The present review summarizes existing data regarding
estrogen metabolism and
hormone-responsive
cancers. Endogenous
estradiol breakdown takes place by oxidation at the A-ring and the D-ring; the resulting metabolites, however, are not inactive substances, as assumed formerly, but elicit different
biological effects, with A- and D-ring metabolites to some extent developing opposite actions. Multiple results are available showing stimulating and inhibiting properties of some metabolites on the growth of
cancer. Among the D-ring metabolites are substances with proliferation-stimulating properties, e.g.
16 alpha-hydroxyestrone, and among the A-ring metabolites, the
catechol estrogens, compounds with inhibiting properties. There are indications that endogenous production of proliferation-stimulating metabolites, especially
16 alpha-hydroxyestrone, which has been shown to be mutagenic, is increased in some
cancers. In these cases the ratio of A- to D-ring metabolism is shifted in favour of the D-ring metabolites. This ratio can be influenced by various substances e.g. by
indole-3-carbinol, an ingredient of cruciferous vegetables, which can increase the body's own production of
catechol estrogens. However, as yet only a few metabolites have been investigated with respect to their influence on
cancer development and growth. Presumably other metabolites may also be able to interfere directly or indirectly with
cancer progression. Thus a great deficit in research work remains in this field. The existing findings on the pathophysiology of
estradiol metabolism on the development and progression of
cancer offer promising opportunities for clinical-pharmacological intervention in the treatment of human
cancer.
2-Methoxyestradiol, physiologically present at low concentrations, seems to be of special interest. Several investigations were able to demonstrate that
2-methoxyestradiol inhibits proliferating tumoric tissues. Inhibition of neoangiogenesis and inhibition of
tubulin polymerization have been revealed as mechanisms. Specific studies on the clinical use of this
estradiol metabolite seem to be justified.