DIFFERENTIAL RESPONSES OF ESTROGEN TARGET TISSUES IN RATS INCLUDING BONE TO CLOMIPHENE, ENCLOMIPHENE, AND ZUCLOMIPHENE

The substituted triphenylethylene antiestrogen clomiphene (CLO) preven ts cancellous bone loss in ovariectomized (OVX'd) rats. However, CLO i s a mixture of two stereoisomers, enclomiphene (ENC) and zuclomiphene (ZUC), which have distinctly different activities on reproductive tiss ues and tumor cells. The purpose of the present dose response study wa s to determine the effects of ENC and ZUC on nonreproductive estrogen target tissues. These studies were performed in 7-month-old female rat s with moderate cancellous osteopenia that was established by ovariect omizing rats 1 month before initiating treatment. OVX resulted in incr eases in body weight, serum cholesterol, endocortical resorption, and indices of cancellous bone turnover, as well as decreases in uterine w eight, uterine epithelial cell height, bone mineral density, bone stre ngth, and cancellous hone area. Estrogen treatment for 3 months restor ed body weight, uterine histology, dynamic bone measurements, and oste oblast and osteoclast surfaces in OVX'd rats to the levels found in th e age-matched shamoperated rats. In contrast, estrogen only partially restored cancellous bone volume and uterine weight, and it reduced ser um cholesterol to subnormal values. CLO was a weak estrogen agonist on uterine measurements and a much more potent agonist on body weight, s erum cholesterol, and dynamic bone measurements. CLO increased trabecu lar 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 e ffects. In contrast, ENC had dose-dependent effects on most measuremen ts similar to CLO and decreased the uterotrophic effects of ZUC. It is concluded that ENC antagonizes the estrogenic effects of ZUC on the u terus but that the beneficial effects of CLO on nonreproductive tissue s in OVX'd rats is conferred by both isomers. Furthermore, the combine d actions of the two isomers on bone volume and architecture were more beneficial than either isomer given alone.