Berrino F, Muti P, Micheli A, Bolelli G, Krogh V, Sciajno R, Pisani P, Panico S, Secreto G
Istituto Nazionale Tumori, Milan, Italy.
J Natl Cancer Inst. 1996 Mar 6;88(5):291-6. doi: 10.1093/jnci/88.5.291.
High levels of androgens and estrogens have been reported to be associated with breast cancer. However, the multiplicity of factors that influence hormone levels and methodologic issues complicate the study of the relationship between steroid sex hormones and breast cancer.
Using an improved study design, we assessed prospectively the relationship between the principal steroid sex hormones in serum and the subsequent occurrence of invasive breast cancer in postmenopausal women.
Four thousand fifty-three healthy postmenopausal women aged 40-69 years, were enrolled from June 1987 through June 1992 in a prospective investigation of hormones and diet in the etiology of breast tumors (ORDET study) as part of a larger volunteer cohort of 10 788 premenopausal and postmenopausal women from Varese Province, northern Italy. At recruitment, blood samples were taken between 8:00 AM and 9:30 AM (after overnight fasting), and sera were preserved in -80 degree Celsius freezers. Women who had received hormone treatment in the 3 months prior to enrollment, who had bilateral ovariectomy, or who had a history of cancer or liver disease were not recruited. Twenty-five women in the final eligible cohort of postmenopausal women developed histologically confirmed, invasive breast cancer during the first 3.5 years of follow-up for the cohort (13 537 women-years). For each case subject, four control subjects were randomly chosen after matching for factors possibly affecting hormone preservation in serum. One case subject and eight control subjects were excluded because premenopausal hormonal patterns were found; thus, after also excluding the four control subjects matched to the ineligible case subject, we included 24 case and 88 control subjects. In the spring of 1994, stored sera of case and control subjects were assayed in a blinded manner for dehydroepiandrosterone sulfate and estradiol (E2) by in-house radioimmunoassay and for total and free testosterone and sex hormone-binding globulin by commercially available nonextraction iodination kits. Mean differences in risk factors were tested by analysis of variance for paired data. Relative risks (RRs) were estimated by conditional logistic regression analysis. All P values resulted from two-sided tests.
Age-adjusted mean values of total testosterone, free testosterone, and E2 were significantly higher in case subjects than in control subjects: total testosterone, 0.34 ng/mL versus 0.25 ng/mL (P<.001); free testosterone, 1.07 pg/ml versus 0.77 pg/mL (P= .006); and E2, 25 pg/mL versus 22 pg/mL (P= .027). Age-adjusted RRs for breast cancer in increasing tertiles were as follows: for total testosterone, 1.0, 4.8, and 7.0 (P for trend =.026); for free testosterone, 1.0, 1.8, and 5.7 (P for trend=.005); and for total E2, 1.0, 7.1, and 5.5 (P for trend= .128).
This prospective study provides further evidence in support of the already established association between elevated estrogen levels and breast cancer. Even more importantly, it provides new evidence that high serum testosterone levels precede breast cancer occurrence.
据报道，高水平的雄激素和雌激素与乳腺癌有关。然而，影响激素水平的多种因素以及方法学问题使甾体性激素与乳腺癌之间关系的研究变得复杂。
采用改进的研究设计，我们前瞻性地评估了血清中主要甾体性激素与绝经后妇女随后发生浸润性乳腺癌之间的关系。
从1987年6月至1992年6月，在一项关于乳腺肿瘤病因中激素与饮食的前瞻性调查（ORDET研究）中，招募了4053名年龄在40 - 69岁的健康绝经后妇女，作为来自意大利北部瓦雷泽省的10788名绝经前和绝经后妇女的更大志愿者队列的一部分。招募时，在上午8:00至9:30之间（过夜禁食后）采集血样，血清保存在 -80摄氏度的冰箱中。在入组前3个月接受过激素治疗、双侧卵巢切除或有癌症或肝病病史的妇女未被招募。在该队列（13537妇女年）的前3.5年随访期间，最终符合条件的绝经后妇女队列中有25名妇女发生了组织学确诊的浸润性乳腺癌。对于每个病例受试者，在匹配可能影响血清中激素保存的因素后随机选择4名对照受试者。由于发现有绝经前激素模式，排除了1例病例受试者和8名对照受试者；因此，在排除与不符合条件的病例受试者匹配的4名对照受试者后，我们纳入了24例病例和88名对照受试者。1994年春季，采用内部放射免疫分析法对病例和对照受试者的储存血清进行盲法检测硫酸脱氢表雄酮和雌二醇（E2），并采用市售非提取碘化试剂盒检测总睾酮、游离睾酮和性激素结合球蛋白。通过配对数据的方差分析检验危险因素的平均差异。通过条件逻辑回归分析估计相对风险（RRs）。所有P值均来自双侧检验。
病例受试者中总睾酮、游离睾酮和E2的年龄调整后平均值显著高于对照受试者：总睾酮，0.34 ng/mL对0.25 ng/mL（P <.001）；游离睾酮，1.07 pg/ml对0.77 pg/mL（P =.006）；E2，25 pg/mL对22 pg/mL（P =.027）。乳腺癌按总睾酮、游离睾酮和总E2升高的三分位数划分的年龄调整后RRs如下：总睾酮，1.0、4.8和7.0（趋势P =.026）；游离睾酮，1.0、1.8和5.7（趋势P =.005）；总E2，1.0、7.1和5.5（趋势P =.128）。
这项前瞻性研究为雌激素水平升高与乳腺癌之间已确立的关联提供了进一步证据。更重要的是它提供了新的证据，表明高血清睾酮水平先于乳腺癌发生。
