Comparative effects of long-term continuous release of 16 alpha-hydroxyestrone and 17 beta-estradiol on bone, uterus, and serum cholesterol in ovariectomized adult rats.
16Alpha-hydroxyestrone (16alpha-OHE(1)), 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 microg/kg/day to be the optimal dose of 16alpha-OHE(1) 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, 17beta-estradiol (E(2)) (33 microg/kg/day) or 16alpha-OHE(1) pellets (2000 microg/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. E(2) completely prevented OVX-induced bone loss, suppressed bone turnover, and induced uterine hypertrophy and hypercholesterolemia. 16alpha-OHE(1) acted as an E(2) agonist on bone, suppressing bone formation and resorption. However, the estrogen metabolite lowered serum cholesterol and was only a partial E(2) agonist on uterine weight and epithelial cell height. These results suggest that 16alpha-OHE(1) 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 16alpha-OHE(1) could have a lower risk for developing postmenopausal osteoporosis than women who produce less-active estrogen metabolites.
Lotinun
Sutada
S
Department of Orthopedics, Mayo Clinic, Rochester, MN 55905, USA. lotinun.sutada@mayo.edu
Westerlind
Kim C
KC
Kennedy
Angela M
AM
Turner
Russell T
RT
D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004958:Estradiol / Q000008:administration & dosage*; D004964:Estriol / Q000008:administration & dosage; D005260:Female; D006894:Hydroxyestrones / Q000008:administration & dosage*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D010024:Osteoporosis / Q000188:drug therapy / Q000517:prevention & control*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014599:Uterus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D003692:Delayed-Action Preparations; D006894:Hydroxyestrones; D004958:Estradiol; D002784:Cholesterol; D004964:Estriol