Prospective study of sex hormone levels and risk of prostate cancer
Prospective study of sex hormone levels and risk of prostate cancer
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DOI：
10.1093/jnci/88.16.1118
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发表时间：
1996-08-21
期刊：
影响因子：
--
通讯作者：
Stampfer, MJ
中科院分区：
文献类型：
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作者：
Gann, PH;Hennekens, CH;Stampfer, MJ
背景：性类固醇，尤其是雄激素，与前列腺癌的发病机制有关。先前比较前列腺癌患者和非前列腺癌男性循环激素水平的研究数据很难解释，因为研究规模有限，在诊断癌症后抽取血液分析激素水平，使用非代表性的对照受试者，激素和激素结合蛋白水平没有同时调整。目的：我们进行了一项前瞻性、巢式病例对照研究，探讨健康男性血浆激素和性激素结合球蛋白（SHBG）水平是否与前列腺癌的后续发展有关。方法：在1982年医师健康研究中提供血浆样本的参与者中，我们确定了222名到1992年3月患前列腺癌的男性。在年龄、吸烟状况和随访时间上与病例患者相匹配的390名对照受试者也被确定。采用免疫分析法测定储存（-82℃）血浆样品中总睾酮、二氢睾酮（DHT）、3 α -雄甾二醇葡萄糖醛酸酯（AAG）、雌二醇、SHBG和催乳素的水平。使用Spearman相关系数(r)评估个体激素水平与对照组血浆中激素水平与SHBG之间的相关性。使用条件logistic回归模型计算其他激素和SHBG调整前后，个体激素四分位数水平与前列腺癌风险相关的比值比（ORs）和95%置信区间（CIs）。报告的P值是双面的。结果：未调整的个体激素或SHBG水平与前列腺癌风险之间没有明确的关联。然而，睾酮水平与SHBG之间存在很强的相关性（r = 0.55），而睾酮水平与雌二醇（r = 0.28）和DHT （r = 0.32）之间存在较弱的相关性（均P < 0.001）。同时调节激素和SHBG水平；血浆睾酮水平升高，前列腺癌风险增加呈明显趋势（or = 1.00、1.41、1.98和2.60 [95% CI = 1.34-5.02]; P = 0.004）， SHBG水平升高，风险呈相反趋势(or = 1.00、0.93、0.61和0.46 [95% CI = 0.24-0.89]；趋势P = 0.01)，并且发现与雌二醇水平升高呈非线性负相关（四分位数or = 1.00, 0.53, 0.40和0.56 [95% CI = 0.32-0.98]；趋势P = 0.03）。未发现二氢睾酮或催乳素水平与前列腺癌风险之间存在关联；对于AAG （5 α还原酶活性的标志），只发现了提示性的证据。当病例患者在3年内确诊时，结果基本不变；血浆收集年数、诊断为局限性（即非侵袭性）疾病的病例患者或前列腺血清抗原水平升高（>2.5 ng/mL）的对照受试者被排除在分析之外。结论：高水平的循环睾酮和低水平的shbg（均在正常内源性范围内）与前列腺癌风险增加相关。低水平的循环雌二醇可能是一个额外的危险因素，循环DHT和AAG水平似乎与前列腺癌风险没有很强的关系。
Background: Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted. Purpose: We conducted a prospective, nested case-control study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) Levels in healthy men were related to the subsequent development of prostate cancer. Methods: Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3 alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 degrees C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided. Results: No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P < .001). When hormone and SHBG levels were adjusted simultaneously; a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a nonlinear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk; for AAG, a marker of 5 alpha-reductase activity, only suggestive evidence of a positive association was found. The results were essentially unchanged when case patients diagnosed within 3; years of plasma collection, case patients diagnosed with localized (i.e., nonaggressive) disease, or control subjects with elevated prostate serum antigen levels (>2.5 ng/mL) were excluded from the analyses. Conclusions: High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor, Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk.