| Preeclampsia is a pregnancy-specific disorder and an important cause of maternal and fetal morbidity and mortality worldwide. It can be further differentiated into mild and severe forms. Patients with severe preeclampsia have severe hypertension, proteinuria, or evidence of other end-organ dysfunction. It remains unclear about the detail pathogenesis of preeclampsia, which make this complex disorder has no effectively treatment approaches. Investigations into the pathophysiology of preeclampsia have provided exciting new insights into potential mechanisms and continue to move the field forward. The initiating event in preeclampsia is generally regarded to be placental-bed vascular insufficient remodeling and then placental ischemia/hypoxia, resulting in the transferring of a variety of factors from the placenta to maternal circulation and systemic vascular endothelium dysfunction and (or) activation.Asymmetric dimethylarginine (ADMA) is a critical endogenous inhibitor of nitric oxide synthetase (NOS). Elevations of ADMA have previously been associated with endothelial dysfunction in preeclampsia. ADMA is degraded mainly by dimethylarginine dimethylaminohydrolase (DDAH) which is reported as reduced expression and activity in preeclampsia.Recent studies show that estrogen and progesterone levels are abnormal in preeclampsia, but there lacks of strong evidence and the specific mechanism is unclear. Over the years generous literatures reported that decrescence of estrogen is related with a variety of cardiovascular diseases like hypertension. So far, the effects of progesterone on cardiovascular function remain controversial. Studies suggest that progesterone may adopt with estrogen synergistically or antagonistically to participate in the regulation of cardiovascular function, however, the mechanism of interaction of progesterone and estrogen in cardiovascular disease is not clear. Research has shown that high levels of progesterone may inhibit eNOS gene transcription and activity through combining with glucocorticoid receptor, and thus NO synthesis decreased, affecting the regulation of blood pressure. The latest research confirms estradiol alleviates asymmetric dimethylarginine (ADMA) increase responded on the reduced expression and activity of dimethylarginine dimethylaminohydrolase(DDAH) through estrogen receptora.During preeclampsia, pathophysiological change of the placenta is the initial onset. Whether there is a relationship of ADMA expression in the placenta and maternal circulation? Whether the dysfunction of syncytiotrophoblast caused by placental ischemia/hypoxia will induce abnormal synthesis and secretion of estrogen and progesterone into the maternal circulation or not? Whether the change of the concentration of estrogen and progesterone are correlated with ADMA level or not? Whether the changes of the levels of estrogen, progesterone and ADMA in maternal peripheral blood is relevant to the clinical manifestation or not? There are currently quite limited studies in the literature.Chapter I Serum and Placental Expression of ADMA in Severe PreeclampsiaOBJECTIVE:To research the serum and placental expression of ADMA in severe preeclampsia and their correlation and to approach the possible role of placenta on ADMA regulation in severe preeclampsia.METHODS:There were62severe preeclampsia patients selected from Second Xiangya Hospital outpatient. At the same period a total of75normotensive pregnant women were selected.30cases were selected among the above women who had a cesarean section in our hospital and their placenta samples were collected. Enzyme-linked immunosorbent assay (ELISA) method was used for measurement of ADMA in maternal serum and placenta.RESULTS:Serum ADMA levels in severe preeclampsia and normal pregnancy control group were1.90±0.21μmol/L and1.30±0.16μmol/L (P=0.000). Moreover, the ADMA content in the homogenate of placental in P and C groups (n=15,15) were2.42±0.23μmol/L,1.98±0.19pmol/L (P=0.000). The placental-homogenate ADMA level in P group is significantly higher than the maternal serum concentration (P=0.000) and both were positively correlated (r=0.65, P=0.009).CONCLUSION:Concentration of ADMA was significantly higher both in the homogenate of placenta and maternal peripheral circulation of severe preeclampsia, and higher content of ADMA in the homogenate of placenta than in the maternal serum was observed as well. There was a positive correlation between the level of ADMA in maternal serum and the homogenate of placenta of severe preeclampsia.Chapter II Serum Estradiol and Progesterone Expression in Severe PreeclampsiaOBJECTIVE:To study serum estradiol and progesterone expression in severe preeclampsia and to investigate their roles in the development of severe preeclampsia. Then to analyze the correlation of serum estradiol, progesterone and ADMA for further understanding of their effect and mechanism in the pathogenesis of severe preeclampsia.METHORDS:There are62severe preeclampsia patients selected from Second Xiangya Hospital outpatient and they are divided into P1sub-group (28+1-32weeksof pregnancy, n=22), P2sub-group (32+1-36weeks of pregnancy, n=20), P3sub-group (36+1-40weeks of pregnancy, n=20) depending on the gestational age. At the same period a total of75normotensive pregnant women were selected and also divided by gestational age into C1sub-group (28+1-32weeks of gestation, n=25), C2sub-group (32+1-36weeks of gestation, n=25), C3sub-group (36+1-40weeks of pregnancy, n=25). Use the chemiluminescence immunoassay (CLIA) method for the determination of serum concentration of estradiol (E2) and progesterone (Pg).RESULTS:1. During the normal pregnancy group, the serum levels of E2in C1, C2, C3sub-groups were:13.31±2.20ng/ml,19.13±1.81ng/ml and22.76±3.17ng/ml respectively and the Pg concentrations were as follows:105.76±14.56ng/ml,138.76±13.72ng/ml and182.68±17.81ng/ml, both of E2and Pg showed an increasing trend following the increasing of gestational age. During severe preeclampsia group, serum estradiol levels of P1, P2, P3sub-groups were:11.71±1.97ng/ml,13.33±2.60ng/ml,17.28±2.88ng/ml, and progesterone content:117.03±17.47ng/ml,149.39±27.70ng/ml,192.16±30.55ng/ml. Both of E2and Pg levels in severe preeclampsia persist the increasing tendency with increasing gestational age, however, between P1and C1sub-groups, P2and C2sub-groups, P3and C3sub-groups, there are significant differences of the distribution of estradiol levels (P<0.05); for progesterone, the only significant difference was observed between P1and C1sub-groups (P<0.05); between P2and C2sub-groups, P3and C3sub-groups, the difference was not significant (P>0.05).2. Progesterone/estradiol (Pg/E2) ratio in severe preeclampsia group (P group, n=62) was10.70(10.14-11.52) which is significantly higher than the Pg/E2ratio in normal pregnancy control group (C group, n=75)(P=0.000).3. In both severe preeclampsia group (P group, n=62) and normal pregnancy control group (C group, n=75), separate E2or Pg has no significant correlation with serum ADMA (r=0.04P=0.785, r=0.015P=0.897; r=0.24P=0.058, r=0.20P=0.094), while there is a significant high positive correlation between Pg/E2ratio of serum ADMA levels (r=0.77,0.57P=0.000).CONCLUSION:1. The estradiol concentration in the peripheral blood serum of severe preeclampsia women continued persistently and significantly reduced level during the third trimester of pregnancy while the progesterone/estradiol (Pg/E2) ratio was significant higher than normal pregnancy women. Therefore, reduced serum estradiol concentration and imbalanced Pg/E2radio may be involved in the pathogenesis of preeclampsia.2. The Pg/E2ratio was positively correlated with the serum ADMA concentration in the peripheral blood of women with severe preeclampsia. Chapter III Correlation between ADMA, Progesterone/Estradiol radio and Clinical Manifestations in Severe Preeclampsia and Their Possible Application in Disease AssessmentOBJECTIVE:To research the correlation between ADMA, Progesterone/Estradiol radio and clinical manifestations in severe preeclampsia for providing new indicators for the assessment of disease progression and treatment. Then to screen important factors in preeclampsia and to provide a preliminary basis for the establishment of sever preeclampsia ideal diadynamic criteria.METHODS:The patient group and normal control group were split as the same as Chapter II. Besides, blood pressure was measured for every woman. For patient group, proteinuria during24hr was also collected and fundus examination was undertaken. In addition, by fundus examination in severe preeclampsia group, observation of pathological changes such as retinal artery spasm, more than1:2of retinal arteriovenous ratio, papilledema, flocculent exudate or hemorrhage and retinal detachment was regarded as positive retinal blood vessels lesions, denoted by1, otherwise, it was treated as negative retinal blood vessels lesions, denoted by0.RESULTS:1. Serum ADMA level in patients with severe preeclampsia has a moderate positive correlation with systolic blood pressure(r=0.422P=0.001) and slight positive correlation with diastolic blood pressure (r=0.292P=0.021). The Pg/E2ratio in the maternal serum of severe preeclampsia has a low positive correlation with systolic blood pressure the patient, the correlation coefficient was0.260(P=0.041).2. ROC curve showed that the area under the curve (AUC) of serum ADMA was0.997(P=0.000,95%CI:0.968-1.0) with98.4%sensitivity and86.0%specificity; the AUC of serum Pg/E2radio was0.993(P=0.000, CI:0.961-0.999) with98.4%sensitivity and95%specificity.CONCLUSION:1. There was a significant positive correlation between serum ADMA level and systolic blood pressure and diastolic blood pressure of severe preeclampsia patients, and the Pg/E2radio was positively correlated with systolic blood pressure of severe preeclampsia patients, suggesting that serum Pg/E2ratio and ADMA levels may provide the basis for the assessment of disease severity.2. Maternal serum ADMA levels and Pg/E2ratio were closely related with severe preeclampsia and may have diagnostic value.7figures,6tables and54references... |
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