OBESITY, DIET, ESTROGENS AND CANCER RISK

我们建议调查肥胖和膳食结构对 人体雌激素合成和代谢。 目的是描述 进一步地，与肥胖相关的雌激素代谢异常， 以确定减肥或饮食控制是否可以减轻这些 异常 使用已建立的辐射测量技术确定 体内C-2和C-16羟基化的程度以及新开发的 放射性方法测定周边芳构化，这三个 可以对主要路径进行评估。 为了探测特定的代谢联系 与肥胖有关，肥胖会增加患乳腺癌的风险， 16 α-羟基雌酮的血浆浓度和尿排泄， 雌酮、硫酸雌酮和雌三醇将通过 放射免疫法 肥胖患者将根据脂肪组织分布和他们的 下面将定量和定性地描述脂肪组织 经皮活检 这些标本中的芳香化酶活性 与体内测量相关，目的是开发体外 这是一种可以准确估计体内反应程度的测定方法。 在女性中已经证实了雌激素的C-16羟基化增加 与乳腺癌和子宫内膜癌，表明代谢的命运， 该反应的最终产物16 α-羟基雌酮可能是一种关键的 雌激素敏感性癌症的因素。 因此，我们建议研究 （6，7- 3 H）-16 α-羟基雌酮在两名正常受试者中的代谢转归 和肥胖患者。 这一提议试图阐明其机制， 由此肥胖可增加雌激素敏感性癌症的风险。 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.