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The Journal of Endocrinology Jul 2020The placenta regulates materno-fetal nutrient transfer and secretes hormones that enable maternal physiological support of the pregnancy. In mice, these functions are...
The placenta regulates materno-fetal nutrient transfer and secretes hormones that enable maternal physiological support of the pregnancy. In mice, these functions are performed by the labyrinth (Lz) and junctional (Jz) zones, respectively. Insulin-like growth factor 2 (Igf2) is an imprinted gene expressed by the conceptus that is important for promoting fetal growth and placenta formation. However, the specific role of Igf2 in the Jz in regulating placental endocrine function and fetal development is unknown. This study used a novel model to investigate the effect of conditional loss of Igf2 in the Jz (Jz-Igf2UE) on placental endocrine cell formation and the expression of hormones and IGF signaling components in placentas from female and male fetuses. Jz-Igf2UE altered gross placental structure and expression of key endocrine and signaling genes in a sexually dimorphic manner. The volumes of spongiotrophoblast and glycogen trophoblast in the Jz were decreased in placentas from female but not male fetuses. Expression of insulin receptor was increased and expression the MAPK pathway genes (Mek1, P38α) decreased in the placental Jz of female but not male fetuses. In contrast, expression of the type-1 and -2 IGF receptors and the MAPK pathway genes (H-ras, N-ras, K-ras) was decreased in the placental Jz from male but not female fetuses. Expression of the steroidogenic gene, Cyp17a1, was increased and placental lactogen-2 was decreased in the placenta of both sexes. In summary, we report that Jz-Igf2UE alters the cellular composition, IGF signaling components and hormone expression of the placental Jz in a manner largely dependent on fetal sex.
Topics: Animals; Endocrine Cells; Female; Insulin-Like Growth Factor II; Male; Mice; Placenta; Placental Lactogen; Pregnancy; Receptor, Insulin; Signal Transduction; Somatomedins; Trophoblasts
PubMed: 32380473
DOI: 10.1530/JOE-20-0128 -
Diabetes Jul 2020Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells in vitro and in vivo...
Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells in vitro and in vivo against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway of endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines whether lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita (Ak) mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS-1 cells, primary rodent and human β-cells in vitro against two distinct ER stressors, tunicamycin and thapsigargin, through activation of the JAK2/STAT5 pathway. Lactogens mitigate expression of proapoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS-1 cells and rodent islets. Transgenic expression of placental lactogen in β-cells of Ak mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Ak littermates. These are the first studies in any cell type demonstrating that lactogens modulate the ER stress pathway, causing enhanced β-cell survival and reduced diabetes incidence in the face of chronic ER stress.
Topics: Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus; Endoplasmic Reticulum Stress; Female; Glucose; Humans; Insulin; Insulin-Secreting Cells; Janus Kinase 2; Male; Mice; Mice, Inbred C57BL; Placental Lactogen; Prolactin; STAT5 Transcription Factor; Signal Transduction
PubMed: 32332156
DOI: 10.2337/db19-0909 -
Journal of Clinical Medicine Apr 2020Placental lactogen (PL) is a peptide hormone secreted throughout pregnancy by both animal and human specialized endocrine cells. PL plays an important role in the... (Review)
Review
Placental lactogen (PL) is a peptide hormone secreted throughout pregnancy by both animal and human specialized endocrine cells. PL plays an important role in the regulation of insulin secretion in pancreatic β-cells, stimulating their proliferation and promoting the expression of anti-apoptotic proteins. Cases of pregnancy affected by metabolic conditions, including obesity and diabetes, are related to alterations in the PL secretion pattern. Whereas obesity is most often associated with lower PL serum concentrations, diabetes results in increased PL blood levels. Disruptions in PL secretion are thought to be associated with an increased prevalence of gestational complications, such as placental dysfunction, diabetic retinopathy, and abnormalities in fetal growth. PL is believed to be positively correlated with birth weight. The impaired regulation of PL secretion could contribute to an increased incidence of both growth retardation and fetal macrosomia. Moreover, the dysregulation of PL production during the intrauterine period could affect the metabolic status in adulthood. PL concentration measurement could be useful in the prediction of fetal macrosomia in women with normal oral glucose tolerance test (OGTT) results or in evaluating the risk of fetal growth restriction, but its application in standard clinical practice seems to be limited in the era of ultrasonography.
PubMed: 32316284
DOI: 10.3390/jcm9041142 -
Psychoneuroendocrinology Jun 2020Placental endocrine insufficiency may increase the risk of depression and anxiety during pregnancy and/or after birth. This study investigated the association between...
BACKGROUND
Placental endocrine insufficiency may increase the risk of depression and anxiety during pregnancy and/or after birth. This study investigated the association between serum human placental lactogen (hPL) and measures of perinatal mental health, accounting for selective serotonin-reuptake inhibitor (SSRI) usage.
METHOD
Caucasian women with singleton, term pregnancies recruited at their pre-surgical appointment prior to an elective caesarean section (ELCS) were studied. Serum hPL levels were measured by ELISA in maternal blood collected at the pre-surgical appointment. Depression and anxiety scores were derived from Edinburgh Postnatal Depression Scale (EPDS) and the trait subscale of the State-Trait Anxiety Inventory (STAI) questionnaires completed at recruitment and three postnatal time points. Data was analysed by unadjusted and adjusted multiple linear regression.
RESULTS
In adjusted linear regressions, term maternal serum hPL levels were negatively associated with postnatal EPDS and STAI score ten weeks postnatal for mothers who had girls (B= -.367, p = .022, 95% CI -.679, -.056; and B= -.776, p = .030, 95% CI -1.475, -.077 respectively). Excluding women prescribed SSRIs strengthened the relationship at 10 weeks and uncovered an earlier association between hPL and mood scores within one week of delivery (EPDS B= -.357, p = .041, 95 % CI -.698, -.015; and STAI B= -.737, p = .027, 95 % CI -1.387, -.086). In mothers who had boys, there were no associations between hPL and mood scores at any time point.
CONCLUSION
Low hPL at term associated with postnatal depression and anxiety symptoms exclusively in mothers of girls. Insufficiency in hPL may contribute to maternal mood symptoms.
Topics: Adult; Anxiety Disorders; Cesarean Section; Depression, Postpartum; Depressive Disorder; Female; Humans; Infant; Infant, Newborn; Placental Lactogen; Pregnancy; Puerperal Disorders; Sex Factors
PubMed: 32247203
DOI: 10.1016/j.psyneuen.2020.104655 -
Current Vascular Pharmacology 2021Normal pregnancy is associated with increased insulin resistance as a metabolic adaptation to the nutritional demands of the placenta and fetus, and this is amplified in... (Review)
Review
Normal pregnancy is associated with increased insulin resistance as a metabolic adaptation to the nutritional demands of the placenta and fetus, and this is amplified in obese mothers. Insulin resistance is normally compensated for by an adaptive increase in pancreatic β-cell mass together with enhanced glucose-stimulated insulin release. Placentally-derived hormones and growth factors are central to the altered pancreatic morphology and function. A failure of β-cells to undergo adaptive change after the first trimester has been linked with gestational diabetes. In the pregnant mouse, an increase in β-cell replication contributes to a 2-3-fold increase in mass peaking in late gestation, depending on the proliferation of existing β-cells, the differentiation of resident progenitor β-cells, or islet cell transdifferentiation. Using mouse models and human studies placenta- and islet of Langerhans-derived molecules have been identified that are likely to contribute to the metabolic adaptations to pregnancy and whose physiology is altered in the obese, glucose-intolerant mother. Maternal obesity during pregnancy can create a pro-inflammatory environment that can disrupt the response of the β-cells to the endocrine signals of pregnancy and limit the adaptive changes in β-cell mass and function, resulting in an increased risk of gestational diabetes.
Topics: Adaptation, Physiological; Animals; Blood Glucose; Cell Proliferation; Cell Transdifferentiation; Diabetes, Gestational; Energy Metabolism; Female; Humans; Inflammation Mediators; Insulin-Secreting Cells; Obesity, Maternal; Oxidative Stress; Pancreas; Placenta; Pregnancy; Pregnancy Outcome; Risk Assessment; Risk Factors
PubMed: 32196450
DOI: 10.2174/1570161118666200320111209 -
Endocrinology, Diabetes & Metabolism... Mar 2020A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of...
SUMMARY
A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered.
LEARNING POINTS
Hormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels. Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins. Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia. Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect. Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.
PubMed: 32168469
DOI: 10.1530/EDM-19-0165 -
PloS One 2020The placenta, a tissue that is metabolically active and rich in mitochondria, forms a critical interface between the mother and developing fetus. Oxidative stress within...
The placenta, a tissue that is metabolically active and rich in mitochondria, forms a critical interface between the mother and developing fetus. Oxidative stress within this tissue, derived from the dysregulation of reactive oxygen species (ROS), has been linked to a number of adverse fetal outcomes. While such outcomes have been associated with mitochondrial dysfunction, the causal role of mitochondrial dysfunction and mitochondrially generated ROS in altering the process of placentation remains unclear. In this study, mitochondrial complex I activity was attenuated using 10 nM rotenone to induce cellular oxidative stress by increasing mitochondrial ROS production in the BeWo choriocarcinoma cell line. Increased mitochondrial ROS resulted in a significant decrease in the transcripts which encode for proteins associated with fusion (GCM1, ERVW-1, and ERVFRD-1) resulting in a 5-fold decrease in the percentage of BeWo fusion. This outcome was associated with increased indicators of mitochondrial fragmentation, as determined by decreased expression of MFN2 and OPA1 along with an increase in a marker of mitochondrial fission (DRP1). Importantly, increased mitochondrial ROS also resulted in a 5.0-fold reduction of human placental lactogen (PL) and a 4.4-fold reduction of insulin like growth factor 2 (IGF2) transcripts; hormones which play an important role in regulating fetal growth. The pre-treatment of rotenone-exposed cells with 5 mM N-acetyl cysteine (NAC) resulted in the prevention of these ROS mediated changes in BeWo function and supports a central role for mitochondrial ROS signaling in the maintenance and function of the materno-fetal interface.
Topics: Cell Fusion; Cells, Cultured; Female; Humans; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Placental Hormones; Pregnancy; Reactive Oxygen Species; Rotenone; Signal Transduction; Trophoblasts
PubMed: 32092105
DOI: 10.1371/journal.pone.0229332 -
Journal of Physiology and Pharmacology... Dec 2019Apelin was thought to be an adipocyte-specific hormone, but recent studies have indicated a link between apelin and placenta function e.g. cell proliferation. The aim of...
Apelin decreased placental hormone secretion by human trophoblast BeWo cells via apelin receptor, protein kinase A and extracellular signal-regulated kinases 1/2 activation.
Apelin was thought to be an adipocyte-specific hormone, but recent studies have indicated a link between apelin and placenta function e.g. cell proliferation. The aim of the study was investigating dose- and time-dependent effect of apelin on hormone secretion including steroids: progesterone (P4) and estradiol (E2) and proteins: chorionic gonadotropin (hCG), human placental lactogen (hPL), placental growth factor (PLGF), as well as protein expression of steroid enzymes (3βHSD, CYP19) and protein hormones (hCG, hPL and PLGF) in placental cells. Syncytiotrophoblast BeWo cells, as human trophoblast models, were treated for 24, 48, and 72 hours with the human recombinant apelin at doses 0.02, 0.2, 2.0, 20 and 200 ng/ml followed by culture medium. Concentrations of the above hormones were studied by ELISA kits. Furthermore, protein expression of steroid enzymes and protein hormones were measured using Western blot. Our results showed that apelin significantly decreased both steroid and protein hormones by inhibiting steroid enzymes or protein hormone expression. Moreover, we demonstrated that apelin at dose 2.0 ng/ml increased phosphorylation of protein kinase A (PKA) from 1 to 60 min of BeWo cell incubation. Inhibitory effect of apelin on P4, E2 and PLGF secretion were abolished when BeWo cells were cultured in the presence of ML221, an apelin receptor antagonist, PD98059, an extracellular signal-regulated kinases (ERK1/2) antagonist and KT5720, a PKA antagonist. In turn, secretion of hCG and hPL occurs only in the presence of ML221 and PD98059. In conclusion, our results indicate that apelin can be considered as a gestational hormone implied in the endocrine function of the human placenta, with an important role in controlling the production of steroid and protein hormones in placental BeWo cells.
Topics: Apelin; Apelin Receptors; Cell Line, Tumor; Choriocarcinoma; Chorionic Gonadotropin; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Female; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Placenta; Placenta Growth Factor; Placental Lactogen; Pregnancy; Time Factors; Trophoblasts
PubMed: 32084650
DOI: 10.26402/jpp.2019.6.08 -
Neuropharmacology May 2020Mammalian pregnancy and lactation is accompanied by a period of infertility that takes place in the midst of a sustained increase in food intake. Indeed, successful... (Review)
Review
Mammalian pregnancy and lactation is accompanied by a period of infertility that takes place in the midst of a sustained increase in food intake. Indeed, successful reproduction in females is dependent on co-ordination of the distinct systems that regulate reproduction and metabolism. Rather than arising from different mechanisms during pregnancy and lactation, we propose that elevations in lactogenic hormones (predominant among these being prolactin and the placental lactogens), are ideally placed to influence both of these systems at the appropriate time. We review the literature examining the impacts of lactogens on fertility and energy homeostasis in the virgin state, during pregnancy and lactation and potential long-term impacts of reproductive experience. Taken together, the literature indicates that duration and pattern of lactogen exposure is a vital factor in the ability of these hormones to alter reproduction and food intake. Transient increases in prolactin, as typically seen in healthy virgin females and males, are unable to exert lasting impacts. Importantly, both suppression of fertility and increased food intake are only observed following exposure to chronically-elevated levels of lactogens. Physiologically, the only time this pattern of lactogenic secretion is maintained in the healthy female is during pregnancy and lactation, when co-ordination between these regulatory systems emerges. This article is part of the special issue on 'Neuropeptides'.
Topics: Animals; Appetite Regulation; Energy Metabolism; Female; Fertility; Humans; Lactation; Male; Placental Lactogen; Pregnancy; Prolactin; Reproduction
PubMed: 32058177
DOI: 10.1016/j.neuropharm.2019.107911 -
Contraception May 2020To examine the possibility that serum or urine concentrations of pregnancy-associated plasma protein A (PAPP-A), a disintegrin and metalloproteinase 12 (ADAM-12),... (Observational Study)
Observational Study
OBJECTIVE
To examine the possibility that serum or urine concentrations of pregnancy-associated plasma protein A (PAPP-A), a disintegrin and metalloproteinase 12 (ADAM-12), placental growth factor (PlGF), human placental lactogen (HPL), glypican-3, pregnancy specific beta-1-glycoprotein 1 (PSG-1) or prolactin could predict gestational age (GA) >70 days, the currently recommended limit for medical abortion in the United States.
STUDY DESIGN
In this exploratory observational study, we collected serum and urine specimens from 245 healthy individuals with singleton intrauterine pregnancies at GA <40 weeks by ultrasound. We assayed the serum specimens for all seven proteins and the urine specimens for PAPP-A and ADAM-12. We used scatterplots and receiver operating characteristic curves to identify a concentration for each protein that would differentiate GAs above and below 70 days.
RESULTS
All seven proteins showed significant ability to distinguish GAs >70 days from earlier gestations. A PAPP-A concentration ≥5.591 ng/ml provided 100% sensitivity and 90% specificity for identifying GAs >70 days. An ADAM-12 concentration of ≥3.11 ng/ml provided 98.5% sensitivity and 77% specificity for identifying GAs >70 days. Serum concentrations of the other compounds showed less diagnostic discrimination. PAPP-A was not detected in urine, and urinary ADAM-12 concentrations were not useful in identifying GAs above 70 days.
CONCLUSION
PAPP-A and ADAM-12 showed considerable promise as bases for a sensitive and specific serum test for identifying pregnancies with GA >70 days. If these results are confirmed by future research, such a test could obviate the need for routine ultrasound before medical abortion.
IMPLICATIONS
Two placental proteins, PAPP-A and ADAM-12, showed considerable promise as bases for a serum test for identifying pregnancies with gestational age >70 days. Such a test could be highly useful in screening patients for eligibility for medical abortion.
Topics: ADAM12 Protein; Adult; Biomarkers; Case-Control Studies; Female; Gestational Age; Humans; Pregnancy; Pregnancy Proteins; Pregnancy Trimester, First; Pregnancy-Associated Plasma Protein-A; ROC Curve; Sensitivity and Specificity; Young Adult
PubMed: 32014519
DOI: 10.1016/j.contraception.2020.01.007