Dose-response of estrogen on bone versus the uterus in ovariectomized mice
Dose-response of estrogen on bone versus the uterus in ovariectomized mice
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DOI：
10.1530/eje.0.1510503
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发表时间：
2004-10-01
影响因子：
5.8
通讯作者：
Khosla, S
中科院分区：
文献类型：
--
作者：
Mödder, UIL;Riggs, BL;Khosla, S
背景：众所周知，雌激素对生殖和非生殖组织都有重要影响。此外，人们对开发可能对骨骼和生殖组织具有选择性作用的化合物越来越感兴趣。方法：由于这些研究中经常使用小鼠模型，我们通过缓释丸给6月龄去卵巢的C57BL/6小鼠递增剂量的雌二醇(E-2)(0~500µg/kg/d)，并评估治疗2个月后的骨骼和子宫反应。结果：小鼠去卵巢后多部位骨质丢失；然而，虽然最低剂量的E-2 5µg/kg/d完全阻止了松质骨的丢失(在腰椎和胫骨干骺端)，但它对子宫没有刺激作用。更高剂量的雌激素会进一步增加骨密度，最终对子宫的刺激剂量为40微克/公斤/天。相比之下，给3月龄C57BL/6小鼠注射相同剂量的E2，并在1个月后进行研究，5µg/kg/d剂量可导致子宫肥大，但不能防止松质骨丢失。结论：这些结果提供了E-2对小鼠骨骼影响的剂量-反应数据，(Ii)表明E-2对骨骼和子宫的相对作用高度依赖于特定的实验条件。在评估对骨骼和生殖组织具有潜在“选择性”影响的药物时，需要考虑这一问题。
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 (E-2) (0 to 500 mug/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 E-2 dose of 5 mug/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 mug/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 mug/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 E-2 on mouse bone and (ii) indicate that the relative effects of E-2 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.