Mechanisms Underlying Testicular Damage and Dysfunction in Mice With Partial IGF-1 Deficiency and the Effectiveness of IGF-1 Replacement Therapy

Castilla‐Cortázar, Inma; Gago, A. M.; Muñoz, Úrsula; Ávila-Gallego, Elena; Guerra-Menéndez, Lucía; Sádaba, María C.; García‐Magariño, Mariano; Santos-Ruiz, M. O; Aguirre, Gabriel A.; Puche, Juan Enrique

doi:10.1016/j.urology.2015.09.012

Cited by 12 publications

(7 citation statements)

References 22 publications

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“…In great detail, clinical trials have been proposed to evaluate risks and benefit of IGF1 treatment in preterm infants, to avoid the consequences on brain, heart, and metabolism due to the preterm delivery (Hellström et al ., ). In murine models, IGF1 replacement therapy showed to restore the damage of blood–testis barrier and of testicular structure induced by IGF1 deficiency (Castilla‐Cortázar et al ., ). Further studies are needed to evaluate the role, if any, of the IGF system on testicular function in humans and whether it mediates the effects of FSH.…”

Section: Discussionmentioning

confidence: 97%

Effects of the insulin‐like growth factor system on testicular differentiation and function: a review of the literature

et al. 2017

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SUMMARYWe recently described the occurrence of cryptorchidism, oligoasthenoteratozoospermia, and genital abnormalities in patients with distal 15q chromosome structural abnormalities. This observation brought us to hypothesize that insulin-like growth factor (IGF) receptor (IGF1R), mapping on the 15q 26.3 chromosomal band, may be involved in testicular function. To further evaluate this topic, we reviewed in vitro and in vivo studies exploring the role of the IGF system [IGF1, IGF2, IGF1R, insulin receptor substrates (IRS)] at the testicular level both in animals and in humans. In animals, IGF1/IGF1R has been found to be involved in testicular development during embryogenesis, in Sertoli cell (SC) proliferation, and in germ cell (GS) proliferation and differentiation. Interestingly, IGF1R seems to mediate follicle-stimulating hormone (FSH) effects through the PI3K/AKT pathway. In humans, IGF1 directly increases testicular volume. The molecular pathways responsible for testicular differentiation and IGF1/IGF1R signaling are highly conserved among species; therefore, the IGF system may be involved in FSH signaling also in humans. We suggest a possible molecular pathway occurring in human SCs, which involves both IGF1 and FSH through the PI3K/AKT pathway. The acknowledgment of an IGF1 mediation of the FSH-induced effects may open new ways for a targeted therapy in idiopathic non-FSH-responder oligoasthenoteratozoospermia.

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Section: Discussionmentioning

confidence: 97%

Effects of the insulin‐like growth factor system on testicular differentiation and function: a review of the literature

et al. 2017

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“…Irs‐2 plays a critical role in testicular development during embryonic and early postnatal development, probably by mediating the effects of IGF‐1 (Castilla‐Cortazar et al. ) or insulin on IGF receptors (Escott et al. ; Griffeth et al.…”

Section: Discussionmentioning

confidence: 99%

“…), most likely by mediating the effects of IGF‐I (Castilla‐Cortazar et al. ) or insulin on insulin growth factor (IGF) receptors (Escott et al. ), as reviewed previously (Griffeth et al.…”

Section: Introductionmentioning

confidence: 97%

Sequential testicular atrophy involves changes in cellular proliferation and apoptosis associated with variations in aromatase P450 expression levels in Irs‐2‐deficient mice

et al. 2018

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Insulin receptor substrate 2 (Irs‐2) is an intracellular protein susceptible to phosphorylation after activation of the insulin receptor. Its suppression affects testis development and its absence induces peripheral resistance to insulin. The aim of this study was to identify changes induced by the deletion of Irs‐2 in the testicular structure and by the altered expression of cytochrome P450 aromatase, a protein necessary for the development and maturation of germ cells. Adult knockout (KO) mice (Irs‐2−/−, 6 and 12 weeks old) and age‐matched wild‐type (WT) mice were used in this study. Immunohistochemistry and Western blot analyses were performed to study proliferation (PCNA), apoptosis (active caspase‐3) and P450 aromatase expression in testicular histological sections. Deletion of Irs‐2 decreased the number of epithelial cells in the seminiferous tubule and rete testis. Aberrant cells were frequently detected in the epithelia of Irs‐2−/− mice, accompanied by variations in spermatogonia, which were shown to exhibit small hyperchromatic nuclei as well as polynuclear and anuclear structures. The amount of cell proliferation was significantly lower in Irs‐2−/− mice than in WT mice, whereas apoptotic processes were more common in Irs‐2−/− mice. Aromatase P450 reactivity was higher in 6‐week‐old KO mice than in WT mice of the same age and was even higher at 12 weeks. Our results suggest that Irs‐2 is a key element in spermatogenesis because silencing Irs‐2 induces the sequential development of testicular atrophy. The effects are observed mainly in germ cells present in the seminiferous tubule, which may be due to changes in cytochrome P450 aromatase expression.

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“…We, thereby, suggest that IGF‐1 replacement therapy would be very beneficial to this patient, accounting to the multiple positive effects related to IGF‐1: longitudinal bone growth, immune function, erythropoiesis, metabolic, antioxidant (aiming for cancer prevalence found in some CHH patients), antiinflammatory, hypogonadism, hepato‐, neuro‐, and mitochondrial protection [Claustres et al, ; Kurtz et al, ; Pascual et al, ; García‐Fernández et al, ; Conchillo et al, ; Puche et al, ; Smith, ; Castilla‐Cortázar et al, , ; Puche and Castilla‐Cortázar, ; Aguirre et al, ].…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular diagnosis of a cartilage‐hair hypoplasia with IGF‐1 deficiency

Castilla‐Cortázar

Ita

Martín-Estal

et al. 2016

American J of Med Genetics Pt A

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Cartilage-hair hypoplasia syndrome (CHH) is a rare autosomal recessive condition characterized by metaphyseal chondrodysplasia and characteristic hair, together with a myriad of other symptoms, being most common immunodeficiency and gastrointestinal complications. A 15-year-old Mexican male initially diagnosed with Hirschsprung disease and posterior immunodeficiency, presents to our department for genetic and complementary evaluation for suspected CHH. Physical, biochemical, and genetic studies confirmed CHH together with IGF-1 deficiency. For this reason, we propose IGF-1 replacement therapy for its well-known actions on hematopoiesis, immune function and maturation, and metabolism. Ó 2016 Wiley Periodicals, Inc.Key words: cartilage-hair hypoplasia; IGF-1; RMRP gene; GHR INTRODUCTIONCartilage-hair hypoplasia syndrome (CHH) is a rare autosomal recessive condition that was originally described by McKusik in 1964 in Amish children. In this population, it accounts for one in 1,300 newborns [McKusick et al., 1965], while in the Finnish population it accounts for one in 23,000 newborns [M€ akitie and Kaitila, 1993]. Outside those populations it is extremely rare, with no incidence data available [M€ akitie and Kaitila, 1993]. The genetic locus for this disease falls within the RNA Component Of Mitochondrial RNA Processing Endoribonuclease (RMRP) gene, localized in chromosome 9p12, which codes for the RMRP, believed to be required for cell cycle, mtDNA replication and rRNA processing [Ridanp€ a€ a et al., 2001;Hermanns et al., 2005;Thiel et al., 2005;Martin and Li, 2007]. The RMRP RNA product associates with at least seven proteins whose interactions and roles remain to be discovered [Welting et al., 2004].The hallmark of this condition is a metaphyseal chondrodysplasia and characteristic hair (fine, sparse with scalp, blond eyelashes-93%), with other several signs and symptoms including short stature and skeletal dysplasia (100%) with varum deformation of lower extremities, hypoplastic anemia during childhood (79%), immunodeficiency (during childhood they may present different recurrent infections secondary to an immunodeficiency that may be humoral, B-cell or T-cell, or combined-56%) [Pierce and Polmar, 1982;M€ akitie et al., 1998, 2000bBaradaran-Heravi et al., 2008] with higher risk of malignancies, skin and nails abnormalities, gastrointestinal diseases (such as Hirschsprung disease [HD], malabsorption, anal stenosis and esophageal atresia-18%) [M€ akitie et al., 2002, 2000a], and failure to thrive [M€ akitie et al., 1992;Glass and Tifft, 1999;Riley et al., 2015]. The growth failure is progressive, owing, partly, to a weak or absent pubertal growth spurt; pubertal maturation is normal; testicular size is abnormal in some patients with normal serum concentrations of testosterone, inhibin B and gonadotropins [M€ akitie et al., 2001].These patients are symptomatic since birth, showing short-limb dwarfism and short puffy hands, with normal head circumference [Giedion, 1998]. The final adult heights range from 100.7 t...

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Mechanisms Underlying Testicular Damage and Dysfunction in Mice With Partial IGF-1 Deficiency and the Effectiveness of IGF-1 Replacement Therapy

Cited by 12 publications

References 22 publications

Effects of the insulin‐like growth factor system on testicular differentiation and function: a review of the literature

Effects of the insulin‐like growth factor system on testicular differentiation and function: a review of the literature

Sequential testicular atrophy involves changes in cellular proliferation and apoptosis associated with variations in aromatase P450 expression levels in Irs‐2‐deficient mice

Clinical and molecular diagnosis of a cartilage‐hair hypoplasia with IGF‐1 deficiency

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