The catechol estrogen, 4-hydroxyestrone, has tissue-specific estrogen actions

Recent data indicate that the catechol estrogen, 2-hydroxyestrone (2-OHE1), has no effect on any target tissue including bone, whereas 1G alpha -hydro xyestrone (16 alpha -OHE1) exerts tissue-selective estrogen agonist activit y. The effect of the catechol estrogen, 4-hydroxyestrone (4-OHE1), putative ly associated with tumorigenesis, has not been studied in the skeleton. The purpose of this study was to assess the effect of 4-OHE1 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 subcu taneously with 2001 mug/kg BW per day with 4-OHE1, 17 beta -estradiol (E-2) or vehicle for three weeks. OVX resulted in uterine atrophy, increased bod y weight, radial bone growth and cancellous bone turnover, and hypercholest erolemia. E-2 prevented these changes with the expected exception that the subcutaneous infusion of this high dose of estrogen did not prevent the hyp ercholesterolemia. 4-OHE1 prevented the increase in blood cholesterol and t he increase in body weight. 4-OHE1 appeared to have partial estrogen activi ty in the uterus; uterine weight and epithelial cell height were significan tly greater than the OVX rats but significantly less (twofold) than the E-2 animals. Analysis of variance indicated that 4-OHE1 slightly decreased the periosteal mineral apposition rate (P<0.05) compared with vehicle-treated rats but had no effect on double-labeled perimeter or bone formation rate. Similarly, 4-OHE1 was a partial estrogen agonist on cancellous bone turnove r. The data suggest that the catechol estrogen, 4-OHE1, unlike 2-OHE1, has estrogen activity. Furthermore, the profile of activity differs from that o f 16<alpha>-OHE1. Our results suggest that estrogen metabolites may selecti vely influence estrogen-target tissues and, concomitantly, modulate estroge n-associated disease risk.