Andrology最新文献

Background and objectives: Epididymal transit renders key competence to mammalian spermatozoa for fertilizing eggs. Generally, the two paralogs of glycogen synthase kinase 3, GSK3α and GSK3β, functionally overlap except in testis and sperm. We showed that GSK3α is essential for epididymal sperm maturation and fertilization. Male infertility is the only phenotype of mice with a global or testis-specific knockout (KO) of Gsk3α. Their sperm maturation is impaired, and sperm cannot fertilize eggs in vitro and in vivo. This suggests that GSK3α is a "male fertility kinase" in mammals and that GSK3α-selective inhibitor is a potential male contraceptive.

Materials and methods: A set of eight heterozygous Gsk3α(±) male mice received daily intraperitoneal injections of BRD0705, an isoform-selective GSK3α inhibitor, at 20 mg/kg body weight for 1 week. Five vehicle-treated and BRD0705-treated mice were tested for in vivo fertility and the remaining mice were sacrificed; their caudal spermatozoa were examined for motility and biochemical properties.

Results: The treated mice did not sire any pups while the control group sired 46 pups with a normal gestation period of 19-23 days. Continued fertility testing up to 6 weeks post-treatment, showed that the treated mice regained fertility siring 56 pups, with 76 in the control group. Sperm motility was impaired, its abnormal morphology increased during epididymal transit, Adenosine triphosphate (ATP) levels were low, and tyrosine-phosphorylation of hexokinase was absent: these phenotypes imitated those observed in Gsk3α KO mice. Tyrosine²⁷⁹-phosphorylation of GSK3α was reduced in sperm from the treated mice showing that the GSK3α activity was inhibited. The altered sperm phenotypes returned to normal following recovery of fertility.

Conclusions: Complete infertility resulted after 1 week of BRD0705-treatment and fertility recovered after cessation of the treatment. Work is ongoing to determine the minimum dose and treatment time and the testing of new compounds with increased selectivity and inhibitory activity against GSK3α.

Background: Although some studies have revealed the close relationship between leptin and premature ejaculation in clinical practice, whether and how leptin participates in the regulation of ejaculatory behaviors are still unknown.

Objective: To explore the role of leptin on ejaculatory behaviors and its underlying mechanism.

Materials and methods: Copulation behavior tests were performed after acute and chronic leptin administration at peripheral and central levels. To compare changes in sympathetic nervous system activity, lumbar sympathetic nervous activity, serum noradrenaline levels, and the distribution of sympathetic fibers in vas deferens and seminal vesicles were analyzed. Construction of virus vector, immunohistochemistry, and optogenetics techniques were used to explore the neural circuit mechanism. The density of dendritic spines in parvocellular region of paraventricular nucleus was measured by Golgi staining.

Results: Acute administration of leptin had no effect on ejaculation behavior in male mice. However, both mount latency and ejaculation latency were significantly shortened, even if serum leptin decreased to normal level, after chronic administration of leptin at peripheral or central level. Additionally, sympathetic fibers in vas deferens and seminal vesicles obviously increased, in which arcuate nucleus‒paraventricular nucleus circuit and glutamatergic neurons in paraventricular nucleus played an important role. Dendritic spine density in parvocellular region increased after chronic leptin administration.

Discussion and conclusion: The role of leptin in regulating ejaculation behavior was chronic, not acute, in which leptin chronically modulated sympathetic neuroplasticity via arcuate nucleus‒paraventricular nucleus circuit and glutamatergic neurons in paraventricular nucleus and promoted ejaculatory behaviors. Increased dendritic spine density in parvocellular region of paraventricular nucleus may be involved as well.

Background: In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is supported by the flagellum, an evolutionarily conserved organelle, which contains dynein motor proteins that provide the mechanical force for sperm propulsion and motility. Primary motility of the sperm cells is acquired during their transit through the epididymis and hyperactivated motility is acquired throughout the journey in the female genital tract by a process called capacitation. These activation processes rely on the micro-environment of the genital tracts. In particular, during capacitation, a panoply of ion transporters located at the surface of the sperm cells mediate complex ion exchanges, which induce an increase in plasma membrane fluidity, the alkalinization of the cytoplasm and protein phosphorylation cascades that are compulsory for sperm hyperactivation and fertilization potential. As a consequence, both structural and functional defects of the sperm flagellum can affect sperm motility, resulting in asthenozoospermia, which constitutes the most predominant pathological condition associated with human male infertility.

Objectives: Herein, we have performed a literature review to provide a comprehensive description of the recent advances in the genetics of human asthenozoospermia.

Results and discussion: We describe the currently knowledge on gene mutations that affect sperm morphology and motility, namely, asthenoteratozoospermia; we also specify the gene mutations that exclusively affect sperm function and activation, resulting in functional asthenozoospermia. We discuss the benefit of this knowledge for patient and couple management, in terms of genetic counselling and diagnosis of male infertility as a sole phenotype or in association with ciliary defects. Last, we discuss the current strategies that have been initiated for the development of potential therapeutical and contraceptive strategies targeting genes that are essential for sperm function and activation.

Background: Evidence indicates a wide range of andrological alterations in patients with the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection and Coronavirus Disease 2019 (COVID-19).

Aim: To provide an update on the andrological effects of SARS-CoV-2 infection and COVID-19.

Methods: PubMed/MEDLINE and Institutional websites were searched for randomized clinical trials, non-systematic reviews, systematic reviews, and meta-analyses.

Results: Fifty-four records were included from 2020 to 2024. The most representative paper categories were non-systematic reviews (n = 26) and systematic reviews/meta-analyses (n = 27). One randomized, prospective, phase 2 trial was also included. Eight topics were identified and discussed as follows: short- and long-term seminal changes attributable to SARS-CoV-2 infection or COVID-19; andrological effects of anti-SARS-CoV-2 vaccines; the potential impact of SARS-CoV-2 infection and COVID-19 on male fertility; the relationship between serum testosterone levels and COVID-19 prognosis in men; fertility care during the pandemic; urinary/genital male system tract impairment in SARS-CoV-2 infection and COVID-19; the effect of SARS-CoV-2 infection and COVID-19 on circulating levels of sex steroid hormones; the impact of SARS-CoV-2 and COVID-19 on sexual function and activity.

Discussion: SARS-CoV-2 can affect the whole testicular function through direct and indirect mechanisms, with a positive relation between the severity of SARS-CoV-2 infection and the level of deterioration of testicular function. Testicular function recovers along with the recovery from the disease. In vitro fertilization techniques ensure similar results in patients with or without previous SARS-CoV-2 infection or COVID-19. Immunization with anti-SARS-CoV-2 vaccines prevents andrological complaints due to naturally occurring infection. Erectile dysfunction and sexual dysfunction are frequently diagnosed in COVID-19 patients due to several contributing factors, including hormonal imbalance and psychosocial complaints related to the pandemic.

Background: The establishment of kinetochore-microtubule attachment is essential for error-free chromosome alignment and segregation during cell division. Defects in chromosome alignment result in chromosome instability, birth defects, and infertility. Kinesin-7 CENP-E mediates kinetochore-microtubule capture, chromosome alignment, and spindle assembly checkpoint in somatic cells, however, mechanisms of CENP-E in germ cells remain poorly understood.

Objectives: This study aimed to explore the functions of CENP-E in the proliferation and self-renewal of spermatogonia.

Materials and methods: A CENP-E heterozygous knockout strain was established in C57BL/6J mice using the CRISPR/Cas9 and Cre/LoxP system. Hematoxylin-eosin staining was performed to study the histology. The inhibition of CENP-E in the GC-1 spg cells was performed using the specific inhibitor GSK923295. The expression and localization of spermatogonial marker proteins were determined by immunofluorescence using confocal microscopy in the control and CENP-E^+/- heterozygous mouse testes. The protein expression level was analyzed using Western blot. The cell-cycle and apoptosis assay were measured using flow cytometry. In addition, karyotype analysis was performed using hypotonic preparation and chromosome spreading.

Results: Here, we reveal that CENP-E haploinsufficiency results in chromosome misalignment, spindle disorganization, and metaphase arrest in spermatogonia, which leads to the loss of spermatogonia, chromosomal instability, and spermatogenic disorders. Notably, CENP-E ablation leads to the activation of spindle assembly checkpoint and aneuploidy, which impairs the proliferation and self-renewal of spermatogonia.

Discussion and conclusion: CENP-E depletion disrupts the recruitment of key checkpoint proteins, including BubR1, Bub1, KIF2C, and Aurora B, indicating a causal relationship between chromosome misalignment and spindle assembly checkpoint activation in spermatogonia. Our findings demonstrate that CENP-E regulates kinetochore-microtubule attachment, chromosome alignment, and spindle assembly checkpoint in spermatogonia.

Background: Accurately judging the efficacy of contraceptives is vital for preventing unintended pregnancy. The Pearl index and life table analysis describe female contraceptive performance. However, they are not ideal for quantifying male contraceptive efficacy given differences between male and female methods. In particular, male contraceptives like condoms are used "on demand" rather than long-term like female contraceptives. Additionally, the number of episodes of sexual intercourse, a key determinant of risk, is not considered. Lastly, men can father concurrent pregnancies in more than one woman. For these reasons, a male-specific measure may provide a more accurate measure of male contraceptive efficacy.

Objectives and methods: As each episode of heterosexual intercourse within a fertile couple is associated with an approximately 3% risk of pregnancy, the chance of an unintended pregnancy with a given number of episodes of sexual intercourse can be modeled with and without contraceptives of various effectiveness.

Results: Such modeling demonstrates that unintended pregnancy is strongly associated with both the number of episodes of sexual intercourse and the efficacy of the method. Based on these models, I propose a novel metric for male contraceptive efficacy called the Probability of Pregnancy₁₀₀, defined as the percent chance of an unintended pregnancy occurring with 100 episodes of intercourse. Probability of Pregnancy₁₀₀ should be easy for men to understand and is applicable to men with multiple sexual partners or men using "on-demand" contraceptives.

Discussion and conclusions: The prevention of unintended pregnancy by a male contraceptive is strongly influenced by both method efficacy and sexual frequency. Probability of Pregnancy₁₀₀ may offer a better measure of male contraceptive efficacy compared to the Pearl index and life table analysis as it takes sexual frequency into account; however, Probability of Pregnancy₁₀₀ will need to be tested prospectively in male contraceptive studies alongside the Pearl index and life table analysis to determine its utility compared to these existing measures of contraceptive efficacy.

Background: The presence of predominantly headless sperm in semen is a hallmark of acephalic spermatozoa syndrome, which is primarily caused by gene mutations in humans.

Purpose: To identify genetic causes for acephalic spermatozoa syndrome.

Methods: Polymerase chain reaction and Sanger sequencing were performed to define mutations in SUN5 and PMFBP1. Whole-exome sequencing was performed on the patients to identify pathogenic mutations for infertility. Western blotting and immunofluorescence analysis detected the expression level and localization of CEP250. Co-immunoprecipitation detected the protein-protein interactions. Cep250-KI mice were generated by the CRISPR-Cas9 system.

Results: Here, 10 patients diagnosed with acephalic spermatozoa syndrome were recruited, and a homozygous loss-of-function mutation in CEP250 (NM_007186: c. 4710_4723del: p. E1570fs*39) was identified from a consanguineous Han Chinese family. Immunofluorescence experiments revealed a decreased CEP250 signal in the neck region of the patient's sperm compared with the normal. Co-immunoprecipitation results indicated reduced interaction between SUN5/PMFBP1 and mutant CEP250 compared with the wild-type, possibly due to the absence of complete 2272-2442 amino acids. Besides, the patient can be effectively treated with intracytoplasmic sperm injections. Nevertheless, Cep250-KI male mice exhibit non-obstructive azoospermia, which indicates the different functions in CEP250 between human and mouse spermatogenesis.

Conclusion: Collectively, CEP250 may represent a novel pathogenic gene for acephalic spermatozoa syndrome in humans, and we provide precise genetic diagnosis and treatment strategies for the patient.

Background: Testicular germ cell tumors are the most common solid malignancies in young men, with increasing incidence worldwide. Broadly classified into seminomas and non-seminomas, they exhibit distinct biological behaviors and responses to treatment. Although metabolic reprogramming is an acknowledged cancer hallmark, metabolic pathways in testicular germ cell tumors remain poorly understood.

Objectives: This study investigates the differential expression of metabolic markers (GLUT-1, MCT1, MCT4, LDHA, HIF-1α) and the epigenetic enzyme KDM3A across various testicular germ cell tumor subtypes, aiming to understand how glycolytic metabolism is related to each histotype and how it may impact tumor aggressiveness, correlating with patient outcomes.

Materials and methods: The study involved 111 testicular germ cell tumor individual tumor components from 90 patients diagnosed and treated at a comprehensive cancer center. Immunohistochemistry was used to ascertain biomarker expression, with a combined score of percentage of stained tumor cells and intensity of staining. In silico analysis of the Cancer Genome Atlas database was performed for additional validation, using cBioPortal. Statistical analyses included Mann-Whitney U, Kruskal-Wallis, and anova tests, with significance set at p < 0.05.

Results: Significant differences in the expression of metabolic markers across testicular germ cell tumor subtypes were disclosed. Embryonal carcinomas showed significantly higher expression of glycolytic markers (GLUT-1, MCT1, MCT4, LDHA) compared to other histotypes, suggesting heightened glycolytic activity. KDM3A depicted an inverse pattern, being significantly more expressed in seminomas. HIF-1α expression was generally low across all histological subtypes. Testicular germ cell tumors with necrosis showed higher expression of the metabolic players investigated.

Discussion and conclusion: We highlighted distinct metabolic profiles among testicular germ cell tumor subtypes, particularly the prominent glycolytic activity in embryonal carcinomas, with higher hypoxia and reliance on lactate transport. Metabolic reprogramming in embryonal carcinoma may underlie the high proliferation of this tumor subtype, which frequently discloses necrosis. These findings suggest that targeted agents such as MCT1 inhibitors may be particularly useful for treating testicular germ cell tumors containing high proportion of embryonal carcinoma.

Background: Although some studies suggest that sleep deprivation may affect ejaculation regulation, related research is limited, and the mechanisms remain unclear.

Aim: This study aimed to explore whether sleep deprivation influences ejaculation regulation through amyloid-beta and to investigate its potential mechanisms.

Materials and methods: Normal ejaculating rats were randomly distributed into three separate groups for the study, and treated with sleep deprivation combined with saline gavage, sleep deprivation combined with sodium butyrate gavage, and control with saline gavage. The levels of amyloid-beta and 5-HT_1A receptors were assessed through Western blotting, PCR, and immunohistochemical techniques. The levels of interleukin-4 and serotonin (5-hydroxytryptamine) in the brain were determined by enzyme-linked immunosorbent assay.

Results: The experiment showed that the rats in the sleep deprivation combined with saline gavage group rats had a significantly faster ejaculation compared to the control combined with saline gavage group rats. Meanwhile, sleep deprivation combined with saline gavage group had the highest levels of amyloid-beta oligomers in the brain tissue. Correlation results revealed that the levels of amyloid-beta oligomers in brain tissue were inversely related to ejaculation latency and positively associated with ejaculation frequency. Furthermore, we found that elevated levels of amyloid-beta oligomers in brain tissue led to upregulation of 5-HT_1A receptor expression. Additionally, elevated levels of amyloid-beta oligomers in brain tissue were found to increase interleukin-4 levels, thereby reducing 5-hydroxytryptamine levels.

Discussion: Sleep deprivation indeed accelerates ejaculation, and this acceleration is closely related to amyloid-beta. Sleep deprivation can increase amyloid-beta levels in brain tissue, mediating a decrease in 5-hydroxytryptamine levels and overexpression of 5-HT_1A receptors, thereby accelerating ejaculation.

Conclusion: There is a significant correlation between elevated amyloid-beta levels in brain tissue because of sleep deprivation and accelerated ejaculation. This study's main findings offer insights into the development of acquired premature ejaculation linked to poor sleep and establish a theoretical framework for investigating potential treatments for this condition.

Background: Current advances in high-throughput sequencing technology enable the precise identification of Y chromosome microdeletion and primary duplication in infertile couples, but the mechanism and clinical significance of these mutations in assisted reproductive techniques remain unclear.

Objectives: To investigate the effects of AZFc (b2/b4, b1/b3, b2/b3, and gr/gr) deletions and primary duplications on the outcomes of the first intracytoplasmic sperm injection (ICSI) treatment cycle.

Methods: Y chromosome microdeletions and primary duplications in infertile men were detected using next-generation sequencing (NGS) technology. A total of 813 patients undergoing their first ICSI treatment were divided into six groups: b2/b4 deletion group (n = 28), three partial AZFc subdeletion groups (b1/b3, n = 13; b2/b3, n = 72; gr/gr, n = 71), primary AZFc duplication group (n = 54), and control group with a normal Y chromosome (n = 575). The multivariate logistic regression analyses were conducted to assess and compare the embryologic and cumulative reproductive outcomes of ICSI treatment across these groups.

Results: Compared with the control group, the b2/b4 deletion group showed a poor ICSI embryologic outcome after ICSI treatment, with a significantly lower fertilization rate per oocytes retrieval (72.22% vs.79.89%; adjusted odds ratio [OR], 0.63; 95% confidence interval [CI], 0.45-0.88, p < 0.01) and 2 pronuclear (2PN) fertilization rate (66.37% vs. 74.80%; adjusted OR, 0.65; 95% CI, 0.47-0.89, p < 0.01) either before or after adjustment for confounding factors. Nevertheless, three partial AZFc deletion groups showed no effect on the ICSI fertilization rate after ICSI treatment. The primary AZFc duplication group had a significantly lower clinical pregnancy rate per transferred embryo (56.25% vs. 65.97%; adjusted OR, 0.64; 95% CI, 0.41-0.99, p < 0.05), and the semen characteristics varied from azoospermia to normozoospermia. In addition, all indicators related to embryo quality, clinical pregnancy, and live birth outcomes in the primary duplication group were inferior to those in the control group.

Conclusion: This study indicates that b2/b4 deletion has a negative effect on ICSI outcomes, particularly the fertilization rates. Partial AZFc deletions have no significant effect on the fertilization rate after ICSI treatment. Primary AZFc duplication can lead to varying seminal phenotypes and has a negative effect on ICSI embryologic and pregnancy outcomes, particularly showing a significant association with low birth weight in newborns after ICSI treatment.