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1.
Steroid hormones and pregnancy.
Noyola-Martínez, N, Halhali, A, Barrera, D
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019;(5):376-384
Abstract
Pregnancy is associated with physiological adjustments in order to allow adequate growth and fetal development. In particular, steroids are necessary to maintain in balance numerous functions during gestation. Steroidogenesis in the maternal, placental and fetal compartments and the biological effects of progestins and estrogens that play a pivotal role before and during pregnancy are described. Although it is well-known that androgens are considered as substrate for estrogens biosynthesis, their biosynthesis and functionality in placental and other tissues have been questioned. As compared with healthy pregnancy, steroid hormones levels have been found altered in complicated pregnancies and hormonal treatments have been used is some pathologies. Therefore, the aim of this work was to review the biosynthesis, function and regulation of progestins, androgens and estrogens during gestation. Furthermore, steroid hormones concentrations during healthy and complicated pregnancy as well hormonal therapies for the prevention of miscarriages and preterm deliveries are discussed in the present review.
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2.
Latest findings on the placenta from the point of view of immunology, tolerance and mesenchymal stem cells.
Macholdová, K, Macháčková, E, Prošková, V, Hromadníková, I, Klubal, R
Ceska gynekologie. 2019;(2):154-160
Abstract
OBJECTIVE Overview of current placental findings from the point of view of immunology, tolerance and mesenchymal stem cells. TYPE OF STUDY Review. SETTING Medicínské centrum Praha. CONCLUSION The placenta is an important organ that connects mother and developing fetus during pregnancy. For the uncomplicated course of pregnancy and fetal development the placental function is crucial. The placenta provides not only the replacement of breathing gases, nutrients and waste materials, but also creates an immunological interface between the mother and the fetus. Maternal tolerance towards the fetus carrying paternal antigens is induced at the fetomaternal interface due to the mutual molecular interactions. Immune tolerance at the interface between placenta and decidua is ensured mainly due to the expression of HLA-C, HLA-E, HLA-F, and HLA-G on trophoblasts and their interactions with receptors expressed on uterine NK cells. Regulatory T cells and DC-10 cells also play an important role at the fetomaternal interface on the mothers side of placenta. However, some fetal cells, such as Hofbauer cells or granulocytic myeloid-derived suppressor cells are also partially involved in inducement of maternal tolerance towards the fetus. Recently, considerable attention is also paid to mesenchymal stem cells derived from both placental and umbilical tissues. These mesenchymal stem cells play an important role in inducement of immune tolerance and exhibit better immunomodulatory properties than mesenchymal stem cells isolated from adult human tissues.
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3.
Integrating Autism Spectrum Disorder Pathophysiology: Mitochondria, Vitamin A, CD38, Oxytocin, Serotonin and Melatonergic Alterations in the Placenta and Gut.
Maes, M, Anderson, G, Betancort Medina, SR, Seo, M, Ojala, JO
Current pharmaceutical design. 2019;(41):4405-4420
Abstract
BACKGROUND A diverse array of data has been associated with autism spectrum disorder (ASD), reflecting the complexity of its pathophysiology as well as its heterogeneity. Two important hubs have emerged, the placenta/prenatal period and the postnatal gut, with alterations in mitochondria functioning crucial in both. METHODS Factors acting to regulate mitochondria functioning in ASD across development are reviewed in this article. RESULTS Decreased vitamin A, and its retinoic acid metabolites, lead to a decrease in CD38 and associated changes that underpin a wide array of data on the biological underpinnings of ASD, including decreased oxytocin, with relevance both prenatally and in the gut. Decreased sirtuins, poly-ADP ribose polymerase-driven decreases in nicotinamide adenine dinucleotide (NAD+), hyperserotonemia, decreased monoamine oxidase, alterations in 14-3-3 proteins, microRNA alterations, dysregulated aryl hydrocarbon receptor activity, suboptimal mitochondria functioning, and decreases in the melatonergic pathways are intimately linked to this. Many of the above processes may be modulating, or mediated by, alterations in mitochondria functioning. Other bodies of data associated with ASD may also be incorporated within these basic processes, including how ASD risk factors such as maternal obesity and preeclampsia, as well as more general prenatal stressors, modulate the likelihood of offspring ASD. CONCLUSION Such a mitochondria-focussed integrated model of the pathophysiology of ASD has important preventative and treatment implications.
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4.
The choice of amniotic fluid in metabolomics for the monitoring of fetus health - update.
Bardanzellu, F, Fanos, V
Expert review of proteomics. 2019;(6):487-499
Abstract
Introduction: In recent years, several studies have highlighted the promising role of metabolomics in the analysis of amniotic fluid (AF), to describe and characterize the interactions occurring between the mother and the fetus during prenatal development. Among the available biological fluids, AF represents an ideal substrate to provide dynamic information regarding fetal organogenesis and metabolism through pregnancy, since it originates from both maternal and fetal tissues and contains substances derived from placenta, fetal skin, lungs, gastric fluid, and fetal urine. Areas covered: In this paper, we provide an update reporting the most recent results on AF metabolomics in the assessment of feto-maternal health, regarding physiological pregnancies but even fields such as prematurity, bronchopulmonary dysplasia, fetal malformations, chromosomopathies, maternal diseases, placental inflammation or infections, maternal diet or exposure to exogenous substances, according to the literature found on MEDLINE since 2015. Expert opinion: Metabolomics shows a promising role in describing both physiology and disease; the goal would be the identification of biomarkers able to precociously and efficaciously detect pathological conditions, allowing the identification of complicated pregnancy and improving their management. However, this field is under development and its reliability still needs to be clarified, especially through more numerous and accurate studies.
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5.
Competition for nutrients in pregnant adolescents: consequences for maternal, conceptus and offspring endocrine systems.
Wallace, JM
The Journal of endocrinology. 2019;(1):T1-T19
Abstract
The competition for nutrients that arises when pregnancy coincides with continuing or incomplete growth in young adolescent girls increases the risk of preterm delivery and low birthweight with negative after-effects for mother and child extending beyond the perinatal period. Sheep paradigms involving nutritional management of weight and adiposity in young, biologically immature adolescents have allowed the consequences of differential maternal growth status to be explored. Although nutrient reserves at conception play a modest role, it is the dietary manipulation of the maternal growth trajectory thereafter which has the most negative impact on pregnancy outcome. Overnourishing adolescents to promote rapid maternal growth is particularly detrimental as placental growth, uteroplacental blood flows and fetal nutrient delivery are perturbed leading to a high incidence of fetal growth restriction and premature delivery of low birthweight lambs, whereas in undernourished adolescents further maternal growth is prevented, and depletion of the maternal body results in a small reduction in birthweight independent of placental size. Maternal and placental endocrine systems are differentially altered in both paradigms with downstream effects on fetal endocrine systems, organ development and body composition. Approaches to reverse these effects have been explored, predominantly targeting placental growth or function. After birth, growth-restricted offspring born to overnourished adolescents and fed to appetite have an altered metabolic phenotype which persists into adulthood, whereas offspring of undernourished adolescents are largely unaffected. This body of work using ovine paradigms has public health implications for nutritional advice offered to young adolescents before and during pregnancy, and their offspring thereafter.
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6.
Diabesity-associated oxidative and inflammatory stress signalling in the early human placenta.
Hoch, D, Gauster, M, Hauguel-de Mouzon, S, Desoye, G
Molecular aspects of medicine. 2019;:21-30
Abstract
Early pregnancy is characterized by a series of complex and tightly regulated events to ultimately establish implantation and early placental development. One of the key events is the opening of the decidual spiral arteries into the intervillous space. It leads to a rise in oxygen tension in the intervillous space and the placenta and will induce transcriptional and translational changes of oxygen-sensitive molecules including antioxidants. Diabetes and/or obesity ('diabesity') are associated with changes in the maternal environment, which can affect any of the distinct developmental processes ensuing modifications of onset or magnitude of oxygen tension changes. This may overwhelm the anti-oxidative defence systems developing in parallel to the physiological rise in oxygen tension. The resulting exacerbated oxidative stress, as it was demonstrated in the first trimester placentas of type 1 diabetes mellitus (T1DM) patients, may impair developmental processes. In addition, many components of the diabesity environment can have distinct molecular effects on a range of molecules, but these need to be identified. Insulin is an important contributor to early placental phenotype, because it is involved in regulation of cytotrophoblast-syncytiotrophoblast fusion and placental surface expansion. Its circulating levels are increased in T1DM, because of pharmacologic treatment, and obesity, because of beta-cell compensation of insulin resistance. This constitutes the (patho)physiological link between diabesity and placental growth changes. Microarray studies have identified several molecular and cellular candidate processes altered by insulin in obese pregnancies, including cell cycle regulation and fatty acid and cholesterol metabolism. Research on early diabesity exposure and the placenta is still in its infant stage. To stimulate further studies we have identified some important and pending questions.
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7.
Foetoplacental epigenetic changes associated with maternal metabolic dysfunction.
Kerr, B, Leiva, A, Farías, M, Contreras-Duarte, S, Toledo, F, Stolzenbach, F, Silva, L, Sobrevia, L
Placenta. 2018;:146-152
Abstract
Metabolic-related diseases are attributed to a sedentary lifestyle and eating habits, and there is now an increased awareness regarding pregnancy as a preponderant window in the programming of adulthood health and disease. The developing foetus is susceptible to the maternal environment; hence, any unfavourable condition will result in foetal physiological adaptations that could have a permanent impact on its health. Some of these alterations are maintained via epigenetic modifications capable of modifying gene expression in metabolism-related genes. Children born to mothers with dyslipidaemia, pregestational or gestational obesity, and gestational diabetes mellitus, have a predisposition to develop metabolic alterations during adulthood. CpG methylation-associated alterations to the expression of several genes in the human placenta play a crucial role in the mother-to-foetus transfer of nutrients and macromolecules. Identification of epigenetic modifications in metabolism-related tissues of offspring from metabolic-altered pregnancies is essential to obtain insights into foetal programming controlling newborn, childhood, and adult metabolism. This review points out the importance of the foetal milieu in the programming and development of human disease and provides evidence of this being the underlying mechanism for the development of adulthood metabolic disorders in maternal dyslipidaemia, pregestational or gestational obesity, and gestational diabetes mellitus.
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8.
Placental control of metabolic adaptations in the mother for an optimal pregnancy outcome. What goes wrong in gestational diabetes?
Hill, DJ
Placenta. 2018;:162-168
Abstract
As pregnancy progresses the placental syncytiotrophoblast increasingly assumes control of maternal glucose homeostasis through the release and counter-balancing effects of placental lactogen (PL) and placental variant growth hormone (GH-V). While local actions of these hormones on placental growth and function are likely to exist, each also exerts indirect actions to ensure fetal nutritional availability through modulation of the maternal insulin/insulin-like growth factor axis. Peripheral insulin resistance results from the increasing levels of GH-V in the maternal circulation and is counter-balanced by an increase in insulin availability through an expansion of maternal pancreatic β-cell mass. GH-V also increases maternal IGF-1 synthesis leading to enhanced placental growth and nutrient transporter activity. Maternal obesity and the presence of diabetes in pregnancy is associated with a disrupted balance in the placental expression of PL and GH-V. Several parallel mechanisms are likely to contribute to the increasing maternal β-cell mass as gestation progresses, including a reactivation of β-cell proliferation, an expansion of subsequent differentiation of resident β-cell progenitors, and α-to β-cell trans-differentiation. Each of these pathways could potentially be modulated during pregnancy to increase β-cell mass and prevent the onset of gestational diabetes.
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9.
Placental Exosomes During Gestation: Liquid Biopsies Carrying Signals for the Regulation of Human Parturition.
Salomon, C, Nuzhat, Z, Dixon, CL, Menon, R
Current pharmaceutical design. 2018;(9):974-982
Abstract
Parturition is defined as the action or process of giving birth to offspring. Normal term human parturition ensues following the maturation of fetal organ systems typically between 37 and 40 weeks of gestation. Our conventional understanding of how parturition initiation is signaled revolves around feto-maternal immune and endocrine changes occurring in the intrauterine cavity. These changes in turn correlate with the sequence of fetal growth and development. These important physiological changes also result in homeostatic imbalances which result in heightened inflammatory signaling. This disrupts the maintenance of pregnancy, thus leading to laborrelated changes. However, the precise mechanisms of the signaling cascades that lead to the initiation of parturition remain unclear, although exosomes may be a mediator of this process. Exosomes are a subtype of extracellular vesicles characterised by their endocytic origin. This involves the trafficking of intraluminal vesicles into multivesicular bodies (MVB) and then exocytosis via the plasmatic membranes. Exosomes are highly stable nanovesicles that are released by a wide range of cells and organs including the human placenta and fetal membranes. Interestingly, exosomes from placental origin have been uncovered in maternal circulation across gestation. In addition, their concentration is higher in pregnancies with complications such as gestational diabetes and preeclampsia. In normal gestation, the concentration of placental exosomes in maternal circulation correlates with placental weight at third trimester. The role of placental exosomes across gestation has not been fully elucidated, although recent studies suggest that placental exosomes are involved in maternal-fetal inmmuno-tolerance, maternal systemic inflammation and nutrient transport. The content of exosomes is of particular importance, encompassing a large range of molecules such as mRNA, miRNAs, DNA, lipids, cell-surface receptors, and protein mediators. These can in turn interact with either adjacent or distal cells to reprogram their phenotype and regulate their function. Many of the pro-parturition proinflammatory mediators reach maternal compartments from the fetal side via circulation, but major impediments remain, such as degradation at various levels and limited halflife in circulation. Recent findings suggest that a more effective mode of communication and signal transport is through exosomes, where signals are protected and will not succumb to degradation. Thus, understanding how exosomes regulate key events throughout pregnancy and parturition will provide an opportunity to understand the mechanisms involved in the maternal and fetal metabolic adaptations during normal and pathological pregnancies. Subsequently, this will assist in identifying those pregnancies at risk of developing complications. This may also allow more appropriate modifications of their clinical management. This review will hence examine the current body of data to summarise our understanding of how signaling pathways lead to the beginning of parturition. In addition, we propose that extracellular vesicles, namely exosomes, may be an integral component of these signaling events by transporting specific signals to prepare the maternal physiology to initiate parturition. Understanding these signals and their mechanisms in normal term pregnancies can provide insight into pathological activation of these signals, which can cause spontaneous preterm parturition. Hence, this review expands on our knowledge of exosomes as professional carriers of fetal signals to instigate human parturition.
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10.
Insulin therapy and its consequences for the mother, foetus, and newborn in gestational diabetes mellitus.
Subiabre, M, Silva, L, Toledo, F, Paublo, M, López, MA, Boric, MP, Sobrevia, L
Biochimica et biophysica acta. Molecular basis of disease. 2018;(9 Pt B):2949-2956
Abstract
Gestational diabetes mellitus (GDM) is a disease characterised by glucose intolerance and first diagnosed in pregnancy. This condition relates to an anomalous placental environment and aberrant placental vascular function. GDM-associated hyperglycaemia changes the placenta structure leading to abnormal development and functionality of this vital organ. Aiming to avoid the GDM-hyperglycaemia and its deleterious consequences in the mother, the foetus and newborn, women with GDM are firstly treated with a controlled diet therapy; however, some of the women fail to reach the recommended glycaemia values and therefore they are passed to the second line of treatment, i.e., insulin therapy. The several protocols available in the literature regarding insulin therapy are variable and not a clear consensus is yet reached. Insulin therapy restores maternal glycaemia, but this beneficial effect is not reflected in the foetus and newborn metabolism, suggesting that other factors than d-glucose may be involved in the pathophysiology of GDM. Worryingly, insulin therapy may cause alterations in the placenta and umbilical vessels as well as the foetus and newborn additional to those seen in pregnant women with GDM treated with diet. In this review, we summarised the variable information regarding indications and protocols for administration of the insulin therapy and the possible outcomes on the function and structure of the foetoplacental unit and the neonate parameters from women with GDM.