Metabolism of estradiol, ethynylestradiol, and moxestrol in rat uterus, vagina, and aorta: Influence of sex steroid treatment

Estrogen replacement therapy for postmenopausal women consists of an estrog enic and a progestagenic compound. The treatment has a positive estrogenic effect on bone, the cardiovascular system, and vagina but is dependent of t he estrogen-progestagen balance in uterus to prevent unwanted proliferation . We were interested in the influence of estrogens and progestagens on estr ogen metabolism in target tissues of estrogen replacement therapy. Therefor e, we studied the metabolism of estradiol, 17 alpha -ethynylestradiol, and moxestrol (11 beta -methoxy-17 alpha -ethynylestradiol) in rat uterus, vagi na, and aorta. In uterus and vagina, estradiol was converted to estrone, es tradiol-3-glucuronide, and estrone-3-glucuronide. These metabolites demonst rate the presence of 17 beta -hydroxysteroid dehydrogenase (17 beta -HSD) a nd UDP-glucuronosyl transferase (UDP-GT) in uterus and vagina. We found tha t the conversion of estradiol by 17 beta -HSD in uterus was increased in an imals treated with estradiol or with a combination of estradiol and progest erone. The conversion of estradiol in uterus by UDP-GT was estradiol-induce d and in contrast, progesterone-suppressed. In the vagina, steroid hormone treatment had no effect on estradiol conversion by 17 beta -HSD or UDP-GT. Ethynylestradiol was glucuronidated only, and this was not affected by ster oid treatment. Moxestrol was not converted in any of the three organs that were studied, indicating that the 11 beta -methoxy substituent renders it a poor substrate for glucuronidation. Overall, the estrogen metabolism, and its regulation by sex steroids, in rat uterus is different compared with hu man uterus. Therefore, the rat may not be the best-suited model to investig ate uterine effects of estradiol-progestagen combined treatment.