[Show abstract][Hide abstract] ABSTRACT: In this review, we focused on the intersection between steroid metabolomics, obstetrics and steroid neurophysiology to give a comprehensive insight into the role of sex hormones and neuroactive steroids (NAS) in the mechanism controlling pregnancy sustaining. The data in the literature including our studies show that there is a complex mechanism providing synthesis of either pregnancy sustaining or parturition provoking steroids. This mechanism includes the boosting placental synthesis of CRH with approaching parturition inducing the excessive synthesis of 3beta-hydroxy-5-ene steroid sulfates serving primarily as precursors for placental synthesis of progestogens, estrogens and NAS. The distribution and changing activities of placental oxidoreductases are responsible for the activation or inactivation of the aforementioned steroids, which is compartment-specific (maternal and fetal compartments) and dependent on gestational age, with a tendency to shift the production from the pregnancy-sustaining steroids to the parturition provoking ones with an increasing gestational age. The fetal and maternal livers catabolize part of the bioactive steroids and also convert some precursors to bioactive steroids. Besides the progesterone, a variety of its 5alpha/beta-reduced metabolites may significantly influence the maintenance of human pregnancy, provide protection against excitotoxicity following acute hypoxic stress, and might also affect the pain perception in mother and fetus.
Physiological research / Academia Scientiarum Bohemoslovaca 11/2010; 60(2):225-41. · 1.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the extensive research during the last six decades the fundamental questions concerning the role of steroids in the initiation of human parturition and origin and function of some steroids in pregnancy were not definitely answered. Based on steroid metabolomic data found in the literature and our so far unpublished results, we attempted to bring new insights concerning the role of steroids in the sustaining and termination of human pregnancy, and predictive value of these substances for estimation of term. We also aimed to explain enigmas concerning the biosynthesis of progesterone and its bioactive catabolites considering the conjunctions between placental production of CRH, synthesis of bioactive steroids produced by fetal adrenal, localization of placental oxidoreductases and sustaining of human pregnancy. Evaluation of data available in the literature, including our recent findings as well as our new unpublished data indicates increasing progesterone synthesis and its concurrently increasing catabolism with approaching parturition, confirms declining production of pregnancy sustaining 5β-pregnane steroids providing uterine quiescence in late pregnancy, increased sulfation of further neuroinhibiting and pregnancy sustaining steroids. In contrast to the established concept considering LDL cholesterol as the primary substrate for progesterone synthesis in pregnancy, our data demonstrates the functioning of alternative mechanism for progesterone synthesis, which is based on the utilization of fetal pregnenolone sulfate for progesterone production in placenta. Close relationships were found between localization of placental oxidoreductases and consistently higher levels of sex hormones, neuroactive steroids and their metabolites in the oxidized form in the fetus and in the reduced form in the maternal compartment.
The Journal of steroid biochemistry and molecular biology 10/2010; 122(4):114-32. · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We focused on the detection of microRNAs in maternal circulation during the course of physiological pregnancy. We tested initially microRNAs (mir-135b and miR-517a) which presence in maternal circulation had been previously demonstrated and those microRNAs (miR-518b and miR-517a) with up-regulated expression profile in placentas derived from pregnancies during the onset of preeclampsia. Further we selected those microRNAs, which were reported to be placenta specific according to the miRNAMap database (these microRNAs were significantly expressed in the placenta and simultaneously showed no or minimal expression in other tissues).
Division of Molecular Biology and Cell Pathology, Department of Gynaecology and Obstetrics, Third Faculty of Medicine, Charles University, Prague.
RNA enriched for small RNAs (including microRNAs) was isolated from 1 ml of maternal plasma during the 12th, 16th and 36th week of gestation and 200 microl of peripheral blood derived from healthy non-pregnant women. Consequently relevant microRNA was transcribed into cDNA using specific stem-loop primer and detected by specific real-time PCR assay.
From the cohort of tested microRNAs we excluded those ones, which were not detectable in maternal circulation during pregnancy (miR-136 and miR-519a) and/or were demonstrated in peripheral blood of healthy non-pregnant women (miR-34c, miR-224, miR-512-5p, miR-515-5p, miR-516-5p, miR-518f*, miR-519d, miR-519e).
On the base of the current study results we finally selected 6 most suitable microRNAs (miR-517*, miR-518b, miR-520a*, miR-520h, miR-525 and miR-526a) for subsequent studies concerning the follow-up of placenta specific microRNAs in maternal circulation during pregnancy and the differentiation between normal and pathologic pregnancies (preeclampsia, IUGR) within the same gestational age.
[Show abstract][Hide abstract] ABSTRACT: Progesterone and estradiol are the foremost steroid hormones in human pregnancy. However, the origin of maternal progesterone has still not been satisfactorily explained, despite the generally accepted opinion that maternal LDL-cholesterol is a single substrate for placental synthesis of maternal progesterone. The question remains why the levels of progesterone are substantially higher in fetal as opposed to maternal blood. Hence, the role of the fetal zone of fetal adrenal (FZFA) in the synthesis of progesterone precursors was addressed. The FZFA may be directly regulated by placental CRH inducing an excessive production of sulfated 3beta-hydroxy-5-ene steroids such as sulfates of dehydroepiandrosterone (DHEAS) and pregnenolone (PregS). Due to their excellent solubility in plasma these conjugates are easily transported in excessive amounts to the placenta for further conversion to the sex hormones. While the significance of C19 3beta-hydroxy-5-ene steroid sulfates originating in FZFA for placental estrogen formation is mostly recognized, the question "Which maternal and/or fetal functions may be served by excessive production of PregS in the FZFA?" - still remains open. Our hypothesis is that, besides the necessity to synthesize de novo all the maternal progesterone from cholesterol, it may be more convenient to utilize the fetal PregS. The activities of sulfatase and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) are substantially higher than the activity of cytochrome P450scc, which is rate-limiting for the placental progesterone synthesis from LDL-cholesterol. However, as in the case of progesterone synthesis from maternal LDL-cholesterol, the relative independence of progesterone levels on FZFA activity may be a consequence of substrate saturation of enzymes converting PregS to progesterone. Some of the literature along with our current data (showing no correlation between fetal and maternal progesterone but significant partial correlations between fetal and maternal 20alpha-dihydroprogesterone (Prog20alpha) and between Prog20alpha and progesterone within the maternal blood) indicate that the localization of individual types of 17beta-hydroxysteroid dehydrogenase is responsible for a higher proportion of estrone and progesterone in the fetus, but also a higher proportion of estradiol and Prog20alpha in maternal blood. Type 2 17beta-hydroxysteroid dehydrogenase (17HSD2), which oxidizes estradiol to estrone and Prog20alpha to progesterone, is highly expressed in placental endothelial cells lining the fetal compartment. Alternatively, syncytium, which is directly in contact with maternal blood, produces high amounts of estradiol and Prog20alpha due to the effects of type 1, 5 and 7 17?-hydroxysteroid dehydrogenases (17HSD1, 17HSD5, and 17HSD7, respectively). The proposed mechanisms may serve the following functions: 1) providing substances which may influence the placental production of progesterone and synthesis of neuroprotective steroids in the fetus; and 2) creating hormonal milieu enabling control of the onset of labor.
Physiological research / Academia Scientiarum Bohemoslovaca 07/2009; 59(2):211-24. · 1.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe fetomaternal transplacental hemorrhage increases the risk of fetal anemia. In the third trimester, the syncytiotrophoblast becomes thinner, especially in areas where it comes into intimate contact with villous capillaries, and forms a vasculosyncytial membrane. Our aim was to determine whether ABO compatibility puts the fetus at a greater risk of severe fetomaternal hemorrhage.
A tertiary care center. Sample and methods. Between 2003 and 2007, we evaluated eight cases of severe fetomaternal transfusion. The Kleihauer-Betke test was used for diagnosis of fetomaternal hemorrhage. We evaluated blood group compatibility between the mother and fetus and assessed the perinatal outcome. The Fischer's factorial test was used for testing a hypothesis.
The incidence of adverse outcomes following transplacental hemorrhage was 75% (six of eight). There were two perinatal deaths and four infants were affected by post-hypoxic damage of varying severity. Fetomaternal ABO compatibility was present in seven of the eight cases. The risk of severe fetomaternal hemorrhage was significantly increased when there was ABO compatibility between the mother and fetus. This was associated with a very poor perinatal outcome.
We recommend that resuscitation in utero by intrauterine transfusion should be considered before the 33rd week of gestation in cases of severe fetal anemia. In later gestation, urgent cesarean section is required with adequate resuscitation of the newborn.
[Show abstract][Hide abstract] ABSTRACT: To evaluate leucocytic infiltration of fetomaternal interface in ectopic pregnancy and to evaluate the changes in cell immunity against trophoblast (AT-CMI) in women with extrauterine pregnancy (GEU) in their medical history. To assess the effect of these factors on possible fertility disorders in a woman.
A retrospective study.
Mother and Child Care Institute, Prague.
In most of the patients, we addressed GEU through laparoscopy. The tube was extirpated in toto and immediately fixed in Baker's solution. Thereafter, it was prepared in a dissection microscope and then processed in a standard way. In order to identify the intensity of AT-CMI, we used the leucocyte migration inhibition test. The cytotrophoblastic cell line JAR was used as an antigen. The degree of inhibition of the migration was monitored by means of a computer image analyser. Inhibition of migration below 75% was rated as favourable.
We monitored the presence of inflammatory infiltrate in the place of implantation and correlated the findings with the hCG levels and the presence of the foetal ovum or its part in the tube. In 28 patients (23.5%) of the total number of 119 patients in the group, we observed an inflammatory infiltrate in the place of implantation. In these patients, the hCG levels were lower and in 17 of them (60.7%) we did not prove the presence of a foetal ovum or its parts. In women with GEU in their medical history, the AT-CMI positivity was established in 61.1% of the women 1 year after surgery, in 56.8% of the women 1-3 years after surgery and in 41.2% of the women 3 years after surgery.
Ectopic pregnancy involves a pathological fetomaternal interface. The leucocytic infiltrate in the area of implantation may be of secondary character and may cause gradual destruction of the ectopically positioned product of conception. The results of our study indicate a possible participation of the increased AT-CMI in the destruction of the ectopically located trophoblast. Persisting anti-trophoblast immunity may influence the occurrence and course of further gravidities.
[Show abstract][Hide abstract] ABSTRACT: Systematic classification of all forms of twins and mechanisms of twinning.
Review of published cases. Morphogenesis based on personal experience related to human blastogenesis including observation of anterior twinning in two early human embryos.
Institute for the Care of Mother and Child, Prague, Department of Gynecology and Obstetrics, 1st Medical Faculty, Charles University, Prague, Department of Medical Genetics, Medical Faculty, Palacký University Olomouc, Institut Unica, Brno.
Analysis of cases described in literature completed by observed cases.
Classification of twins. A) Separated twins: 1. dichorial a) monozygotic (very rare), b) dizygotic (most frequent); 2. monochorial (always monozygotic) a) diamnial, b) monoamnial. B) Conjoined twins (always monozygotic) 1. isopagi (equal conjoined twins) a) originating from peripheral fusions of two germ discs, b) originating from duplications of axial structures; 2. heteropagi (unequal conjoined twins): autosit (main twin), heterosit (parasitic twin).
The developmental mechanisms of twinning are discussed, special attention is paid to equal conjoined twins and to the possibilities of their early prenatal ultrasonographic diagnostics.
[Show abstract][Hide abstract] ABSTRACT: A pathologic human embryo 3 mm long affected by a "ventral prolaps" was present in a product of conception implanted within the Fallopian tube. The gestational age was 7 weeks. The malformation was characterized by a deep protrusion of the embryonal body (containing the medullary tube and the notochord adherent to the ceiling of the yolk sac) through the umbilical ring of the germ disc delineated by ectoderm covered mesenchymal streaks with primordia of the umbilical veins. Similar two affected embryos were depicted by Kollmann in his Handatlas in 1907, but were considered normal.
Institute for the Care of Mother and Child, Prague, Institute for Postgraduate Medical Education, Prague.
Implanted product of conception found within the Fallopian tube exhibited a characteristic embryonic defect described as the "ventral prolaps".
Ventral prolaps of the embryo represents a characteristic embryonal malformation of unknown developmental significance.
[Show abstract][Hide abstract] ABSTRACT: Description of a very rare case of primary omental pregnancy.
Institute for the Care of Mother and Child, Prenatal Diagnostic Centre, Prague, Institute for Postgraduate Medical Education, Prague.
Implanted product of spontaneous conception was found in the omentum. The gestational sac on omentum had the appearance of a haemorrhagic tumor 2 cm in diameter.
After dissection, an intact embryo of 7 mm with a 4 mm yolk sac was discovered.
[Show abstract][Hide abstract] ABSTRACT: Case report of a very rare case of ovarian implantation after IVF and ET treated by laparoscopy.
Institute for the Care of Mother and Child, Prenatal Diagnostic Centre and Trophoblastic Disease Centre, Prague, Institute for Postgraduate Medical Education, Prague.
We observed implanted product of conception found within the ovarian stroma 35 days after ET. At laparoscopy, the genital sac appeared as an inconspicious haemorrhagic cyst, 2 cm in diameter. After dissection, in the intact sac appeared amorphous 2 mm embryo and 3 mm yolk sac. The trophoblast of the anchoring chorionic villi exhibited marked hyperproliferation and was classified as a proliferating mole.
The intact early product of conception exhibited trophoblastic hyperplasia.
[Show abstract][Hide abstract] ABSTRACT: Massive fetomaternal transplacental hemorrhage is not simply a problem of possible alloimunization in Rh incompatibility but also endangers the fetus (newborn) by massive anemization. Bleeding from placental vessels can occur after small trauma to the gravid uterus with mild or no clinical signs (bleeding or spotting, pain, hypertonus). The rupture of anchoring villi related to early uterine contractions is also possible. In the case of slow blood loss, the fetus reacts by adequate or inadequate compensatory reactions (hydrops fetus). Rapid and massive blood loss is followed by perinatal hypoxic damage and finally death. Our goal was to map out the diagnostic and therapeutic possibilities in regard to specific neonatal care.
We evaluated four cases of fetomaternal transfusion during a 2-year period with special regard to postpartum adaptation of the newborn and the perinatal outcome. The incidence of adverse outcomes following massive fetomaternal transplacental hemorrhage was 50% (2 of 4). There was one perinatal death and one infant was affected by spastic quadriplegia.
For diagnosis, it is possible to use cardiotocography (decreased variability, sinusoid pattern), ultrasound (biophysical profile) and special hematological tests for quantitative determination of fetal erythrocytes in the maternal blood. For the treatment of such cases one should consider premature termination of pregnancy or intraumbilical transfusion.
Medical science monitor: international medical journal of experimental and clinical research 7(2):308-11. · 1.22 Impact Factor