An advocacy for investigation of a "new" estrogen metabolite as a stable epoxide.

This mini review addresses the need to draw attention to the existence of an unknown estrogen metabolite, 5α,6α-epoxy-estrone, that was identified recently. The importance of metabolism of the primary steroid hormones from the gonads and adrenal glands has become even more evident in recent years. A recent review on the metabolism of endogenous and exogenous estrogens has revealed its importance in all aspects of estrogen action in women. Its hypothetical structure had been reported earlier but was only recently confirmed by LC-MS/MS. A brief account is given of its discovery using radiolabeled estrone as substrate in incubations with tissues from the reproductive system of the boar. Noteworthy was failure to detect it using nonlabeled substrate; there was no aromatic ring A and no characteristic UV absorption. It was present largely in the steroid conjugated fraction as a sulfate. Studies were made later with the lesser amounts of material in the unconjugated fractions. Brief descriptions of the work and findings include a third oxygen located at C6. Epoxidase action likely formed the hypothesized chemical structure (5α,6α-epoxy-estrone). It was later found that sulfatase activity resulted in only E1, no 5α,6α-epoxy-E1. Therefore identification would have to be done as a sulfate. This was later achieved using LC-MS/MS with stallion jugular blood. It is stressed that no chemical synthesis has been done and without a reference standard there are no data on biological significance. A discussion follows as to methods to address this in human subjects where epoxy-E1 is assuredly present, as reported for several other species.