Platelet Glycoprotein Receptor Ia-C807T and IIIa-PlA1/PlA2 Genetic Polymorphisms Are Associated With Enhanced Platelet Function in Women With Recurrent Miscarriages.

INTRODUCTION: Thrombophilic genetic polymorphisms of the platelet glycoproteins Ia (GpIa) and IIIa (GpIIIa) have been associated with an increased risk of recurrent miscarriages. The aim of this study was to investigate the association of genetic polymorphisms GpIa-C807T and GpIIIa-T1565C-PlA1/PlA2 with platelet function in women with unexplained spontaneous recurrent miscarriages. METHODS: This cross-sectional study comprised 196 unrelated nulliparous Greek women with a history of unexplained recurrent miscarriages. Patients were genotyped for the presence of the GpIa-C807T (rs1126643) and GpIIIa-T1565C-PlA1/PlA2 (rs5918) genetic polymorphisms by pyrosequencing, and the collagen/epinephrine closure time (COL/EPI CT) of the subjects was assessed using the platelet function analyzer (PFA)-100. RESULTS:  In the total population of women with recurrent miscarriages, the COL/EPI CT ranged from 70 to 160 seconds (median: 122 seconds, interquartile range (IQR): 102.3-138 seconds). In comparison with the double homozygotes CC/PlA1PlA1 that had the most prolonged CT (mean: 131.9 ± 17.5 seconds), the COL/EPI CT was statistically significantly shorter for the GpIa-807T single carriers (mean: 120.3 ± 20.9 seconds) (p=0.011) (absolute difference: 11.6 seconds, 95% confidence interval (CI): 21.2 to -2.0 seconds; relative difference: -9%, 95% CI: -16% to -2%), and the GpIIIa-PlA2 single carriers also displayed a trend for shorter COL/EPI CT (mean: 121.3 ± 23.7 seconds) (p=0.141) (absolute difference: -10.6 seconds, relative difference: -8%), whereas the combined carriers of the GpIa-807T and the GpIIIa-PlA2 alleles exhibited the shortest COL/EPI CT (mean: 104.1 ± 19.7 seconds) (absolute difference: -27.7 seconds, 95% CI: -39.1 to -16.3 seconds; relative difference: -21%, 95% CI: -30% to -12%) (p<0.001). In comparing genotype frequencies in the lower half with those in the upper half of the COL/EPI CT range, the GpIa-807T and the GpIIIa-PlA2 single carriers were associated with higher odds of COL/EPI CT < 122 seconds (odds ratio (OR)=3.4, 95% CI: 1.5 to 7.5, p=0.002, and OR=2.6, 95% CI: 1.0 to 7.2, p=0.053, respectively). The association was strongest for the combined carriers with OR of 15.0 (95% CI: 5.2 to 43.2, p<0.001) for COL/EPI CT below the median and OR of 35.5 (95% CI: 4.4 to 284.5, p<0.001) for COL/EPI CT < 100 seconds. CONCLUSION: The GpIa-C807T and GpIIIa-PlA1/PlA2 polymorphisms and more pronouncedly the combined carriers of the risk variants are associated with enhanced platelet reactivity expressed via shorter COL/EPI CT. These findings provide further evidence for the role of platelet-associated genetic thrombophilia in the pathogenesis of recurrent miscarriages and promote the analysis of platelet function as a diagnostic tool in the evaluation of this disorder.

Human Leukocyte Antigen Alleles Compatibility and Immunophenotypic Profile Associations in Infertile Couples.

INTRODUCTION: The maternal immune system has a major role in the successful embryo implantation and maintenance of the pregnancy. This study aimed to investigate the maternal immunophenotyping profile (percentage of Natural Killer [NK] cells and the CD4/CD8 [cluster designation] ratio in peripheral blood lymphocytes) and the HLA (Human Leukocyte Antigen)-DQA1 alleles sharing in infertile couples. METHODS: This cross-sectional study included 78 women who had experienced at least two spontaneous miscarriages and 110 women with a history of recurrent implantation failures after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) (IVF-ET failures). The NK cell percentage and the CD4/CD8 ratio were determined by flow cytometry. Genotyping of the HLA-DQA1 alleles was carried out for all women and their partners, and couple HLA-DQA1 compatibility was expressed as the percentage of common HLA-DQA1 alleles (totaling 35 alleles) shared between spouses to the sum of the unique alleles observed. RESULTS: In women with recurrent miscarriages, high values (%) of the NK population with a median (interquartile range [IQR]) of 10.3% (7.7% to 12.5%) and CD4/CD8 ratio (1.7) (1.5 to 2.1) were found. In women with IVF-ET failures, the (%) NK population (10.5%) (8.6% to 12.5%) and CD4/CD8 ratio (1.8) (1.5 to 2.1) were similarly increased (p=0.390, and p=0.490, respectively). The proportion of women with >10% NK cells was 53.8% and 58.2% in women with miscarriages and IVF-ET failures, respectively (p=0.554). The prevalence of HLA-DQA1*5 allele carriage was elevated in women with miscarriages as well as those with IVF-ET failures (52.6% and 61.8%, respectively; p=0.206). The proportion of couples with high (>50%) HLA-DQA1 sharing was 65.4% in the group with miscarriages and 73.6% in the group with IVF-ET failures, respectively (p=0.222). The CD4/CD8 ratio was statistically significantly positively correlated with the (%) NK population in women with IVF-ET failures (rho = 0.297, p=0.002) and with the (%) HLA-DQA1 sharing in the group with miscarriages (rho = 0.266, p=0.019). The couples in which both spouses were carriers of the HLA-DQA1*5 allele had an increased probability of high (>50%) HLA-DQA1 compatibility compared with the couples in which neither of the spouses carried the allele in the miscarriage group (OR = 24.3, 95% CI: 3.0 to 198.9, p<0.001), and the IVF-ET failure group (OR = 10.5, 95% CI: 2.2 to 49.8, p<0.001). CONCLUSION: The peripheral NK (%) population and CD4/CD8 ratio, as well as the prevalence of the HLA-DQA1*5 allele, were elevated in women with recurrent miscarriages and IVF-ET failures. Furthermore, these couples with negative reproductive outcomes had a high percentage of HLA-DQA1 allele similarity. The presence of the HLA-DQA1*5 allele in spouses was strongly associated with overall couple HLA-DQA1 compatibility, implying that it could be used as a surrogate marker for assessing overall immunological compatibility in infertile couples.

Association of the PECAM-1 (Leu125Val) and P-Selectin (Thr715Pro) Gene Polymorphisms With Unexplained Spontaneous Miscarriages.

INTRODUCTION: The aim of this study was to investigate the possible effect of the PECAM-1-C373G (Leu125Val) and P-Selectin-A37674C (Thr715Pro) polymorphisms in unexplained spontaneous abortions. METHODS: In a case-control design, Greek nulligravida women with recurrent idiopathic miscarriages <20 weeks of gestation and fertile controls were genotyped by pyrosequencing. RESULTS: There was no significant association of the PECAM-1-C373G (Leu125Val) polymorphism with recurrent abortions. Although the P-Selectin-A37674C (Thr715Pro) polymorphism was not associated with miscarriages overall, the association was statistically significant for younger women (carriers of the P-Selectin-37674C allele: <35 years: odds ratio (OR) = 3, 95% confidence interval (CI): 1.13-7.97, p = 0.023; <30 years: OR = 6.75, 95%CI: 2.02-22.58, p = 0.002). In comparison with CC/AA genotype, the combined carriers of the PECAM-1-373G and P-Selectin-37674C alleles had OR =8.81 (95%CI: 1.07-72.50, p = 0.024). The association of the coexistence of the two polymorphisms was stronger in younger women (<35 years: OR = 12.07, 95%CI: 1.38-105.68, p = 0.014; <30 years: OR = 65, 95%CI: 3.38-1251.28, p = 0.001), and late (OR = 10.64, 95%CI: 1.16-97.60, p = 0.024) and second-trimester miscarriages (OR = 26, 95%CI: 1.84-367.71, p = 0.014). The association between carriage of the P-Selectin-37674C allele and recurrent miscarriages was significant for younger women. CONCLUSION: The coexistence of the PECAM-1-373G and P-Selectin-37674C alleles increased the miscarriage risk for the total population studied, suggesting an interaction between the two polymorphisms, more pronouncedly in younger women and the association was stronger for late fetal loss.

MTHFR Polymorphisms in Girls with Anorexia Nervosa: Implications on Body Weight.

The development of atypical vs typical anorexia nervosa (AN) might be explained by the genetic background. We assessed the link between the subtypes of AN and the genetic polymorphisms of the thrombotic panel and the methyltetrahydrofolate reductase (MTHFR) gene. This cross-sectional pilot study recruited 48 girls with AN and 10 age-matched control girls with normal menstruation. We recorded anthropometric parameters and obtained blood samples for genotyping and hormonal assessment. Classification of AN was performed according to the DSM-V criteria. Girls with AN had 2.66 times higher odds of carrying at least one genetic polymorphism from the MTHFR panel (C677T and A1298C) compared with girls without AN (OR = 2.660, p-value = 0.041; CI 95% 1.057-6.720). The presence of atypical vs typical AN was associated independently with the presence of any of the assessed MTHFR polymorphisms (C677T, OR = 4.929, 95% CI 1.076-22.579, p-value = 0.040; A1298C, OR = 0.097, 95% CI 0.011-0.866, p-value = 0.037) in age and estrogen adjusted models. The atypical presentation of AN is mainly linked with higher prevalence of the MTHFR C677T and lower prevalence of the A1298C polymorphism.

Associations of combined polymorphisms of the platelet membrane glycoproteins Ia and IIIa and the platelet-endothelial cell adhesion molecule-1 and P-Selectin genes with IVF implantation failures.

The aim of the study was to investigate the combined impact of the genetic heterogeneity of the glycoproteins Ia (GpIa) and IIIa (GpIIIa) and the platelet-endothelial cell adhesion molecule-1 (PECAM-1) and P-Selectin genes on IVF embryo transfer implantation failures (IVF-ET failures). Sixty nulligravida women with previous IVF-ET failures and 60 fertile controls were genotyped for the GpIa-C807T, GpIIIa-PlA1/PA2, PECAM-1-C373G (Leu125Val) and P-Selectin-A37674C (Thr715Pro) polymorphisms by pyrosequencing. Compared with wild-type combined homozygotes, carriers of combinations of risk alleles in two gene loci were at significantly increased risk for IVF-ET failure, whereas carriers of the combination of GpIa-807T, GpIIIa-PlA2 and PECAM-1-373G alleles had OR = 52.50 (95%CI: 4.05-680.95, p < .001). The area under the receiver-operating characteristic curve (AUC) based on the number of polymorphisms and the number of risk alleles per subject was 75.4% (95%CI: 66.7%-82.8%, p < .001) and 72.5% (95%CI: 63.6%-80.3%, p < .001), respectively. The OR per polymorphism and risk allele increase was 4.26 (95%CI: 2.15-8.41, p < .001) and 2.85 (95%CI: 1.71-4.76, p < .001), respectively. The above associations were more robust among younger women. The combined analysis of these polymorphisms revealed strong association of combined carriers with IVF-ET failures especially for younger women and provided a genetic risk score with good diagnostic accuracy in the prediction of IVF-ET failures.

Polymorphisms of Platelet Glycoprotein Receptors and Cell Adhesion Molecules in Fetuses with Fetal Growth Restriction and Their Mothers As Detected with Pyrosequencing.

BACKGROUND: Vascular thrombotic tendency may lead to fetal growth restriction (FGR). Altered platelet function and genetic heterogeneity may play a role in this procedure. We investigated whether maternal or fetal genotypic frequencies of genes polymorphisms for certain platelet receptor and cell adhesion molecules are altered in FGR. MATERIALS AND METHODS: We compared the maternal and fetal genotypic frequencies of single nucleotide polymorphisms (SNPs) in four genes coding for platelet receptors and cell adhesion molecules [integrin alpha subunit 2 (ITGA2)C807T, integrin subunit beta 3(ITGB3) T1565C, platelet cell adhesion protein 1 (PECAM1) CTG-GTG and selectin P(SELP)A/C]. A total of 32 fetuses with fetal growth restriction and their mothers were matched with 18 normal controls. Using maternal venous blood and umbilical cord blood samples, nucleotide sequences were determined from pyrograms. Genotypic frequencies were calculated and analyzed using appropriate tests and logistic regression. RESULTS: There was no statistical difference in the proportion of heterozygotes or homozygotes for any of the genotypic frequencies between FGR and control groups in mothers or fetuses. CONCLUSION: Our study demonstrated no association of maternal or fetal ITGA2 C807T SNP, ITGB3 T1565C SNP, PECAM1 CTG - GTG and SELP A/C polymorphisms with FGR.

Genetic heterogeneity of platelet glycoproteins Ia and IIIa and the risk of spontaneous miscarriages.

OBJECTIVE: The aim of this study was to investigate the association between the genetic heterogeneity of platelet glycoproteins Ia (GpIa-C807T) and IIIa (GpIIIa-PlA1/PlA2) and spontaneous abortions. STUDY DESIGN: Two hundred and twenty two women with a history of unexplained spontaneous miscarriages and no successful pregnancy, and 60 fertile women serving as controls were genotyped for the GpIa-C807T and GpIIIa-PlA1/PlA2 polymorphisms by pyrosequencing. RESULTS: In comparison with the common alleles homozygotes, GpIa-807T and GpIIIa-PlA2 carriers had an increased risk of fetal loss (OR = 3.36, 95%CI: 1.85-6.11, p < 0.001, and OR = 2.58, 95%CI: 1.30-5.13, p = 0.006, respectively). For subjects who were combined carriers of the GpIa-807T and GpIIIa-PlA2 alleles, the risk increased further (OR = 9.13, 95%CI: 2.99-27.82, p < 0.001). The above ORs were highest for women who were younger than 30 years of age. CONCLUSIONS: The GpIa-C807T and GpIIIa-PlA1/PlA2 polymorphisms and more pronouncedly their combination are associated with increased risk of spontaneous abortions. The correlations were stronger for younger patients. Our results indicate that GpIa-807T and GpIIIa-PlA2 are susceptibility alleles for fetal loss in the Greek population.

The effect of hormone therapy on biochemical and ultrasound parameters associated with atherosclerosis in 46,XY DSD individuals with female phenotype.

The aim of this study was to evaluate the effect of hormone therapy (HT) in the endothelial function of 46,XY disorders of sexual development (DSD) patients with female phenotype. Biochemical and ultrasound measurements were performed in 20 patients at initiation of oral 2 mg 17ß-estradiol/1 mg norethisterone acetate, and after 6 months of therapy. Lipid profile, including total cholesterol (TC), LDL, HDL, triglycerides (TG) and Atherogenic Index of Plasma (AIP), as well as levels of VE-Cadherin, E-Selectin, Thrombomodulin and vWf were determined. Ultrasonographic examinations included evaluation of flow-mediated dilatation (FMD) and measurement of Carotid and Femoral Intima Media Thickness (IMT). HT raised HDL (35.4 mg/dl versus 40.1 mg/dl, p = 0.019) while lowering TG (166 mg/dl versus 109 mg/dl, p = 0.026) and AIP (0.24 versus 0.04, p = 0.007). No changes were noted in TC and LDL (215.7 mg/dl versus 192.25 mg/dl and 87.46 mg/dl versus 76.35 mg/dl, respectively). There was significant reduction of VE-Cadherin (4.05 ng/ml versus 2.20 ng/ml, p = 0.002) and E-selectin (73.98 ng/ml versus 56.73 ng/ml, p = 0.004). No change was observed in Thrombomodulin and vWf (11.76 ng/ml versus 13.90 ng/ml and 80.75% versus 79.55%, respectively). FMD improved significantly (5.4% versus 8.15%, p = 0.003), while only carotid bulb IMT decreased significantly (0.65 mm versus 0.60 mm, p = 0.018). Overall, HT was found to improve biochemical and ultrasound markers of endothelial function in 46,XY DSD patients with female phenotype.

Desferrioxamine Attenuates Pancreatic Injury after Major Hepatectomy under Vascular Control of the Liver: Experimental Study in Pigs.

Introduction. Pancreatic injury can manifest after major hepatectomy under vascular control. The main mechanism involved seems to be remote oxidative injury due to "spillage" of reactive oxygen species and cytokines from the liver. The aim of this study is to evaluate the role of desferrioxamine in the prevention of pancreatic injury following major hepatectomy. Methods. Twelve Landrace pigs were subjected to a combination of major hepatectomy (70-75%), using the Pringle maneuver for 150 minutes, after constructing a porta-caval side-to-side anastomosis. The duration of reperfusion was 24 hours. Animals were randomly divided into a control group (n = 6) and a desferrioxamine group (DFX, n = 6). DFX animals were treated with continuous IV infusion of desferrioxamine 100 mg/kg. Pancreatic tissue injury, c-peptide and amylase concentrations, and pancreatic tissue oxidative markers were evaluated. Results. Desferrioxamine-treated animals showed decreased c-peptide levels, decreased acinar cell necrosis, and decreased tissue malondialdehyde levels 24 hours after reperfusion compared with the control group. There was no difference in portal pressure or serum amylase levels between the groups. Conclusions. Desferrioxamine seems to attenuate pancreatic injury after major hepatectomy under vascular control possibly by preventing and reversing production and circulation of oxidative products.

Pancreatic injury after major hepatectomy: a study in a porcine model.

PURPOSE: The aim of this study was to investigate the pathophysiology of pancreatitis after major hepatectomy. METHODS: The study used ten female pigs. Three served as sham animals (sham group) and were killed after laparotomy to obtain normal tissue samples. Seven animals were subjected to major hepatectomy (70-75%), using the Pringle maneuver for 150 min, after constructing a portacaval side-to-side anastomosis (hepatectomy group). Duration of reperfusion was 24 h. RESULTS: Pancreatic tissue sampled 24 h after reperfusion had increased necrosis and edema in comparison to sham group and to tissue sampled at 12 h. Tissue malondialdehyde (MDA) did not differ significantly between samples at 12 and 24 h but was increased in the hepatectomy group in comparison to sham animals. Percentage increase in portal MDA content during reperfusion was greater at 12 h of reperfusion in comparison to the increase after 24 h. Portal pressure increased significantly after 12 h of reperfusion. Serum amylase and C-peptide increased during reperfusion in comparison to baseline levels. CONCLUSIONS: The findings suggest that intraoperative portal congestion is not the only cause of the development of pancreatitis after major hepatectomy. The oxidative markers suggest that reactive oxygen species produced during vascular control may be responsible as well.

Antepartum and postpartum serum heme oxygenase-1 levels in preeclamptic and normotensive pregnant women.

AIM: To determine antepartum and postpartum serum heme oxygenase-1 (HO-1) levels in pre-eclamptic (PE) and normotensive pregnant women and to investigate the relationship between HO-1 levels and severity of PE. PATIENTS AND METHODS: Ten normotensive women were compared to 9 women with mild PE and 12 women with severe PE. Serum HO-1 levels were measured at 30-34 gestational weeks and 12-14 weeks postpartum. RESULTS: The severe PE group had significantly higher serum HO-1 levels antepartum compared to the mild PE and normotensive groups (5.50 ± 1.54 vs. 3.04 ± 0.72 ng/ml, p=0.0003, and 5.50 ± 1.54 vs. 3.12 ± 1.57 ng/ml, p=0.002, respectively). Serum HO-1 levels decreased significantly postpartum in the normotensive group only (3.12 ± 1.57 vs. 2.00 ± 0.97 ng/ml, p=0.0005). In the severe PE group, HO-1 levels antepartum were positively correlated to mean blood pressure (r=+0.79, p=0.004). CONCLUSION: Severe PE is associated with elevated serum HO-1 levels both antepartum and postpartum, suggesting a key role of chronic oxidative stress in the pathogenesis of PE and the endothelial dysfunction of these patients later in their life.

Sp1 collagen I A1 polymorphism in women with stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) is in part attributed to qualitative and quantitative changes in connective tissue of the urogenital tract. We examined the association of collagen type I a1 (COLIA 1) Sp1 polymorphism with the risk of SUI. METHODS: Forty-five postmenopausal women suffering from urodynamically verified SUI (study group) were compared to 45 healthy volunteers (control). DNA was extracted from peripheral blood. The genotyping concerning the type 1 a1 collagen gene Sp1 polymorphism was performed with polymerase chain reaction. RESULTS: The polymorphic T allele was overrepresented in the SUI patients (63.2% versus 36.8%, p = 0.016). Odds ratio for SUI in women harboring the T allele was 2.19 (95% CI 1.149-4.176) compared to women with the wild-type genotype. CONCLUSIONS: The COLIA1 Sp1 polymorphism is associated with increased prevalence of stress urinary incontinence in postmenopausal women.

Measurable serum markers of oxidative stress response in women with endometriosis.

OBJECTIVE: To evaluate the hypothesis of increased systemic oxidative stress in patients with endometriosis. SETTING: Tertiary care university hospital. DESIGN: Cross-sectional study. PATIENT(S): Sixty-six women of reproductive age undergoing laparoscopy. INTERVENTION(S): All women were investigated for endometriotic foci during laparoscopy. Forty-five women had laparoscopically and histologically confirmed endometriosis, and 21 women did not have endometriosis. MAIN OUTCOME MEASURE(S): Four markers of oxidative stress were assessed in the serum of each patient: heat shock protein 70 (HSP70), HSP70b', thioredoxin (TRX), and ischemia-modified albumin (IMA). RESULT(S): Mean serum HSP 70b' level was higher in patients with endometriosis compared with controls (0.178 ng/mL, SD 0.103, and 0.135 ng/mL, SD 0.014, respectively). The disease stage did not affect HSP70b' levels. Heat shock protein 70, IMA, and TRX levels did not differ between patients with endometriosis and controls. Women with a history of arterial hypertension had higher mean IMA levels compared with women with normal blood pressure independently of the presence of endometriosis (106.7 [SD 25.4] U/mL and 85.0 [SD 11.5] U/mL, respectively). CONCLUSION(S): Endometriosis is associated with increased systemic oxidative stress. The implication of increased systemic oxidative stress in disease progression or the association with other oxidative stress-related pathologic conditions needs to be addressed in further studies.

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.

Circulating chemoattractants RANTES, negatively related to endogenous androgens, and MCP-1 are differentially suppressed by hormone therapy and raloxifene.

BACKGROUND: The cardinal role of chronic inflammation in the development of atherosclerosis is increasingly being recognized. Estrogens may prevent the evolution of atherosclerosis by suppressing immune response. Furthermore, the conflicting reports on the cardiovascular effects of hormone therapy between observational and clinical trials have triggered interest on the effect of alternative therapies on the cardiovascular system. OBJECTIVE: The aim of this study was to assess the effect of estrogen, estrogen-progestin, tibolone and raloxifene therapy on circulating markers of chemotaxis 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 0.5mg (E(2)/NETA), (3) tibolone 2.5mg, (4) raloxifene HCl 60 mg or (5) no treatment. Serum monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T-cell expressed and secreted (RANTES) were measured at baseline and at 3 months. RESULTS: Endogenous testosterone and free androgen index (FAI) correlated negatively, while SHBG correlated positively with serum RANTES (testosterone: r=-0.27, p=0.033; FAI: r=-0.43, p=0.004: SHBG: r=0.34, p=0.026). Serum MCP-1 decreased significantly in the CEE group (baseline 125.3+/-51 pg/ml, 3 months 84.5+/-36.1 pg/ml, p=0.043), while no difference was detected between baseline and post-treatment levels in the other groups. Furthermore, a significant decrease in serum RANTES was observed at the end of 3 months only in the E2/NETA and the raloxifene group (E2/NETA baseline 8690.6+/-3880.0 pg/ml, 3 months 6894.0+/-1720.0 pg/ml, p=0.007; raloxifene baseline 9042.4+/-3765.6 pg/ml, 3 months 6718.1+/-2366.2 pg/ml, p=0.011). CONCLUSION: Endogenous androgens may suppress chemotactic response. Postmenopausal hormone therapy and raloxifene may inhibit the expression of chemoattractant molecules and thus attenuate inflammation. The relevance of these findings in terms of clinically established caridoprotection remains to be clarified.

Intrauterine growth restriction and circulating neurotrophin levels at term.

BACKGROUND: Intrauterine growth restricted (IUGR) fetuses are those with estimated weight <10th customized centile, displaying signs of chronic malnutrition and hypoxia leading to brain sparing effect. Neurotrophins, [Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), Neurotrophin-4 (NT-4)] are important for pre- and post-natal brain development. AIMS: To investigate circulating NGF, BDNF, NT-3 and NT-4 levels in IUGR and appropriate for gestational age (AGA) fullterm fetuses and neonates (day-1 [N1] and day-4 [N4]) and in their mothers. STUDY DESIGN: Prospective case control study. SUBJECTS: 60 mothers and their single 30 IUGR and 30 AGA fullterm fetuses and neonates. OUTCOME MEASURES: Determination, by enzyme immunoassays, of NGF, BDNF, NT-3 and NT-4 plasma levels. RESULTS: No statistically significant differences existed between IUGR and AGA maternal, fetal and neonatal levels of BDNF, NT-3 and NT-4. NGF was significantly higher in AGA than IUGR maternal (p=0.007), fetal (p=0.01), neonatal day 1 (p=0.043) and 4 (p=0.003) plasma, and positively correlated with the infants' centiles and birthweights. IUGR and AGA maternal neurotrophins were higher than the respective fetal and neonatal ones and no correlation with gender or delivery mode in both groups was observed. CONCLUSIONS: In the perinatal period, circulating levels of BDNF, NT-3 and NT-4 do not differ in IUGR and AGA pregnancies, in contrast to NGF levels, which are higher in the AGA group. NGF is the only neurotrophin correlating with customized centiles and birthweights of the infants. Neurotrophin concentrations are higher in maternal plasma and do not depend on gender.

Elevated circulating IL-1beta 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.