title: Regulation of uterine progesterone receptors by the nonsteroidal anti-androgen hydroxyflutamide.
abstract: We have recently reported that the anti-androgen hydroxyflutamide causes delayed implantation and exhibits antideciduogenic activity in the rat. The present experiments were conducted to examine whether hydroxyflutamide binds to the uterine progesterone receptors and/or alters the progesterone binding sites in the uterus. Cytosol and nuclear fractions from decidualized rat uterus were incubated with [3H]-R5020 without or with increasing concentrations of radioinert R5020, RU486, dihydrotestosterone, or hydroxyflutamide. From the log-dose inhibition curves, the relative binding affinity of both hydroxyflutamide and dihydrotestosterone was less than 0.1% and 2%, compared with R5020 (100%) for displacing [3H]-R5020 bound to uterine cytosol and nuclear fractions, respectively. Injection of estradiol-17 beta (1 microgram/rat) to ovariectomized prepubertal rats induced a 1.85-fold increase in uterine weight by 24 h. Hydroxyflutamide at 2.5 or 5.0 mg did not significantly alter the estrogen-induced increase in uterine weight. Compared to vehicle alone, estrogen induced an approximately 5-fold increase in uterine cytosolic progesterone binding sites. Hydroxyflutamide at both 2.5- and 5.0-mg doses significantly attenuated the estrogen-induced elevation in uterine progesterone binding sites. These studies demonstrate that hydroxyflutamide does not bind with high affinity to progesterone receptors, but suppresses the estrogen-induced elevation in progesterone receptor levels in the uterus.
authors.affiliation: Department of Physiology, University of Western Ontario, London, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Chandrasekhar
authors.forename: D T
authors.initials: DT
authors.lastname: Armstrong
mesh_terms: D000726:Androgen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005485:Flutamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011397:Promegestone / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011980:Receptors, Progesterone / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*
chemical_list: D000726:Androgen Antagonists; D011980:Receptors, Progesterone; D014316:Tritium; C014290:hydroxyflutamide; D004958:Estradiol; D005485:Flutamide; D011397:Promegestone