Dose-response of estrogen on bone versus the uterus in ovariectomized mice

Background: Estrogen is known to have important effects on both reproductive and non-reproductive tissues. Moreover, there is increasing interest in developing compounds that may have selective effects on bone versus reproductive tissues. Methods: Since mouse models are often used in these studies, we administrated increasing doses of estradiol (E₂) (0 to 500 μg/kg/day) by slow release pellets to ovariectomized 6-month-old C57BL/6 mice and assessed skeletal and uterine responses following 2 months of treatment. Results: The mice lost bone at multiple sites following ovariectomy (OVX); however, while the lowest E₂ dose of 5 μg/kg/day completely prevented loss of cancellous bone (at the lumbar spine and tibial metaphysis), it had no stimulatory effects on the uterus. Higher doses of E₂ resulted in further increases in bone mineral density, with eventual stimulation of the uterus at a dose of 40 μg/kg/day. By contrast, when 3-month-old C57BL/6 mice were administered the same doses of E₂ and studied after 1 month, the 5 μg/kg/day dose resulted in uterine hypertropy, but was not able to prevent loss of cancellous bone. Conclusions: Thus these results (i) provide data on the dose-response for the effects of E₂ on mouse bone and (ii) indicate that the relative effects of E₂ on bone versus the uterus are highly dependent on the particular experimental conditions used. This issue needs to be considered in evaluating agents with potential 'selective' effects on bone versus reproductive tissues.