DESCRIPTION (provided by applicant):
The goal of this study is to develop a rapid, sensitive method for analysis of
estrogen metabolites in a small volume of plasma, for use in large-scale
epidemiological studies of cancer risk. In addition to the major endogenous
estrogens, specific estrogen metabolites such as 16 alpha-hydroxyestrone,
4-hydroxyestrone and 4-hydroxyestradiol have been hypothesized to play
important roles in the etiology of cancer. Despite the potential significance
of these compounds in carcinogenesis, blood levels have not yet been evaluated
in epidemiological studies. In fact, no methods are available which can
measure the extremely low concentrations at which these compounds are likely
present in blood. Gas Chromatography/Mass Spectrometry (GC/MS) has better
specificity than immunoassay methods for the analysis of estrogens, and stable
isotope-labelled internal standards can be used to correct for recovery during
analysis. For these reasons, GC/MS has become the "gold standard" for the
measurement of sex steroids in biological samples such as urine. However,
current GC/MS methods lack sufficient sensitivity for the measurement of the
low levels found in blood. Negative Ion Chemical Ionization Mass Spectrometry
(NCI-MS) of halogenated, electron-capturing derivatives has been used
successfully to measure picogram quantities of compounds such as aromatic
amines in biological fluids, and similar derivatives can be prepared for
estrogens. We propose to develop and validate a sensitive and specific
GC/NCI-MS method for analysis of estrogen metabolites in blood.
Pre-purification of samples by previously developed high performance liquid
chromatography (HPLC) methods will also improve detection limits. Analysis of
blood samples from postmenopausal women, where estrogen levels are very low,
will validate the sensitivity and precision of the method. Development of a
rapid and sensitive method for the measurement of estrogen metabolites in a
small volume of plasma will enable epidemiologists to perform prospective
studies on the associations between estrogen metabolites and cancer risk.
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