Estrogen hydroxylation in osteoporosis.

Estrogen is metabolized predominantly via two competing pathways, the 2-hydroxyl (nonestrogenic) and the 16alpha-hydroxyl (estrogenic) pathways. Studies have indicated that these pathways are important determinants of bone mineral density (BMD) in postmenopausal women. Women with predominant metabolism through the 2-hydroxyl pathway have accelerated postmenopausal bone loss and lower BMD compared to those with predominant 16alpha-hydroxylation who are protected from bone loss. Increased 2-hydroxylation has been observed in women with a positive family history of osteoporosis suggesting that the increased risk of osteoporosis in those with family history may, in part, be related to inherited differences in estrogen metabolism. Polymorphisms in the cytochrome P450 (CYP450) enzymes that metabolize estrogen are believed to result in alteration in the activity of these enzymes leading to differences in estrogen hydroxylation. It is the resulting "estrogen tone" generated from the variable accumulation of metabolic products with divergent estrogenic activity that has been hypothesized to modify the risks for hormone-dependent disorders associated with these polymorphisms, for example, osteoporosis. In support of this notion is the finding of lower BMD in women with the A allele for the C4887A polymorphism of the CYP1A1 gene, who are found to have accelerated rate of estrogen hydroxylation. These findings may have broader clinical significance as recent data indicate that women with predominance of the 2-hydroxyl pathway appear to have better BMD response to estrogen/hormone replacement therapy (ERT/ HRT) compared to those with predominant 16alpha-hydroxylation. It is likely that individual responses to ERT/HRT may vary according to patterns of estrogen hydroxylation, in turn a result of varying activity of the different CYP450 enzyme variants, thus, allowing the future possibility of identifying responders by genetic and/or metabolic profiling.