New insights to the mechanisms of varicocele-induced infertility
| Autor: | Jane-Dar Lee, 李建達 |
|---|---|
| Rok vydání: | 2006 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 95 Varicocele, described as an abnormal tortuosity and dilatation of internal spermatic veins (ISV) within the spermatic cord, is a common anomaly in adolescent and adult males, with an incidence of 15-20% of the general population. Several anatomic features contribute to the predominance of left-side varicoceles (more than 90%). It is the most common cause of male infertility in adults. Approximately 30%∼40% of men evaluated for infertility have varicocele. The mechanisms that how the varicocele causing male infertility, however, are not clear. The surgical treatment for varicocele is safe and simple but the post-operative recurrence rates are 2%∼14%. Based on the above-mentioned reasons, to investigate the pathogenesis of ISV and testicular cell apoptosis could led us to more understand more about the mechanisms of varicocele causing male infertility. Several theories of varicocele effects on the testicles have been postulated: elevated intratesticular temperature, gonadal hormonal imbalance, renal or adrenal vein blood refluxes to ISV, and local testis hypoxia. This paper includes a series of experiments that focus on the hypoxic factor in varicocele disease. These studies contain (1) expression of HIF-1α in the ISV of patients with varicocele; (2) expression of HIF-1α in the ISV of rats with experimental-induced left varicocele (ELV). Kilinc et al. (2004) and Barqawi et al. (2004) found that either HIF-1α expression or germ cell apoptosis increased in the testes of rats with ELV, respectively, indicating the occurrence of hypoxia and increase of cell apoptosis in the testes of rats with ELV. Hence, (3) activated caspase-3 (apoptotic protein) expression in testicular germ cell of rats with ELV; and (4) apoptotic pathway of testicular tissues in rats with ELV were studied. The results of the series of experiments are (1) HIF-1α expression in the ISV of patients with varicocele was significantly higher (7-fold) than in the control group. Moreover, expression of HIF-1α in the smooth muscle of the ISV was predominant in patients with varicocele. These data revealed that hypoxia related pathophysiological changes occurred in the ISV of patients with varicocele and that hypoxia might also occurr in the testicular tissue. To our knowledge, this is the first report on HIF-1α expression in human ISV; (2) expression of HIF-1α in the ISV of rats with ELV was significantly higher than that of the control group, especially at 2, 4, and 8 weeks after varicocele creation. This finding is compatible with the same hypoxic occurrence found in the ISV of patients with varicocele; (3) this animal study also demonstrated a significant increase on expression of activated caspase-3 protein in the testicular germ cells at 8 and 12 weeks after varicocele creation. Which indicated apoptosis of germ cells in the rats with ELV increased gradually. It may be a factor of varicocele causing male infertility in human due to increase apoptosis of testicular germ cell; (4) moreover, analyses of the apoptosis-related proteins expression in the testes of rats with ELV, e.g. Bcl-2, caspase-9, caspase-8, and activated caspase-3, showed down-regulation of Bcl-2 and gradually up-regulation of caspase-9 and activated caspase-3 expressions at 8 and 12 weeks after varicocele creation. There is no significant difference of caspase-8 expression between varicocele and control groups. So it is suggested that increased apoptosis of testicular tissue of rats with ELV was through the intrinsic pathway. According to the results of human and animal experiments, varicocele was demonstrated to lead to testicular tissue hypoxia and increase of germ cell apoptosis through intrinsic pathway. The new insights reveal the mechanisms of varicocele and the relationship between varicocele and male infertility. These findings will shad light on the treatment of varicocele and prevention of recurrence in the future. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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