Molecular Mechanisms of Syndromic Cryptorchidism: Data Synthesis of 50 Studies and Visualization of Gene-Disease Network

Background: Cryptorchidism is one of the most frequent congenital birth defects in male children and is present in 2–4% of full-term male births. It has several possible health effects including reduced fertility, increased risk for testicular neoplasia, testicular torsion, and psychological consequences. Cryptorchidism is often diagnosed as comorbid; copresent with other diseases. It is also present in clinical picture of several syndromes. However, this field has not been systematically studied. The aim of the present study was to catalog published cases of syndromes which include cryptorchidism in the clinical picture and associated genomic information.Methods: The literature was extracted from Public/Publisher MEDLINE and Web of Science databases, using the keywords including: syndrome, cryptorchidism, undescended testes, loci, and gene. The obtained data was organized in a table according to the previously proposed standardized data format. The results of the study were visually represented using Gephi and karyotype view.Results: Fifty publications had sufficient data for analysis. Literature analysis resulted in 60 genomic loci, associated with 44 syndromes that have cryptorchidism in clinical picture. Genomic loci included 38 protein-coding genes and 22 structural variations containing microdeletions and microduplications. Loci, associated with syndromic cryptorchidism are located on 16 chromosomes. Visualization of retrieved data is presented in a gene-disease network.Conclusions: The study is ongoing and further studies will be needed to develop a complete catalog with the data from upcoming publications. Additional studies will also be needed for revealing of molecular mechanisms associated with syndromic cryptorchidism and revealing complete diseasome network

Estudio de la fertilidad en pacientes operados de criptorquidia

INTRODUCCIÓN Y MOTIVACIÓN La criptorquidia es la malformación genital más frecuente en el hombre. Afecta al nacer al 3% de la población masculina y al año de vida la incidencia es del 1%. A pesar de su alta incidencia, los efectos a largo plazo y las consecuencias en el potencial de paternidad todavía son objeto de controversia. Este estudio está motivado en el único parámetro de interés para los afectados, la paternidad. Intenta alejarse de los tradicionales métodos de estudio de este tema a largo plazo basados en biopsias. DESARROLLO TEÓRICOEn el Hospital Infantil de Zaragoza ha dado seguimiento a un grupo de pacientes intervenidos de criptorquidia desde los años 70 mediante la recopilación de datos desde el momento de la cirugía, seguido de un estudio ecográfico 14 años después . Los objetivos del estudio son: OBJETIVO PRINCIPAL- Comparar las tasas de paternidad de adultos operados de criptorquidia en edad infantil con adultos sanos. OBJETIVOS SECUNDARIOS - Analizar si los hábitos tabáquicos, alcohólicos o exposición a substancias y ambientes de trabajo afectan la paternidad de los pacientes con antecedente de criptorquidia en comparación con un grupo control. -Analizar en el adulto las características ecográficas de los testes intervenidos de criptorquidia sobre la base de su localización en quirófano, tamaño y edad de tratamiento quirúrgico- Analizar en el adulto el volumen de los testes intervenidos de criptorquidia y contralaterales, según las curvas de crecimiento testicular normal. Para alcanzar el objetivo los datos se han analizado dividiéndolos en 2 grupos. El primer grupo es el compuesto por todos los pacientes, de forma global, dividida en sí mismo en 3 subgrupos. Los pacientes con criptorquidia unilateral, los pacientes con criptorquidia bilateral y los pacientes sanos. El segundo grupo es el estudio estadístico de los pacientes con criptorquidia en términos de unidades testiculares. CONCLUSIÓN 1. No hay diferencia en la tasa de paternidad entre los pacientes operados de criptorquidia respecto a un grupo control de hombres sanos. 2. No hay diferencias en las tasas de paternidad de los pacientes operados de criptorquidia en relación a la edad de intervención quirúrgica o el número de hijos.3. El teste intervenido presenta un volumen testicular menor que el teste contralateral de descenso normal.4. A mayor edad de tratamiento quirúrgico, mayor afectación del volumen postpuberal del teste con criptorquidia en relación a los volúmenes testiculares normales.5. Los testículos con disyunción epidídimo testicular completa, tienen menor volumen que los testículos con una unión epidídimo testicular normal.6. No hay relación entre la localización testicular extra-abdominal y el volumen testicular postoperatorio.7. No encontramos una asociación entre la exposición a una substancia tóxica específica con una afectación de la paternidad. Por lo tanto, basado en nuestros resultados, si una substancia afecta la paternidad, este impacto es igual en ambos grupos sin afectar de forma especial a los individuos intervenidos de criptorquidia.8. El excesivo consumo de tabaco y alcohol tiene una repercusión negativa sobre la paternidad, sin alcanzar significación estadística en nuestro estudio.9. Los pacientes con antecedente de criptorquidia, pueden tener alteración de su satisfacción sexual aunque esta insatisfacción no tenga repercusión estadística en la paternidad.RESUMEN BIBLIOGRAFIA- Sadov S, Koskenniemi JJ, Virtanen HE, Perheentupa A, Petersen JH, Skakkebaek NE, et al. Testicular Growth During Puberty in Boys With and Without a History of Congenital Cryptorchidism. J Clin Endocrinol Metab. 2016;101(6):2570-7.-Van der Plas EM, Zijp GW, Froeling FM, van der Voort-Doedens LM, Meij-de Vries A, Goede J, et al. Long-term testicular volume after orchiopexy at diagnosis of acquired undescended testis. J Urol. 2013;190(1):257-62.-Virtanen HE, Adamsson A. Cryptorchidism and endocrine disrupting chemicals. Mol Cell Endocrinol. 2012;355(2):208-20.-Lee PA, Coughlin MT. Fertility after bilateral cryptorchidism. Evaluation by paternity, hormone, and semen data. Horm Res. 2001;55(1):28-32.- Lee PA, Coughlin MT. The single testis: paternity after presentation as unilateral cryptorchidism. J Urol. 2002;168(4 Pt 2):1680-2; discussion 2-3.- Chua ME, Mendoza JS, Gaston MJ, Luna SL, Morales ML. Hormonal therapy using gonadotropin releasing hormone for improvement of fertility index among children with cryptorchidism: a meta-analysis and systematic review. J Pediatr Surg. 2014;49(11):1659-67.-Thorup J, McLachlan R, Cortes D, Nation TR, Balic A, Southwell BR, et al. What is new in cryptorchidism and hypospadias--a critical review on the testicular dysgenesis hypothesis. J Pediatr Surg. 2010;45(10):2074-86.-Pettersson A, Richiardi L, Nordenskjold A, Kaijser M, Akre O. Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med. 2007;356(18):1835-41.-Wood HM, Elder JS. Cryptorchidism and testicular cancer: separating fact from fiction. J Urol. 2009;181(2):452-61.-Cortes D, Thorup JM, Visfeldt J. Cryptorchidism: aspects of fertility and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism. Horm Res. 2001;55(1):21-7.-Nataraja RM, Asher CM, Nash R, Murphy FL. Is routine excision of testicular remnants in testicular regression syndrome indicated? J Pediatr Urol. 2015;11(3):151.e1-5.-Spinelli C, Strambi S, Busetto M, Pucci V, Bianco F. Effects on normalized testicular atrophy index (TAIn) in cryptorchid infants treated with GnRHa pre and post-operative vs surgery alone: a prospective randomized trial and long-term follow-up on 62 cases. Pediatr Surg Int. 2014;30(10):1061-7.-Ateş F, Soydan H, Okçelik S, Çırakoğlu A, Yılmaz İ, Malkoç E, et al. Clinical and histopathological results of the adult patients with unilateral cryptorchidism. Turk J Urol. 2016;42(2):74-9.-Promm M, Schröder A, Neissner C, Eder F, Rösch WH, Schröder J. Acquired cryptorchidism: More harm than thought? J Pediatr Urol. 2016;12(4):236.e1-6.-Penna FJ, Nguyen HT, Passerotti CC, Sandy NS, Nelson CP, Diamond DA. The concordance of testicular anatomic location in bilateral cryptorchidism. J Pediatr Urol. 2011;7(1):52-6.<br /

Gubernaculum, antsėklidžio ir sėklidės nusileidimas: literatūros apžvalga

Cryptorchidism is a common disorder in boys that has been widely studied both experimentally and clinically. The role of the gubernaculum, a mesenchymal tissue extending from the fetal testis and epididymis to the developing scrotum, is still unclear. Even the name is debated: ‘gubernaculum epididymis’ or ‘gubernaculum testis’. This review does not aim to provide a global overview of competing theories on testicular descent, but focuses on the role of the gubernaculum in epididymo-testicular descent. We identified four major pitfalls of gubernaculum research: the role of the gubernaculum, of insulin-like peptide 3, anti-Müllerian hormone, and androgens. The major critical issues were that the gubernaculum plays a guiding role for the epididymis, descending prior to the testis and expanding the inguinal canal; insulin-like peptide 3 is not as important for the process of descent in humans as the rate of insulin-like peptide 3 mutations is low; anti-Müllerian hormone plays no significant role in epididymo-testicular descent; androgens and gonadotropins play a crucial role in epididymo-testicular descent. The role of the epididymis in the complex process of gubernaculum, epididymis, and testis migration is underestimated and should be included in future research

Decreased expression of FGFR1, SOS1, RAF1 genes in cryptorchidism

In recent years, several genes were found to be involved in the process of epididymo-testicular descent, the most frequently cited ones include INSL3, HOXA10, GNRHR, and KAL1. In this study, we analyzed the differences in gene expression profiles between cryptorchid and descended testes. In particular, we analyzed expression of all recently published genes known to be associated with undescended testis

Insulin 3-like hormone and its role in epididymo-testicular descent

PURPOSE: The role of insulin 3-like (Insl3) hormone signaling in the testicular descent process has been demonstrated. The purpose of the present study was to evaluate epididymal development in Insl3-deficient mice. MATERIALS AND METHODS: Heterozygous and homozygous Insl3 mutants of a mixed CD1 X 129/Sv genetic background were generated by breeding Insl3-/- females with Insl3+/- males, and their genotypes were determined by polymerase chain reaction. On the first postnatal day, newborn males were sacrificed, embedded in paraffin, and cut in 4 &micro;m sections. Sections were stained with hematoxylin/eosin and immunoreacted with anti-&plusmn; actin antibody. RESULTS: An analysis of stained sections indicated an arrest in the development of the epididymis in all homozygous mice. The cauda and corpus of the epididymis were undersized. Compared to the heterozygous epididymis, the homozygous epididymis had fewer peritubular layers and dwarfish musculature. We confirmed this with immunostaining with monoclonal antibodies against &plusmn; -smooth muscle actin. CONCLUSION: Defective development of the smooth musculature in the epididymis of Insl3 homozygous mutant mice, combined with its high intraabdominal undescended position, supports previous observations regarding the importance of intact epididymis morphology and function for descent of the epididymo-testicular unit