Effects Of Raloxifene And Conjugated Equine Estrogen On Prethrombotic State In Ovariectomized Rats

Objective:Raloxifene,a selective estrogen receptor modulator(SERM) of the second generation,presents an estrogen-like action on bone and an anti-estrogen effect on uterus and breast,which makes it be widely used in prevention and treatment of osteoporosis of postmenopausal women.However,poor compliance is observed since it worsens the vasomotor symptoms in the users.Estrogens,effective in prevention and treatment of bone loss caused by low estrogen level,present a satisfactory effect on eliminate the climacteric symptoms but stimulate uterus and breast.Considering that both agents presenting similar protective effects on bone while counteracting effects on each others' side effects,we hypothesized that combined administration might probably achieve maximal clinical outcomes.Our previous study has demonstrated that the combination did not reduce the protective effect on ovariectomized rats and presented no harmful action on their uteri,breasts and aorta.Yet the combined effect on thrombosis and embolism is still not known,and because of that,we designed this study using ovariectomized rats trying to obtain safety parameters for further application.Methods:Postmenopausal model was prepared using female SD rats of 9-10 months that were ovariectomized.After one week of rehabiliation,ten weeks of treatment was given.Blood samples were collected for detection of plasma concentration of the following:FIB,ATâ…¢activity,PAI-1,D-D,vWF,NO,PGI2 and TXB2.Results:After menopause,the plasma concentration of FIB and PAI-1 and the ATâ…¢activity was elevated.No change was observed in D-D concentration.NO concentration declined dramatically and the vWF antigen increased,the PGI2 and TXA2 concentration increased simultaneously.Regarding coagulation and anticoagulation,the FIB in RLX group was apparently higher than that of postmenopausal control,and the plasma FIB of CEE group was higher than that of premenopausal baseline but almost equal to that of the premenopausal control.The ATâ…¢activity of RLX group was obviously higher than that of premenopausal state and paralleled to that of postmenopausal state,while the ATâ…¢activity of CEE group was nearing that of premenopausal state.In the combined administration group,the FIB level was similar to that of RLX group,and the ATâ…¢activity was between those of RLX group and CEE group,indicating that estrogen would not increase the present thromboembolism risks caused by RLX.As far as fibrinolysis and anti-fibrinolysis is concerned,the PAI-1 level increased on the basis of high level after menopause and the PAI-1 in CEE also presented a dramatic raise.After combined administration,the plasma PAI-1 increased more,suggesting a synergetic effect with a higher risk of thrombosis.But the pivot exclusive index,plasma D-D level was not different between the groups.Regarding the endothelial function,RLX was opposite to CEE.RLX increased the vWF antigen level and did not affect the NO level very much,while the CEE dramatically decreased vWF antigen level and increased NO level.Combined administration showed a medial effect on vWF and NO,but the RLX plus high dose CEE group presented more protective effect that was similar to that of premenopausal state. This indicates that CEE has protective effect on endothelium and counteracts the adverse effect of RLX in some extent.For those vasomotor parameters,menopause induced simultaneous increase in plasma PGI2 and TXA2,while either RLX or CEE decreased them.Combined administration did not show a stronger effect than either drug,which means no addition effect was exerted by combination of RLX and CEE.Conclusion:In the different aspects of thrombosis,RLX presented different effects and may increase the risk.Estrogen and RLX are synergetic or protective in these different aspects.In general,the risk of thrombosis is not further increased by combined administration.