Clinical management, differential diagnosis, follow-up and biomarkers of infertile men with nonobstructive azoospermia.
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ABSTRACT:
SUBMITTER: Azizi H
PROVIDER: S-EPMC10932646 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Clinical management, differential diagnosis, follow-up and biomarkers of infertile men with nonobstructive azoospermia.
Azizi Hossein H Hashemi Karoii Danial D Skutella Thomas T
Translational andrology and urology 20240226 2
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Project description:The clinical management of men with nonobstructive azoospermia (NOA) seeking fertility has been a challenge for andrologists, urologists, and reproductive medicine specialists alike. This review presents a personal perspective on the clinical management of NOA, including the lessons learned over 15 years dealing with this male infertility condition. A five-consecutive-step algorithm is proposed to manage such patients. First, a differential diagnosis of azoospermia is made to confirm/establish that NOA is due to spermatogenic failure. Second, genetic testing is carried out not only to detect the males in whom NOA is caused by microdeletions of the long arm of the Y chromosome, but also to counsel the affected patients about their chances of having success in sperm retrieval. Third, it is determined whether any intervention prior to a surgical retrieval attempt may be used to increase sperm production. Fourth, the most effective and efficient retrieval method is selected to search for testicular sperm. Lastly, state-of-art laboratory techniques are applied in the handling of retrieved gametes and cultivating the embryos resulting from sperm injections. A coordinated multidisciplinary effort is key to offer the best possible chance of achieving a biological offspring to males with NOA.
| S-EPMC4430952 | biostudies-other
Project description:BackgroundThe molecular mechanism of nonobstructive azoospermia (NOA) remains unclear. The aim of this study was to identify gene expression changes in NOA patients and to explore potential biomarkers and therapeutic targets.MethodsThe gene expression profiles of GSE45885 and GSE145467 were collected from the Gene Expression Omnibus (GEO) database, and the differences between NOA and normal spermatogenesis were analyzed. Enrichment analysis was performed to explore biological functions for common differentially expressed genes (DEGs) in GSE45885 and GSE145467. Coexpression analysis of DEGs in GSE45885 was performed, and two modules with the highest correlation with NOA were screened. Key genes were then screened from the intersection genes of the two modules and common DEGs and PPI network. The expression of key genes was validated by quantitative real-time polymerase chain reaction (qRT-PCR) experiments. Finally, through miRTarBase, miRDB, and RAID, the miRNAs were predicted to regulate key genes, respectively.ResultsA total of 345 common DEGs were identified and they were mainly related to spermatogenesis, insulin signaling pathway. Coexpression analysis of DEGs in GSE45885 yielded eight modules; MEblack and MEturquoise had the highest correlation with NOA. Six genes in MEturquoise and RNF141 in MEblack were identified as key genes. qRT-PCR experiments validated the differential expression of key genes between NOA and control. Furthermore, RNF141 was regulated by the largest number of miRNAs.ConclusionOur findings suggest that the significant change expression of key genes may be potential markers and therapeutic targets of NOA and may have some impact on the development of NOA.
| S-EPMC8211532 | biostudies-literature
Project description:BACKGROUND:The genetic basis of nonobstructive azoospermia is unknown in the majority of infertile men. METHODS:We performed array comparative genomic hybridization testing in blood samples obtained from 15 patients with azoospermia, and we performed mutation screening by means of direct Sanger sequencing of the testis-expressed 11 gene (TEX11) open reading frame in blood and semen samples obtained from 289 patients with azoospermia and 384 controls. RESULTS:We identified a 99-kb hemizygous loss on chromosome Xq13.2 that involved three TEX11 exons. This loss, which was identical in 2 patients with azoospermia, predicts a deletion of 79 amino acids within the meiosis-specific sporulation domain SPO22. Our subsequent mutation screening showed five novel TEX11 mutations: three splicing mutations and two missense mutations. These mutations, which occurred in 7 of 289 men with azoospermia (2.4%), were absent in 384 controls with normal sperm concentrations (P=0.003). Notably, five of those TEX11 mutations were detected in 33 patients (15%) with azoospermia who received a diagnosis of azoospermia with meiotic arrest. Meiotic arrest in these patients resembled the phenotype of Tex11-deficient male mice. Immunohistochemical analysis showed specific cytoplasmic TEX11 expression in late spermatocytes, as well as in round and elongated spermatids, in normal human testes. In contrast, testes of patients who had azoospermia with TEX11 mutations had meiotic arrest and lacked TEX11 expression. CONCLUSIONS:In our study, hemizygous TEX11 mutations were a common cause of meiotic arrest and azoospermia in infertile men. (Funded by the National Institutes of Health and others.).
| S-EPMC4470617 | biostudies-literature
Project description:The objective of this systemic review was to evaluate the benefit of repairing clinical varicocele in infertile men with nonobstructive azoospermia (NOA). The surgically obtained sperm retrieval rate (SRR) and pregnancy rates following assisted reproductive technology (ART) with the use of retrieved testicular sperm were the primary outcomes. The secondary outcomes included the presence of viable sperm in postoperative ejaculate to avoid the testicular sperm retrieval and pregnancy rates (both assisted and unassisted) using postoperative ejaculated sperm. An electronic search to collect the data was performed using the MEDLINE and EMBASE databases until April 2015. Eighteen studies were included in this systematic review and accounted for 468 patients who were diagnosed with NOA and varicocele. These patients were subjected to either surgical varicocele repair or percutaneous embolization. Three controlled studies evaluating sperm retrieval outcomes indicated that in patients who underwent varicocelectomy, SRR increased compared to those without varicocele repair (OR: 2.65; 95% CI: 1.69-4.14; P< 0.001). Although pregnancy rates with the use of testicular sperm favored the varicocelectomy group, results were not statistically significant (clinical pregnancy rate OR: 2.07; 95% CI: 0.92-4.65; P= 0.08; live birth rate OR: 2.19; 95% CI: 0.99-4.83; P= 0.05). The remaining fifteen studies reported postoperative semen analysis results. In 43.9% of the patients (range: 20.8%-55.0%), sperm were found in postoperative ejaculates. Pregnancy rates for unassisted and assisted (after IVF/ICSI) were 13.6% and 18.9% in the group of men with sperm in postoperative ejaculates, respectively. Our findings indicate that varicocelectomy in patients with NOA and clinical varicocele is associated with improved SRR. In addition, approximately 44% of the treated men will have enough sperm in the ejaculate to avoid sperm retrieval. Limited data on pregnancy outcomes with both postoperative ejaculated sperm and harvested testicular sperm preclude any firm conclusion with regard to the possible increased fertility potential in treated individuals. In conclusion, the results of our study indicate that infertile men with NOA and clinical varicocele benefit from varicocelectomy. Given the low/moderate quality of evidence available, it is advisable that doctors discuss with their patients with NOA the risks and benefits of varicocele repair.
| S-EPMC4770494 | biostudies-literature
Project description:ObjectiveTo identify gene dosage changes associated with nonobstructive azoospermia (NOA) using array comparative genomic hybridization (aCGH).DesignProspective study.SettingMedical school.Patient(s)One hundred ten men with NOA and 78 fertile controls.Intervention(s)None.Main outcome measure(s)The study has four distinct analytic components: aCGH, a molecular karyotype that detects copy number variations (CNVs); Taqman CNV assays to validate CNVs; mutation identification by Sanger sequencing; and histological analyses of testicular tissues.Result(s)A microduplication at 20q11.22 encompassing E2F transcription factor-1 (E2F1) was identified in one of eight men with NOA analyzed using aCGH. CNVs were confirmed and in an additional 102 men with NOA screened using Taqman CNV assays, for a total of 110 NOA men analyzed for CNVs in E2F1. Eight of 110 (7.3%) NOA men had microduplications or microdeletions of E2F1 that were absent in fertile controls.Conclusion(s)E2F1 microduplications or microdeletions are present in men with NOA (7.3%). Duplications or deletions of E2F1 occur very rarely in the general population (0.011%), but E2F1 gene dosage changes, previously reported only in cancers, are present in a subset of NOA men. These results recapitulate the infertility phenotype seen in mice lacking or overexpressing E2f1.
| S-EPMC4282601 | biostudies-literature
Project description:As a crucial transcription factor for spermatogenesis, GATA-binding protein 4 (GATA4) plays important roles in the functioning of Sertoli and Leydig cells. Conditional knockout of GATA4 in mice results in age-dependent testicular atrophy and loss of fertility. However, whether GATA4 is associated with human azoospermia has not been reported. Herein, we analyzed the GATA4 gene by direct sequencing of samples obtained from 184 Chinese men with idiopathic nonobstructive azoospermia (NOA). We identified a missense mutation (c.191G>A, p.G64E), nine single-nucleotide polymorphisms (SNPs), and one rare variant (c.*84C>T) in the 3´ untranslated region (UTR). Functional studies demonstrated that the p.G64E mutation did not affect transactivation ability of GATA4 for spermatogenesis-related genes (claudin-11 and steroidogenic acute regulatory protein, Star), and the 3´ UTR rare variant c.*84C>T did not generate microRNA-binding sites to repress GATA4 expression. To our knowledge, this is the first report to investigate the association between GATA4 and azoospermia; our results indicate that mutations in GATA4 may not be pathogenic for NOA in Chinese men.
| S-EPMC7991814 | biostudies-literature
Project description:Nonobstructive azoospermia (NOA) refers to the failure of spermatogenesis, which affects approximately 1% of the male population and contributes to 10% of male infertility. NOA has an underlying basis of endocrine imbalances since proper human spermatogenesis relies on complex regulation and cooperation of multiple hormones. A better understanding of subtle hormonal disturbances in NOA would help design and improve hormone therapies with reduced risk in human fertility clinics. The purpose of this review is to summarize the research on the endocrinological aspects of NOA, especially the hormones involved in hypothalamic-pituitary-testis axis (HPTA), including gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, estradiol, sex hormone binding globulin, inhibin B, anti-Müllerian hormone, and leptin. For the NOA men associated with primary testicular failure, the quality of currently available evidence has not been sufficient enough to recommend any general hormone optimization therapy. Some other NOA patients, especially those with hypogonadotropic hypogonadism, could be treated with hormonal replacement. Although these approaches have succeeded in resuming the fertility in many NOA patients, the prudent strategies should be applied in individuals according to specific NOA etiology by balancing fertility benefits and potential risks. This review also discusses how NOA can be induced by immunization against hormones.
| S-EPMC9226686 | biostudies-literature
Project description: Not available
| S-EPMC8161617 | biostudies-literature
Project description:The genetic background of the non-obstructive azoospermia (NOA) remains poorly known. However, recent studies employing next generation sequencing techniques were able to uncover some NOA causative genes, among which was the TKTL1 gene. In this article we aim to understand the function of the TKTL1 gene in human spermatogenesis by inducing its overexpression in human testicular primary cells (hTPc), which we verified in male gonad tissue samples collected from NOA patients by uncovering the genes cluster regulated by TKTL1. Successful overexpression of the TKTL1 gene was achieved in hTP cells, the TKTL1 gene expression level was significantly higher in modified cells compared to both control groups (p<0.01). Using RNA-seq, we selected 20 genes which expression levels significantly differed in the modified hTP cells overexpressing TKTL1 gene in comparison to both controls. Male gonad tissue samples collected from NOA patients harbouring a mutation in the TKTL1 gene showed a significant downregulation (p<0.05) in HERC5, CSF3, HES1 and HSPA1B genes, compared to both controls, which was in accordance with the results obtained for hTPc cells, as the overexpression of the TKTL1 gene correlated with an increased expression level of the named genes compared to control groups.
2025-05-01 | GSE262557 | GEO
Project description: Not available
| S-EPMC10521963 | biostudies-literature