Hormones And Ec

Studies by Sasaki et al. (42) contend that the metabolic activation of estradiol is a key factor in endometrial carcinogenesis. Particular attention was given to the role of 4-hydroxy estrogen metabolites that result from catalytic effects directed by the CYP1B1 gene in the malignant transformation of endometrium. Specifically, 4-hydroxy estrogens can bind with DNA through a pathway involving their quinone metabolites, which then contribute to oxidative damage, and they have estrogenic effects on the endometrium through their binding with ER sites. The highest level of CYP1B1 expression is in the endometrium. Six polymorphisms of the CYP1B1 gene have been described of which four result in amino acid substitutions: 1-13C^T, codon 48C^G, codon 119 G^T, codon 432C^G, codon 449T^C, and codon 453A^G. Polymorphisms on exons 2 and 3 have significant effects on the catalytic function of CYP1B1. These authors concluded that inherited alterations in CYP1B1 hydroxylation activity appear to be associated with significant pathogenic alterations in the pathway involved in estrogen-mediated carcinogenesis in the endometrium.

In another study, Sasaki et al. (43) investigated polymorphic CAG repeats in the N-terminal domain, which are contained in the human androgen receptor (AR) gene and, which influence transcription efficiency. Because androgens have an antiprolifera-tive effect on endometrial cells, the authors hypothesize that the length of CAG repeats on the AR gene may be a predictor for an increased incidence of EC. To test this hypothesis the distributions of CAG repeats on AR gene polymorphisms were investigated in EC patients and healthy controls. Genotyping revealed that the distribution of CAG repeats was significantly longer in EC patients than in normal healthy controls (p < 0.001). The longer CAG repeats on the AR gene may contribute to a decrease in the transactivation function in the receptor and thereby weaken an antiproliferative effect on endometrial cells and promote carcinogenesis.

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