Human placenta, chorion, amnion and decidua express different variants of corticotropin-releasing factor receptor messenger RNA.

Human placenta is a major source of corticotropin-releasing factor (CRF), and local effects of CRF in fetal membranes and placenta have been shown, i.e., adrenocorticotropic hormone (ACTH) and oxytocin release from cultured placental cells, as well as prostaglandin release from amnion, chorion and decidua. Two distinct CRF receptors (CRF-R1 and CRF-R2) have been characterized: CRF-R1 consists of two isoforms (CRF-R1alpha and CRF-R1beta) while CRF-R2 has at least three different splice variants (CRF-R2alpha, CRF-R2beta and CRF-R2gamma). To date, CRF-R1 receptor has been identified in human placenta and in pregnant myometrium, while no evidence for placental CRF-R2 receptor isoforms has been provided. The present study investigated whether the different isoforms of CRF-R1 and CRF-R2 receptor mRNA are expressed in fetal membranes and placenta. Tissues were collected after spontaneous vaginal delivery (38-40 weeks) or elective caesarean section (39-41 weeks). The gene expression of CRF receptors was first studied by reverse transcriptase-polymerase chain reaction (RT-PCR), and the presence of CRF-R1alpha, but not of CRF-R1beta, in human placental trophoblast, amnion/chorion and decidua was shown. In addition, among the three CRF-R2 splice variants, only CRF-R2beta mRNA was expressed by trophoblast and fetal membranes. By using in situ hybridization, CRF-R1 and CRF-R2 probes positively hybridized trophoblast and related membranes. CRF-R1 was localized in the syncytiotrophoblast cells, chorionic trophoblast and decidua with a small amount in the amnion. CRF-R2 probe mainly hybridized syncytiotrophoblast cells, but cytotrophoblast also contained discreet amounts of CRF-R2 mRNA signal. The CRF-R2 hybridization signal was also observed within the structure of the villi (blood vessels), chorionic trophoblast and decidual cells, but it was faint or absent in the amniotic epithelium. There was no significant difference in the distribution of CRF-R1 or CRF-R2 mRNA signal between placentas collected from vaginal delivery or caesarean section. The evidence that intrauterine tissues differently express CRF-R1alpha and CRF-R2beta supports possible different local roles of CRF and related peptides into intrauterine tissues during pregnancy.

Influence of non-gonadotrophic hormones on gonadal function.

Inhibins and activins are dimeric glycoproteins, member of the transforming growth factor beta (TGF beta) superfamily. The main source and targets of inhibins during the fertile age, in non pregnant women, are the ovaries, while during pregnancy placental production becomes predominant. Activin is produced from several organs: brain, ovary, uterus, placenta and spleen. During the menstrual cycles, inhibin B concentrations rise in the follicular phase with a peak after the ovulation peak of LH, inhibin A becomes predominant in the luteal phase. During reproductive life no significant change of activin A serum concentrations have been demonstrated. Inhibins and activins play an important biological role in the regulation of the HPO axis. The evaluation of inhibins and activins change is useful in understanding the pathophysiology of gynecological diseases and in the diagnosis of obstetric and gynecological pathologies.

Allopregnanolone and dehydroepiandrosterone response to corticotropin-releasing factor in patients suffering from Alzheimer's disease and vascular dementia.

OBJECTIVE: Neurosteroids have been suggested to be involved in the regulation of cognitive performances. A major neurosteroid gamma-aminobutyric acid (GABA) agonist is allopregnanolone: the main source of circulating allopregnanolone is the adrenal cortex. Studies indicated that a disturbance of the central regulation of the hypothalamic-pituitary-adrenocortical axis occurs in both senile (Alzheimer's disease: AD) and vascular dementia (VD). DESIGN: The aim of the present study was to evaluate the levels of circulating allopregnanolone, dehydroepiandrosterone (DHEA) and cortisol and their response to corticotropin-releasing factor (CRF) test in AD and VD. METHODS: Three groups of 12 subjects were included in the study: AD, VD and age-matched control subjects. CRF test was performed in all subjects and allopregnanolone, DHEA and cortisol levels were measured every 15min for 2h. RESULTS: Mean +/- s.e.m. allopregnanolone and DHEA basal levels were significantly lower in AD and VD than in controls, while cortisol levels were significantly higher than in controls (P<0.01). Allopregnanolone and DHEA levels increase in response to CRF test in all subjects but the area under curve (AUC) in patients was significantly lower than in controls (P<0.01). Cortisol secretion appeared to be very sensitive in response to CRF stimulation: in fact, cortisol response to CRF test in AD and VD subjects was higher (both as AUC and as % max increase) than in controls (P<0.01). CONCLUSIONS: The present study firstly showed that allopregnanolone levels are reduced both in AD and in VD and that dementia has a preserved stimulated response of allopregnanolone to CRF. Overall, however, the total response of allopregnanolone to CRF remains reduced in respect to controls. Further studies are necessary for a better understanding of the role of neurosteroids in the regulation of cognitive function.

Placental corticotropin-releasing factor. An update.

Corticotropin-releasing factor (CRF) produced in placenta has paracrine effects within placenta, decidua, and myometrium and endocrine effects on mother and fetus. CRF is a potent local regulator of myometrial contractility and of prostaglandin release, Recently, urocortin, a new member of the CRF family, has been localized in human placenta and membranes. Urocortin mimics some of the local effects of CRF in intrauterine tissues, that is, increase of adrenocorticotrophic hormone (ACTH) and prostagiandin release and myometrial contractility. A local CRF-BP modulates the paracrine effects of CRF and urocortin. The various CRF receptor subtypes are well distributed in placenta and membranes. CRH also acts on placental blood vasculature and has an action on fetal adrenal gland to stimulate the production of the steroid DHEA-S. In nonpregnant women, plasma CRF levels are low; they become higher during the first and second trimesters of pregnancy. A clear increase is evident at term and when CRF-BP levels decrease. Women with preterm labor show high CRF and low CRF-BP levels, supporting an involvement of this pathway in mechanism of parturition.

Maternal plasma calcitonin gene-related peptide levels do not change during labor and are not influenced by delivery route.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) circulates in maternal circulation throughout pregnancy, and specific receptors for CGRP (CGRPrs) are expressed by human myometrium. Because CGRP induces a dose-dependent relaxation of human myometrium, we examined a role for CGRP in modulation of myometrial smooth muscle contractility during pregnancy and labor. The aim of the present study was to evaluate the changes of maternal serum CGRP levels during parturition, according to the mode of delivery and in relation to cervical dilatation. METHODS: Circulating CGRP levels were measured in the following groups of healthy women: nonpregnant women, during the follicular phase of the menstrual cycle (n = 19); at term pregnancy (39-40 weeks; n = 24); after elective cesarean delivery (39-40 weeks; n = 20); and at spontaneous vaginal delivery (39-40 weeks; n = 16). In a subgroup of women, blood samples were collected longitudinally throughout labor at various cervical dilatations in the progress of labor (n = 8). RESULTS: Pregnant women at term not in labor had significantly higher CGRP levels than nonpregnant women (P =.021). No significant difference was found between women who delivered vaginally and those who had elective cesarean, and there were no correlations between CGRP plasma levels and cervical dilatation. CONCLUSIONS: Parturition is characterized by no significant changes in maternal serum CGRP levels, and no significant correlation exists between plasma CGRP levels and cervical dilatation during labor.

Second-trimester levels of maternal serum human chorionic gonadotropin and inhibin a as predictors of preeclampsia in the third trimester of pregnancy.

OBJECTIVE: To determine whether second-trimester maternal serum levels of inhibin A, human chorionic gonadotropin (hCG), unconjugated estriol (uE3), and alpha-fetoprotein (AFP) are predictive of the later onset of preeclampsia in pregnancy. METHODS: Retrospective evaluation of serum analyte levels in 60 women with preeclampsia compared with 300 controls. Levels of each analyte were compared in women with preeclampsia and controls using matched rank analysis. Analytes that were significantly different between groups were examined with univariate and bivariate Gaussian distribution analysis. RESULTS: Second-trimester inhibin A (1.36 multiples of the median [MoM]) and hCG (1.40 MoM) levels were significantly but modestly elevated in women who later developed preeclampsia. A combination test of maternal age plus inhibin A and hCG predicted 23% of cases of preeclampsia with 95% specificity. There was a statistically significant trend for inhibin A, but not hCG, levels to be higher when the onset of preeclampsia occurred within a shorter (<17 weeks) interval after collection of the second-trimester screening sample. CONCLUSIONS: Second-trimester serum levels of inhibin A and hCG are modest predictors of the later onset of preeclampsia. Inhibin A may be a better predictor of early-onset preeclampsia, which is associated with a higher maternal and perinatal morbidity and mortality, than preeclampsia at or near term.

[Pathological monolateral Doppler velocimetry of the uterine artery and materno-fetal outcome]. / Flussimetria monolaterale patologica dell'arteria uterina ed outcome materno-fetale.

BACKGROUND: The purpose of this study was to assess pathologic monolateral Doppler velocimetry of the uterine arteries as a screening test for preeclampsia and retarded intrauterine growth. METHODS: In this prospective longitudinal study carried out at the Obstetrics and Gynaecological Clinic of the University of Udine from January 200 to January 2001, 1008 utero-placental velocimetries at the 20th week of gestation were carried out by two operators; at the 24th, 111 velocimetric examinations were confirmed abnormal owing to the presence of a monolateral notch or of an increased resistance index in one of the two uterine arteries. The control group consisted of 729 patients with regular velocimetry comparable for age, race, BMI and parity. The materno-fetal outcomes were therefore assessed in both study groups. RESULTS: The incidence of preeclampsia and of retarded intrauterine growth retardation (IUGR) was respectively 3.6% and 7.2% in patients with monolateral abnormal Doppler velocimetry. The positive predictive value (PPV) of the screening test for preeclampsia was 3% and the negative value (NPV) 99%. CONCLUSIONS: The use of Doppler velocimetry of the uterine arteries with mono lateral alteration cannot be employed alone as a screening test for preeclampsia or retarded intrauterine growth in all pregnancies.

[Induction of fetal lung maturation in the prevention of hyaline membrane disease: the connection with neonatal sepsis]. / Induzione della maturazione polmonare fetale nella profilassi della malattia da membrane ialine e sepsi neonatale.

BACKGROUND: The aim of this study was to evaluate the effect of antenatal maternal corticosteroid treatment on the frequency of neonatal outcomes and perinatal infectious morbidity among singleton pregnancies complicated by preterm delivery. METHODS: A nonrandomized analysis was performed on 189 neonates of 24-34 weeks' gestation who were born at the Department of Obstetrics and Gynecology, University of Udine, between January 2000 to December 2001. The neonates were subdivided into 3 groups: 1) 143 neonates received 2 doses of corticosteroids in a 24-hour interval and repeated after 10 days; 2) 26 neonates received 2 doses; 3) 20 neonates did not receive any treatment. Data were analysed with the Fisher exact test. p<0.05 was considered significant. RESULTS: The incidence of respiratory distress syndrome (RDS), neonatal mortality and intraventricular hemorrhage was respectively 43.4%, 3.2 % and 6.3 %. The rate of early-onset neonatal sepsis was 4.9% in the 1st group, 3.9% in the 2nd group and 5% in the 3rd group. There were no significant differences in the early-onset neonatal sepsis and the antenatal corticosteroids treatment. CONCLUSIONS: The single or the multiple courses of antenatal steroids did not apparently increase neonatal sepsis in patients with preterm delivery.

Evaluation of reactive oxygen metabolites with micromethod in neonates: determination of standards of normality in full-term babies.

We have evaluated the value of reactive oxygen metabolites (ROMs) in 98 full-term neonates at 72 +/- 6 hours of life with a new colorimetric simple and rapid method (d-ROMs Test, Diacron s.r.l.) to establish the normal values for infants. The mean value of ROMs we have obtained in the total of the population was 127.9 +/- 39.2 U.Carr. We have then considered subgroups of infants on the basis of vaginal delivery vs cesarean section, and asphyxia vs non asphyxia during the delivery. We have found no difference within these groups and between the subgroups and the total population for the value of ROMs. We have preferred to consider as reference value for normality that of babies without intrapartum asphyxia, independently of the mode of delivery. This value is 125.2 +/- 27.6 U.Carr. The value of normality for full-term infants is lower than that reported for adults (between 250-300 U.Carr). This can be interpreted as a particular response of full-term baby to oxidative stress.

The addition of activin A and inhibin A measurement to uterine artery Doppler velocimetry to improve the early prediction of pre-eclampsia.

OBJECTIVE: To evaluate whether the measurement of maternal serum activin A and inhibin A adds any clinically relevant information for the prediction of pre-eclampsia in women with altered uterine artery Doppler velocimetry at 24 weeks of gestation. METHODS: This was a prospective, controlled, hospital-based study involving 58 asymptomatic pregnant women at 24 weeks' gestation in whom a diastolic notch of the uterine artery waveform was noted at routine Doppler examination. Doppler assessment of the uterine artery waveform and measurement of maternal activin A and inhibin A serum levels by specific two-site enzyme immunoassays were performed. The cut-off points for defining 'high' serum activin A and inhibin A levels for prediction of pre-eclampsia were chosen by receiver-operating characteristics (ROC) curve analysis. The probability of developing pre-eclampsia was calculated for several combinations of results of hormone testing. RESULTS: Activin A and inhibin A levels were higher in patients who developed pre-eclampsia (n = 18; mean +/- standard error: 2.69 +/- 0.35 ng/mL and 131.2 +/- 22.7 pg/mL, respectively) than in those who did not present with pre-eclampsia at follow-up (n = 40; activin A: 1.79 +/- 0.18 ng/mL and inhibin A: 91.9 +/- 6.2 pg/mL; P < 0.05). Activin A at the cut-off value of 1.7 multiples of the median (MoM) achieved a sensitivity of 61% and a specificity of 89%, whereas inhibin A at the cut-off value of 1.8 MoM combined a sensitivity of 39% with a specificity of 92% for prediction of pre-eclampsia. The probability of pre-eclampsia was 31% in the whole study population, 86% if both activin A and inhibin A were elevated and 17% if both hormone markers were unaltered. CONCLUSION: The measurement of serum activin A and inhibin A levels may add significant prognostic information for predicting pre-eclampsia in pregnant women showing specific Doppler alterations in the late second trimester.