Comparative effects of long-term continuous release of 16α-hydroxyestrone and 17β-estradiol on bone, uterus, and serum cholesterol in ovariectomized adult rats

16α-Hydroxyestrone (16α-OHE1), an endogenous estrogen metabolite, is associated with increased bone density in postmenopausal women. This study was designed to evaluate the long-term activity of this metabolite on bone, uterus, and serum cholesterol in an animal model for postmenopausal bone loss. A preliminary dose–response study performed in weanling rats determined 2000 μg/kg/day to be the optimal dose of 16α-OHE1 for studying estrogenic effect on bone. The long-term experiment was performed in 6-month-old animals that were either sham-operated or OVX. The OVX rats were implanted sc with 60-day continuous-release carrier, 17β-estradiol (E2) (33 μg/kg/day) or 16α-OHE1 pellets (2000 μg/kg/day). OVX decreased uterine weight, increased body weight, serum cholesterol, and all dynamic bone histomorphometric measurements in cortical and cancellous bone, and resulted in a 54% bone loss at the tibial metaphysis. E2 completely prevented OVX-induced bone loss, suppressed bone turnover, and induced uterine hypertrophy and hypercholesterolemia. 16α-OHE1 acted as an E2 agonist on bone, suppressing bone formation and resorption. However, the estrogen metabolite lowered serum cholesterol and was only a partial E2 agonist on uterine weight and epithelial cell height. These results suggest that 16α-OHE1 is an estrogen agonist on bone and may be responsible, in part, for the cholesterol-lowering activity attributed to estrogen. As a consequence of its skeletal effects, older women who produce high levels of 16α-OHE1 could have a lower risk for developing postmenopausal osteoporosis than women who produce less-active estrogen metabolites.