Gann P H, Hennekens C H, Ma J, Longcope C, Stampfer M J
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
J Natl Cancer Inst. 1996 Aug 21;88(16):1118-26. doi: 10.1093/jnci/88.16.1118.
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.
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.
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.
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 non-linear 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 4 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.
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.
性类固醇，尤其是雄激素，被认为与前列腺癌的发病机制有关。以往比较前列腺癌患者与非前列腺癌患者循环激素水平的研究数据难以解释，因为这些研究规模有限，在癌症诊断后采集的血液中分析激素水平，使用的对照受试者不具代表性，且未同时调整激素和激素结合蛋白水平。
我们进行了一项前瞻性巢式病例对照研究，以调查健康男性的血浆激素和性激素结合球蛋白（SHBG）水平是否与随后前列腺癌的发生有关。
在1982年提供血浆样本的医生健康研究参与者中，我们确定了到1992年3月患前列腺癌的222名男性。还确定了390名对照受试者，根据年龄、吸烟状况和随访时间与病例患者匹配。使用免疫测定法测量储存于-82℃的血浆样本中总睾酮、双氢睾酮（DHT）、3α-雄烷二醇葡糖苷酸（AAG）、雌二醇、SHBG和催乳素的水平。通过Spearman相关系数（r）评估对照受试者血浆中个体激素水平之间以及激素水平与SHBG之间的相关性。使用条件逻辑回归模型计算四分位数水平的个体激素与前列腺癌风险相关的优势比（OR）和95%置信区间（CI），在调整其他激素和SHBG前后。报告的P值为双侧。
未发现未调整的个体激素或SHBG水平与前列腺癌风险之间有明显关联。然而，观察到睾酮水平与SHBG水平之间有很强的相关性（r = 0.55），并且在睾酮水平与雌二醇水平（r = 0.28）和DHT水平（r = 0.32）之间检测到较弱的相关性（所有P < 0.001）。当同时调整激素和SHBG水平时，观察到随着血浆睾酮水平升高，前列腺癌风险有很强的增加趋势（四分位数的OR = 1.00、1.41、1.98和2.60 [95% CI = 1.34 - 5.02]；趋势P = 0.004），随着SHBG水平升高，风险呈相反趋势（四分位数的OR = 1.00、0.93、0.61和0.46 [95% CI = 0.24 - 0.89]；趋势P = 0.01），并且随着雌二醇水平升高发现非线性负相关（四分位数的OR = 1.00、0.53、0.40和0.56 [95% CI = 0.32 - 0.98]；趋势P = 0.03）。未检测到DHT或催乳素水平与前列腺癌风险之间的关联；对于5α-还原酶活性的标志物AAG，仅发现有阳性关联的提示性证据。当分析中排除血浆采集后4年内诊断的病例患者、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）的对照受试者时，结果基本不变。
循环睾酮水平高和SHBG水平低——均在正常内源性范围内——与前列腺癌风险增加有关。循环雌二醇水平低可能是另一个风险因素。循环DHT和AAG水平似乎与前列腺癌风险没有强烈关联。
