RESUMEN
Androgen insensitivity syndrome (AIS) is a hereditary condition in patients with a 46,XY karyotype in which loss-of-function mutations of the androgen receptor (AR) gene are responsible for defects in virilization. The aim of this study was to investigate the consequences of the lack of AR activity on germ cell survival and the degree of testicular development reached by these patients by analyzing gonadal tissue from patients with AIS prior to Sertoli cell maturation at puberty. Twenty-three gonads from 13 patients with AIS were assessed and compared to 18 testes from 17 subjects without endocrine disorders. The study of the gonadal structure using conventional microscopy and the ultrastructural characteristics of remnant germ cells using electron microscopy, combined with the immunohistochemical analysis of specific germ cell markers (MAGE-A4 for premeiotic germ cells and of OCT3/4 for gonocytes), enabled us to carry out a thorough investigation of germ cell life in an androgen-insensitive microenvironment throughout prepuberty until young adulthood. Here, we show that germ cell degeneration starts very early, with a marked decrease in number after only 2 years of life, and we demonstrate the permanence of gonocytes in AIS testis samples until puberty, describing 2 different populations. Additionally, our results provide further evidence for the importance of AR signaling in peritubular myoid cells during prepuberty to maintain Sertoli and spermatogonial cell health and survival.
Asunto(s)
Síndrome de Resistencia Androgénica/patología , Pubertad/metabolismo , Pubertad/fisiología , Síndrome de Resistencia Androgénica/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Niño , Preescolar , Células Germinativas/metabolismo , Humanos , Inmunohistoquímica , Lactante , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Espermatogonias/metabolismo , Espermatogonias/patología , Testículo/metabolismo , Testículo/patologíaRESUMEN
All malignant testicular germ cell tumors (TGCT) of adult men are preceded by an in situ stage (CIS) of protracted evolution. The adult CIS is well characterized, but there is debate on the phenotype of infantile CIS, its distinction from delayed maturation of germ cells and prognostic potential. A large series of 43 patients with Disorders of Sex Development (DSD) and dysgenetic testes (90% ranging from neonates to 12 years, mean age 4.7 years), was studied by quantifying dysgenetic features, degree of germ cell abnormalities/atypia (GCA), expression of OCT 3/4 (a pluripotency-undifferentiation marker), germ cell ploidy and evolution to CIS and invasive TGCT. Findings were compared with those of normal testes. The type of gonads present defined three groups of patients: bilateral testes (BT-DSD, n = 21), one testis and one streak gonad (CT-DSD, C for combined, n = 13), and ovarian-testicular combinations (OT-DSD, n = 9). There were 5 boys with infantile CIS, bilateral in 3 (total of 8 infantile CIS) and two patients with adult CIS, bilateral in one (total of 3 adult CIS). Two patients had bilateral seminomas one at 12-17 and the other at 23 years. Histological dysgenesis was significantly higher in CT-DSD (p < 0.05), that had only 1 CIS. The highest frequency of GCA was in BT-DSD (p < 0.05), which coincided with a total of 11CIS + Seminomas. In all patients, aneuploidy was significantly higher (63%) than diploidy (p < 0.02), and GCA were more frequent in aneuploid than in diploid samples (p < 0.02). All CIS and TGCT were OCT 3/4 positive. Finally, there was a significant association between the triad Aneuploidy + GCA + OCT 3/4 positivity and the incidence of CIS (Fisher Exact test p < 0.002, relative risk 7.0). The degree of testicular dysgenesis (derived from abnormal organization of Sertoli cells in fetal testicular cords) is inversely related to the incidence of CIS. Our data demonstrate that the combined use of OCT 3/4 expression, quantification of germ cell abnormalities-atypia and ploidy in dysgenetic testes can satisfactorily identify infantile CIS with high risk of malignant evolution and set it aside from delayed germ cell maturation with lower or nil neoplastic potential.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma in Situ/genética , Disgenesia Gonadal/genética , Seminoma/genética , Desarrollo Sexual/genética , Neoplasias Testiculares/genética , Adolescente , Argentina/epidemiología , Carcinoma in Situ/química , Carcinoma in Situ/epidemiología , Carcinoma in Situ/patología , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Disgenesia Gonadal/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Factor 3 de Transcripción de Unión a Octámeros/análisis , Fenotipo , Ploidias , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Seminoma/química , Seminoma/epidemiología , Seminoma/patología , Neoplasias Testiculares/química , Neoplasias Testiculares/epidemiología , Neoplasias Testiculares/patología , Adulto JovenRESUMEN
Fertility rates have been declining worldwide and most developed countries have fertility rates below the population replacement level. To a large extent, this change can be explaine d by the socioeconomic development. However, increasing fertility problems might play a role as well as there seems to have been a temporal decline in semen quality and an increase in male reproductive diseases like testicular cancer and genital malformations. These male reproductive problems are associated and in some cases proposed to be part of a testicular dysgenesis syndrome. This syndrome is hypothesized to originate in fetal life due to suboptimal androgen activity during a critical developmental period. Genetics may play a role in the development of the syndrome but the rapid increase in male reproductive disorders indicates that environmental factors, including endocrine disrupting compounds, are likely crucial. It is of great importance that the fertility trends are reversed as a fertility rate only slightly below the replacement level causes a significant decline in the population of women in the reproductive age within only a few generations.
Asunto(s)
Animales , Análisis de Semen/veterinaria , Fertilidad/fisiologíaRESUMEN
Fertility rates have been declining worldwide and most developed countries have fertility rates below the population replacement level. To a large extent, this change can be explaine d by the socioeconomic development. However, increasing fertility problems might play a role as well as there seems to have been a temporal decline in semen quality and an increase in male reproductive diseases like testicular cancer and genital malformations. These male reproductive problems are associated and in some cases proposed to be part of a testicular dysgenesis syndrome. This syndrome is hypothesized to originate in fetal life due to suboptimal androgen activity during a critical developmental period. Genetics may play a role in the development of the syndrome but the rapid increase in male reproductive disorders indicates that environmental factors, including endocrine disrupting compounds, are likely crucial. It is of great importance that the fertility trends are reversed as a fertility rate only slightly below the replacement level causes a significant decline in the population of women in the reproductive age within only a few generations.(AU)
Asunto(s)
Animales , Análisis de Semen/veterinaria , Fertilidad/fisiologíaRESUMEN
PURPOSE: The frequency of testicular cancer and male infertility has been increasing in the past several decades. This article examines the relationship between male infertility and testicular cancer, concentrating particularly on causal links. RESULTS: Both of these disorders are associated with testicular dysgenesis syndrome and have also been traced to mutations in genes involving DNA repair and tumor suppression, as well as environmental exposure. CONCLUSION: The identification and examination of these common points of origin supports the integration of testicular cancer screenings into the routine evaluation of infertile men.