No abstract

Abstract2-Hydroxyestrone (2-OHE 1 ) and 16 -hydroxyestrone (16 -OHE 1 ) have been reported to be risk factors for negative bone balance and breast cancer, respectively. The roles of these two metabolites of estrone as estrogen agonists or antagonists with respect to estrogen target tissues, or both, are poorly defined. The purpose of this study was to characterize metabolite and tissue-specific differences between the actions of hydroxylated estrones on selected reproductive and non-reproductive estrogen target tissues in growing rats. First, the effects of ovariectomy were determined. Ovariectomy had the expected effects, including increases in all dynamic bone measurements at the proximal tibial epiphysis, without induction of bone loss. Second, ovariectomized growing rats were continuously treated for 3 weeks with 2-OHE 1 , 16 -OHE 1 , 17 -estradiol (E 2 ), a combination of E 2 and 2-OHE 1 (E 2 +2-OHE 1 ), or a combination of E 2 and 16 -OHE 1 (E 2 +16 -OHE 1 ), using controlled release subcutaneous implanted pellets containing 5 mg 2-OHE 1 , 5 mg 16 -OHE 1 , 0·05 mg E 2 or placebo. E 2 reduced body weight gain and radial and longitudinal bone growth as well as indices of cancellous bone turnover, and increased serum cholesterol, uterine wet 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 -OHE 1 antagonized the E 2 -stimulated increase in epithelial cell height. 2-OHE 1 had no effect on cortical bone, whereas 16 -OHE 1 was an estrogen agonist with respect to all cortical bone measurements. 16 -OHE 1 also behaved as an estrogen agonist with respect to serum cholesterol and cancellous bone measurements. 2-OHE 1 had no effect on most E 2 -regulated indices of cancellous bone growth and turnover, but was a weak estrogen agonist with respect to mineral apposition rate and bone formation rate. Neither estrogen metabolite influenced body weight gain. Third, weanling rats were treated for 1 week with vehicle, E 2 (200 µg/kg per day) or 16 -OHE 1 (30, 100, 300, 1000 and 3000 g/kg per day) to confirm uterotropic effects of daily subcutaneous (s.c.) administration of 16 -OHE 1 . 16 -OHE 1 increased uterine weight in a dose-response manner to values that did not differ from rats treated with E 2 . We conclude that the estrogen metabolites 2-OHE 1 and 16 -OHE 1 have target tissue-specific biological activities which differ from one another as well as from E 2 . These findings add further support to the concept that there are several classes of estrogens with distinct biological activities. Furthermore, differences in the route of administration could influence the tissue specificity of estrogen metabolites.

Recent data indicate that the catechol estrogen, 2-hydroxyestrone (2-OHE 1 ), has no effect on any target tissue including bone, whereas 16 -hydroxyestrone (16 -OHE 1 ) exerts tissue-selective estrogen agonist activity. The effect of the catechol estrogen, 4-hydroxyestrone (4-OHE 1 ), putatively associated with tumorigenesis, has not been studied in the skeleton. The purpose of this study was to assess the effect of 4-OHE 1 on tibia, uterine and mammary gland histology and blood cholesterol in ovariectomized (OVX'd) growing rats. Ten-week-old female Sprague-Dawley rats were injected subcutaneously with 200 µg/kg BW per day with 4-OHE 1 , 17 -estradiol (E 2 ) or vehicle for three weeks. OVX resulted in uterine atrophy, increased body weight, radial bone growth and cancellous bone turnover, and hypercholesterolemia. E 2 prevented these changes with the expected exception that the subcutaneous infusion of this high dose of estrogen did not prevent the hypercholesterolemia. 4-OHE 1 prevented the increase in blood cholesterol and the increase in body weight. 4-OHE 1 appeared to have partial estrogen activity in the uterus; uterine weight and epithelial cell height were significantly greater than the OVX rats but significantly less (twofold) than the E 2 animals. Analysis of variance indicated that 4-OHE 1 slightly decreased the periosteal mineral apposition rate (P<0·05) compared with vehicletreated rats but had no effect on double-labeled perimeter or bone formation rate. Similarly, 4-OHE 1 was a partial estrogen agonist on cancellous bone turnover. The data suggest that the catechol estrogen, 4-OHE 1 , unlike 2-OHE 1 , has estrogen activity. Furthermore, the profile of activity differs from that of 16 -OHE 1 . Our results suggest that estrogen metabolites may selectively influence estrogen-target tissues and, concomitantly, modulate estrogen-associated disease risk.