title: Mechanisms Underlying Testicular Damage and Dysfunction in Mice With Partial IGF-1 Deficiency and the Effectiveness of IGF-1 Replacement Therapy.
abstract: OBJECTIVE
  To determine whether insulin-like growth factor (IGF-1) deficiency can cause testicular damage and to examine changes of the testicular morphology and testicular function-related gene expression caused by IGF-1 deficiency. Therefore, this study aims to determine the benefits of low doses of IGF-1 and to explore the mechanisms underlying the IGF-1 replacement therapy.
  
  
  METHODS
  A murine model of IGF-1 deficiency was used to avoid any factor that could contribute to testicular damage. Testicular weight, score of histopathological damage, and gene expressions were studied in 3 experimental groups of mice: controls (wild-type Igf1(+/+)), heterozygous Igf1(+/-) with partial IGF-1 deficiency, and heterozygous Igf1(+/-) treated with IGF-1.
  
  
  RESULTS
  Results show that the partial IGF-1 deficiency induced testicular damage and altered expression of genes involved in IGF-1 and growth hormone signaling and regulation, testicular hormonal function, extracellular matrix establishment and its regulation, angiogenesis, fibrogenesis, inflammation, and cytoprotection. In addition, proteins involved in tight junction expression were found to be reduced. However, low doses of IGF-1 restored the testicular damage and most of these parameters.
  
  
  CONCLUSIONS
  IGF-1 deficiency caused the damage of the blood-testis barrier and testicular structure and induced the abnormal testicular function-related gene expressions. However, low doses of IGF-1 constitute an effective replacement therapy that restores the described testicular damage. Data herein show that (1) cytoprotective activities of IGF-1 seem to be mediated by heat shock proteins and that (2) connective tissue growth factor could play a relevant role together with IGF-1 in the extracellular matrix establishment.
authors.affiliation: Fundación de Investigación HM Hospitales, Madrid, Spain; Escuela Nacional de Medicina, Tecnológico de Monterrey, Nuevo León, Mexico. Electronic address: iccortazar@itesm.mx.
authors.forename: Inma
authors.initials: I
authors.lastname: Castilla-Cortázar
authors.affiliation: Department of Physiology, Institute of Applied Molecular Medicine (IMMA), School of Medicine, University CEU-San Pablo, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gago
authors.affiliation: Department of Physiology, Institute of Applied Molecular Medicine (IMMA), School of Medicine, University CEU-San Pablo, Madrid, Spain.
authors.forename: Úrsula
authors.initials: Ú
authors.lastname: Muñoz
authors.affiliation: Department of Physiology, Institute of Applied Molecular Medicine (IMMA), School of Medicine, University CEU-San Pablo, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Ávila-Gallego
authors.affiliation: Department of Physiology, Institute of Applied Molecular Medicine (IMMA), School of Medicine, University CEU-San Pablo, Madrid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Guerra-Menéndez
authors.affiliation: Department of Physiology, Institute of Applied Molecular Medicine (IMMA), School of Medicine, University CEU-San Pablo, Madrid, Spain.
authors.forename: María Cruz
authors.initials: MC
authors.lastname: Sádaba
authors.affiliation: Fundación de Investigación HM Hospitales, Madrid, Spain; Escuela Nacional de Medicina, Tecnológico de Monterrey, Nuevo León, Mexico.
authors.forename: Mariano
authors.initials: M
authors.lastname: García-Magariño
authors.affiliation: Fundación de Investigación HM Hospitales, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Olleros Santos-Ruiz
authors.affiliation: Fundación de Investigación HM Hospitales, Madrid, Spain; Escuela Nacional de Medicina, Tecnológico de Monterrey, Nuevo León, Mexico.
authors.forename: G A
authors.initials: GA
authors.lastname: Aguirre
authors.affiliation: Fundación de Investigación HM Hospitales, Madrid, Spain; Department of Physiology, Institute of Applied Molecular Medicine (IMMA), School of Medicine, University CEU-San Pablo, Madrid, Spain.
authors.forename: Juan Enrique
authors.initials: JE
authors.lastname: Puche
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000818:Animals; D001814:Blood-Testis Barrier / Q000737:chemistry*; D018821:CD18 Antigens / Q000235:genetics; D015820:Cadherins / Q000032:analysis; D055513:Connective Tissue Growth Factor / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D000072196:Fertilins; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D005838:Genotype; D007265:Inhibins / Q000235:genetics; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D045726:Metalloproteases / Q000235:genetics; D051379:Mice; D009929:Organ Size; D011509:Proteoglycans / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics; D011962:Receptors, FSH / Q000032:analysis; D011986:Receptors, Somatotropin / Q000032:analysis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013737:Testis / Q000737:chemistry / Q000473:pathology* / Q000503:physiopathology*; D019108:Tight Junctions / Q000737:chemistry; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D062826:Zonula Occludens-1 Protein / Q000032:analysis; D051176:beta Catenin / Q000032:analysis
chemical_list: C526318:CCN2 protein, mouse; D018821:CD18 Antigens; D015820:Cadherins; D016326:Extracellular Matrix Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D011962:Receptors, FSH; D011986:Receptors, Somatotropin; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; C519530:insulin-like growth factor-1, mouse; D055513:Connective Tissue Growth Factor; D007265:Inhibins; D007334:Insulin-Like Growth Factor I; C517429:Cyp3a25 protein, mouse; D051544:Cytochrome P-450 CYP3A; D017526:Receptor, IGF Type 1; D045726:Metalloproteases; D051722:ADAM Proteins; D000072196:Fertilins