Asian journal of andrology最新文献

Lichen sclerosus (LS) is a chronic inflammatory dermatosis significantly associated with urethral stricture disease (USD), particularly affecting the genitalia in both sexes. While topical corticosteroids remain the first-line therapy for LS, their efficacy for deep urethral involvement is limited. Surgical intervention, primarily urethroplasty utilizing buccal mucosa grafts or lingual mucosa grafts, is often required for LS-associated USD but is associated with risks of recurrence and complications. This review explores the etiology, highlighting the roles of immune dysregulation, genetic factors, and the resulting fibrosis. Furthermore, we emphasize the emerging potential of urethral tissue engineering, which uses scaffolds seeded with progenitor or stem cells, as a promising approach for reconstructing complex LS-related strictures, although clinical translation remains limited. Future research should focus on optimizing tissue engineering solutions.

Men frequently present to their health practitioners with concerns that they are not "normal" in the domains of sexual anatomy and function. This narrative review aims to synthesize the existing evidence on the general male population's perception of normative sexual anatomy (penile length) and function (erectile and ejaculatory function). A structured literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, limited to English language studies that involved adult participants from non-medical backgrounds. Of the 1098 studies identified, only seven met the predefined inclusion and exclusion criteria, indicating an insufficiency in research directly addressing men's perceptions of normative sexual anatomy and function. The studies included in this review found that there was an inaccurate understanding of what empirically constitutes "normal". Men considered above-average penis lengths to be common and perceived themselves as "small" despite being within the normal range. They tended to overestimate typical intercourse durations and were inaccurate in self-diagnosing ejaculatory dysfunction and erectile dysfunction. The inability to differentiate normal and abnormal sexual function reflects a poor understanding of what constitutes normal. These findings may inform future research and provide guidance for educating clinicians and the public to improve sexual health.

Non-obstructive azoospermia (NOA) and cryptozoospermia are two significant conditions contributing to male infertility. However, the underlying genetic factors in most cases remain unknown. In our study, whole exome sequencing identified novel biallelic variants in TBC1 domain family member 8 (TBC1D8) in two patients. Patient P1 with NOA harbored c.890C>T (p.A297V) and c.2461G>A (p.V821I), and patient P2 with cryptozoospermia carried c.854C>T (p.P285L) and c.1912G>A (p.D638N). Bioinformatic analyses predicted that all identified TBC1D8 variants were likely pathogenic. Compared with a normal control, patient P1 showed reduced expression of TBC1D8 in testicular tissue. Subsequently, hematoxylin-eosin staining and immunofluorescence analysis of testicular sections showed defective acrosome formation and the absence of elongated spermatids in patient P1, resulting from abnormal autophagy. Additionally, intracytoplasmic sperm injection treatment was beneficial for patient P2 with cryptozoospermia. In conclusion, our results suggest that TBC1D8 is a potentially novel candidate gene for male infertility associated with NOA or cryptozoospermia in humans.

Maternal sleep deprivation (SD) during pregnancy is prevalent and associated with adverse outcomes. However, the effect of SD on reproductive development in postpubertal male offspring remains incompletely understood. We investigated the effects of maternal SD during mid-gestation (gestational day 8 to delivery) and late gestation (gestational day 15 to delivery) on reproductive development in a 8-week-old male offspring of C57BL/6J mice. We analyzed the underlying oxidative stress mechanisms implicated in these effects. SD was induced for 16 h per day using the modified multiple platform method. Sperm parameters of the offspring (n = 8 per group) were analyzed, including serum reproductive hormones (testosterone, follicle-stimulating hormone, and luteinizing hormone), testicular oxidative stress markers (superoxide dismutase and malondialdehyde), and key proteins in the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/Akt/mTOR) signaling pathway. Among the offspring, the mid-gestation SD (MSD) group showed significantly lower sperm count, sperm motility, and follicle-stimulating hormone concentrations than the respective control groups (all P < 0.05). The late-gestation SD (LSD) group showed lower luteinizing hormone concentrations than the control group (P < 0.05). Testosterone, follicle-stimulating hormone, and luteinizing hormone concentrations were lower in the MSD group than those in the LSD group (all P < 0.05). Superoxide dismutase activity was lower in the MSD group than that in the control group (P < 0.05). No significant changes were observed in PI3K/Akt/mTOR pathway protein expression. In conclusion, maternal SD, particularly from mid-gestation to delivery, impairs spermatogenesis in postpubertal male offspring, which may be mediated through sex hormone dysregulation and testicular oxidative stress.

Male infertility is one of the most prevalent disorders affecting the male reproductive system, with the majority of cases originating from sperm abnormalities. Autophagy, a highly conserved cellular process, plays critical roles in spermatogenesis, sperm maturation, and functional maintenance. Aberrant autophagic activity is closely associated with various sperm abnormalities, including oligozoospermia, asthenozoospermia, teratozoospermia, and azoospermia. In this narrative review, we provide a comprehensive overview of the current knowledge on the role of autophagy in sperm abnormality-related male infertility, detailing the relationship between autophagic dysfunction and various sperm disorders. We compile and synthesize findings from major clinical studies, basic science research, and relevant reviews to highlight the role of autophagy and its therapeutic potential. These insights may contribute to advancing the clinical management of male infertility through the identification of novel therapeutic targets related to autophagic regulation.

Androgen insensitivity syndrome (AIS; Online Mendelian Inheritance in Man [OMIM; #300068]) is an X-linked recessive disorder caused by pathogenic variants in the androgen receptor (AR) gene located in the Xq11-q13 region. In this retrospective study of 30 patients with AIS, next-generation sequencing identified 24 variants in AR, including 20 missense, 1 nonsense, and 3 splice-site variants. Seven novel variants were detected in 8 patients. Of the 24 variants, 15 were classified as likely pathogenic, 8 as pathogenic, and 1 as of uncertain significance. Variants included 5 de novo and 24 familial cases. These AR variants were predominantly located in the functional domains, with the ligand-binding domain (LBD) harboring 10 variants, the DNA-binding domain (DBD) harboring 5 variants, the N-terminal domain (NTD) harboring 2 variants, and the hinge region (HR) harboring 1 variant. The highest variant detection rate occurred in exon 5 (11/30), followed by exon 3 (9/30). These findings advance our understanding of genotype including 20 missense, 1 nonsense, and 3 splice-site variants through the identification of 7 novel variants.

Genetic variants in the dynein axonemal heavy chain 17 (DNAH17) have been implicated in multiple morphological abnormalities of the sperm flagella (MMAF) and asthenoteratozoospermia (ATZS). The aim of this study is to identify novel DNAH17 variants associated with MMAF and ATZS and to evaluate the impact of these variants on sperm motility, sperm morphology, the ultrastructure of sperm flagella, and the outcomes of intracytoplasmic sperm injection (ICSI). In the present study, we identified one novel homozygous and three compound heterozygous DNAH17 variants in one consanguineous and three nonconsanguineous families. Semen analysis revealed significant reductions in sperm motility and notable morphological changes. Transmission electron microscopy (TEM) revealed the absence of outer dynein arms (ODAs), loss of peripheral doublet microtubules (DMTs) 4-7, and multiple mitochondrial sheath (MS) abnormalities in the sperm flagella. Functional analyses indicated that these variants disrupted the expression and localization of the DNAH17 protein in the sperm flagella. Tandem mass tagging proteomics and immunofluorescence demonstrated a significant reduction in the expression of proteins associated with the assembly of ODA-associated proteins into the axoneme from individuals with DNAH17 variants. Notably, successful pregnancies were achieved through ICSI combined with assisted oocyte activation (AOA) treatment in the female partner of these probands. This study identified seven novel homozygous or compound heterozygous DNAH17 variants in both consanguineous and nonconsanguineous families, highlighting their detrimental effects on sperm motility, morphology, and flagellar ultrastructure. These findings provide valuable insights for the genetic diagnosis of MMAF and may enhance future genetic counseling strategies.

Multiple morphological abnormalities of sperm flagellum (MMAF) is a rare cause of primary infertility. Genetic variants in cilia- and flagella-associated protein 43 (CFAP43) are associated with asthenoteratospermia and MMAF; however, the detailed pathogenic mechanisms are still to be completely elucidated. Here, we identified novel compound heterozygous mutations in CFAP43, c.1859_1860+8delinsGT, and c.3071A>G (p.N1024S), by whole-exome sequencing (WES). The proband had a typical MMAF phenotype; Sanger sequencing confirmed these mutations and showed that they cosegregated within the family. Further analysis of the patient's sperm samples indicated that the CFAP43 mutations result in aberrant RNA splicing. Additionally, we observed disturbance and partial deletion of the mitochondrial sheath, along with a significant reduction in translocase of outer mitochondrial membrane 20 (TOM20) expression. This study suggests that infertility associated with CFAP43 loss of function may be linked to mitochondrial dysfunction. Finally, assisted reproductive technology using intracytoplasmic sperm injection (ICSI) resulted in a successful pregnancy and live birth. Our study expands the spectrum of pathogenic CFAP43 mutations and provides valuable insights for genetic counseling and personalized reproductive strategies in patients with MMAF.

Human spermatogonial stem cells (SSCs) are crucial for spermatogenesis and male reproduction. Although abnormal pyroptosis caused by inflammation impacts male fertility, the molecular mechanisms underlying the pyroptosis of human SSCs are elusive. To induce pyroptosis, lipopolysaccharide (LPS) was introduced into the vas deferens of mice. RNA sequencing (RNA-Seq) of human SSCs was employed to identify NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and RNA interference (RNAi) was used to determine the function and mechanism of NLRP3 in controlling pyroptosis of human SSCs. Guanylate-binding protein 4 (GBP4) was analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) analyses, and the impact of GBP4 on NLRP3 in human SSCs was subsequently assessed using GBP4 short hairpin RNA (shRNA). LPS reduced the testicular weight of mice, disrupted spermatogenesis, and increased the levels of inflammatory factors (interleukin-18 [IL-18] and interleukin-1β [IL-1β]). NLRP3 siRNAs antagonized the LPS-induced increases in IL-18 and IL-1β, proliferative inhibition, and pyroptosis (Caspase 1 and Gasdermin D) in human SSCs. An association between GBP4 and NLRP3 in human SSCs was identified by co-immunoprecipitation (Co-IP). Human SSCs with stable GBP4 shRNA decreased the expression level of NLRP3 in human SSCs under inflammatory conditions. Collectively, these results imply that LPS-induced NLRP3 activation enhances the pyroptosis of human SSCs via the regulation of GBP4. This study offers novel insights into molecular mechanisms underlying the fate determinations of human SSCs.

Varicocele-induced decline in sperm quality is a common cause of male infertility. While varicocelectomy improves semen parameters, the mechanisms remain unclear. Recent studies suggested that small noncoding RNAs (sncRNAs) in sperm play a significant role in male reproductive health. This study investigated whether varicoceles and surgical treatment influence the expression profiles of sperm sncRNAs and explored the related epigenetic mechanisms. This study included 63 infertile males undergoing varicocelectomy. Semen analysis was performed, followed by high-throughput deep sequencing of sperm sncRNAs both before and after surgery. The results indicated that semen parameters improved significantly following varicocelectomy. The expression profiles of sncRNAs were altered, with 10 microRNAs (miRNAs; 3 upregulated: hsa-miR-486-3p, hsa-miR-486-5p, and hsa-miR-874-3p; and 7 downregulated: hsa-miR-132-3p, hsa-miR-202-3p, hsa-miR-34c-5p, hsa-miR-499a-5p, hsa-miR-499b-3p, hsa-miR-520a-3p, and hsa-miR-92b-3p) showing significant changes post-surgery, which correlated with the improvement in sperm quality. Microinjection experiments demonstrated that the abnormally elevated expression of miRNAs in zygotes (miR-132-3p, miR-34c-5p, and miR-520a-3p) may negatively affect early embryonic development. Together, these results suggest that abnormal miRNA expression is a potential epigenetic mechanism underlying varicocele-associated sperm quality impairment. Moreover, the study findings provide evidence that varicocelectomy can relieve this process. Furthermore, the differentially expressed miRNAs may serve as potential predictors for diagnosing different pathological types of infertility and represent new molecular targets for improving fertility in males with varicoceles.