臺灣博碩士論文加值系統

局部睪丸缺血(testicular ischemia)與系統性低氧(systemic hypoxia)影響男性生殖與內分泌功能。睪丸缺血造成男性不孕，本研究利用精索扭轉(testicular torsion)之動物模式，探討睪丸局部缺血對於睪丸細胞凋亡與睪酮分泌的影響。將成年雄鼠進行單側睪丸扭轉720度後，發現睪丸缺血僅需2小時，即顯著抑制PDK1/SGK1/FOXO3a的訊息傳遞磷酸化，並造成精原細胞凋亡，且顯著增加血漿中醣皮質素濃度、降低血漿黃體促素與睪酮濃度，及損害萊氏細胞與睪丸間質細胞分泌睪酮能力。此外，利用長期間歇性低氧(chronic intermittent hypoxia)的動物模式探討對大鼠睪酮分泌的影響。將大鼠放入12% O2的飼養箱中，每日8小時，共14天。結果顯示，長期間歇性低氧顯著增加血漿睪酮濃度與降低黃體促素濃度，此可能透過增加萊氏細胞黃體促素接受器表現量、17β-HSD與 P450scc活性，進而提高萊氏細胞分泌睪酮的能力。此外，長期間歇性低氧顯著增加精索與全身血清內的血管內皮生長因子濃度，並刺激睪丸的血管新生。本研究有助於了解間歇性低氧調節睪酮分泌的詳細機制，以及SGK1在睪丸缺血中所誘發的細胞凋亡中扮演的角色，對於未來在需要提升或補充體內雄性素的病患，提供非侵入性與非激素製劑的方式，且提供治療睪丸扭轉/解除扭轉或缺血/再灌注傷害之類疾患的併用藥物可能研發方向。

Systemic hypoxia and testicular ischemia affect the male reproductive and endocrine function. The present study investigated 1) whether torsion-induced apoptosis is associated with changes in phosphoinositide-dependent protein kinase 1 (PDK1), serum- and glucocorticoid-inducible kinase 1 (SGK1), and forkhead transcription factor FOXO3a expression and/or phosphorylation in rats and to determined 2) the effects and mechanisms of intermittent hypoxia on testosterone production. Sprague-Dawley male rats were performed for unilateral torsion. Our results suggest that torsion induces spermatogonia apoptosis occurs at least partially via the PDK1/SGK1/FOXO3a signaling cascade and impairs the testosterone secretion capacity of the testes after only 2 h of torsion. Furthermore, after torsion stimulation, the plasma corticosteroid level was increased, plasma LH and testosterone levels were decreased, and the testosterone secretion capacity of Leydig cells and testicular interstitial cells were impaired. Moreover, male rats were housed in a 12 % O2 hypoxic chamber, 8 h/d for 14 days. Normoxic rats were used as control animals. Our results reveal that 14-d systemic chronic intermittent hypoxia increasd plasma testosterone via the induction of the functional capacity to secrete testosterone, and might partially through the mechanisms involving the inducing of luteinizing hormone receptor expression, P450scc activity, 17β-HSD, and calcium-related pathway in rat Leydig cells. In addition, the angiogenesis has been observed in the hypoxic testis. This ischemia/hypoxia animal study helps the understanding of the detailed mechanisms in hypoxic-regulated testosterone secretion. The results suggest that SGK1 plays a crucial role in regulating torsion-induced apoptosis in rats. We hope that the concepts acquired from the present study will potentially provide non-invasive and non-hormonal preparation methods for the patients who need the androgen supplemention and a new consideration for curing torsion/detorsion damage (ischemia/reperfusion injury).

目 次
圖 次………………… iv
表 次………….. vi
中英文名詞對照與英文縮寫表 vii
中文摘要……….. 1
英文摘要……… 2
第壹章、文獻回顧 4
一、概 述 4
二、下視丘－腦下腺－性腺軸線調控男性生殖功能 5
三、睪丸在男性生殖功能中扮演的角色 6
四、睪酮對雄性生理的重要調節功能 8
五、睪丸缺血 8
六、系統性低氧 12
七、缺血/低氧對男性生殖內分泌系統的影響 14
八、研究目的 16
第貳章、研究材料與方法 17
一、實驗動物 17
二、睪丸間質細胞與萊氏細胞製備 17
三、放射免疫測定 18
四、酵素免疫測定 18
五、蛋白質表現分析法 18
六、基因表現分析法 18
七、統計分析 18
第叁章、局部睪丸缺血對睪酮分泌與三種激酶蛋白表現的影響 18
一、緒 言 18
二、材料與方法 18
三、結 果 18
四、討 論 18
第肆章、長期間歇性低氧對大鼠睪酮分泌與黃體促素受體表現之影響 18
一、緒 言 18
二、材料與方法 18
三、結 果 18
四、討 論 18
第伍章、結 論 18
參考文獻………… 18
附 錄…………… 18

References

1.Akgur, F.M., K.Kilinc, and T.Aktug. 1993. Reperfusion injury after detorsion of unilateral testicular torsion. Urol. Res. 21:395-399.
2.Altay, B., M.Hekimgil, A.KEFi, and N.Cikili. 2001. Histopathological examination of both ipsilateral and contralateral testes with different obstructive models in prepubertal and adult rats. BJU. Int. 88:84-89.
3.Anderson, J.B. and R.C.Williamson. 1990. Fertility after torsion of the spermatic cord. Br. J. Urol. 65:225-230.
4.Anderson, M.J., J.K.Dunn, L.I.Lipshultz, and M.Coburn. 1992. Semen quality and endocrine parameters after acute testicular torsion. J. Urol. 147:1545-1550.
5.Andreucci, M., A.Michael, C.Kramers, K.M.Park, A.Chen, T.Matthaeus, A.Alessandrini, S.Haq, T.Force, and J.V.Bonventre. 2003. Renal ischemia/reperfusion and ATP depletion/repletion in LLC-PK(1) cells result in phosphorylation of FKHR and FKHRL1. Kidney Int. 64:1189-1198.
6.Aoyama, T., T.Matsui, M.Novikov, J.Park, B.Hemmings, and A.Rosenzweig. 2005. Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response. Circulation 111:1652-1659.
7.Arena, F., P.A.Nicotina, C.Romeo, G.Zimbaro, S.Arena, B.Zuccarello, and G.Romeo. 2006. Prenatal testicular torsion: ultrasonographic features, management and histopathological findings. Int. J. Urol. 13:135-141.
8.Baker, L.A. and T.T.Turner. 1995. Leydig cell function after experimental testicular torsion despite loss of spermatogenesis. J. Androl 16:12-17.
9.Barnholt, K.E., A.R.Hoffman, P.B.Rock, S.R.Muza, C.S.Fulco, B.Braun, L.Holloway, R.S.Mazzeo, A.Cymerman, and A.L.Friedlander. 2006. Endocrine responses to acute and chronic high-altitude exposure (4,300 meters): modulating effects of caloric restriction. Am. J. Physiol Endocrinol. Metab 290:E1078-E1088.
10.Basu, M., K.Pal, A.S.Malhotra, R.Prasad, and R.C.Sawhney. 1995. Free and total thyroid hormones in humans at extreme altitude. Int. J. Biometeorol. 39:17-21.
11.Basu, M., K.Pal, R.Prasad, A.S.Malhotra, K.S.Rao, and R.C.Sawhney. 1997. Pituitary, gonadal and adrenal hormones after prolonged residence at extreme altitude in man. Int. J. Androl 20:153-158.
12.Bell, L.M., M.L.Leong, B.Kim, E.Wang, J.Park, B.A.Hemmings, and G.L.Firestone. 2000. Hyperosmotic stress stimulates promoter activity and regulates cellular utilization of the serum- and glucocorticoid-inducible protein kinase (Sgk) by a p38 MAPK-dependent pathway. J. Biol. Chem. 275:25262-25272.
13.Benton, L., L.X.Shan, and M.P.Hardy. 1995. Differentiation of adult Leydig cells. J. Steroid Biochem. Mol. Biol. 53:61-68.
14.Biondi, R.M., A.Kieloch, R.A.Currie, M.Deak, and D.R.Alessi. 2001. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J. 20:4380-4390.
15.Brickley, D.R., C.A.Mikosz, C.R.Hagan, and S.D.Conzen. 2002. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1). J. Biol. Chem. 277:43064-43070.
16.Bruder, E.D., A.K.Nagler, and H.Raff. 2002. Oxygen-dependence of ACTH-stimulated aldosterone and corticosterone synthesis in the rat adrenal cortex: developmental aspects. J. Endocrinol. 172:595-604.
17.Brunet, A., J.Park, H.Tran, L.S.Hu, B.A.Hemmings, and M.E.Greenberg. 2001. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell Biol. 21:952-965.
18.Budas, G.R., A.Sukhodub, D.R.Alessi, and A.Jovanovic. 2006. 3'Phosphoinositide-dependent kinase-1 is essential for ischemic preconditioning of the myocardium. FASEB J. 20:2556-2558.
19.Burgher, S.W. 1998. Acute scrotal pain. Emerg. Med. Clin. North Am. 16:781-809, vi.
20.Burton, J.A. 1972. Atrophy following testicular torsion. Br. J. Surg. 59:422-426.
21.Caesar, R.E. and G.W.Kaplan. 1994. Incidence of the bell-clapper deformity in an autopsy series. Urology 44:114-116.
22.Casamayor, A., N.A.Morrice, and D.R.Alessi. 1999. Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem. J. 342 ( Pt 2):287-292.
23.Chang, L.L., W.S.Wun, and P.S.Wang. 2008. Mechanisms of inhibition of dehydroepiandrosterone upon corticosterone release from rat zona fasciculata-reticularis cells. J. Cell Biochem. 104:359-368.
24.Chen, J.J., S.W.Wang, E.J.Chien, and P.S.Wang. 2003. Direct effect of propylthiouracil on progesterone release in rat granulosa cells. Br. J. Pharmacol. 139:1564-1570.
25.Chen, S.Y., A.Bhargava, L.Mastroberardino, O.C.Meijer, J.Wang, P.Buse, G.L.Firestone, F.Verrey, and D.Pearce. 1999. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc. Natl. Acad. Sci. U. S. A 96:2514-2519.
26.Chiao, Y.C., W.L.Cho, and P.S.Wang. 2002. Inhibition of testosterone production by propylthiouracil in rat Leydig cells. Biol. Reprod. 67:416-422.
27.Choi, D.W. 1990. Cerebral hypoxia: some new approaches and unanswered questions. J. Neurosci. 10:2493-2501.
28.Chong, Z.Z. and K.Maiese. 2007. Erythropoietin involves the phosphatidylinositol 3-kinase pathway, 14-3-3 protein and FOXO3a nuclear trafficking to preserve endothelial cell integrity. Br. J. Pharmacol. 150:839-850.
29.Cleaver, O. and D.A.Melton. 2003. Endothelial signaling during development. Nat. Med. 9:661-668.
30.Closset, J., A.Gothot, B.Sente, M.L.Scippo, A.Igout, M.Vandenbroeck, D.Dombrowicz, and G.Hennen. 1989. Pituitary hormones dependent expression of insulin-like growth factors I and II in the immature hypophysectomized rat testis. Mol. Endocrinol. 3:1125-1131.
31.Cooke, B.A., M.C.Choi, G.Dirami, M.P.Lopez-Ruiz, and A.P.West. 1992. Control of steroidogenesis in Leydig cells. J. Steroid Biochem. Mol. Biol. 43:445-449.
32.Cosentino, M.J., J.Sheinfeld, E.Erturk, and A.T.Cockett. 1986. The effect of graded unilateral testicular biopsy on the reproductive capacity of male rats. J. Urol. 135:155-158.
33.Costa, R.R., W.A.Varanda, and C.R.Franci. 2010. A calcium-induced calcium-release mechanism supports Luteinizing Hormone (LH) induced testosterone secretion in mice Leydig cells. Am. J. Physiol Cell Physiol.
34.Cuzzocrea, S., D.P.Riley, A.P.Caputi, and D.Salvemini. 2001. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol. Rev. 53:135-159.
35.Dunkel, L., X.C.Jia, K.Nishimori, I.Boime, and A.J.Hsueh. 1993. Deglycosylated human chorionic gonadotropin (hCG) antagonizes hCG stimulation of 3',5'-cyclic adenosine monophosphate accumulation through a noncompetitive interaction with recombinant human luteinizing hormone receptors. Endocrinology 132:763-769.
36.Edelsberg, J.S. and Y.S.Surh. 1988. The acute scrotum. Emerg. Med. Clin. North Am. 6:521-546.
37.Farias, J.G., E.Bustos-Obregon, P.J.Tapia, E.Gutierrez, A.Zepeda, C.Juantok, G.Cruz, G.Soto, J.Benites, and J.G.Reyes. 2008. Time course of endocrine changes in the hypophysis-gonad axis induced by hypobaric hypoxia in male rats. J. Reprod. Dev. 54:18-21.
38.Filho, D.W., M.A.Torres, A.L.Bordin, T.B.Crezcynski-Pasa, and A.Boveris. 2004. Spermatic cord torsion, reactive oxygen and nitrogen species and ischemia-reperfusion injury. Mol. Aspects Med. 25:199-210.
39.Firestone, G.L., J.R.Giampaolo, and B.A.O'Keeffe. 2003. Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem. 13:1-12.
40.Foresta, C. and R.Mioni. 1993. The role of calcium ions in rat Leydig cell steroidogenesis induced by atrial natriuretic peptide. Acta Endocrinol. (Copenh) 128:274-280.
41.Gamper, N., S.Fillon, S.M.Huber, Y.Feng, T.Kobayashi, P.Cohen, and F.Lang. 2002. IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflugers Arch. 443:625-634.
42.Gonzalez-Robayna, I.J., A.E.Falender, S.Ochsner, G.L.Firestone, and J.S.Richards. 2000. Follicle-Stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-lnduced kinase (Sgk): evidence for A kinase-independent signaling by FSH in granulosa cells. Mol. Endocrinol. 14:1283-1300.
43.Gosney, J.R. 1984. The effects of hypobaric hypoxia on the corticotroph population of the adenohypophysis of the male rat. J Pathol. 142:163-168.
44.Gosney, J.R. 1986. Morphological changes in the pituitary and thyroid of the rat in hypobaric hypoxia. J Endocrinol. 109:119-124.
45.Griffin, D.K., P.J.Ellis, B.Dunmore, J.Bauer, M.H.Abel, and N.A.Affara. 2010. Transcriptional profiling of luteinizing hormone receptor-deficient mice before and after testosterone treatment provides insight into the hormonal control of postnatal testicular development and Leydig cell differentiation. Biol. Reprod. 82:1139-1150.
46.Guerra-Garcia, R., A.Velasquez, and J.Coyotupa. 1969. A test of endocrine gonadal function in men: urinary testosterone after the injection of HCG. A different response of the high altitude native. J. Clin. Endocrinol. Metab 29:179-182.
47.Hadziselimovic, F., R.Geneto, and L.R.Emmons. 1997. Increased apoptosis in the contralateral testis in patients with testicular torsion. Lancet 350:118.
48.Hampton-Smith, R.J. and D.J.Peet. 2009. From polyps to people: a highly familiar response to hypoxia. Ann. N. Y. Acad. Sci. 1177:19-29.
49.Hardy, M.P., H.B.Gao, Q.Dong, R.Ge, Q.Wang, W.R.Chai, X.Feng, and C.Sottas. 2005. Stress hormone and male reproductive function. Cell Tissue Res. 322:147-153.
50.Hsia, S.M., W.Chiang, Y.H.Kuo, and P.S.Wang. 2006. Downregulation of progesterone biosynthesis in rat granulosa cells by adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) bran extracts. Int. J. Impot. Res. 18:264-274.
51.Hsu, W.L., T.H.Chiu, D.J.Tai, Y.L.Ma, and E.H.Lee. 2009. A novel defense mechanism that is activated on amyloid-beta insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling. Cell Death. Differ. 16:1515-1529.
52.Huang, W.J., J.Y.Yeh, S.F.Kan, L.S.Chang, and P.S.Wang. 2001. Effects of hyperprolactinemia on testosterone production in rat Leydig cells. J. Cell Biochem. 80:313-320.
53.Hunter, T. 1995. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80:225-236.
54.Hunter, T. 2000. Signaling--2000 and beyond. Cell 100:113-127.
55.Hwang, G.S., C.Y.Jian, T.J.Chen, S.T.Chen, and S.W.Wang. 2009. Effects of Hypoxia on Testosterone Release in Rat Leydig cells. Am. J. Physiol Endocrinol. Metab.
56.Hwang, G.S., S.W.Wang, W.M.Tseng, C.H.Yu, and P.S.Wang. 2007. Effect of Hypoxia on the Release of Vascular Endothelial Growth Factor and Testosterone in Mouse TM3 Leydig cells. Am. J. Physiol Endocrinol. Metab.
57.Imaizumi, K., M.Tsuda, A.Wanaka, M.Tohyama, and T.Takagi. 1994. Differential expression of sgk mRNA, a member of the Ser/Thr protein kinase gene family, in rat brain after CNS injury. Brain Res. Mol. Brain Res. 26:189-196.
58.Janetschek, G., F.Schreckenberg, G.Mikuz, and M.Marberger. 1988. Experimental testicular torsion: effect on endocrine and exocrine function and contralateral testicular histology. Urol. Res. 16:43-47.
59.Jarow, J.P. 1990. Intratesticular arterial anatomy. J. Androl 1990 May-Jun;11:255-259.
60.Jung, F., J.Haendeler, J.Hoffmann, A.Reissner, E.Dernbach, A.M.Zeiher, and S.Dimmeler. 2002. Hypoxic induction of the hypoxia-inducible factor is mediated via the adaptor protein Shc in endothelial cells. Circ. Res. 91:38-45.
61.Kadish, H.A. and R.G.Bolte. 1998. A retrospective review of pediatric patients with epididymitis, testicular torsion, and torsion of testicular appendages. Pediatrics 102:73-76.
62.Karaguzel, G., G.Gedikoglu, F.C.Tanyel, N.Buyukpamukcu, and A.Hicsonmez. 1995. Subsequent biological effects of chemical sympathectomy in rats undergoing unilateral testicular torsion. Eur. Urol. 28:147-151.
63.Karmazyn, B., R.Steinberg, L.Kornreich, E.Freud, S.Grozovski, M.Schwarz, N.Ziv, and P.Livne. 2005. Clinical and sonographic criteria of acute scrotum in children: a retrospective study of 172 boys. Pediatr. Radiol. 35:302-310.
64.Kass, E.J. and B.Lundak. 1997. The acute scrotum. Pediatr. Clin. North Am. 44:1251-1266.
65.Kaytor, M.D. and H.T.Orr. 2002. The GSK3 beta signaling cascade and neurodegenerative disease. Curr. Opin. Neurobiol. 12:275-278.
66.Kiang, J.G. and K.T.Tsen. 2006. Biology of hypoxia. Chin J. Physiol 49:223-233.
67.King, L.F.A.U., S.F.A.U.Sekaran, D.F.Sauer, and F.N.Schwentker. 1974. Untwisting in delayed treatment of torsion of the spermatic cord. J. Urol. 112:217-221.
68.King, S.R., T.Ronen-Fuhrmann, R.Timberg, B.J.Clark, J.Orly, and D.M.Stocco. 1995. Steroid production after in vitro transcription, translation, and mitochondrial processing of protein products of complementary deoxyribonucleic acid for steroidogenic acute regulatory protein. Endocrinology 136:5165-5176.
69.Kirby, E.D., A.C.Geraghty, T.Ubuka, G.E.Bentley, and D.Kaufer. 2009. Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proc. Natl. Acad. Sci. U. S. A 106:11324-11329.
70.Kis, A., D.M.Yellon, and G.F.Baxter. 2003. Second window of protection following myocardial preconditioning: an essential role for PI3 kinase and p70S6 kinase. J. Mol. Cell Cardiol. 35:1063-1071.
71.Kizilcan, F.F., I.F.Bernay, F.A.U.Tanyel FC, N.F.Buyukpamukcu, C.F.Bekdik, and A.Hicsonmez. 1992. Ipsilateral and contralateral testicular blood flows during unilateral testicular torsion by 133Xe clearance technique. Int. Urol. Nephrol. 24:515-520.
72.Kobayashi, T. and P.Cohen. 1999. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem. J. 339 ( Pt 2):319-328.
73.Kobayashi, T., M.Deak, N.Morrice, and P.Cohen. 1999. Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem. J. 344 Pt 1:189-197.
74.Lang, F., C.Bohmer, M.Palmada, G.Seebohm, N.Strutz-Seebohm, and V.Vallon. 2006. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev. 86:1151-1178.
75.Lang, F. and P.Cohen. 2001. Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Sci. STKE. 2001:RE17.
76.Lang, F., K.Klingel, C.A.Wagner, C.Stegen, S.Warntges, B.Friedrich, M.Lanzendorfer, J.Melzig, I.Moschen, S.Steuer, S.Waldegger, M.Sauter, M.Paulmichl, V.Gerke, T.Risler, G.Gamba, G.Capasso, R.Kandolf, S.C.Hebert, S.G.Massry, and S.Broer. 2000. Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc. Natl. Acad. Sci. U. S. A 97:8157-8162.
77.Leong, M.L., A.C.Maiyar, B.Kim, B.A.O'Keeffe, and G.L.Firestone. 2003. Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a cell survival response to multiple types of environmental stress stimuli in mammary epithelial cells. J. Biol. Chem. 278:5871-5882.
78.Lin, H., S.W.Wang, S.C.Tsai, J.J.Chen, Y.C.Chiao, C.C.Lu, W.J.Huang, G.J.Wang, C.F.Chen, and P.S.Wang. 1998. Inhibitory effect of digoxin on testosterone secretion through mechanisms involving decreases of cyclic AMP production and cytochrome P450scc activity in rat testicular interstitial cells. Br J Pharmacol 125:1635-1640.
79.Lin, H., S.W.Wang, R.Y.Wang, and P.S.Wang. 2001. Stimulatory effect of lactate on testosterone production by rat Leydig cells. J Cell Biochem 83:147-154.
80.Lu, A., Y.Tang, R.Ran, J.F.Clark, B.J.Aronow, and F.R.Sharp. 2003. Genomics of the periinfarction cortex after focal cerebral ischemia. J. Cereb. Blood Flow Metab 23:786-810.
81.Luboshitzky, R., A.Aviv, A.Hefetz, P.Herer, Z.Shen-Orr, L.Lavie, and P.Lavie. 2002. Decreased pituitary-gonadal secretion in men with obstructive sleep apnea. J. Clin. Endocrinol. Metab 87:3394-3398.
82.Lysiak, J.J., Q.A.Nguyen, and T.T.Turner. 2002. Peptide and nonpeptide reactive oxygen scavengers provide partial rescue of the testis after torsion. J. Androl 23:400-409.
83.Lysiak, J.J., S.D.Turner, Q.A.Nguyen, K.Singbartl, K.Ley, and T.T.Turner. 2001. Essential role of neutrophils in germ cell-specific apoptosis following ischemia/reperfusion injury of the mouse testis. Biol. Reprod. 65:718-725.
84.Macome, J.C., L.E.Costa, I.H.Martin, and A.C.Taquini. 1977. Steroid biosynthesis by gonads of rats submitted to chronic hypobaric hypoxia. Acta Physiol Lat. Am. 27:249-257.
85.Maiyar, A.C., A.J.Huang, P.T.Phu, H.H.Cha, and G.L.Firestone. 1996. p53 stimulates promoter activity of the sgk. serum/glucocorticoid-inducible serine/threonine protein kinase gene in rodent mammary epithelial cells. J. Biol. Chem. 271:12414-12422.
86.Marmorston, J., J.M.Weiner, C.E.Hopkins, and E.Stern. 1966. Abnormalities in urinary hormone patterns in lung cancer and emphysema. Cancer 19:985-995.
87.Marshall, W.A. and J.M.Tanner. 1970. Variations in the pattern of pubertal changes in boys. Arch. Dis. Child 45:13-23.
88.McFarland, K.C., R.Sprengel, H.S.Phillips, M.Kohler, N.Rosemblit, K.Nikolics, D.L.Segaloff, and P.H.Seeburg. 1989. Lutropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 245:494-499.
89.Melekos, M., Asbach HW, and S.A.Markou. 1988. Etiology of acute scrotum in 100 boys with regard to age distribution. J. Urol. 139:1023-1025.
90.Michiels, C. 2004. Physiological and pathological responses to hypoxia. Am. J. Pathol. 164:1875-1882.
91.Mikosz, C.A., D.R.Brickley, M.S.Sharkey, T.W.Moran, and S.D.Conzen. 2001. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J. Biol. Chem. 276:16649-16654.
92.Mordes, J.P., F.D.Blume, S.Boyer, M.R.Zheng, and L.E.Braverman. 1983. High-altitude pituitary-thyroid dysfunction on Mount Everest. N. Engl. J. Med. 308:1135-1138.
93.Nagler, H.F.A.U. and R.D.White. 1982. The effect of testicular torsion on the contralateral testis. J. Urol. 128:1343-1348.
94.Nishida, Y., T.Nagata, Y.Takahashi, M.Sugahara-Kobayashi, A.Murata, and S.Asai. 2004. Alteration of serum/glucocorticoid regulated kinase-1 (sgk-1) gene expression in rat hippocampus after transient global ischemia. Brain Res. Mol. Brain Res. 123:121-125.
95.Noske, H.F.A.U., S.F.A.U.Kraus, B.F.A.U.Altinkilic, and W.Weidner. 1998. Historical milestones regarding torsion of the scrotal organs. J. Urol. 159:13-16.
96.Ozkan, K.F.A.U., C.F.Boran, M.F.Kilinc, M.F.Garipardic, and E.B.Kurutas. 2004. The effect of zinc aspartate pretreatment on ischemia-reperfusion injury and early changes of blood and tissue antioxidant enzyme activities after unilateral testicular torsion-detorsion. J. Pediatr. Surg. 39:91-95.
97.Papadopoulou, N., I.Charalampopoulos, K.Alevizopoulos, A.Gravanis, and C.Stournaras. 2008. Rho/ROCK/actin signaling regulates membrane androgen receptor induced apoptosis in prostate cancer cells. Exp. Cell Res. 314:3162-3174.
98.Park, J., M.L.Leong, P.Buse, A.C.Maiyar, G.L.Firestone, and B.A.Hemmings. 1999. Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J. 18:3024-3033.
99.Payne, A.H. 1990. Hormonal regulation of cytochrome P450 enzymes, cholesterol side-chain cleavage and 17 alpha-hydroxylase/C17-20 lyase in Leydig cells. Biol. Reprod. 42:399-404.
100.Petersson, F., R.G.Andersson, B.A.A:son, and M.Hammar. 1988. Early effects of hCG on human testicular cyclic AMP content, protein kinase activity, in-vitro progesterone conversion and the serum concentrations of testosterone and oestradiol. Int. J. Androl 11:179-186.
101.Petrack, E.M. and W.Hafeez. 1992. Testicular torsion versus epididymitis: a diagnostic challenge. Pediatr. Emerg. Care 8:347-350.
102.Pillai, S.B. and G.E.Besner. 1998. Pediatric testicular problems. Pediatr. Clin. North Am. 45:813-830.
103.Pon, L.A., L.F.Epstein, and N.R.Orme-Johnson. 1986. Acute cAMP stimulation in Leydig cells: rapid accumulation of a protein similar to that detected in adrenal cortex and corpus luteum. Endocr. Res. 12:429-446.
104.Pu, H.F., S.W.Wang, C.I.Tseng, H.L.Huang, C.W.Lin, J.M.Hsu, M.J.Chen, Y.C.Chow, and P.S.Wang. 2006. Mechanisms of digoxin and digitoxin on the production of corticosterone in zona fasciculata-reticularis cells of ovariectomized rats. J. Cell Biochem. 97:303-313.
105.Raff, H., J.J.Hong, M.K.Oaks, and E.P.Widmaier. 2003. Adrenocortical responses to ACTH in neonatal rats: effect of hypoxia from birth on corticosterone, StAR, and PBR. Am J Physiol Regul. Integr. Comp Physiol 284:R78-R85.
106.Richards, J.S. 2001. New signaling pathways for hormones and cyclic adenosine 3',5'-monophosphate action in endocrine cells. Mol. Endocrinol. 15:209-218.
107.Richards, J.S., S.L.Fitzpatrick, J.W.Clemens, J.K.Morris, T.Alliston, and J.Sirois. 1995. Ovarian cell differentiation: a cascade of multiple hormones, cellular signals, and regulated genes. Recent Prog. Horm. Res. 50:223-254.
108.Rivier, C. and S.Rivest. 1991. Effect of stress on the activity of the hypothalamic-pituitary-gonadal axis: peripheral and central mechanisms. Biol. Reprod. 45:523-532.
109.Romero, F.R., R.P.Gomes, F.Lorenzini, T.R.Erdmann, and F.R.Tambara. 2009. Ipsilateral testicular necrosis and atrophy after 1,080-degree torsion of the spermatic cord in rats. Acta Cir. Bras. 24:118-123.
110.Rozansky, D.J., J.Wang, N.Doan, T.Purdy, T.Faulk, A.Bhargava, K.Dawson, and D.Pearce. 2002. Hypotonic induction of SGK1 and Na+ transport in A6 cells. Am. J. Physiol Renal Physiol 283:F105-F113.
111.Rusai, K., B.Wagner, M.Roos, C.Schmaderer, M.Strobl, K.M.Boini, A.Grenz, D.Kuhl, U.Heemann, F.Lang, and J.Lutz. 2009. The serum and glucocorticoid-regulated kinase 1 in hypoxic renal injury. Cell Physiol Biochem. 24:577-584.
112.Rybkiewicz, M. 2001. Long-term and late results of treatment in patients with a history of testicular torsion. Ann. Acad. Med. Stetin. 47:61-75.
113. Sawhney, R.C., P.C.Chhabra, A.S.Malhotra, T.Singh, S.S.Riar, and R.M.Rai. 1985. Hormone profiles at high altitude in man. Andrologia 17:178-184.
114. Schoenebeck, B., V.Bader, X.R.Zhu, B.Schmitz, H.Lubbert, and C.C.Stichel. 2005. Sgk1, a cell survival response in neurodegenerative diseases. Mol. Cell Neurosci. 30:249-264.
115. Semple, P.D., G.H.Beastall, T.M.Brown, K.W.Stirling, R.J.Mills, and W.S.Watson. 1984. Sex hormone suppression and sexual impotence in hypoxic pulmonary fibrosis. Thorax 39:46-51.
116.Shanmugam, I., G.Cheng, P.F.Terranova, J.B.Thrasher, C.P.Thomas, and B.Li. 2007. Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival. Cell Death. Differ. 14:2085-2094.
117.Shioda, N., T.Ishigami, F.Han, S.Moriguchi, M.Shibuya, Y.Iwabuchi, and K.Fukunaga. 2007. Activation of phosphatidylinositol 3-kinase/protein kinase B pathway by a vanadyl compound mediates its neuroprotective effect in mouse brain ischemia. Neuroscience 148:221-229.
118.Shiraishi, K., K.Naito, and K.Yoshida. 2000. Inhibition of calpain but not caspase protects the testis against injury after experimental testicular torsion of rat. Biol. Reprod. 63:1538-1548.
119. Shiraishi, K., K.Naito, and K.Yoshida. 2001. Nitric oxide promotes germ cell necrosis in the delayed phase after experimental testicular torsion of rat. Biol. Reprod. 65:514-521.
120.Sordello, S., N.Bertrand, and J.Plouet. 1998. Vascular endothelial growth factor is up-regulated in vitro and in vivo by androgens. Biochem. Biophys. Res. Commun. 251:287-290.
121.Sriraman, V. and R.A.Jagannadha. 2004. Evaluation of the role of FSH in regulation of Leydig cell function during different stages of its differentiation. Mol. Cell Endocrinol. 224:73-82.
122. Stichel, C.C., B.Schoenebeck, M.Foguet, B.Siebertz, V.Bader, X.R.Zhu, and H.Lubbert. 2005. sgk1, a member of an RNA cluster associated with cell death in a model of Parkinson's disease. Eur. J. Neurosci. 21:301-316.
123.Sukhotnik, I., I.Miselevich, M.Lurie, O.Nativ, A.G.Coran, and J.G.Mogilner. 2005. The time relationship between ipsilateral testicular ischemia and germ cell apoptosis in the contralateral testis in rat. Pediatr. Surg. Int. 21:512-516.
124.Suzuki, M., K.Muraki, Y.Imaizumi, and M.Watanabe. 1992. Cyclopiazonic acid, an inhibitor of the sarcoplasmic reticulum Ca(2+)-pump, reduces Ca(2+)-dependent K+ currents in guinea-pig smooth muscle cells. Br. J. Pharmacol. 107:134-140.
125.Takihara, H., M.J.Cosentino, J.Sakatoku, and A.T.Cockett. 1987. Significance of testicular size measurement in andrology: II. Correlation of testicular size with testicular function. J. Urol. 137:416-419.
126. Tanyel, F., N.Buyukpamukcu, and A.Hicsonmez. 1989. Contralateral testicular blood flow during unilateral testicular torsion. Br. J. Urol. 63:522-524.
127. Tsai, K.J., S.K.Chen, Y.L.Ma, W.L.Hsu, and E.H.Lee. 2002. sgk, a primary glucocorticoid-induced gene, facilitates memory consolidation of spatial learning in rats. Proc. Natl. Acad. Sci. U. S. A 99:3990-3995.
128. Tsai, S.C., J.J.Chen, Y.C.Chiao, C.C.Lu, H.Lin, J.Y.Yeh, M.J.Lo, M.M.Kau, S.W.Wang, and P.S.Wang. 1997. The role of cyclic AMP production, calcium channel activation and enzyme activities in the inhibition of testosterone secretion by amphetamine. Br J Pharmacol 122:949-955.
129. Tsai, S.C., Y.C.Chiao, C.C.Lu, M.L.Doong, Y.H.Chen, H.C.Shih, C.Liaw, S.W.Wang, and P.S.Wang. 1996. Inhibition by amphetamine of testosterone secretion through a mechanism involving an increase of cyclic AMP production in rat testes. Br J Pharmacol 118:984-988.
130.Tumeh, S.S., C.B.Benson, and J.P.Richie. 1991. Acute diseases of the scrotum. Semin. Ultrasound CT MR 12:115-130.
131.Tunckiran, A., S.Cayan, M.Bozlu, N.Yilmaz, D.Acar, and E.Akbay. 2005. Protective effect of vascular endothelial growth factor on histologic changes in testicular ischemia-reperfusion injury. Fertil. Steril. 84:468-473.
132.Turner, T.T. 1985. Acute experimental testicular torsion. No effect on the contralateral testis. J. Androl. 6:65-72.
133. Turner, T.T., H.J.Bang, and J.J.Lysiak. 2005. Experimental testicular torsion: reperfusion blood flow and subsequent testicular venous plasma testosterone concentrations. Urology 65:390-394.
134.Turner, T.T. and K.J.Brown. 1993. Spermatic cord torsion: loss of spermatogenesis despite return of blood flow. Biol. Reprod. 49:401-407.
135. Vallon, V. and F.Lang. 2005. New insights into the role of serum- and glucocorticoid-inducible kinase SGK1 in the regulation of renal function and blood pressure. Curr. Opin. Nephrol. Hypertens. 14:59-66.
136.Waldegger, S., P.Barth, J.N.Forrest, Jr., R.Greger, and F.Lang. 1998. Cloning of sgk serine-threonine protein kinase from shark rectal gland - a gene induced by hypertonicity and secretagogues. Pflugers Arch. 436:575-580.
137. Waldegger, S., P.Barth, G.Raber, and F.Lang. 1997. Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. Proc. Natl. Acad. Sci. U. S. A 94:4440-4445.
138.Waldegger, S., K.Klingel, P.Barth, M.Sauter, M.L.Rfer, R.Kandolf, and F.Lang. 1999. h-sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116:1081-1088.
139. Wang, S.W., H.Lin, J.J.Hwang, and P.S.Wang. 1999. Inhibition of testosterone secretion by digitoxin in rat testicular interstitial cells. J. Cell Biochem. 74:74-80.
140. Warntges, S., B.Friedrich, G.Henke, C.Duranton, P.A.Lang, S.Waldegger, R.Meyermann, D.Kuhl, E.J.Speckmann, N.Obermuller, R.Witzgall, A.F.Mack, H.J.Wagner, A.Wagner, S.Broer, and F.Lang. 2002. Cerebral localization and regulation of the cell volume-sensitive serum- and glucocorticoid-dependent kinase SGK1. Pflugers Arch. 443:617-624.
141.Webster, M.K., L.Goya, and G.L.Firestone. 1993a. Immediate-early transcriptional regulation and rapid mRNA turnover of a putative serine/threonine protein kinase. J. Biol. Chem. 268:11482-11485.
142. Webster, M.K., L.Goya, Y.Ge, A.C.Maiyar, and G.L.Firestone. 1993b. Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol. Cell Biol. 13:2031-2040.
143. Weir, E.K., M.Obreztchikova, A.Vargese, J.A.Cabrera, D.A.Peterson, and Z.Hong. 2008. Mechanisms of oxygen sensing: a key to therapy of pulmonary hypertension and patent ductus arteriosus. Br. J. Pharmacol. 155:300-307.
144.Wenger, R.H., D.P.Stiehl, and G.Camenisch. 2005. Integration of oxygen signaling at the consensus HRE. Sci. STKE. 2005:re12.
145.Williamson, R.C. 1976. Torsion of the testis and allied conditions. Br. J. Surg. 63:465-476.
146. Yang, W., N.G.Dolloff, and W.S.El-Deiry. 2008. ERK and MDM2 prey on FOXO3a. Nat. Cell Biol. 10:125-126.
147. Yazawa, H., I.Sasagawa, Y.Suzuki, and T.Nakada. 2001. Glucocorticoid hormone can suppress apoptosis of rat testicular germ cells induced by testicular ischemia. Fertil. Steril. 75:980-985.
148. Zhang, R.D., X.H.Wen, L.S.Kong, X.Z.Deng, B.Peng, A.P.Huang, Y.Wan, and Z.W.Yang. 2002. A quantitative (stereological) study of the effects of experimental unilateral cryptorchidism and subsequent orchiopexy on spermatogenesis in adult rabbit testis. Reproduction. 124:95-105.
149.Zheng, X., L.Xie, J.Qin, H.Shen, Z.Chen, and Y.Jin. 2008. Effects of wortmannin on phosphorylation of PDK1, GSK3-beta, PTEN and expression of Skp2 mRNA after ischemia/reperfusion injury in the mouse kidney. Int. Urol. Nephrol. 40:185-192.
150.Zirkin, B.R. and H.Chen. 2000. Regulation of Leydig cell steroidogenic function during aging. Biol. Reprod. 63:977-981.