ENDOGENOUS SEX HORMONES, GENETICS, AND PROSTATE CANCER

在美国男性中，前列腺癌是最常见的癌症，也是癌症死亡的第二大原因。实验和临床证据表明，内源性雄激素可能与前列腺癌的病因有关。然而，流行病学研究得出了模棱两可的结果。其中一些研究包括相对较少的受试者，或者在诊断前列腺癌后测量激素水平。即使在克服了这些问题的研究中，也没有研究激素水平与影响激素代谢的酶或这些激素作用的雄激素受体的遗传决定因素之间可能存在的相互作用。我们建议在胡萝卜素和视黄醇疗效试验（CARET）中进行一项病例对照研究，这是一项涉及18,314名参与者的随机对照试验。我们将检查大约300名在入组（1985年开始）后至少6个月患上前列腺癌的CARET参与者和300名年龄、种族、抽血时间、研究中心和干预组相匹配的对照组的血液样本。我们将检验前列腺癌风险与以下因素相关的假设：1)血清中睾酮、性激素结合球蛋白、雄烯二酮、硫酸脱氢表雄酮、3- α -雄烯二醇葡萄糖醛酸和雌二醇的浓度；2) 5 α -还原酶II型基因多态性，可能影响5 α -还原酶将睾酮转化为二氢睾酮（一种更活跃的雄激素）的能力；3)雄激素受体基因多态性，可能影响前列腺对循环激素和前列腺内激素的敏感性。由于这项研究的规模，在诊断前至少6个月的激素水平测量，以及对可能影响病因的遗传决定特征的评估（特别是当与激素水平一起考虑时），我们相信这项研究有可能大大提高我们对前列腺癌病因学的理解。

Among American men, prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death. Experimental and clinical evidence suggests that endogenous androgens could be contributors to the etiology of prostate cancer. However, epidemiologic studies have produced ambiguous findings. Some of these studies included a relatively small number of subjects, or have measured hormone levels following the diagnosis of prostate cancer. Even among the studies that have overcome these problems, none have examined a possible interaction between hormone levels and genetic determinants either of enzymes that influence hormone metabolism or of the androgen receptor on which these hormones act. We propose to conduct a case- control study nested within the Carotene and Retinol Efficacy Trial (CARET), a randomized control trial involving 18,314 participants. We will examine blood specimens obtained from approximately 300 CARET participants who developed prostate cancer at least six months after enrollment (which began in 1985) and 300 controls matched for age, race, time of blood draw, study center, and intervention arm. We will test the hypotheses that the risk of prostate cancer is related to: 1) serum concentrations of testosterone, sex hormone binding globulin, androstenedione, dehydroepiandrosterone sulfate, 3-alpha-androstanediol glucuronide, and estradiol; 2) polymorphisms of the 5 alpha-reductase type II gene, which may influence the ability of 5 alpha-reductase to convert testosterone into dihydrostestosterone, a more active androgen; and 3) polymorphisms of the androgen receptor gene, which may influence the sensitivity of the prostate to circulating and intraprostatic hormones. Because of the size of the proposed study, the measurement of hormone levels present at least six months before diagnosis, and the assessment of genetically-determined characteristics that may influence etiology (especially when considered jointly with hormone levels), we believe the study has the potential to substantially advance our understanding of the etiology of prostate cancer.