Different Effects Of Conjugated Equine Estrogen And Medroxyprogesterone Acetate On The Cardiovascular Of Ovariectomized Rats In The Initial Menopausal Stage And The Advanced Stage

【Objective】The discrepancy between estrogen's beneficial cardiovasculareffects found in animal studies and observational studies in women compared with therecently published randomized clinical trials have stimulated a great deal ofcontroversy. Possibilities for the discrepancy include the age of the women, number ofyears postmenopausal, and cardiovascular disease state and complication (necrosisand inflammation) present when hormone therapy is initiated. There is a need forstudies assessing the age and menopausal time when the treatment initiate may affectheart disease risk and cardiovascular outcomes in postmenopausal women with HRT.We conducted a randomized, placebo-controlled trial of HRT in ovariectomized rat indifferent menopausal age and treat with conjugated equine estrogens (CEE) withcontinuous administration of medroxyprogesterone (MPA) to determine whether HRThad the different effects on blood biochemistry parameter association tocardiovascular disease and on the pathology change in cardiovascular in differentinitial time and then provide evidence for the applicability of HRT on cardiovasculardisease in postmenopausal women.【Methods】1. Middle age female Sprague-Dawley rats were ovariectomized atthe same estrous cycle stage to induce menopausal model. All menopausal rats wererandomized into 2 groups on the basis of their diet that were Cholesterol-free diet(fCho) and cholesterol diet (Cho) respectively. Each group was divided into 2groups on the basis of the initial time of HRT treatment. We defined the time of 3 daysafter OVX to approximate the initial-stage of menopause for women and 4 mothesafter OVX to approximate the advanced-stage of menopause for women respectively.On the same time, some rats were set aside for the control groups which did not sufferany treatment but sacrificed in the time of HRT initiated from initial-stage andadvanced-stage. All the treatment groups were administered normal saline (placebogroup), 0.1mg/kg/day CEE plus MPA (lower-dose group), 0.5mg/kg/day CEE plusMPA (higher-dose group) respectively. The 0.1mg/kg/day dose of CEE was chosen toapproximate a dose of 0.625mg/kg/day for women, and the 0.5mg/kg/day dose was selected refering to other studies. All rats were administered daily by gavage fortotally 3months. Then each rats was sacrificed for measurement of some risk factors(high-sensitive C-reactive protein, nitric oxide, fibrinogen) in blood associated tocardiovascular disease and for histopathological evaluation of arteries and aorta tissue.【Results】1. Both age and menopausal duration could affect the blood biochemistryparameter association to cardiovascular disease and the histopathological change incardiovascular system. In advanced-stage of menopause, both the TC and H DL levelsincreased significantly in rats fed with cholesterol-free diet (P＜0.05). Yet the TC,TGand LDL were all increased (P＜0.05) respectively and it kead to the hyperlipoidemiaand overweight in rats fed with cholesterol diet. At the same time, both the C-reactiveprotein and the nitric oxide levels decreased in menopausal rats of advanced-stagefeding with cholesterol-free and cholesterol diet (P＜0.05). The extent and severity ofarteries pathologic changes in all the initial-stage rats were lighter than those of therats in advanced-stage. It indicated that with the prolonging of age and themenopausal duration, those risk factors in blood associated to cardiovascular diseasehad significant changes and the histopathology of cardiovascular tissue becameunhealthy gradually. 2. The different initial time of HRT had different effects on thelevels of risk factors associated to cardiovascular disease and the istopathology ofcardiovascular tissue. The HRT began from initial-stage acted the best effect oncontrolling rats weight with cholesterol-free diet. To those rats fed with cholesteroldiet (P＜0.05), treatment with high-dose CEE+MPA can control the rats weight ingroups both beginging from initial-stage and advanced-stage (P＜0.05). In rats fedwith cholesterol-free diet, treatment with CEE+MPA regimens decreased TC,TG andHDL levels in groups initiated from initial-stage (P＜0.05), but in groups initiatedfrom advanced-stage only the TC level decreased significantly (P＜0.01). In rats fedwith cholesterol diet, the treatment initiated from initial-stage had the effects ondecreasing TC, TG and LDL respectively (P＜0.01). And the same effect was seen inthose groups which treatment initial from advanced-stage (P＜0.01). HRT alsocontributed the effect of increasing the fibrinogen level in plasma, the C-reactiveprotein and the nitric oxide level in serum significantly (P＜0.05). The same treatment initiated from advanced-stage increased the C-reactive protein and the nitricoxide level respectively (P＜0.05). HRT results in a little vascular change in all thearteries in groups initiated from initial-stage. However in groups initiated fromadvanced-stage, typical atherosclerosis were found in a few of arteries in each of thegroups, but none in the groups of early stage. Treatment with CEE+MPA initiatedfrom initial-stage resulted in a marked decrease in the extent of arteries pathologicchanges according to the scores. The extent and severity of pathologic changes (thelumen area and the thick of vessel wall) in all groups initiated from initial-stage werelighter than those of the groups in advanced-stage. There were no different effect onvascular changes between different groups fed with different diet and there were alsono different effect on vascular changes between HRT and placebo. It indicated thatHRT initiated from different stages that was initiated-stage and advanced-stage haddifferent effect on some cardiovascular risk factors and the histopathological changes.HRT initiated from initial-stage of menopause induced perfect and favorable changes in bloodlipids, effectively in rats fed with cholesterol diet. And those cardiovascular risk factors changedobviously when HRT initiated from initial-stage. Moreover the extent and severity ofpathologic changes were lighter in the same groups initiate from initial-stage.【Conclusion】1. Respecting the different influence result from different age,menopausal duration and diet, both the blood biochemical parameters level and thefundamental vascular conditions were different between different menopausal stagesbefore the HRT initiate. With the prolonging of age and the menopausal duration,those risk factors in blood associated to cardiovascular disease had significant changesand the histopathology of cardiovascular tissue became unhealthy gradually. And thismight be the reason that induced different outcomes of HRT initiated in differentmenopausal stage. 2. The different initial time of HRT had different effects on thelevels of risk factors associated to cardiovascular disease and the istopathology ofcardiovascular tissue. Treatment with different dose of CEE+MPA initiated fromdifferent stages of post-menopause had different effects on some risk factorsassociated with cardiovascular disease and the histopathological changes in rats fedwith different diet. HRT initiated from initial-stage of menopause induced perfect and favorable changes in blood lipids, especially in rats fed with cholesterol diet. Andthose cardiovascular risk factors changed obviously when HRT initiated frominitial-stage. Moreover, the extent and severity of pathologic changes were lighter inthe same groups initiate from initial-stage. HRT initiated from the advanced-stageresult in the severe abnormal pathologic changes such as the atherosclerosis and theplaques in some arteries. 3. Treatment with HRT in different menopausal stages, thelevels' changes of those cardiovascular disease risk factors was not coincidence withthe outcomes of cardiovascular changes in the end point. The way of concluded thecardiovascular outcome according to those risk factor's changes was not reasonablerelatively. It might induced the discrepance about the effects of HRT oncardiovascular.