Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, 130 DeSoto Street, Pittsburgh, PA 15261, USA.
Cancer Epidemiol Biomarkers Prev. 2012 Nov;21(11):2022-32. doi: 10.1158/1055-9965.EPI-12-0759. Epub 2012 Aug 29.
In the Women's Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16α-hydroxyestrone (16α-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16α-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio.
In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1,690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16α-OHE1 levels were measured by enzyme immunoassay at baseline, and for those randomized to active treatment (n = 1,259), at 1 year.
The 1-year increase in 16α-OHE1 was greater with E+P than E-alone (median 55.5 pg/mL vs. 43.5 pg/mL, P < 0.001), but both increased 2-OHE1 by ∼300 pg/mL. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and for estrogen receptor+/progesterone+ cases only, higher baseline 16α-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant.
Although E+P modestly increased 16α-OHE1 more than E-alone, increase in 16α-OHE1 was not associated with breast cancer.
Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT, which may explain smaller than expected increase in breast cancer compared with endogenous estrogens.
在妇女健康倡议激素试验（WHI-HT）中，雌激素加孕激素（E+P）增加了乳腺癌风险，但单独使用雌激素（E-仅）则没有。我们假设 E+P 会优先代谢为 16α-羟基雌酮（16α-OHE1）而不是 2-羟基雌酮（2-OHE1），并且乳腺癌风险与基线和 1 年的雌激素代谢物变化有关：16α-OHE1 水平升高与乳腺癌风险相关，而 2-OHE1-和 2:16 比值水平降低与乳腺癌风险相关。
在 WHI-HT 中嵌套的前瞻性病例对照研究中，845 例确诊的乳腺癌病例按年龄和种族与 1690 例对照相匹配。使用储存的血清，通过酶免疫测定法在基线时和随机分配到活性治疗组（n = 1259）的患者中测量了 2-OHE1 和 16α-OHE1 水平。
E+P 治疗组的 1 年 16α-OHE1 增加量大于 E-仅治疗组（中位数为 55.5 pg/mL 比 43.5 pg/mL，P < 0.001），但两者均使 2-OHE1 增加了约 300 pg/mL。乳腺癌风险与基线水平较高的 2-OHE1 和 2:16 比值略有相关，并且仅与雌激素受体+/孕激素+病例相关，与基线水平较高的 16α-OHE1 水平相关。对于随机分配到活性治疗组的患者，乳腺癌风险与 2-OHE1 和 2:16 比值的增加有关，但关联无统计学意义。
尽管 E+P 使 16α-OHE1 的增加量略高于 E-仅，但 16α-OHE1 的增加与乳腺癌无关。
研究结果无法解释 WHI-E+P 和 WHI-E-仅乳腺癌结果之间的差异，但口服激素治疗的代谢可能解释了与内源性雌激素相比，乳腺癌的预期增加较小。
