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Risk factors for cryptorchidism.

ABSTRACT: Undescended testis - known as cryptorchidism - is one of the most common congenital abnormalities observed in boys, and is one of the few known risk factors for testicular cancer. The key factors that contribute to the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases in fetal development - between 8-15 weeks (the first phase of decent) and 25-35 weeks gestation (the second phase of descent); the failure of a testis to descend permanently is probably caused by disruptions to one or both of these phases, but the causes and mechanisms of such disruptions are still unclear. A broad range of putative risk factors have been evaluated in relation to the development of cryptorchidism but their plausibility is still in question. Consistent evidence of an association with cryptorchidism exists for only a few factors, and in those cases in which evidence seems unequivocal the factor is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor could vary considerably between mother-son pairs depending on an array of genetic, maternal, placental and fetal factors - all of which could vary between regions. Thus, the role of causative factors in aetiology of cryptorchidism requires further research.

SUBMITTER: Gurney JK

PROVIDER: S-EPMC5815831 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Risk factors for cryptorchidism.

Gurney Jason K JK McGlynn Katherine A KA Stanley James J Merriman Tony T Signal Virginia V Shaw Caroline C Edwards Richard R Richiardi Lorenzo L Hutson John J Sarfati Diana D

Nature reviews. Urology 20170627 9

Undescended testis - known as cryptorchidism - is one of the most common congenital abnormalities observed in boys, and is one of the few known risk factors for testicular cancer. The key factors that contribute to the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases in fetal development - between 8-15 weeks (the first phase of decent) and 25-35 weeks gestation (the second phase of descent); the failure of a testis to des ...[more]

PMID: 28654092

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Project description:BackgroundCryptorchidism is a common congenital malformation strongly related to future oligospermia and male infertility. Normally functioning early-stage spermatogonia are vital to ensure fertility. The present study aimed to identify new differentially expressed genes (DEGs) associated with signaling pathways related to spermatogonial stem cell (SSC) maintenance during early spermatogenesis.MethodsGEO2R was used to screen for genes differentially regulated in cryptorchidism using mRNA expression profiling data in the GEO database. DAVID was used to perform GO and KEGG enrichment analysis of DEGs to analyze their functions. A protein-protein interaction (PPI) network of DEGs was constructed using the STRING database. The hub genes in the PPI networks were identified using Maximal Clique Centrality (MCC) in Cytohubba, and the top 50 genes were displayed as hub genes using Cytoscape software. Then, the miRNAs targeting hub genes were predicted using miRWalk and an mRNA-miRNA interaction network was constructed using Cytoscape. We took the intersection of these target miRNAs and the differentially expressed miRNAs identified from a non-coding RNA sequencing dataset, GSE149084. Furthermore, the intersected miRNAs and their predicted target genes were validated in the testicular tissue of rats with cryptorchidism.ResultsA total of 474 DEGs were identified, most of which were annotated to the PI3K-AKT-mTOR signaling pathway. Hub genes related to the pathway were predicted to be targeted by 27 miRNAs. Further miRNA mining revealed that miRNA-7-5p and miRNA-519d-3p were both dysregulated in cryptorchidism patients. Further, we found that these two miRNAs were predicted with high confidence to share a common target gene, AKT3. In the testicular tissue of rats with cryptorchidism, miRNA-519d-3p was upregulated while miRNA-7-5p and AKT3 were downregulated. We also found that AKT3 plays an essential role in regulating SSC state through the PI3K-AKT-mTOR signaling pathway and that AKT3 is one of the key genes related to SSC self-renewal, proliferation, and differentiation.ConclusionsThe PI3K-AKT-mTOR signaling pathway functions in SSC maintenance, and alterations in this pathway may explain defects in spermatogenesis. AKT3-related miRNAs, including hsa-miR-7-5p and hsa-miR-519d-3p, might be responsible for cryptorchidism and cryptorchidism-induced azoospermia and serve as potential biomarkers.

Project description:BackgroundAn evidence-based Consensus on the treatment of undescended testis (UT) was recently published, recommending to perform orchidopexy between 6 and 12 months of age, or upon diagnosis and to avoid the use of hormones. In Italy, current practices on UT management are little known. Our aim was to describe the current management of UT in a cohort of Italian children in comparison with the Consensus guidelines. As management of retractile testis (RT) differs, RT cases were described separately.MethodsOurs is a retrospective, multicenter descriptive study. An online questionnaire was filled in by 140 Italian Family Paediatricians (FP) from Associazione Culturale Pediatri (ACP), a national professional association of FP. The questionnaire requested information on all children with cryptorchidism born between 1/01/2004 and 1/01/2006. Data on 169 children were obtained. Analyses were descriptive.ResultsOverall 24% of children were diagnosed with RT, 76% with UT. Among the latter, cryptorchidism resolved spontaneously in 10% of cases at a mean age of 21.6 months. Overall 70% of UT cases underwent orchidopexy at a mean age of 22.8 months (SD 10.8, range 1.2-56.4), 13% of whom before 1 year. The intervention was performed by a paediatric surgeon in 90% of cases, with a success rate of 91%. Orchidopexy was the first line treatment in 82% of cases, while preceded by hormonal treatment in the remaining 18%. Hormonal treatment was used as first line therapy in 23% of UT cases with a reported success rate of 25%. Overall, 13 children did not undergo any intervention (mean age at last follow up 39.6 months). We analyzed the data from the 5 Italian Regions with the largest number of children enrolled and found a statistically significant regional difference in the use of hormonal therapy, and in the use of and age at orchidopexy.ConclusionsOur study showed an important delay in orchidopexy. A quarter of children with cryptorchidism was treated with hormonal therapy. In line with the Consensus guidelines, surgery was carried out by a paediatric surgeon in the majority of cases, with a high success rate.

Project description:PurposeBased on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal.Materials and methodsWe excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum.ResultsWe identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum.ConclusionsThese data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling.

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Risk factors for cryptorchidism.

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Risk factors for cryptorchidism.

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