Morphologic changes due to human chorionic gonadotropin in the rat testis: Role of vascular endothelial growth factor

DOI: 10.4236/ojped.2013.32016   PDF   HTML     3,439 Downloads   5,685 Views   Citations


Introduction: Human chorionic gonadotropin (hCG) has an important role in the regulation of reproductive system and a high capacity to stimulate angiogenesis by secretion of vascular endothelial growth factor (VEGF). It could be also used for medical treatment of cryptorchidism, as it stimulates Leydig cells to produce testosterone, but its use has been discussed. Aim of the study was to evaluate the testicular morphological changes due to cyclic administration of hCG possibly related to VEGF effect. Methods: 80 pre-puberal male Sprague-Dawley rats were randomly divided in two groups hCG (50 U/I/ Kg) (n = 55/S) and placebo (n = 25/C) treated. The animals were sacrificed respectively after one (S1 n = 10; C1 n = 5), two (S2 n = 10; C2 n = 5) and three weeks of hCG or placebo treatment (S3 n = 35; C3 n = 15); a blood serum was obtained for evaluation of plasmatic testosterone. The testis, prostates, epididymides and seminal vesicles were drawn and weighted. Specimens were fixed in formalin and coloured by hematoxylin-eosin. Morphometric analysis of Leydig cell number, nuclear area and perimeter was carried out. Immunoistochemistry for VEGF has been performed with the avidin-biotin peroxidase technique. Statistical differences between groups, each of different age, were calculating using Student’s T-test. Results: After the first week of hCG treatment it has been observed an increased testicular weight and volume (+/6%) in experimental respect to control group. This result was not observed after the second and third week of treatment. Significant variations were also observed in the mean prostate weight, whereas mean seminal vesicles weight was significant in the S2 and S3 groups respect to control. In the hCG treated rats it has been observed a poor differentiation of the seminiferous epithelium, with high Leydig cell evidence and increased intertubular eosinophilic material. An interstitial edema was demonstrated without inflammatory cell changes. Morphometric analysis confirmed an increased number of Leydig cells that were always strongly immunostained for VEGF. Low-medium reactivity was present in spermatogonial, peritubular, endothelial and Sertoli cells. Testosterone plasmatic values showed a statistically significant and progressive increase. Conclusions: hCG treatment clutters the germinative line and modifies VEGF testicular expression, suggesting its role in male reproductive system. The increased number of Leydig cells and the immunostaining for VEGF suggests an intense interstitial and metabolic arrangement. The morphologic modifications induced by hCG treatment and its influence on testis function raise the question about its use in the medical treatment of cryptorchidism.

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Papparella, A. , Nino, F. , Noviello, C. , Romano, M. , Papparella, S. , Paciello, O. and Sinisi, A. (2013) Morphologic changes due to human chorionic gonadotropin in the rat testis: Role of vascular endothelial growth factor. Open Journal of Pediatrics, 3, 85-91. doi: 10.4236/ojped.2013.32016.

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The authors declare no conflicts of interest.


[1] Ergun, S., Kilic, N., Fiedler, W. and Mukhopadhyay, A.K. (1997) Vascular endothelial growth factor and its recaptors in normal human testicular tissue. Molecular and Cellular Endocrinology, 131, 9-20. doi:10.1016/S0303-7207(97)00082-8
[2] Ergün, S., Luttmer, W., Fiedler, W. and Holstein, A.F. (1998) Functional expression and localization of vascular endothelial growth factor and its receptors in the human epididymis. Biology of Reproduction, 58, 160-168. doi:10.1095/biolreprod58.1.160
[3] Reisinger, K., Baal, N., McKinnona, T., Munstedt, K. and Zygmunta, M. (2007) The gonadotropins: Tissue-specific angiogenic factors? Molecular and Cellular Endocrinology, 269, 65-80. doi:10.1016/j.mce.2006.11.015
[4] Ferrara, N. and Davis-Smyth, T. (1997) The biology of vascular endothelial growth factor. Endocrine Reviews, 18, 4-25. doi:10.1210/er.18.1.4
[5] Nalbandian, A., Dettin, L., Dym, M. and Ravindranath N. (2003) Expression of vascular endothelial growth factor receptors during male germ cell differentiation in the mouse. Biology of Reproduction, 69, 985-994. doi:10.1095/biolreprod.102.013581
[6] Thomas, O.D. and Dale, A. (2000) Endothelial signal integration in vascular assembly. Annual Review of Physiology, 62, 649-671. doi:10.1146/annurev.physiol.62.1.649
[7] Christiansen, P., Muller, J., Buhl, S., et al. (1988) Treatment of cryptorchidism with human chorionic gonadotropin or gonadotropin releasing hormone. Hormone Research, 30, 187-192. doi:10.1159/000181058
[8] Bergh, A., Damber, J.E. and Hjertkvist, M. (1996) Human chorionic gonadotropin induced testicular inflammation may be related to increased sensitivity to interleukin1. International Journal of Andrology, 19, 229-236. doi:10.1111/j.1365-2605.1996.tb00467.x
[9] Cortes, D., Thorup, J. and Visfeldt, J. (2000) Hormonal treatment may harm the germ cells in 1-to 3-year-old boys with cryptorchidism. Journal of Urology, 163, 1290-1292. doi:10.1016/S0022-5347(05)67763-4
[10] Friedman, R.M., Lopez, F.J., Tucker, J.A., King, L.R. and Negro-Vilar, A. (1994) Fertility after cryptorchidism: A comparative analysis of early orchidopexy with and without concomitant hormonal therapy in the young male rat. Journal of Urology, 151, 227-233.
[11] Leon, M.D., Calvo, J.C., Charreau, E.H. and Chemes, H.E. (1990) Developmental changes in testicular interstitial cell populations, LH receptors and in the response to hCG in the rat. International Journal of Andrology, 13, 110-122. doi:10.1111/j.1365-2605.1990.tb00968.x
[12] LeCouter, J., Kowalski, J., Foster, J., Hass, P., et al. (2001) Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature, 412, 877-884. doi:10.1038/35091000
[13] LeCouter, J., Lin, R. and Ferrara, N. (2002) Endocrine gland-derived VEGF and emerging hypothesis of organspecific regulation of angiogenesis. Nature Medicine, 8, 913-917. doi:10.1038/nm0902-913
[14] Rudolfsson, S.H., Wikstrom, P., Jonsson, A., Collin, O. and Bergh, A. (2004) Hormonal regulation and functional role of vascular endothelial growth factor A in the rat testis. Biology of Reproduction, 70, 340-347. doi:10.1095/biolreprod.103.016816
[15] Bergh, A. and Damber, J.-E. (1993) Vascular controls in testicular physiology. In: deKretser, D.M., Ed., Molecular Biology of the Male Reproductive System, Academic Press Inc., New York, 439-468.
[16] Brown, L.F., Yeo, K., Berse, B., Morgentaler, A., Dvorak, H.F. and Rosen, S. (1995) Vascular permeability factor (vascular endothelial growth factor) is strongly expressed in the normal male genital tract and is present in substantial quantities in semen. Journal of Urology, 154, 576-579. doi:10.1016/S0022-5347(01)67114-3
[17] Huminiecki, L., Chan, H.Y., Poulsom, R., Stamp, G., Harris, A.L. and Bicknell, R. (2001) Vascular endothelial cell growth factor transgenic mice exhibit reduced male fertility and placental rejection. Molecular Human Reproduction, 7, 255-264. doi:10.1093/molehr/7.3.255
[18] Anand, R.J.K., Paust, H.-J., Altenpohl, K. and Mukhopadhyay, A.K. (2003) Regulation of vascular endothelial growth factor production by leydig cells in vitro: The role of protein kinase A and mitogen-activated protein kinase cascade. Biology of Reproduction, 68, 1663-1673. doi:10.1095/biolr eprod.102.009795
[19] Schwarzenbach, H., Chakrabarti, G., Joachim Paust, H. and Mukhopadhyay, A.K. (2004) Gonadotropin mediated regulation of the murine VEGF expression in MA-10 Leydig cells. Journal of Andrology, 25, 128-139.
[20] Salama, N., Bergh, A. and Damber, J.-E. (2003) The changes in testicular vascular permeability during progression of the experimental varicocele. European Urology, 43, 84-91. doi:10.1016/S0302-2838(02)00501-8
[21] Ludwikowski, B. and González, R. (2013) The controversy regarding the need for hormonal treatment in boys with unilateral cryptorchidism goes on: A review of the literature: European Journal of Pediatrics, 172, 5-8. doi:10.1007/s00431-012-1711-y
[22] Thorsson, A.V., Christiansen, P. and Ritzèn, M. (2007) Efficacy and safety of hormonal treatment of cryptorchidism: Current state of the art. Acta Paediatrica, 96, 628-630.
[23] Martin Ritzén, E., Bergh, A., Bjerknes, R., Christiansen, P., Cortes, D., Haugen, S., Jorgensen, N., Kollin, C., Lindahl, S., Lackgren, G., Main, K., Nordenskjold, A., Rajpert-De Meyts, E., Sader, O., Taskinen, S., Thorsson, A., Thorup, J., Toppari, J. and Virtanen, H. (2007), Nordic consensus on treatment of undescended testes. Acta Paediatrica, 96, 638-643. doi:10.1111/j.1651-2227.2006.00159.x
[24] Papparella, A., Coppola, S., Nino, F., Andrade Barrientos, M. and Gasparini, N. (2013) Epidemiology and treatment of cryptorchidism and retractile testis: Retrospective study in the area of Naples. Minerva Pediatrica, 65, 77-82.
[25] Korpelainen, E.I., Karkkainen, M.J., Tenhunen, A., Lakso, M., Rauvala, H., Vierula, M., et al. (1998) Overexpression of VEGF in testis and epididymis causes infertility in transgenic mice: Evidence for non-endothelial targets for VEGF. Journal of Cell Biology, 143, 1705-1712. doi:10.1083/jcb.143.6.1705
[26] Shiraishi, K. and Naito, K. (2008) Involvement of vascular endothelial growth factor on spermatogenesis in testis with varicocele. rtility and Sterility, 90, 1313-1316. doi:10.1016/j.fertnstert.2007.08.030
[27] Hyder, S.M. and Stancel, G.M. (2000) Regulation of VEGF in the reproductive tract by sex-steroid hormones. Histology and Histopathology, 15, 325-334.

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