Differential effects of estrogen metabolites on bone and reproductive tissues of ovariectomized rats.
The effects of 17 beta-estradiol and the important estrogen metabolites, 2-hydroxyestrone (2-OHE1) and 16 alpha-hydroxyestrone (16 alpha-OHE1) on bone, mammary gland, and uterine histology, and on blood cholesterol were investigated in ovariectomized growing rats. Rats were treated with 200 micrograms/kg of body weight/day of each of the test compounds for 3 weeks. Ovariectomy resulted in uterine and mammary gland atrophy, increased body weight, bone turnover and tibia growth, and hypercholesterolemia. 17 beta-estradiol treatment prevented these changes, with the exception that this high dose of estrogen did not prevent hypercholesterolemia. 2-OHE1 had no effect on any of the measurements. 16 alpha-OHE1 resulted in bone measurements that did not differ from the 17 beta-estradiol-treated rats and prevented the increase in serum cholesterol. In contrast, 16 alpha-OHE1 resulted in increases in uterine weight, uterine epithelial cell height, and mammary gland cell proliferation that were significantly less than the 17 beta-estradiol treatment. These findings demonstrate that 16 alpha-hydroxylation of estrone results in tissue-selective estrogen agonistic activity, whereas 2-hydroxylation resulted in no measured activity. Furthermore, they suggest that factors that modulate the synthesis of these metabolites could selectively influence estrogen target tissues.
Westerlind
K C
KC
AMC Cancer Research Center, Denver, Colorado, USA.
Gibson
K J
KJ
Malone
P
P
Evans
G L
GL
Turner
R T
RT
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002393:Estrogens, Catechol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D005260:Female; D006894:Hydroxyestrones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000517:prevention & control; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000473:pathology; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013329:Structure-Activity Relationship; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D014599:Uterus / Q000187:drug effects* / Q000473:pathology
D016588:Anticarcinogenic Agents; D002393:Estrogens, Catechol; D006894:Hydroxyestrones; C026702:16-hydroxyestrone; D004958:Estradiol; D002784:Cholesterol; D039181:Steroid 16-alpha-Hydroxylase; C024980:2-hydroxyestrone