Emmanuel Economou

Maternal serum levels of TNF-alpha and IL-6 long after delivery in preeclamptic and normotensive pregnant women.

Aim. To evaluate maternal TNF-alpha and IL-6 plasma levels in normotensive pregnant women, women with preeclampsia, and to examine the temporal changes in their levels from theantepartum to the postpartum period correlated with the regression of preeclampsia. Method. A prospective study was performed in the 2nd Department of Obstetrics and Gynecology, University of Athens. Blood samples were obtained: (1) antepartum at the time of clinical diagnosis of the syndrome, 2. 12-14 weeks postpartum. Results. No statistically significant differences were found in IL-6 levels, whereas a difference was found in TNF-alpha levels between preeclamptic and controls in antepartum period (0.80 pg/ml versus 0.60 pg/ml, P : .04). Long after delivery, TNF-alpha levels were significantly higher in preeclamptic compared to normotensive controls (0.86 pg/ml versus 0.60 pg/ml, P : .004). No difference was observed in TNF-alpha before and after delivery in both groups. No difference was noticed in IL-6 levels in women of normotensive group long after delivery compared to that before delivery. Long after delivery IL-6 levels were statistically significant higher in preeclamptic women compared to normal controls (3.53 ± 0.52 pg/ml versus 1.69 ± 0.48 pg/ml, P : .02). Conclusion. Preeclamptic women remain under a status of increased inflammatory stress up to 12-14 weeks postpartum despite the fact that all the other signs of preeclampsia are resolved.

Elevated circulating IL-1β and TNF-alpha, and unaltered il-6 in first-trimester pregnancies complicated by threatened abortion with an adverse outcome

The purpose of the present study was to examine the profile of selected proinflammatory cytokines in maternal serum of first-trimester pregnancies complicated by threatened abortion (TACP) and its relevance to obstetric outcome. Serum levels of Th1-type cytokines interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and Th2-type cytokine interleukin 6 (IL-6) were measured, by ELISA, in 22 women with TACP and adverse outcome at admission (group A) and compared with the corresponding levels of 31 gestational age-matched women with TACP and successful outcome at admission (group B1) and discharge (group B2) and 22 gestational age-matched women with first-trimester uncomplicated pregnancy (group C) who served as controls. Mann-Whitney U or Wilcoxon test was applied as appropriate to compare differences between groups. IL-1beta and TNF-alpha were detected with significantly higher levels in group A, compared to all other groups. On the contrary, IL-6 levels were detected with no significant difference among all the other groups studied. It is concluded that in first-trimester TACP with adverse outcome, a distinct immune response, as reflected by elevated maternal IL-1beta, TNF-alpha, and unaltered IL-6 levels, is relevant to a negative obstetric outcome.

The Varying Patterns of Neurotrophin Changes in the Perinatal Period

Abstract:  Neurotrophins (NTs), nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), NT‐3, and NT‐4 are of major importance in prenatal and postnatal brain development, due to their neuroprotective action. Developmental changes alter the neuronal responsiveness to certain NTs, which subsequently are variously expressed, to properly balance their action. The following study aimed at examining the pattern of perinatal changes of the four NTs—NGF, BDNF, NT‐3, and NT‐4 in 30 appropriate for gestational age (AGA) full‐term fetuses and neonates by determining their circulating levels at characteristic time points. This study show a gradual decrease of circulating levels of the NTs, NT‐3 and NT‐4 from umbilical cord (UC) to neonates day 4 (N4), while circulating levels of NGF and BDNF present the opposite pattern: an increase from UC to N4. These patterns of perinatal changes differ according to their impact on the process of neuronal development and their reaction to perinatal stress. NT3 and NT4 have been documented to act at early stages of neuronal development and to decrease after hypoxia‐ischemia, while NGF and BDNF to increase. Further studies should investigate these patterns in premature or full‐term infants, presenting various pathological conditions in the perinatal period.

Vascular Endothelial Growth Factor and Placenta Growth Factor in Intrauterine Growth-Restricted Fetuses and Neonates

The angiogenic factors vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) are respectively up- and downregulated by hypoxia. We aimed to study circulating levels of the above factors in intrauterine growth restriction (IUGR) and to correlate their levels with the customized centiles of the infants. The study included 25 IUGR and 25 appropriate for gestational age (AGA) full-term, singleton infants and their mothers. Maternal (MS), fetal (UC), and neonatal day 1 (N1) and 4 (N4) blood was examined. MS and N1 PlGF, as well as UC VEGF levels correlated with the customized centiles of the infants (r= 0.39, P=.007, r=0.34, P=.01, and r= -0.41, P=.004, resp). Furthermore, UC, N1, and N4 VEGF levels were higher in girls (r=0.36, P=.01, r=0.33, P=.02, and r=0.41, P=.005 resp). In conclusion, positive and negative correlations of examined factors with the customized centiles of the infant could rely on placental function and intrauterine oxygen concentrations-both being usually lower in IUGR cases-while higher VEGF levels in girls should possibly be attributed to the stimulating action of estrogens.

Circulating leptin and ghrelin are differentially influenced by estrogen/progestin therapy and raloxifene.

BACKGROUND Leptin and ghrelin are increasingly being recognized as cardiotropic hormones, promoting or inhibiting the atherosclerotic process, respectively. Apoptosis may be one pathway through which the actions of these hormones are mediated. Sex hormones are reported to influence the secretion and action of ghrelin and leptin. OBJECTIVE To evaluate (1) the association of circulating ghrelin and leptin with selected markers of receptor-mediated apoptosis and (2) the effect of estrogen monotherapy, low dose estrogen-progestin therapy, tibolone and raloxifene on serum ghrelin and leptin in healthy postmenopausal women. METHODS Eighty eight postmenopausal women aged 44-62 years were randomly allocated to daily (1) conjugated equine estrogens 0.625 mg (CEE), (2) 17beta-estradiol 1mg plus norethisterone acetate 0.5 mg (E(2)/NETA), (3) tibolone 2.5mg, (4) raloxifene HCl 60 mg or (5) no treatment. Serum markers of apoptosis sFas, Fas-ligand (Fas-L) and caspase-1 were measured at baseline. Serum leptin and ghrelin were measured at baseline and at 3 months. RESULTS Body Mass Index (BMI) and estradiol levels correlated positively, while FSH correlated negatively with serum leptin (BMI: r=0.646, p=0.005, estradiol: r=0.432, p=0.001, FSH: r=-0.401, p=0.002). Insulin levels associated positively with circulating leptin (r=0.394, p=0.011) and negatively with circulating ghrelin (r=-0.401, p=0.009). Serum leptin decreased significantly in E2/NETA group (baseline: 2.882+/-0.76 ng/ml, 3 months: 2.687+/-0.66 ng/ml, p=0.043), while it increased significantly in the raloxifene group (baseline: 2.671+/-0.54 ng/ml, 3 months: 2.839+/-0.47 ng/ml). Ghrelin levels decreased significantly only in the raloxifene group (baseline: 1634+/-592 pg/ml, 3 months: 1408+/-534 pg/ml). CONCLUSION Apoptosis may be a pathway through which leptin exerts a pro-atherogenic effect. Low dose HT may act cardioprotectively by decreasing leptin levels in healthy recently menopaused women.

The Role of the Anti-Angiogenic Factor Endostatin in Intrauterine Growth Restriction

Objective: To study the impact of intrauterine growth restriction (IUGR) on anti-angiogenesis, by determining and comparing circulating levels of the potent anti-angiogenic factor endostatin, in full-term IUGR (under the 10th customized centile) and appropriate for gestational age (AGA)fetuses, neonates, as well as their mothers, granted that IUGR implies hypoxia and endostatin is down-regulated by the latter. Methods: In 20 IUGR cases (mainly due to hypertension or preeclampsia) and 20 AGA controls we detenmined circulating endostatin levels, by enzyme immunoassay in the serum of mothers (MS), umbilical cords (UC-mixed arteriovenous blood)-representing the fetal state, and asymptomatic neonates on day 1 (N1) and 4 (N4) of lfe-signifying transition and stabilization to extrauterine life, respectively. Results: Endostatin levels were significantly higher in AGA than IUGR UC, N1, and N4 (P <. 0000, P = .0006, P = .024, respectively). Furthermore, UC endostatin levels positively correlated with the customized centiles of the infants (Spearman correlation coefficient 0. 69, P = .00001). Conclusions: IUGR is characterized by lower circulating endostatin concentrations in the fetus and neonate, possibly because under lower oxygen concentrations an unbalanced state of angiogenesis stimulators versus inhibitors takes place.

Differential effect of hormone therapy and tibolone on lipids, lipoproteins, and the atherogenic index of plasma

The aim of our study was to assess the effect of various regimens and doses of hormone therapy and tibolone on the Atherogenic Index of Plasma (AIP). A total of 519 postmenopausal women attending our menopause clinic were studied in a prospective design. Women with climacteric symptoms were randomly assigned to receive 1 of the following regimens: tibolone 2.5 mg, conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA), 17β-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA), or 17β-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA). Serum parameters were assessed at baseline and after 6 months and included total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein A1 and apolipoprotein B. The AIP was assessed as the log (triglycerides [mmol/L]/HDL-C [mmol/L]). CEE/MPA treatment associated with lower mean LDL-C but higher mean triglyceride levels (−15.5 mg/dL±3.6, P=0.0001; 12.6 mg/dL±4.8, P=0.01). Furthermore, CEE/MPA treatment resulted in higher AIP levels (0.073±0.021, P=0.001). On the contrary, both E2/NETA regimens and tibolone associated with lower mean triglyceride and HDL-C levels (E2/NETA, triglycerides: −9.8 mg/dL±5.0, P=0.049; HDL-C: −4.9 mg/dL±1.8, P=0.01, low E2/NETA triglycerides: −12.5 mg/dL±4.1, P=0.003; HDL-C: −4.7 mg/dL±1.3, P=0.001; tibolone, triglycerides: −21.9 mg/dL±2.7, P=0.0001; HDL-C: −12.7 mg/dL±1.1, P=0.0001). None of the 3 regimens had any effect on AIP. The effect of a particular regimen of hormone therapy on the lipid-lipoprotein profile differs depending on the parameter assessed. The use of unified markers such as AIP will be helpful in evaluating the overall effect of lipid-lipoprotein modulation on the cardiovascular system. In fact, the concurrent assessment of the therapy effect on both LDL-C and AIP may be more dependable in evaluating the cardiovascular impact of a given regimen.

Angiopoietin-2 in the perinatal period and the role of intrauterine growth restriction

Background. Angiopoietin‐2, an angiogenic factor, causing destabilization and postnatal remodeling of blood vessels, is upregulated by hypoxia. We hypothesized that circulating Angiopoietin‐2 levels might differ in intrauterine growth restricted and appropriate for gestational age fetuses and neonates, as the former have restricted growth and development and suffer from in utero hypoxia. Methods. This is a prospective, controlled study, including forty asymmetric, mainly due to hypertension or pre‐eclampsia intrauterine growth restricted (0–9 customized centiles, corrected for gestational age, sex, maternal weight, height, ethnic group, and parity), and 20 appropriate for gestational age (42–82 customized centiles) full‐term infants, as well as their mothers. Blood samples were drawn from mothers, from the doubly clamped umbilical cord (mixed arteriovenous blood, representing fetal state), and from neonates on days 1 (N1) and 4 (N4) of life (representing transition and stabilization to extrauterine life, respectively). Circulating angiopoietin‐2 levels were measured by enzyme immunoassay and the statistical analysis involved t‐test and Pearson correlation. Results. Angiopoietin‐2 levels were significantly higher in intrauterine growth restricted cases only in N4 (p=0.04). No dependence on the mode of delivery and gender was documented. Conclusions. These findings may suggest that intrauterine hypoxia possibly does not upregulate circulating angiopoietin‐2 levels in intrauterine growth restricted fetuses and day 1 neonates; however, increased angiopoietin‐2 on N4, after stabilization to extrauterine life, might signify initiation of catch‐up growth‐related angiogenesis and stimulation of angiogenic factors, granted that angiopoietin‐2 is critically involved in postnatal vascular remodeling.

Circulating levels of atherogenesis-associated adipocytokines and apoptotic markers are differentially influenced by hormone therapy, tibolone and raloxifene in healthy postmenopausal women.

Objective Estrogen agonist compounds may exert cardioprotective activity by modulating adipocytokine concentration and apoptosis. The objective of this study was to evaluate the effects of hormone therapy, tibolone and raloxifene on the serum adipocytokines resistin and adiponectin as well as on circulating markers of receptor-mediated apoptosis. Design Randomized, open-label, intervention study in the Menopause Clinic of a University Hospital. Methods One hundred healthy postmenopausal women were randomized to the following groups: conjugated equine estrogens 0.625 mg (CEE) (n = 16); 17β-estradiol 1 mg plus norethisterone acetate 0.5 mg (E2/NETA) (n = 15); tibolone 2.5 mg (n = 18); raloxifene HCl 60 mg (n = 20); and no treatment (n = 19). Eighty-eight women completed the 3-month study period. Main outcome measures were levels of serum adiponectin, resistin, soluble Fas and Fas ligand. Results Levels of serum adiponectin decreased significantly in the tibolone group (baseline: 10 556.7 ± 4213.5 ng/ml; 3 months: 7856.3 ± 3450.7 ng/ml; p = 0.0001) and increased in the CEE group (baseline: 9268.1 ± 5158 ng/ml; 3 months: 11 302.6 ± 4980.9 ng/ml; p = 0.01). Serum resistin values increased only in the tibolone group (baseline: 2.81 ± 0.89 ng/ml; 3 months: 3.55 ± 1.31 ng/ml; p = 0.04), while the level of Fas ligand decreased significantly in the E2/NETA (baseline: 70.4 ± 21.9 pg/ml; 3 months: 62.1 ± 18.6 pg/ml; p = 0.02) and tibolone group (baseline: 68.2 ± 25.7 pg/ml; 3 months: 59.2 ± 21.7 pg/ml; p = 0.01). Conclusions Of the regimens investigated, only unopposed estrogens may exert an atheroprotective effect through the increase of adiponectin and a resultant favorable lipid and anti-inflammatory profile.

Endothelin 1-21 Plasma Concentrations on Days 1 and 4 of Life in Healthy and III Preterm Neonates

Endothelins (ETs) are highly vasoconstrictive 21-amino acid peptides possessing also cell-proliferative properties. They have been implicated in a variety of perinatal pathologic conditions, and their plasma concentrations have been found elevated in humans at birth. The purpose of this study was to determine ET 1-21 plasma concentrations in healthy and ill preterm infants and to investigate possible concentration changes with time from birth in cases of normal and abnormal adaptation to extrauterine life. The study comprised 36 preterm infants. Twenty-eight, comprising group A, were healthy (22/28) or minimally affected (6/28) and 8, comprising group B, were moderately (2/8) or severely ill (6/8) requiring continuous positive airway pressure or intermittent positive pressure ventilation as well as surfactant administration. All infants in group B had intraventricular hemorrhage grade > or = II. Venous blood from all neonates was drawn on days 1 and 4 and ET 1-21 plasma concentrations were determined by radioimmunoassay (Amersham kit RPA 5559). ET 1-21 plasma concentrations were on day 1: 16.25 +/- 8.14 and 21.81 +/- 5.87 and on day 4: 12.89 +/- 4.56 and 16.16 +/- 5.43 pmol/l, for groups A and B, respectively. The statistical analysis showed a significant reduction in plasma ET concentrations on day 4 in both groups (p = 0.009 and p = 0.025, respectively). Nevertheless, ET 1-21 plasma concentrations were on day 4 significantly higher in ill preterm infants presenting symptoms from tissues involved in the elimination of ETs from the circulation as well as in their production.