5% to 83.5%) groups. There was no significant difference in response rate between the 2 groups after controlling for strata factors and homogeneous tests. No treatment-related adverse events were reported. CLINICAL IMPLICATIONS: Low-intensity pulsed ultrasound therapy displays similar efficacy and safety for mild-to-moderate ED when administered thrice or twice per week for 16 sessions. This study provides two options to suit patients' needs. STRENGTHS & LIMITATIONS: This is a large-sample, randomized, controlled, noninferiority trial study. Short-term follow-up and mostly younger patients are the main limitations. CONCLUSION: Low-intensity pulsed ultrasound therapy thrice and twice per week showed equivalent therapeutic effects and safety for mild-to-moderate ED in a young and generally healthy population. This therapy warrants further investigation of its potential value in rehabilitation of ED. Chen, H., Li Z., Li X., et al. The Efficacy and Safety of Thrice vs Twice per Week Low-Intensity Pulsed Ultrasound Therapy for Erectile Dysfunction: A Randomized Clinical Trial. J Sex Med 2022;19:1536-1545.
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Disfunción Eréctil , Método Doble Ciego , Humanos , Masculino , Erección Peniana , Pene , Resultado del Tratamiento , Ondas UltrasónicasRESUMEN
The corpus cavernosum is the most important structure for penile erection, and its dysfunction causes many physiological and psychological problems. However, its cellular heterogeneity and signalling networks at the molecular level are poorly understood because of limited access to samples. Here, we profile 64,993 human cavernosal single-cell transcriptomes from three males with normal erection and five organic erectile dysfunction patients. Cell communication analysis reveals that cavernosal fibroblasts are central to the paracrine signalling network and regulate microenvironmental homeostasis. Combining with immunohistochemical staining, we reveal the cellular heterogeneity and describe a detailed spatial distribution map for each fibroblast, smooth muscle and endothelial subcluster in the corpus cavernosum. Furthermore, comparative analysis and related functional experiments identify candidate regulatory signalling pathways in the pathological process. Our study provides an insight into the human corpus cavernosum microenvironment and a reference for potential erectile dysfunction therapies.