Sibonga J D, Dobnig H, Harden R M, Turner R T
Department of Orthopedic Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
Endocrinology. 1998 Sep;139(9):3736-42. doi: 10.1210/endo.139.9.6172.
We examined the specificity of the steroidal antiestrogen ICI 182,780 (ICI) on bone and reproductive tissues in adult and growing female rats. Using a 1.5-mg/kg dose (s.c.), we evaluated the effects of ICI on the bone, body weight, uterine weight, serum cholesterol, and serum estradiol in either adult and/or growing rats. ICI increased serum estradiol cholesterol in ovary-intact rats, had no effect on uterine weight in ovariectomized rats, and resulted in uterine atrophy in ovary-intact animals comparable with ovariectomy. In contrast, ICI had no effect on body weight. In bone, ICI significantly increased the rate of periosteal bone formation in long bones of growing and mature female rats. In contrast, ICI had no effect on longitudinal bone growth in rapidly growing rats. When ICI was administered to mature rats with or without ovaries, two-factor ANOVA revealed significant interaction (P < or = 0.05) between ovariectomy and ICI treatment for cancellous bone area and labeled bone perimeter. ICI increased skeletal indices of bone turnover in the cancellous bone of ovary-intact rats but reduced these indices of bone turnover in the cancellous bone of ovariectomized rats. The increase in bone turnover was associated with a reduction in cancellous bone area in the ovary-intact rats. A reduction in bone turnover was similarly associated with an increase in bone area in the ICI-treated ovariectomized rats. In summary, ICI exhibited complete estrogen antagonism in cortical and cancellous bone, partial agonism in cancellous bone, and no activity on tibial longitudinal growth rate of growing ovary-intact rats. The effects in adult rats were influenced by circulating levels of estradiol. ICI had no activity on body weight and complete antagonism on uterine weight. These results demonstrate that a ligand with high binding affinity to the estrogen receptor(s) can elicit an array of estrogen-mediated regulation of bone metabolism.
我们研究了甾体类抗雌激素药物 ICI 182,780（ICI）对成年和生长中的雌性大鼠骨骼及生殖组织的特异性作用。采用 1.5 mg/kg 的剂量（皮下注射），我们评估了 ICI 对成年和/或生长中大鼠的骨骼、体重、子宫重量、血清胆固醇及血清雌二醇的影响。ICI 可使卵巢完整的大鼠血清雌二醇胆固醇升高，对去卵巢大鼠的子宫重量无影响，且可导致卵巢完整动物的子宫萎缩，程度与去卵巢相当。相比之下，ICI 对体重无影响。在骨骼方面，ICI 显著提高了生长中和成熟雌性大鼠长骨的骨膜骨形成速率。相反，ICI 对快速生长大鼠的纵向骨生长无影响。当对有或无卵巢的成熟大鼠给予 ICI 时，双因素方差分析显示去卵巢与 ICI 处理之间对于松质骨面积和标记骨周长存在显著交互作用（P≤0.05）。ICI 增加了卵巢完整大鼠松质骨的骨转换骨骼指标，但降低了去卵巢大鼠松质骨的这些骨转换指标。骨转换增加与卵巢完整大鼠的松质骨面积减少相关。骨转换降低同样与 ICI 处理的去卵巢大鼠的骨面积增加相关。总之，ICI 在皮质骨和松质骨中表现出完全的雌激素拮抗作用，在松质骨中表现出部分激动作用，对生长中的卵巢完整大鼠的胫骨纵向生长速率无活性作用。成年大鼠中的作用受雌二醇循环水平影响。ICI 对体重无活性作用，对子宫重量有完全拮抗作用。这些结果表明，与雌激素受体具有高结合亲和力的配体可引发一系列雌激素介导的骨代谢调节作用。
