Tissue-selective effects of continuous release of 2-hydroxyestrone and 16 alpha-hydroxyestrone on bone, uterus and mammary gland in ovariectomized growing rats

2-Hydroxyestrone (2-OHE1) and 16 alpha -hydroxyestrone (16 alpha -OHE1) hav e been reported to be risk factors for negative bone balance and breast can cer, respectively. The roles of these two metabolites of estrone as estroge n agonists or antagonists with respect to estrogen target tissues, or bath, are poorly defined. The purpose of this study was to characterize metaboli te and tissue-specific differences between the actions of hydroxylated estr ones on selected reproductive and non-reproductive estrogen target tissues in growing rats. First, the effects of ovariectomy were determined. Ovariec tomy had the expected effects, including increases in all dynamic bone meas urements at the proximal tibial epiphysis, without induction of bone loss. Second, ovariectomized growing rats were continuously treated for 3 weeks w ith 2-OHE1, 16 alpha -OHE1, 17 beta -estradiol (E-2), a combination of E-2 and 2-OHE1 (E-2+2-OHE1), or a combination of E-2 and 16 alpha -OHE1 (E-2+16 alpha -OHE1), using controlled release subcutaneous implanted pellets cont aining 5 mg 2-OHE1, 5 mg 16 alpha -OHE1, 0.05 mg E-2 or placebo. E-2 reduce d body weight gain and radial and longitudinal bone growth as well as indic es of cancellous bone turnover, and increased serum cholesterol, uterine we t weight and epithelial cell height, and proliferative cell nuclear antigen labeling in mammary gland. The hydroxylated estrones did not alter uterine wet weight and 16 alpha -OHE1 antagonized the E-2-stimulated increase in e pithelial cell height. 2-OHE had no effect on cortical bone, whereas 16 alp ha -OHE1 was an estrogen agonist with respect to all cortical bone measurem ents. 16 alpha -OHE1 also behaved as an estrogen agonist with respect to se rum cholesterol and cancellous bone measurements. 2-OHE, had no effect on m ost E-2-regulated indices of cancellous bone growth and turnover, but was a weak estrogen agonist with respect to mineral apposition rate and bone for mation rate. Neither estrogen metabolite influenced body weight gain. Third , weanling rats were treated for 1 week with vehicle, E-2 (200 mug/kg per d ay) or 16 alpha -OHE1, (30, 100, 300, 1000 and 3000 mug/kg per day) to conf irm uterotropic effects of daily subcutaneous (s.c.) administration of 16 a lpha -OHE1. 16 alpha -OHE, increased uterine weight in a dose-response mann er to values that did not differ from rats treated with E-2. We conclude th at the estrogen metabolites 2-OHE1 and 16 alpha -OHE, have target tissue-sp ecific biological activities which differ from one another as well as from E-2. These findings add further support to the concept that there are sever al classes of estrogens with distinct biological activities. Furthermore, d ifferences in the route of administration could influence the tissue specif icity of estrogen metabolites.