OBESITY, DIET, ESTROGENS AND CANCER RISK

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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.