TY - JOUR T1 - Metabolism of Estradiol, Ethynylestradiol, and Moxestrol in Rat Uterus, Vagina, and Aorta: Influence of Sex Steroid Treatment JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 76 LP - 81 VL - 29 IS - 1 AU - Maarten J. Blom AU - Marjolein Groot Wassink AU - Helenius J. Kloosterboer AU - Antwan G. H. Ederveen AU - Jan G. D. Lambert AU - Henk J. Th. Goos Y1 - 2001/01/01 UR - http://dmd.aspetjournals.org/content/29/1/76.abstract N2 - Estrogen replacement therapy for postmenopausal women consists of an estrogenic and a progestagenic compound. The treatment has a positive estrogenic effect on bone, the cardiovascular system, and vagina but is dependent of the estrogen-progestagen balance in uterus to prevent unwanted proliferation. We were interested in the influence of estrogens and progestagens on estrogen metabolism in target tissues of estrogen replacement therapy. Therefore, we studied the metabolism of estradiol, 17α-ethynylestradiol, and moxestrol (11β-methoxy-17α-ethynylestradiol) in rat uterus, vagina, and aorta. In uterus and vagina, estradiol was converted to estrone, estradiol-3-glucuronide, and estrone-3-glucuronide. These metabolites demonstrate the presence of 17β-hydroxysteroid dehydrogenase (17β-HSD) and UDP-glucuronosyl transferase (UDP-GT) in uterus and vagina. We found that the conversion of estradiol by 17β-HSD in uterus was increased in animals treated with estradiol or with a combination of estradiol and progesterone. The conversion of estradiol in uterus by UDP-GT was estradiol-induced and in contrast, progesterone-suppressed. In the vagina, steroid hormone treatment had no effect on estradiol conversion by 17β-HSD or UDP-GT. Ethynylestradiol was glucuronidated only, and this was not affected by steroid treatment. Moxestrol was not converted in any of the three organs that were studied, indicating that the 11β-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 human uterus. Therefore, the rat may not be the best-suited model to investigate uterine effects of estradiol-progestagen combined treatment. The American Society for Pharmacology and Experimental Therapeutics ER -