OBESITY, DIET, ESTROGENS AND CANCER RISK

我们建议调查肥胖和饮食结构对 人类雌激素的合成和代谢。其目的是为了刻画 此外，雌激素代谢异常与肥胖和 为了确定减肥或饮食控制是否可以缓解这些 异常现象。使用已建立的辐射测量技术来确定 体内C-2和C-16羟基化程度及其新进展 测定周围芳构化的放射计量法，这三种 可以对主要路径进行评估。去探索特定的代谢环节 肥胖会增加患乳腺癌的风险， 16α-羟雌酮的血药浓度和尿液排泄量 雌酮、硫酸雌酮和雌三醇将用 放射免疫分析。 肥胖患者将根据脂肪组织分布和他们的 下面将对脂肪组织进行定量和定性的描述 经皮活组织检查。这些标本中的芳香酶活性将是 与体内测量相关联，目的是开发一种体外 能够准确估计体内反应程度的检测方法。 雌激素的C-16羟基化增加已经在女性中表现出来 乳腺癌和子宫内膜癌，表明代谢的命运 这一反应的最终产物16α-羟雌酮可能是一个关键的 雌激素敏感型癌症的因素。因此，我们建议研究 (6，7-~3H)-16α-羟雌酮在两名正常人体内的代谢去向 和肥胖的病人。这一提议试图阐明这一机制， 肥胖可能会增加患雌激素敏感型癌症的风险。 此外，我们希望确定是否部分或全部观察到的 异常可以通过减肥和/或饮食控制来逆转。

We propose to investigate the impact of obesity and dietary composition on human estrogen synthesis and metabolism. The aim is to characterize further the aberrations in estrogen metabolism associated with obesity and to determine whether weight loss or dietary manipulation can mitigate these abnormalities. Using the established radiometric technique for determining the extent of in vivo C-2 and C-16 hydroxylation and the newly developed radiometric method for determining peripheral aromatization, these three major pathways can be assessed. To probe for the specific metabolic link associated with obesity that confers the increased risk of breast cancer, plasma concentrations and urinary excretion of 16 Alpha-hydroxyestrone, estrone, estrone sulfate and estriol will be quantitated by radioimmunoassay. Obese patients will be stratified by adipose tissue distribution and their adipose tissue will be described quantitatively and qualitatively following percutaneous biopsy. Aromatase activity in these specimens will be correlated with in vivo measurements with the aim of developing an in vitro assay which can accurately estimate the extent of the in vivo reactions. The increased C-16 hydroxylation of estrogens already demonstrated in women with breast and endometrial cancer, suggests that the metabolic fate of the endproduct of this reaction, 16 Alpha-hydroxyestrone, may be a critical factor in estrogen sensitive cancers. Thus, we propose to study the metabolic fate of (6, 7-3H)-16 Alpha-hydroxyestrone in both normal subjects and obese patients. This proposal attempts to elucidate the mechanism, whereby obesity may increase the risk for estrogen sensitive cancers. Furthermore, we wish to determine whether some or all of the observed abnormalities can be reversed by weight loss and/or dietary manipulation.