DIFFERENTIAL-EFFECTS OF ESTROGEN METABOLITES ON BONE AND REPRODUCTIVETISSUES OF OVARIECTOMIZED RATS

The effects of 17 beta-estradiol and the important estrogen metabolite s, 2-hydroxyestrone (2-OHE1) and 16 alpha-hydroxyestrone (16 alpha-OHE 1) on bone, mammary gland, and uterine histology, and on blood cholest erol were investigated in ovariectomized growing rats. Rats were treat ed with 200 mu g/kg of body weight/day of each of the test compounds f or 3 weeks, Ovariectomy resulted in uterine and mammary gland atrophy, increased body weight, bone turnover and tibia growth, and hyperchole sterolemia. 17 beta-estradiol treatment prevented these changes, with the exception that this high dose of estrogen did not prevent hypercho lesterolemia. 2-OHE1 had no effect on any of the measurements. 16 alph a-OHE1 resulted in bone measurements that did not differ from the 17 b eta-estradiol-treated rats and prevented the increase in serum cholest erol, In contrast, 16 alpha-OHE1 resulted in increases in uterine weig ht, uterine epithelial cell height, and mammary gland cell proliferati on that were significantly less than the 17 beta-estradiol treatment. These findings demonstrate that 16 alpha-hydroxylation of estrone resu lts in tissue-selective estrogen agonistic activity, whereas 2-hydroxy lation resulted in no measured activity. Furthermore, they suggest tha t factors that modulate the synthesis of these metabolites could selec tively influence estrogen target tissues.