Martel C, Picard S, Richard V, Bélanger A, Labrie C, Labrie F
MRC Group in Molecular Endocrinology, Laboratory of Molecular Endocrinology, CHUL Research Center and Laval University, 2705 Laurier Boulevard, G1V 4G2, Québec, Canada.
J Steroid Biochem Mol Biol. 2000 Sep;74(1-2):45-56. doi: 10.1016/s0960-0760(00)00087-x.
Some undesirable effects are associated with chronic estrogen and progestin administration used to prevent bone loss in postmenopausal women, thus leading to poor compliance and the need for improved therapeutic and preventive agents. We have thus studied the ability of the new antiestrogen EM-800 (SCH 57050) to prevent bone loss and lower serum cholesterol levels and compared its effects with those of raloxifene. Ovariectomized (OVX) female rats were treated by oral gavage for 37 weeks with increasing daily doses (0.01, 0.03, 0.1, 0. 3 or 1 mg/kg) of EM-800 or raloxifene. At 35 weeks after OVX, lumbar spine bone mineral density (BMD) was 19% lower than in intact animals (P<0.01), while the OVX animals given EM-800 or raloxifene had 90-93 and 85-90%, respectively, of the BMD values observed in intact rats. Similar effects were observed on femoral BMD. Bone histomorphometry measurements were performed on proximal tibia. At the 0.01 mg/kg dose, EM-800 prevented the effect of OVX on TBV by 34% (P<0.01), while raloxifene had no detectable effect. Treatment with 1 mg/kg EM-800 and raloxifene resulted in, respectively, 68% (P<0.01) and 64% (P<0.01) prevention of the OVX-induced decrease in TBV. In addition, the administration of 0.01 and 0.03 mg/kg EM-800 caused, respectively, 54% (P<0.01) and 56% (P<0.01) inhibitions of serum cholesterol levels, while raloxifene administered at the same doses caused, respectively, 24% (P<0.01) and 41% (P<0.01) decreases of the value of the same parameter. At the highest doses used (0.1-1 mg/kg), both compounds lowered serum cholesterol levels by approximately 65% (P<0.01). No stimulatory effect of EM-800 was observed on the endometrial epithelial cells at doses up to 1 mg/kg, while hypertrophy of uterine epithelium was observed with raloxifene. EM-800 and raloxifene achieve the same degree of effectiveness on bone and serum cholesterol at higher doses, but EM-800 is at least three to ten times more potent than raloxifene at lower concentrations and has no stimulatory effect on uterine epithelium. The present data show the potent effect of EM-800 preventing bone loss and lower serum cholesterol levels without the negative effect on the endometrium, thus suggesting the particular interest of this new fully tissue-specific selective estrogen receptor modulator.
用于预防绝经后女性骨质流失的长期雌激素和孕激素给药会产生一些不良影响，从而导致依从性差，并需要改进治疗和预防药物。因此，我们研究了新型抗雌激素药物EM - 800（SCH 57050）预防骨质流失和降低血清胆固醇水平的能力，并将其效果与雷洛昔芬进行了比较。对去卵巢（OVX）的雌性大鼠进行为期37周的灌胃治疗，每日给予递增剂量（0.01、0.03、0.1、0.3或1 mg/kg）的EM - 800或雷洛昔芬。在OVX后35周，腰椎骨密度（BMD）比完整动物低19%（P<0.01），而给予EM - 800或雷洛昔芬的OVX动物的BMD值分别为完整大鼠的90 - 93%和85 - 90%。在股骨BMD上也观察到了类似的效果。对近端胫骨进行骨组织形态计量学测量。在0.01 mg/kg剂量下，EM - 800使OVX对骨小梁体积（TBV）的影响降低了34%（P<0.01），而雷洛昔芬未观察到可检测到的效果。用1 mg/kg的EM - 800和雷洛昔芬治疗分别使OVX诱导的TBV降低得到了68%（P<0.01）和64%（P<0.01）的预防。此外，给予0.01和0.03 mg/kg的EM - 800分别使血清胆固醇水平抑制了54%（P<0.01）和56%（P<0.01），而相同剂量的雷洛昔芬分别使该参数值降低了24%（P<0.01）和41%（P<0.01）。在使用的最高剂量（0.1 - 1 mg/kg）下，两种化合物均使血清胆固醇水平降低了约65%（P<0.01）。在高达1 mg/kg的剂量下，未观察到EM - 800对子宫内膜上皮细胞有刺激作用，而雷洛昔芬则观察到子宫上皮肥大。EM - 800和雷洛昔芬在较高剂量下对骨骼和血清胆固醇具有相同程度的有效性，但在较低浓度下，EM - 800的效力至少是雷洛昔芬的三到十倍，并且对子宫上皮没有刺激作用。目前的数据显示了EM - 800在预防骨质流失和降低血清胆固醇水平方面的强效作用，且对子宫内膜没有负面影响，因此表明这种新型的完全组织特异性选择性雌激素受体调节剂具有特殊的意义。
