Estrogen is essential in the termination of delayed implantation and the initiation of implantation in both mice and rats. The mechanisms whereby estrogen reactivates the delayed implanting embryo that has been rendered metabolically dormant, stimulates vasodilatory and vasopermability changes in the endometrium at the implantation site, and then initiates attachment of the embryo to the uterine epithelium are unknown. We suggest that the conversion of estrogen to catechol estrogen is an important step, possibly essential step, in the initiation of implantation on the basis that; 1) prostaglandins are thought to be involved in the process of implanation and prostaglandin levels are elevated at the implantation site, 2) catechol estrogens are potent stimulators of prostaglandin production in vitro, whereas estrogen, in contrast to its effects in vivo, is rather ineffective, suggesting that metabolites of estrogen are involved in the stimulation of prostaglandin production in vivo, 3) catechol estrogens, 2-hydroxy and 4-hydroxy metabolites of estrogen, have been shown to be uterotropic, have positive and negative effects on the hypothalamo-hypophseal axis, and more recently, capable of inducing implantation in progesterone treated delayed implanting mice. As a first step in determining whether catechol estrogens are involved in embryo development and the initiation of implantation, we propose to; i) develop assay systems for the catechol estrogen forming capacity (2-hydroxylase and 4-hydroxylase) in mouse embryos and endometrium using radioenzymatic and product isolation techniques and compare the level of enzyme activity during stages of the implantation process, ii) determine the effects of catechol estrogens on prostaglandin production in embryo and endometrial preparations by in vitro incubation with both primary and catechol estrogens under a variety of experimental conditions. Information from these studies will greatly advance our understanding of mechanisms of estrogen action and help develop a working hypothesis on the mechanism of embryo implantation. Development of such a hypothesis is an important goal because implanation is crucial in the establishment of pregnancy in all mammals and an understanding of the mechanisms involved may provide significant new insights into future methods of fertility regulation.
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