Dissociation between increased apoptosis and expression of the tumor necrosis factor-alpha system in term placental villi with preeclampsia.

OBJECTIVE: To analyse in situ the placental expression of tumor necrosis factor-alpha (TNF-alpha), its receptors TNFRp55 and TNFRp75, and apoptosis in normotensive and preeclamptic pregnancies. DESIGN AND METHODS: We simultaneously analyzed the immunostaining of TNF-alpha, its receptors and apoptosis in term placentas of 15 patients with preeclampsia and 15 normotensive pregnant women as controls. RESULTS: In normotensive villi TNF-alpha and TNFRp75 were expressed more in syncytiotrophoblasts than cytotrophoblasts or stromal cells, and were almost absent in endothelial cells. TNFRp55 was expressed uniformly in all types of placental cells. Apoptosis was more marked in syncytiotrophoblasts than cytotrophoblasts. In preeclamptic trophoblasts apoptosis was exaggerated whereas expression of TNF-alpha and its receptors remained unchanged. CONCLUSIONS: Placental expression of TNF-alpha and TNFRp75 appear inter-adaptative and follow the same pattern, whereas TNFRp55 and TNF-alpha appear independent. In addition, the exaggerated apoptosis of preeclamptic trophoblasts may be dependent on factors other than the TNF-alpha system alone.

Early occurrence of metabolic syndrome after hypertension in pregnancy.

OBJECTIVE: The objective of the present study was to evaluate the cardiovascular risk profile and the prevalence of metabolic syndrome among women with a history of pregnancy-induced hypertension (PIH). METHODS: From a cohort of 3,799 nulliparous women prospectively recruited between 1989 and 1997, we performed an observational study on 168 case-control pairs 7.8 years after delivery. Participants were scheduled for a visit with a research nurse to evaluate their cardiovascular risk profile using a questionnaire, anthropometric measurements and blood specimen analysis. RESULTS: One hundred sixty-eight women with prior PIH (105 with gestational hypertension and 63 with preeclampsia) and 168 controls matched for age and year of index delivery were evaluated. The women with PIH (34.6 +/- 4.4 years) were more obese and had higher systolic (115 mm Hg versus 108 mm Hg) and diastolic (75 mm Hg versus 70 mm Hg) blood pressures (P < .001) than the 168 controls (35.1 +/- 4.5 years). They had lower high-density lipoprotein cholesterol level (1.30 mmol/L versus 1.42 mmol/L; P < .001), increased fasting blood glucose concentration (5.2 mmol/L versus 5.0 mmol/L; P = .002), and higher insulin levels (119 versus 91 pmol/L; P < .001). The prevalence of the metabolic syndrome was higher in the PIH group (unadjusted odds ratio = 4.9; 95% confidence interval 2.1-10.9) compared with controls, even after adjustment for confounders (adjusted odds ratio = 3.6; 95% confidence interval 1.4 -9.0). CONCLUSION: In white women in their mid-30s, the prevalence of the metabolic syndrome is 3- to 5-fold increased in those with a history of PIH in their first pregnancy. This emphasizes the importance of long-term follow-up assessment for cardiovascular risk factors in these women.

Human chorionic gonadotropin (hCG) may be a marker of systemic oxidative stress in normotensive and preeclamptic term pregnancies.

OBJECTIVES: In vitro studies on placental function have revealed interactions between levels of secretion of human chorionic gonadotropin (hCG) by trophoblastic cells and oxidative stress generated by hydrogen peroxide (H2O2). Here, we have examined the relationship between maternal levels of hCG and H2O2 in vivo in term pregnancies with and without preeclampsia. DESIGN AND METHODS: We measured serum levels of hCG and H2O2 in twenty preeclamptic and twenty normotensive term pregnant women (controls), using an enzymatic immunoassay and an electrochemical method, respectively. RESULTS: Higher levels of serum hCG and H2O2 were observed in patients with preeclampsia in comparison to controls. A significant positive correlation between serum hCG concentration and H2O2 production was found. CONCLUSION: Our results show that: (1) systemic hCG levels are correlated with an oxidative stress state in term pregnant women with preeclampsia and (2) circulating hCG may be a monitoring tool of oxidative stress during pregnancy.

Deficient expression of tumor necrosis factor receptor type 2 in the endometrium of women with endometriosis.

PROBLEM: Tumor necrosis factor-alpha (TNF-alpha) is secreted mainly during the menstrual phase and has been suggested to play a role in induction of apoptosis in endometrial cells and menstrual shedding. TNF-alpha receptor type 2 (TNF-RII) is believed to play a central role in TNFalpha-mediated cytotoxic, mitogenic, anti-proliferative and apoptotic effects. The aim of this study was to assess whether TNF-RII maybe expressed differentially in the endometrium of women with different degrees of endometriosis. METHOD OF STUDY: TNF-RII expression in the endometrial tissue of women with and without endometriosis was investigated by immunohistochemical techniques and in situ hybridization. RESULTS: In histological sections, we observed TNF-RII mRNA and the corresponding protein localized mainly in endometrial glandular cells, with only very faint immunostaining in the surrounding stromal cells. Statistical analysis of our data showed a significant decrease in protein and mRNA expression of TNF-RII in endometrial glandular cells of patients with stages I and II endometriosis compared to normal subjects. TNF-RII expression was also found to decrease significantly in the secretory phase of the menstrual cycle in women with early endometriosis stages (I and II). CONCLUSIONS: In view of the relevant role of TNF-RII in the modulation of the inflammatory and the proapoptotic effects of TNFalpha, deficient expression of TNF-RII mRNA in the endometrium of women at the earliest stages of endometriosis may play a significant role in the pathophysiology of this disease.

Trophoblastic remodeling in normal and preeclamptic pregnancies: implication of cytokines.

OBJECTIVE: To summarize the recent knowledge on the implications of placenta and cytokines in normal and preeclamptic pregnancies. DATA SOURCES: A literature search was conducted of applicable articles related to interactions between trophoblast and cytokines in generating preeclampsia. CONCLUSIONS: The initiating event in preeclampsia has been postulated to be the reduced uteroplacental perfusion as a result of abnormal extravillous cytotrophoblast invasion and remodeling of the uterine spiral arteries. Focal ischemia and hypoxia, deportation of hypoxemic trophoblast cells and abnormal expression of various placental biologic molecules, particularly the cytokines, are thought to lead to widespread dysfunction of the maternal vascular endothelium resulting in overproduction of endothelin and thromboxane, enhanced vascular sensitivity to angiotensin II, and reduced secretion of vasodilators such as nitric oxide and prostacyclin. These alterations, in turn, cause hypertension, proteinuria and edema, and pathologies in many organ systems (kidney, lung, liver, brain).

Soluble interleukin-1 receptor type II blocks monocyte chemotactic protein-1 secretion by U937 cells in response to peripheral blood serum of women with endometriosis.

OBJECTIVE: To assess the ability of peripheral blood serum from women with endometriosis to induce monocyte chemotactic protein-1 (MCP-1) secretion by monocytes and the putative role of the interleukin-1 (IL-1) system in endometriosis-associated monocyte activation. DESIGN: Cultures of U937 monocytic cells exposed to serum from normal women (control group) or women with endometriosis. SETTING: Gynecology clinic and human reproduction research laboratory. PATIENT(S): Seventy-nine women with endometriosis and 38 control women with no evidence of endometriosis at laparoscopy. INTERVENTION(S): Peripheral blood obtained a few days before laparoscopy. MAIN OUTCOME MEASURE(S): MCP-1 secretion in the culture medium and serum concentrations of soluble IL-1 receptor type II (sIL-1RII), IL-1beta, and IL-1alpha by ELISA or by enzyme immunometric assay. RESULT(S): Serum concentrations of sIL-1RII were significantly lower in women with stage I-II endometriosis than in control women, whereas serum concentrations of IL-1beta and IL-1alpha were comparable between the two groups. The serum of women with endometriosis induced higher secretion of MCP-1 by U937 cells than that of control women, particularly in the initial stages of endometriosis (stages I-II), and recombinant IL-1RII (rIL-1RII) significantly blocked that secretion. CONCLUSION(S): These findings point toward a deficiency in the mechanisms involved in the down-regulation of IL-1 actions at the systemic level and reveal sIL-1RII as a key factor involved in that process.

Pathophysiology and maternal biologic markers of preeclampsia.

Preeclampsia-increased blood pressure and proteinuria appearing after the twentieth week of pregnancy--is a major cause of materal and neonatal morbidity, leading to iatrogenic prematurity. Several lines of evidence suggest that the disorder is owing to diminished invasion of spiral arteries by trophoblastic cells, followed by reduced perfusion of the fetoplacental unit and oxidative stress. These alterations, in the presence of maternal predisposition, lead to endothelial dysfunction and occurrence of the clinical syndrome of preeclampsia (multisystemic lesions). Although the pathophysiology of preeclampsia is still unknown, progress has been made during the past 10 yr, and the early identification of at-risk women with the use of biochemical; ultrasonographic; and, more recently, genetic susceptibility markers has been the subject of intense research. In the present review, markers of maternal predisposition, placental implantation, oxidative stress, vasomotor regulation, and endothelial dysfunction are investigated as candidate markers in the early prediction of preeclampsia. Unfortunately, at the present time, no marker has been proven to have a clinically useful predictive performance in the general pregnant population, and, therefore, more research in that area is warranted.