臺灣博碩士論文加值系統

全國性的B型肝炎注射疫苗計畫在台灣實施之後，有效地降低學童的帶原率及肝癌發生率，但約有5-10 %的孩童對B型肝炎疫苗為不反應性或低反應性。一些研究顯示，B型肝炎疫苗的效果有性別與種族的變異性：男性為不反應性的比率高於女性；B型肝炎疫苗對原住民族群的保護效力低於一般族群。因此本研究以92-94學年度，就讀於花蓮縣內高中職學校、出生於實施全國性B型肝炎疫苗注射計畫之後、入學健康檢查HBsAg 及anti-HBs皆為陰性、且有補接種一劑B型肝炎疫苗的男性新生為研究對象。依其對補接種B型肝炎疫苗的反應性區分為不反應性組與慢反應性組，分別從原住民族群與漢人族群，依不反應性組與慢反應性組比為1：2，隨機選取196人為研究樣本。本研究並以PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism)法，進行IGF2 G820A、IGFBP3 A-202C及SRD5A2 V89L之基因定性，且檢測研究對象補接種B型肝炎疫苗前之血漿睪固酮(testosterone)、性荷爾蒙結合球蛋白(SHBG)與膽固醇(cholesterol)濃度。本研究結果顯示在帶有低5a-還原酶活性的SRD5A2 L對偶基因的受試對象中，高睪固酮濃度及高TC比值(睪固酮/膽固醇)者，皆有顯著較高的疫苗不反應性風險；且不論在不同種族或基因分層下，較高的SHBG/睪固酮比值，均有較低的疫苗不反應性風險。
本研究結果顯示，性荷爾蒙會影響個體對於補接種B型肝炎疫苗之反應性。尤其是帶有低5a-還原酶活性的SRD5A2 L對偶基因者，會因體內有較高濃度的睪固酮，而有較高的疫苗不反應性風險。此外，本研究的結果也顯示，ST比值可作為預測B型肝炎疫苗不反應性的指標。

In Taiwan, the implement of universal hepatitis B (HB) vaccination program (UHBVP) had successfully reduced the rates of HBsAg-seropositivity and hepatocellular carcinoma incidence in children. However, approximately 5-10% of vaccinated-children were low- or non-response to hepatitis B vaccine. Several researches had shown that there were gender and ethnic variations in the response to hepatitis B vaccine. The non-response rate was higher in male children than in female children and the efficacy of HB vaccination was lower in indigenous children than in Hans children. Accordingly, the specific aim of the present study was to investigate the effects of sex hormones and genetic polymorphisms of several important genes that are involved in development and metabolism of sex hormone in male indigenous and Hans adolescents. The inclusion criteria included male students who entered senior high schools during Sep 2003 to Sep 2005, born after the start of HBUVP, had both HBsAg and anti-HBs seronegativities, and received a booster dose of 20 ug of HB vaccine. Based on their responses and ethnicity, eligible subjects were divided into four groups, which were low-response indigenes, non-response indigenes, low-response Hans, and non-response Hans. There were 32 non-response indigenes and 32 non-response Hans. Two folds of the number of non-responders were randomly selected from low-response indigenes and Hans separately. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the IGF2 G820A, IGFBP3 A-202C and SRD5A2 V89L genetic polymorphisms. Concentrations of testosterone, sex hormone-binding globulin (SHBG) and cholesterol in plasma were also detected for each subject. We found that in those subjects carrying SRD5A2 L allele, higher testosterone concentration and higher testosterone-to-cholesterol (TC) ratio were both significantly associated with higher risk of non-response to HB vaccine. Higher SHBG-to-testosterone (ST) ratio was consistently associated with lower risk of non-response to HB vaccine in different ethnic and genetic strata.
In conclusion, our results indicate that sex hormones maybe influence the immune response to booster HB vaccination, especially in subjects who carry the SRD5A2 L allele. Our results also suggest that the ST ratio is a good predictor of the responsiveness to HB vaccine.

致謝------------------------------------------------------- I
中文摘要--------------------------------------------------- II
英文摘要--------------------------------------------------- III
目錄------------------------------------------------------- IV
圖目錄----------------------------------------------------- VI
表目錄----------------------------------------------------- VII
第一章 前言------------------------------------------------ 1
第二章 文獻探討-------------------------------------------- 2
第一節 B型肝炎病毒----------------------------------------- 2
2.1.1 B型肝炎病毒的發現---------------------------------- 2
2.1.2 B型肝炎病毒的結構---------------------------------- 2
2.1.3 B型肝炎病毒基因------------------------------------ 2
2.1.4 B型肝炎病毒進入人體與複製-------------------------- 3
2.1.5 B型肝炎病毒的傳染途徑------------------------------ 4
2.1.6 B型肝炎病毒引發的免疫反應-------------------------- 4
第二節 B型肝炎與肝細胞癌的流行病學研究--------------------- 6
2.2.1 B型肝炎表面抗原陽性率肝癌的流行病學---------------- 6
2.2.2 感染B型肝炎病毒、肝細胞癌發生率與死亡率的性別差異-- 6
2.2.3 感染B型肝炎病毒的種族差異-------------------------- 7
第三節 B型肝炎疫苗----------------------------------------- 7
第四節 全國性B型肝炎疫苗注射計畫--------------------------- 8
第五節 台灣B型肝炎疫苗的防治成效與性別差異----------------- 10
第六節 對全國性B型肝炎疫苗注射計畫的挑戰與種族差異--------- 12
第七節 荷爾蒙---------------------------------------------- 12
第八節 雄性荷爾蒙的作用與SRD5A2基因------------------------ 14
2.8.1 睪固酮與DHT的作用機制------------------------------ 14
2.8.2 SRD5A2基因多形性----------------------------------- 15
第九節 類胰島素生長因子與類胰島素結合蛋白------------------ 16
第十節 IGF2及IGFBP3基因多形性------------------------------ 16
第三章 材料與方法------------------------------------------ 19
第一節 研究對象與疫苗反應性分組---------------------------- 19
第二節 實驗室分析------------------------------------------ 20
3.2.1 血液的處理與檢驗項目------------------------------- 20
3.2.2 分析基因多形性------------------------------------- 22
第三節 統計分析-------------------------------------------- 25
第四章 結果------------------------------------------------ 26
第一節 不同族群之基本資料---------------------------------- 26
第二節 不同疫苗反應性之基本資料與迴歸分析------------------ 27
第三節 不同族群之迴歸分析---------------------------------- 28
第四節 分層分析-依不同基因型者之迴歸分析------------------- 30
4.4.1 帶有IGF2 AA或AG基因型者---------------------------- 30
4.4.2 帶有IGF2 GG基因型者-------------------------------- 30
4.4.3 帶有IGFBP3 AC或CC基因型者-------------------------- 30
4.4.4 帶有IGFBP3 AA基因型者------------------------------ 31
4.4.5 帶有SRD5A2 VL或LL基因型者-------------------------- 31
4.4.6 帶有SRD5A2 VV基因型者------------------------------ 32
第五節 統整迴歸分析結果與多因子對數迴歸分析---------------- 33
第六節 不同基因多形性之荷爾蒙濃度-------------------------- 33
第七節 荷爾蒙變項之淨相關---------------------------------- 34
第五章 討論------------------------------------------------ 35
參考文獻--------------------------------------------------- 39

1. Blumberg BS, Alter HJ, Visnich S. A "new" antigen in leukemia sera. JAMA 1965; 191:541-6.
2. Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet 1970; 1:695-8.
3. World Health Organization. WHO/CDS/CSR/LYO/2002.2: Hepatitis B. 2002.
4. World Health Organization. Viral hepatitis. Report of a WHO scientific group. World Health Organ Tech Rep Ser 1973; 512:1-52.
5. Wen YM. Structural and functional analysis of full-length hepatitis B virus genomes in patients: Implications in pathogenesis. J Gastroenterol Hepatol 2004; 19:485-9.
6. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004; 78:12725-34.
7. Wang XW, Hussain SP, Huo TI, et al. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology 2002; 181-182:43-7.
8. Yeh CT, Lai HY, Chu SP, Tseng IC. Anti-sense expression of a metallopeptidase gene enhances nuclear entry of HBV-DNA. Biochem Biophys Res Commun 2004; 323:32-7.
9. Gripon P, Cannie I, Urban S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol 2005; 79:1613-22.
10. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med 2004; 350:1118-29.
11. Jung MC, Pape GR. Immunology of hepatitis B infection. Lancet Infect Dis 2002; 2:43-50.
12. Chisari FV. Cytotoxic T cells and viral hepatitis. J Clin Invest 1997; 99:1472-77.
13. El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol 2002; 35:S72-8.
14. McGlynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2005; 19:3-23.
15. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002; 347:168-74.
16. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340:745-50.
17. Chen CJ, You SL, Lin LH, Hsu WL, Yang YW. Cancer epidemiology and control in Taiwan: a brief review. Jpn J Clin Oncol 2002; 32:S66-81.
18. Jan CF, Chen CJ, Chen HH. Causes of increased mortality from hepatocellular carcinoma in high incidence country: Taiwan experience. J Gastroenterol Hepatol 2005; 20:521-6.
19. Lee CM, Lu SN, Changchien CS, et al. Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection. Cancer 1999; 86:1143-50.
20. Tong MJ, Sun SC, Schaeffer BT, Chang NK, Lo KJ, Peters RL. Hepatitis-associated antigen and hepatocellular carcinoma in Taiwan. Ann Intern Med 1971; 75:687-91.
21. Sung JL, Chen DS, Lai MY, et al. Epidemiological study on hepatitis B virus infection in Taiwan. Chin J Gastroenterol 1984; 1:1-9.
22. Michielsen PP, Francque SM, van Dongen JL. Viral hepatitis and hepatocellular carcinoma. World J Surg Oncol 2005; 3:27.
23. Chen CJ, Liang KY, Chang AS, et al. Effects of hepatitis B virus, alcohol drinking, cigarette smoking and familial tendency on hepatocellular carcinoma. Hepatology 1991; 13:398-406.
24. Lee CL, Ko YC. Hepatitis B vaccination and hepatocellular carcinoma in Taiwan. Pediatrics 1997; 99:351-3.
25. Lin DB, Wang HM, Lee YL, Ling UP, Changlai SP, Chen CJ. Immune status in preschool children born after mass hepatitis B vaccination program in Taiwan. Vaccine 1998; 16:1683-7.
26. Lin HH, Lin SS, Chiang YM, et al. Trend of hepatitis B virus infection in freshmen classes at two high schools in Hualien, Taiwan from 1991 to 1999. J Med Virol 2002; 67:472-6.
27. Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med. 1975; 292:771-4.
28. Chen CH, Chen YY, Chen GH, et al. Hepatitis B virus transmission and hepatocarcinogenesis: a 9 year retrospective cohort of 13676 relatives with hepatocellular carcinoma. J Hepatol 2004; 40:653-9.
29. Poland GA, Jacobson RM. Clinical practice: prevention of hepatitis B with the hepatitis B vaccine. N Engl J Med 2004; 351:2832-8.
30. Yu MW, Chang HC, Liaw YF, et al. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 2000; 92:1159-64.
31. Chiou SS, Obata H, Takasaki T, et al. Hepatitis viruses in southern Taiwan--mass survey of 2985 inhabitants. Gastroenterol Jpn 1984; 19:344-50.
32. Yu MW, Tsai SF, Hsu KH, et al. Epidemiologic characteristics of malingnant neoplasms in Taiwan: II. liver cancer. J Natl Public Health Assoc (ROC): 1988; 8:125-138.
33. Lin HH, Kao JH, Chang TC, Hsu HY, Chen DS. Secular trend of age-specific prevalence of hepatitis B surface and e antigenemia in pregnant women in Taiwan. J Med Virol 2003; 69:466-70.
34. Lee CL, Hsieh KS, Ko YC. Trends in the incidence of hepatocellular carcinoma in boys and girls in Taiwan after large-scale hepatitis B vaccination. Cancer Epidemiol Biomarkers Prev 2003; 12:57-9.
35. Huang YH, Wu JC, Chen CH, et al. Comparison of recurrence after hepatic resection in patients with hepatitis B vs. hepatitis C-related small hepatocellular carcinoma in hepatitis B virus endemic area. Liver Int 2005; 25:236-41.
36. Chang MH, Shau WY, Chen CJ, et al. Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA 2000; 284:3040-2.
37. Chung DC, Ko YC, Chen CJ, et al. Seroepidemiological studies on hepatitis B and D viruses infection among five ethnic groups in southern Taiwan. J Med Virol 1988; 26:411-8.
38. Lin HH, Li YH, Yu JH, et al. Ethnic and geographic variations in the prevalence of hepatitis A, B and C among aboriginal villages in Hualien, Taiwan. Infection 2000; 28:205-8.
39. Chan CY, Lee SD, Lo KJ. Legend of hepatitis B vaccination: the Taiwan experience. J Gastroenterol Hepatol 2004; 19:121-6.
40. Specter S. Viral hepatitis: diagnosis, therapy, and prevention. Totowa, NJ: Humana Press Inc., 1999.
41. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis 2002; 2:395-403.
42. Beasley RP, Hwang LY, Stevens CE, et al. Efficacy of hepatitis B immune globulin for prevention of perinatal transmission of the hepatitis B virus carrier state: final report of a randomized double-blind, placebo-controlled trial. Hepatology 1983; 3:135-41.
43. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997; 336:1855-9.
44. Huang K, Lin S. Nationwide vaccination: a success story in Taiwan. Vaccine 2000; 18:S35-8.
45. Hsu HM, Lee SC, Wang MC, Lin SF, Chen DS. Efficacy of a mass hepatitis B immunization program after switching to recombinant hepatitis B vaccine: a population-based study in Taiwan. Vaccine 2001; 19:2825-9.
46. Lin YC, Chang MH, Ni YH, Hsu HY, Chen DS. Long-term immunogenicity and efficacy of universal hepatitis B virus vaccination in Taiwan. J Infect Dis 2003; 187:134-8.
47. Hsu HM, Lu CF, Lee SC, Lin SR, Chen DS. Seroepidemiologic survey for hepatitis B virus infection in Taiwan: the effect of hepatitis B mass immunization. J Infect Dis 1999; 179:367-70.
48. Ni YH, Chang MH, Huang LM, et al. Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Intern Med 2001; 135:796-800.
49. Wu JS, Hwang LY, Goodman KJ, Beasley RP. Hepatitis B vaccination in high-risk infants: 10-year follow-up. J Infect Dis 1999; 179:1319-25.
50. Fitzsimons D, Francois G, Hall A, et al. Long-term efficacy of hepatitis B vaccine, booster policy, and impact of hepatitis B virus mutants. Vaccine 2005; 23:4158-66.
51. West DJ, Calandra GB. Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination. Vaccine 1996; 14:1019-27.
52. Murray RK, Granner DK, Mayes PA, Rodwell VW. Harper's Biochemistry (25th ed). Stamford, Appleton & Lange, 2000.
53. Bouman A, Heineman MJ, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update 2005; 11:411-23.
54. Shahidi NT. A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids. Clin Ther 2001; 23:1355-90.
55. Jin Y, Penning TM. Steroid 5alpha-reductases and 3alpha-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism. Best Pract Res Clin Endocrinol Metab 2001; 15:79-94.
56. Gonzales E, Cresteil D, Baussan C, Dabadie A, Gerhardt MF, Jacquemin E. SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase deficiency: evidence for primary genetic defect. J Hepatol 2004; 40:716-8.
57. Baker ME. Albumin, steroid hormones and the origin of vertebrates. J Endocrinol 2002; 175:121-7.
58. Means GD, Mahendroo MS, Corbin CJ, et al. Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. J Biol Chem 1989; 264:19385-91.
59. Somner J, McLellan S, Cheung J, et al. Polymorphisms in the P450 c17 (17-hydroxylase/ 17,20-Lyase) and P450 c19 (aromatase) genes: association with serum sex steroid concentrations and bone mineral density in postmenopausal women. J Clin Endocrinol Metab 2004; 89:344-51.
60. Kaminski RM, Marini H, Kim WJ, Rogawski MA. Anticonvulsant activity of androsterone and etiocholanolone. Epilepsia 2005; 46:819-27.
61. Bagatell CJ, Bremner WJ. Androgens in Health and Disease. Totowa, NJ: Humana Press Inc., 2003.
62. Makridakis N, Ross RK, Pike MC, et al. A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Res 1997; 57:1020-22.
63. Tanaka K, Sakai H, Hashizume M, Hirohata T. Serum testosterone: estradiol ratio and the development of hepatocellular carcinoma among male cirrhotic patients. Cancer Res 2000; 60:5106-10.
64. Yu MW, Yang YC, Yang SY, et al. Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among men. J Natl Cancer Inst 2001; 93:1644-51.
65. Yu MW, Cheng SW, Lin MW, et al. Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma. J Natl Cancer Inst 2000; 92:2023-8.
66. Yu MW, Chen CJ. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res 1993; 53:790-4.
67. Heald AH, Ivison F, Anderson SG, Cruickshank K, Laing I, Gibson JM. Significant ethnic variation in total and free testosterone concentration. Clin Endocrinol (Oxf) 2003; 58:262-6.
68. Allen NE, Forrest MS, Key TJ. The association between polymorphisms in the CYP17 and 5alpha-reductase (SRD5A2) genes and serum androgen concentrations in men. Cancer Epidemiol Biomarkers Prev 2001; 10:185-9.
69. Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular interactions of the IGF system. Cytokine Growth Factor Rev 2005; 16:421-39.
70. Clark R. The somatogenic hormones and insulin-like growth factor-1: stimulators of lymphopoiesis and immune function. Endocr Rev 1997; 18:157-79.
71. Kozak RW, Haskell JF, Greenstein LA, Rechler MM, Waldmann TA, Nissley SP. Type I and II insulin-like growth factor receptors on human phytohemagglutinin-activated T lymphocytes. Cell Immunol 1987; 109:318-31.
72. Tapson VF, Boni-Schnetzler M, Pilch PF, Center DM, Berman JS. Structural and functional characterization of the human T lymphocyte receptor for insulin-like growth factor I in vitro. J Clin Invest 1988; 82:950-7.
73. Baudler S, Baumgartl J, Hampel B, et al. Insulin-like growth factor-1 controls type 2 T cell-independent B cell response. J Immunol 2005; 174:5516-25.
74. Kooijman R, Coppens A. Insulin-like growth factor-I stimulates IL-10 production in human T cells. J Leukoc Biol 2004; 76:862-7.
75. Harrela M, Koistinen H, Kaprio J, et al. Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. J Clin Invest 1996; 98:2612-5.
76. O'Dell SD, Miller GJ, Cooper JA, et al. ApaI polymorphism in insulin-like growth factor II (IGF2) gene and weight in middle-aged males. Int J Obes Relat Metab Disord 1997; 21:822-5.
77. Cruickshank JK, Heald AH, Anderson S, et al. Epidemiology of the insulin-like growth factor system in three ethnic groups. Am J Epidemiol 2001; 154:504-13.
78. Hopkins KD, Lehmann ED, Jones RL, et al. Ethnicity affects IGFBP-3 and IGF-II in normal healthy young adult subjects. Clin Endocrinol (Oxf) 1996; 45:327-31.
79. Deal C, Ma J, Wilkin F, et al. Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators. J Clin Endocrinol Metab 2001; 86:1274-80.
80. Iizuka N, Oka M, Yamada-Okabe H, et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res 2002; 62:3939-44.
81. Nikolic JA, Todorovic V, Bozic M, et al. Serum insulin-like growth factor (IGF)-II is more closely associated with liver dysfunction than is IGF-I in patients with cirrhosis. Clin Chim Acta 2000; 294:169-77.
82. Dong ZZ, Yao DF, Yao DB, et al. Expression and alteration of insulin-like growth factor II-messenger RNA in hepatoma tissues and peripheral blood of patients with hepatocellular carcinoma. World J Gastroenterol 2005; 11:4655-60.
83. Tsai JF, Jeng JE, Chuang LY, et al. Serum insulin-like growth factor-II as a serologic marker of small hepatocellular carcinoma. Scand J Gastroenterol 2005; 40: 68-75.
84. Li Volti S, Caruso-Nicoletti M, Biazzo F, et al. Hyporesponsiveness to intradermal administration of hepatitis B vaccine in insulin dependent diabetes mellitus. Arch Dis Child 1998; 78:54-7.
85. Julier C, Hyer RN, Davies J, et al. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 1991; 354:155-9.
86. Vafiadis P, Grabs R, Goodyer CG, Colle E, Polychronakos C. A functional analysis of the role of IGF2 in IDDM2-encoded susceptibility to type 1 diabetes. Diabetes 1998; 47:831-6.
87. Kelly MA, Rayner ML, Mijovic CH, Barnett AH. Molecular aspects of type 1 diabetes. Mol Pathol 2003; 56:1-10.
88. Kim MS, Polychronakos C. Immunogenetics of type 1 diabetes. Horm Res 2005; 64:180-8.
89. Kooijman R, van Buul-Offers SC, Scholtens LE, Reijnen-Gresnigt RG, Zegers BJ. T and B cell development in pituitary deficient insulin-like growth factor-II transgenic dwarf mice. J Endocrinol 1997; 155:165-70.
90. Hansenne I, Renard-Charlet C, Greimers R, Geenen V. Dendritic cell differentiation and immune tolerance to insulin-related peptides in igf2-deficient mice. J Immunol 2006; 176:4651-7.
91. Goya M, Miyamoto S, Nagai K, et al. Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors. Cancer Res 2004; 64:6252-8.
92. Colon E, Svechnikov KV, Carlsson-Skwirut C, Bang P, Soder O. Stimulation of steroidogenesis in immature rat Leydig cells evoked by interleukin-1alpha is potentiated by growth hormone and insulin-like growth factors. Endocrinology 2005; 146:221-30.
93. Patel R, Lim DS, Reddy D, et al. Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. J Mol Cell Cardiol 2000; 32:2369-77.
94. Ren Z, Cai Q, Shu XO, et al. Genetic polymorphisms in the IGFBP3 gene: association with breast cancer risk and blood IGFBP-3 protein levels among Chinese women. Cancer Epidemiol Biomarkers Prev 2004; 13:1290-5.
95. Kanda N, Tsuchida T, Tamaki K. Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells. Clin Exp Immunol 1996; 106:410-15.
96. Oettel M, Hubler D, Patchev V. Selected aspects of endocrine pharmacology of the aging male. Exp Gerontol 2003; 38:189-98.
97. Baker ME. Evolution of adrenal and sex steroid action in vertebrates: a ligand-based mechanism for complexity. Bioessays 2003; 25:396-400.
98. Samy TS, Knoferl MW, Zheng R, Schwacha MG, Bland KI, Chaudry IH. Divergent immune responses in male and female mice after trauma-hemorrhage: dimorphic alterations in T lymphocyte steroidogenic enzyme activities. Endocrinology 2001; 142:3519-29.
99. Zheng R, Samy TS, Schneider CP, Rue LW 3rd, Bland KI, Chaudry IH. Decreased 5alpha-dihydrotestosterone catabolism suppresses T lymphocyte functions in males after trauma-hemorrhage. Am J Physiol Cell Physiol 2002; 282:C1332-8.
100. Makridakis NM, di Salle E, Reichardt JK. Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics 2000; 10:407-13.
101. Ntais C, Polycarpou A, Ioannidis JP. SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2003; 12: 618-24.
102. Hsu HY, Chang MH, Ho HN, et al Association of HLA-DR14-DR52 with low responsiveness to hepatitis B vaccine in Chinese residents in Taiwan. Vaccine 1993; 11:1437-40.
103. Hsu HY, Chang MH, Hsieh RP, Ni YH, Chi WK. Humoral and cellular immune responses to hepatitis B vaccination in hepatitis B surface antigen-carrier children who cleared serum-hepatitis B surface antigen. Hepatology 1996; 24:1355-60.
104. Godkin A, Davenport M, Hill AV. Molecular analysis of HLA class II associations with hepatitis B virus clearance and vaccine nonresponsiveness. Hepatology 2005; 41:1383-90.
105. Wu YF, Wang LY, Lee TD, et al. HLA phenotypes and outcomes of hepatitis B virus infection in Taiwan. J Med Virol 2004; 72:17-25.
106. Giron-Gonzalez JA, Moral FJ, Elvira J, et al. Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared with women. 2000; 143:31-6.
107. Goncalves L, Albarran B, Salmen S, et al. The nonresponse to hepatitis B vaccination is associated with impaired lymphocyte activation. Virology 2004; 326:20-8.
108. Bauer T, Jilg W. Hepatitis B surface antigen-specific T and B cell memory in individuals who had lost protective antibodies after hepatitis B vaccination. Vaccine 2006; 24:572-7.
109. Monti S, Di Silverio F, Lanzara S, et al. Insulin-like growth factor-I and -II in human benign prostatic hyperplasia: relationship with binding proteins 2 and 3 and androgens. Steroids 1998; 63:362-6.