RESUMO
In 2007 the Nordic group came to the following unanimous conclusions: In general, hormonal treatment is not recommended, considering the poor immediate results and the possible long-term adverse effects on spermatogenesis. Thus, surgery is to be preferred. However, defective mini puberty inducing insufficient gonadotropin secretion is one of the most common causes of nonobstructive azoospermia in men suffering from congenital isolated unilateral or bilateral cryptorchidism. The extent of alteration in the unilateral undescended testis correlate with the contralateral descended testis, indicating that unilateral cryptorchidism is a bilateral disease. Idiopathic central hypogonadism explains the phenomenon of defective mini puberty in otherwise healthy cryptorchid boys. We therefore recommend hormonal treatment for cryptorchid boys with defective mini puberty. Gonadotropin releasing hormone agonist (GnRHa) treatment following surgery to correct cryptorchidism restores mini puberty via endocrinological and transcriptional effects and prevents adult infertility in most cases. Several genes are important for central hypogonadotropic hypogonadism in mammals, including many that are transcribed in both the brain and testis. At the molecular level, there is no convincing evidence that heat shock is responsible for the observed pathological testicular changes. Thus, impaired transformation of gonocytes is not the result of temperature stress but rather a hormonal imbalance. Cryptorchidism should therefore be considered a serious andrological problem that cannot be successfully treated by early orchidopexy alone.
Assuntos
Azoospermia , Criptorquidismo , Hipogonadismo , Infertilidade Masculina , Masculino , Animais , Humanos , Testículo/patologia , Criptorquidismo/tratamento farmacológico , Criptorquidismo/cirurgia , Criptorquidismo/genética , Infertilidade Masculina/prevenção & controle , Infertilidade Masculina/genética , Fertilidade , Hipogonadismo/tratamento farmacológico , MamíferosRESUMO
BACKGROUND: Cryptorchidism is one of the most common congenital disorders in boys and it is associated with a higher risk of sub-fertility and testicular cancer. Testicular descent occurs during embryo-fetal development in two phases, transabdominal and inguino-scrotal. In the latter process, androgens play a leading role. The androgen receptor has in its N-terminal domain, two aminoacidic repeats encoded by polymorphic nucleotide repetitions: (CAG)nCAA and GGN. The number of repetitions of these trinucleotides has been associated with different transactivation capacities and sensitivities of the androgen receptor response. OBJECTIVE: To determine whether pediatric Chilean individuals with idiopathic inguinal cryptorchidism have a different number of CAG and/or GGN repeats polymorphisms compared with controls. MATERIALS AND METHODS: A total of 109 cases with idiopathic inguinal cryptorchidism (26 bilateral and 83 unilateral) were studied by polymerase chain reaction amplification from DNA extracted from peripheral blood, followed by fragment size analysis by capillary electrophoresis, which were compared with 140 controls. RESULTS: The CAG26 repeats allele was increased in the total cases (8.3% vs. 1.4%; p = 0.012; odds ratio = 6.21, 95% confidence interval 1.31-29.4), and in bilateral cases compared to controls (11.5% vs. 1.4%; p = 0.028; odds ratio = 9 CI 95% 1.43-56.8). Similarly, CAG > 22 alleles were increased in the total cases (62.4% vs. 49.3%, p = 0.041), and more significantly in bilateral cases (73.1% vs. 49.3%; p = 0.032; odds ratio = 2.79, 95% confidence interval 1.1-7.1). In addition, CAG < 18 alleles were not observed among cases, but were present in 5.7% of controls (p = 0.01). Regarding the GGN repeats, no differences were observed between cases and controls either when analyzing separately unilateral and bilateral cryptorchidism. The joint analysis of the distribution of CAG and GGN alleles showed that the CAG26 allele was present with GGN23, hence the combination CAG26/GGN23 alleles was equally increased in bilateral cases compared with controls (11.5% vs. 1.4%). In contrast, CAG < 18 was preferably observed in the combination CAG < 18/GGN≠23 and was absent in the total cases (4.3% vs. 0%; p = 0.037). DISCUSSION: These results suggest that greater lengths of CAG alleles may contribute to a diminished androgen receptor function. The CAG26 allele alone or in combination with GGN23 was associated with a higher risk of bilateral cryptorchidism. On the other hand, CAG < 18 and the CAG < 18/GGN≠23 allele combination may reduce the probability of cryptorchidism.
Assuntos
Criptorquidismo , Neoplasias Testiculares , Criança , Humanos , Masculino , Chile , Criptorquidismo/genética , Receptores Androgênicos/genética , Neoplasias Testiculares/genética , Repetições de TrinucleotídeosRESUMO
INTRODUCTION: Cryptorchidism is a hereditary anomaly characterized by the incomplete descent of one or both testicles to the scrotum. One of the challenges of this anomaly is that the retained testicle maintains its endocrine function. As a consequence, cryptorchid animals produce hormone-tainted meat in comparison to castrated animals and are likely to be more aggressive. Cryptorchidism can lead to reduced animal welfare outcomes and cause economic losses. Identifying genetic markers for cryptorchidism is an essential step toward mitigating these negative outcomes and may facilitate genome manipulation to reduce the occurrence of cryptorchidism. Attempts to identify such markers have used genome-wide association studies. Using whole-exome sequencing, we aimed to identify single nucleotide polymorphisms (SNPs) in the coding regions of cryptorchid pigs and to characterize functional pathways concerning these SNPs. METHODS: DNA was extracted and sequenced from 5 healthy and 5 cryptorchid animals from the Landrace breed, using the Illumina HiSeq 2500 platform. Data were pre-processed using the SeqyClean tool and further mapped against the swine reference genome (Sus scrofa 11.1) using BWA software. GATK was used to identify polymorphisms (SNPs and InDels), which were annotated using the VEP tool. Network prediction and gene ontology enrichment analysis were conducted using the Cytoscape platform, and STRING software was used for visualization. RESULTS: A total of 63 SNPs were identified across the genes PIGB, CCPG1, COMMD9, LDLRAD3, TRIM44, MYLPF, SEPTIN, ZNF48, TIA1, FAIM2, KRT18, FBP1, FBP2, CTSL, DAPK1, DHX8, GPR179, DEPDC1B, ENSSSCG00000049573, ENSSSCG00000016384, ENSSSCG00000022657, ENSSSCG00000038825, and ENSSSCG00000001229. Using pathway enrichment analyses and network prospection, we have identified the following significant adjusted p value threshold of 0.001 involved with the biological function pathways of estrogen signaling, cytoskeleton organization, and the pentose phosphate pathway. CONCLUSION: Our data suggest the involvement of new SNPs and genes in developing cryptorchidism in pigs. However, further studies are needed to validate our results in a larger cohort population. Variations in the GPR179 gene, with implications at the protein level, may be associated with the appearance of this anomaly in the swine. Finally, we are showing that the estrogen signaling pathway may be involved in the pathophysiological mechanisms of this congenital anomaly as previously reported in GWAS.
Assuntos
Criptorquidismo , Masculino , Humanos , Animais , Criptorquidismo/genética , Criptorquidismo/veterinária , Estudo de Associação Genômica Ampla , Sequenciamento do Exoma , Transdução de Sinais , Polimorfismo de Nucleotídeo Único/genética , Manosiltransferases/genética , Manosiltransferases/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Helicases DEAD-box/metabolismo , Proteínas Ativadoras de GTPase/genéticaRESUMO
BACKGROUND: Differences of sex development (DSD) is a term used for conditions in which the chromosomal, gonadal or phenotypical sex is atypical. 46,XY DSD patients frequently present undervirilized external genitalia. The expression of different miRNAs in many organs of the male genital system has been reported, and these miRNAs have been associated with testicular function and its disorders, but no description has been related to DSD conditions. This study aimed to evaluate the plasma expression of miR-210 in 46,XY DSD patients who presented atypical genitalia at birth. METHODS: Eighteen 46,XY DSD patients who presented atypical genitalia (undescended testis and/or hypospadias, bifid scrotum or micropenis) at birth and 36 male control individuals were selected. Plasma levels of miR-210 and reference miR-23a were measured using RT-qPCR and the data were analysed by the 2-ΔCt method. RESULTS: MiR-210 plasma levels were significantly higher in 46,XY DSD patients with atypical genitalia than in male control subjects (p = 0.0024). A positive association between miR-210 levels and the presence of cryptorchidism and hypospadias (p = 0.0146 and p = 0.0223) was found in these patients. Significantly higher levels of miR-210 were observed in patients with 46,XY DSD and cryptorchidism than in control subjects (p = 0.0118). These results are in agreement with previous literature reports, in which increased levels of miR-210 expression were observed in human testicular tissue from adult males with undescended testes in comparison with samples of descended testes. CONCLUSION: Our study showed a positive association between the presence of atypical genitalia and plasma levels of miR-210 expression in the group of patients with 46,XY DSD of unknown aetiology studied. These findings contribute to reveal a new perspective on the role of miRNAs in the development of male external genitalia and the broad spectrum of phenotypes presented by patients with 46,XY DSD.
Assuntos
Criptorquidismo , Transtorno 46,XY do Desenvolvimento Sexual , Hipospadia , MicroRNAs , Humanos , Recém-Nascido , Masculino , Criptorquidismo/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Genitália , Hipospadia/genética , MicroRNAs/genética , Desenvolvimento SexualRESUMO
OBJECTIVES: Cryptorchidism is the most common genitourinary birth defect in live newborn males and is considered as an important risk factor for testicular germ cell tumors and infertility. The Androgen Receptor gene is important in this pathology due to its participation, mainly, in the inguinoscrotal phase of testicular descent. We determine the length of the CAG tract in the Androgen Receptor (AR) gene in Mexican patients with nonsyndromic cryptorchidism. METHODS: One hundred and 15 males were included; of these, 62 had nonsyndromic cryptorchidism and 53 were healthy volunteers. DNA was extracted from a peripheral blood samples, subsequently, the CAG tract in exon 1 of AR gene was amplified by PCR and sequenced. RESULTS: Mexican patients with nonsyndromic cryptorchidism presented 25.03 ± 2.58 repeats of CAG tract in the AR gene compared to 22.72 ± 3.17 repeats of CAG tract in Mexican healthy individuals (p≤0.0001; t value of 4.3). Furthermore, the deletion of codon 57 that corresponds to the deletion of a leucine residue at position 57 (Del L57) in the AR gene was found for the first time in a nonsyndromic cryptorchidism patient. This molecular alteration has been related previously to testicular germ cell tumor (TGCT). CONCLUSIONS: The CAG tract in the AR gene is longer in patients with nonsyndromic cryptorchidism than in healthy individuals, supporting the association between this polymorphism of the AR gene and nonsyndromic cryptorchidism in the Mexican population.
Assuntos
Criptorquidismo/genética , Receptores Androgênicos/genética , Repetições de Trinucleotídeos , Humanos , MasculinoRESUMO
OBJECTIVE: Undescended testis (UDT) is a urogenital disease that affects fertility. This study looked into the cytogenetic abnormalities of Iranian infertile patients with UDT. METHODS: Our study included 522 infertile patients with UDT (case group) and two control groups, one with 300 infertile men without UDT and another with 268 fertile men. RESULTS: Chromosomal abnormalities were found in 45 patients with UDT (8.62%). Seven of the alterations were considered as normal features. Klinefelter syndrome and mosaicism were the most common anomalies. Chromosomal abnormalities were found in 31 infertile men in the control group (10.33%), 13 of which deemed normal and 18 (6%) anomalous. Nine chromosomal abnormalities were found in the second control group with fertile men (3.35%), six deemed normal and three (1.11%) anomalous. CONCLUSION: Despite the high rate of abnormalities in infertile controls (6%) and the higher rate seen in infertile individuals with UDT indicate a significant prevalence of chromosomal abnormalities in the Iranian population, particularly when the literature suggests that the normal rate of abnormal karyotypes should be within the 0.7-1% range in the general population. The incidence of abnormal karyotypes increased when infertile patients had additional conditions such as UDT.
Assuntos
Criptorquidismo/genética , Infertilidade Masculina/diagnóstico , Síndrome de Klinefelter/diagnóstico , Adulto , Análise Citogenética , Fertilidade/genética , Humanos , Infertilidade Masculina/genética , Irã (Geográfico) , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
ABSTRACT The anti-Müllerian hormone triggers the regression of uterus and fallopian tubes in male embryos; if there are problems in the synthesis or action of this protein, Müllerian structures persist in an otherwise phenotypic male. The most frequent clinical presentation of Persistent Mullerian Duct syndrome is cryptorchidism and inguinal hernia. The few cases reported in adults are incidental findings or inguinal hernias. However, we present an adult male with history of bilateral cryptorchidism with unsuccessful orchidopexy, who presents with a large abdominal mass with the finding of a seminomatous tumor and persistence of Müllerian structures, in whom the variant c.916delC (p.Leu306Cysfs*29) in the AMHR2 gene not previously reported was documented.
Assuntos
Humanos , Masculino , Adulto , Fenótipo , Transtorno 46,XY do Desenvolvimento Sexual/genética , Homozigoto , Mutação , Síndrome , Neoplasias Testiculares/cirurgia , Neoplasias Testiculares/genética , Seminoma/cirurgia , Seminoma/genética , Colômbia , Análise Citogenética , Criptorquidismo/cirurgia , Criptorquidismo/genética , Hormônio Antimülleriano/genética , Transtorno 46,XY do Desenvolvimento Sexual/cirurgia , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/cirurgiaRESUMO
The anti-Müllerian hormone triggers the regression of uterus and fallopian tubes in male embryos; if there are problems in the synthesis or action of this protein, Müllerian structures persist in an otherwise phenotypic male. The most frequent clinical presentation of Persistent Mullerian Duct syndrome is cryptorchidism and inguinal hernia. The few cases reported in adults are incidental findings or inguinal hernias. However, we present an adult male with history of bilateral cryptorchidism with unsuccessful orchidopexy, who presents with a large abdominal mass with the finding of a seminomatous tumor and persistence of Müllerian structures, in whom the variant c.916delC (p.Leu306Cysfs*29) in the AMHR2 gene not previously reported was documented.
Assuntos
Transtorno 46,XY do Desenvolvimento Sexual/genética , Homozigoto , Mutação , Fenótipo , Adulto , Hormônio Antimülleriano/genética , Colômbia , Criptorquidismo/genética , Criptorquidismo/cirurgia , Análise Citogenética , Transtorno 46,XY do Desenvolvimento Sexual/cirurgia , Humanos , Masculino , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/cirurgia , Seminoma/genética , Seminoma/cirurgia , Síndrome , Neoplasias Testiculares/genética , Neoplasias Testiculares/cirurgiaRESUMO
Cryptorchidism is one of the most common congenital disorders in boys, and several genetic, hormonal, and environmental factors have been proposed as possible causes for this genitourinary defect. Genetic factors have been intensively searched, but relatively few pathogenic variants have been described. Cryptorchidism is a frequent finding in patients with RASopathies, a group of syndrome caused by mutations in genes of the Ras/MAPK pathway. Our aim was to determine whether patients with isolated cryptorchidism (IC) exhibit Ras/MAPK pathway gene variants associated with RASopathies. Two hundred thirty-nine patients with IC were recruited after orchidopexy. Determination of Ras/MAPK pathway gene variants was performed by high-resolution melting (HRM) analysis followed by sequencing. Restriction or allele-specific amplification assay was applied to (i) variant confirmation; (ii) search in healthy controls; and (iii) segregation analysis. Controls correspond to 100 healthy Chilean adults without a history of cryptorchidism. Molecular analysis showed one synonymous substitution (BRAF_p.Q456Q) in two patients and four missense substitutions (SOS1_ p.R497Q, BRAF_ p.F595L, NRAS_ p.T50I, and MAP2K2_ p.Y134C) in five patients. Our results suggest that some patients with isolated cryptorchidism, but with no evidence of dysmorphic features suggestive of RASopathies, may harbor Ras/MAPK pathway gene alterations.
Assuntos
Criptorquidismo/genética , GTP Fosfo-Hidrolases/genética , MAP Quinase Quinase 2/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteína SOS1/genética , Adolescente , Criança , Pré-Escolar , Chile , Variação Genética , Humanos , Lactente , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Transdução de Sinais/fisiologia , Proteínas ras/genéticaRESUMO
Cryptorchidism is a frequent genitourinary malformation considered as an important risk factor for infertility and testicular malignancy. The aetiology of cryptorchidism is multifactorial in which certain SNPs, capable of inhibiting the development of the gubernaculum, are implicated. We analysed 16 SNPs by allelic discrimination and automated sequencing in 85 patients and 99 healthy people, with the objective to identify the association between these variants and isolated cryptorchidism. In two different patients with unilateral cryptorchidism, we found the variants rs121912556 and p.R105R of INSL3 gene in a heterozygous form associated with cryptorchidism, so we could considered them as risk factors for cryptorchidism. On the other hand, SNPs rs10421916 of INSL3 gene, as well as the variants rs1555633 and rs7325513 in the RXFP2 gene, and rs3779456 variant of the HOXA10 gene were statistically significant, when the patients and controls were compared and could be considered as protective factors since are predominantly present in controls. The genotype-phenotype correlation did not show statistical significance. With these results, we could conclude that these polymorphisms can be considered as important variants in our population and would contribute in the future knowledge of the aetiology and physiopathology of cryptorchidism.