Turner R T, Evans G L, Sluka J P, Adrian M D, Bryant H U, Turner C H, Sato M
Department of Orthopedics and Biochemistry, Mayo Graduate School of Medicine, Rochester, Minnesota 55905, USA.
Endocrinology. 1998 Sep;139(9):3712-20. doi: 10.1210/endo.139.9.6177.
The substituted triphenylethylene antiestrogen clomiphene (CLO) prevents cancellous bone loss in ovariectomized (OVX'd) rats. However, CLO is a mixture of two stereoisomers, enclomiphene (ENC) and zuclomiphene (ZUC), which have distinctly different activities on reproductive tissues and tumor cells. The purpose of the present dose response study was to determine the effects of ENC and ZUC on nonreproductive estrogen target tissues. These studies were performed in 7-month-old female rats with moderate cancellous osteopenia that was established by ovariectomizing rats 1 month before initiating treatment. OVX resulted in increases in body weight, serum cholesterol, endocortical resorption, and indices of cancellous bone turnover, as well as decreases in uterine weight, uterine epithelial cell height, bone mineral density, bone strength, and cancellous bone area. Estrogen treatment for 3 months restored body weight, uterine histology, dynamic bone measurements, and osteoblast and osteoclast surfaces in OVX'd rats to the levels found in the age-matched sham-operated rats. In contrast, estrogen only partially restored cancellous bone volume and uterine weight, and it reduced serum cholesterol to subnormal values. CLO was a weak estrogen agonist on uterine measurements and a much more potent agonist on body weight, serum cholesterol, and dynamic bone measurements. CLO increased trabecular thickness in osteopenic rats and was the most effective treatment in improving cancellous bone volume and architecture. ZUC was a potent estrogen agonist on all tissues investigated and had dose-dependent effects. In contrast, ENC had dose-dependent effects on most measurements similar to CLO and decreased the uterotrophic effects of ZUC. It is concluded that ENC antagonizes the estrogenic effects of ZUC on the uterus but that the beneficial effects of CLO on nonreproductive tissues in OVX'd rats is conferred by both isomers. Furthermore, the combined actions of the two isomers on bone volume and architecture were more beneficial than either isomer given alone.
取代三苯乙烯类抗雌激素药物克罗米芬（CLO）可预防去卵巢（OVX）大鼠的松质骨丢失。然而，CLO是两种立体异构体，即恩氯米芬（ENC）和珠氯米芬（ZUC）的混合物，它们对生殖组织和肿瘤细胞具有明显不同的活性。本剂量反应研究的目的是确定ENC和ZUC对非生殖雌激素靶组织的影响。这些研究在7月龄中度松质骨减少的雌性大鼠中进行，松质骨减少是通过在开始治疗前1个月对大鼠进行卵巢切除建立的。OVX导致体重、血清胆固醇、骨内膜吸收以及松质骨转换指标增加，同时子宫重量、子宫上皮细胞高度、骨矿物质密度、骨强度和松质骨面积减少。对OVX大鼠进行3个月的雌激素治疗可使体重、子宫组织学、动态骨测量以及成骨细胞和破骨细胞表面恢复到年龄匹配的假手术大鼠的水平。相比之下，雌激素仅部分恢复松质骨体积和子宫重量，并将血清胆固醇降至低于正常的值。CLO在子宫测量方面是一种弱雌激素激动剂，而在体重、血清胆固醇和动态骨测量方面是一种更强效的激动剂。CLO增加了骨质疏松大鼠的小梁厚度，是改善松质骨体积和结构最有效的治疗方法。ZUC对所有研究的组织都是一种强效雌激素激动剂，并具有剂量依赖性作用。相比之下，ENC对大多数测量的剂量依赖性作用与CLO相似，并降低了ZUC的子宫营养作用。结论是，ENC拮抗ZUC对子宫的雌激素作用，但CLO对OVX大鼠非生殖组织的有益作用是由两种异构体共同赋予的。此外，两种异构体对骨体积和结构的联合作用比单独给予任何一种异构体更有益。
