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

Abstract

Recent data indicate that the catechol estrogen, 2-hydroxyestrone (2-OHE1), has no effect on any target tissue including bone, whereas 16α-hydroxyestrone (16α-OHE1 exerts tissue-selective estrogen agonist activity. The effect of the catechol estrogen, 4-hydroxyestrone (4-OHE1), putatively 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 subcutaneously with 200μg/kg BW per day with 4-OHE1, 17β-estradiol (E2) or vehicle for three weeks. OVX resulted in uterine atrophy, increased body weight, radial bone growth and cancellous bone turnover, and hypercholesterolemia. E2 prevented these changes with the expected exception that the subcutaneous infusion of this high dose of estrogen did not prevent the hypercholesterolemia. 4-OHE1 prevented the increase in blood cholesterol and the increase in body weight. 4-OHE1 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 E2 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 turnover. The data suggest that the catechol estrogen, 4-OHE1, unlike 2-OHE1, has estrogen activity. Furthermore, the profile of activity differs from that of 16α-OHE1. Our results suggest that estrogen metabolites may selectively influence estrogen-target tissues and, concomitantly, modulate estrogen-associated disease risk.