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

Bone. 2003 Jul;33(1):124-31. doi: 10.1016/s8756-3282(03)00081-4.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone and Bones / cytology
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism
  • Cholesterol / blood*
  • Delayed-Action Preparations / administration & dosage
  • Estradiol / administration & dosage*
  • Estriol / administration & dosage
  • Female
  • Hydroxyestrones / administration & dosage*
  • Osteogenesis / drug effects
  • Osteogenesis / physiology
  • Osteoporosis / drug therapy
  • Osteoporosis / prevention & control*
  • Ovariectomy
  • Rats
  • Rats, Sprague-Dawley
  • Uterus / cytology
  • Uterus / drug effects*
  • Uterus / metabolism


  • Delayed-Action Preparations
  • Hydroxyestrones
  • Estradiol
  • Cholesterol
  • Estriol