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American Journal of Physiology.... Oct 2023Growth differentiation factor 15 (GDF15) is a stress-induced cytokine. Although the exact physiological function of GDF15 is not yet fully comprehended, the significant... (Comparative Study)
Comparative Study
Growth differentiation factor 15 (GDF15) is a stress-induced cytokine. Although the exact physiological function of GDF15 is not yet fully comprehended, the significant elevation of circulating GDF15 levels during gestation suggests a potential role for this hormone in pregnancy. This is corroborated by genetic association studies in which GDF15 and the GDF15 receptor, GDNF family receptor alpha like (GFRAL) have been linked to morning sickness and hyperemesis gravidarum (HG) in humans. Here, we studied GDF15 biology during pregnancy in mice, rats, macaques, and humans. In contrast to macaques and humans, mice and rats exhibited an underwhelming induction in plasma GDF15 levels in response to pregnancy (∼75-fold increase in macaques vs. ∼2-fold increase in rodents). The changes in circulating GDF15 levels were corroborated by the magnitude of mRNA and GDF15 protein expression in placentae from mice, rats, and macaques. These species-specific findings may help guide future studies focusing on GDF15 in pregnancy and on the evaluation of pharmacological strategies to interfere with GDF15-GFRAL signaling to treat severe nausea and HG. In the present study pregnancy-induced changes in circulating growth differentiation factor 15 (GDF15) in rodents, rhesus macaques, and humans are mapped. In sum, it is demonstrated that humans and macaques exhibit a tremendous increase in placental and circulating GDF15 during pregnancy. In contrast, GDF15 is negligibly increased in pregnant mice and rats, questioning a physiological role for GDF15 in pregnancy in rodents.
Topics: Animals; Female; Humans; Mice; Pregnancy; Rats; Cytokines; Growth Differentiation Factor 15; Macaca mulatta; Obesity; Placenta
PubMed: 37584611
DOI: 10.1152/ajpendo.00134.2023 -
International Journal of Molecular... Dec 2023Thrombocytes play an essential role in hemostasis and thrombosis. Moreover, the controlled activation of thrombocytes is required in reproduction and fertility. The... (Review)
Review
Thrombocytes play an essential role in hemostasis and thrombosis. Moreover, the controlled activation of thrombocytes is required in reproduction and fertility. The platelet-activating factor and the controlled activation of platelets have important roles in folliculogenesis, ovulation, placental development, implantation and embryo development. Activated platelets accumulate in the follicular vessels surrounding the follicle and, due to its released soluble molecules (factors, mediators, chemokines, cytokines, neurotransmitters), locally increase oocyte maturation and hormone secretion. Furthermore, activated platelets are involved in the pathogenesis of ovarian hyperstimulation syndrome (OHSS) and preeclampsia. Low-dose aspirin can prevent OHSS during ovulation induction, while intrauterine or intraovarian administration of platelet-rich plasma (PRP) increases the endometrium thickness and receptivity as well as oocyte maturation. Activated thrombocytes rapidly release the contents of intracellular granules and have multiple adhesion molecules and receptors on their surface. Considering the numerous homeostatic endocrine functions of thrombocytes, it is reasonable to suppose a platelet-associated regulatory system (PARS) in reproduction. Although we are far from a complete understanding of the regulatory processes, the results of PARS research and the therapeutic application of aspirin and PRP during in vitro fertilization are promising.
Topics: Pregnancy; Female; Humans; Blood Platelets; Placenta; Fertility; Fertilization in Vitro; Embryo Implantation; Ovarian Hyperstimulation Syndrome; Platelet-Rich Plasma; Aspirin
PubMed: 38139165
DOI: 10.3390/ijms242417336 -
Journal of Pineal Research Dec 2023Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre-eclampsia (PE), a gestational complication, is a leading cause of maternal and...
Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre-eclampsia (PE), a gestational complication, is a leading cause of maternal and perinatal morbidity and mortality. Aberrant elevation of testosterone (T ) synthesis, reduced estradiol (E ), and melatonin productions have been identified in preeclamptic placentas. However, the precise contribution of disrupted homeostasis among these hormones to the occurrence of PE remains unknown. In this study, we established a strong correlation between suppressed melatonin production and decreased E as well as elevated T synthesis in PE placentas. Administration of the T analog testosterone propionate (TP; 2 mg/kg/day) to pregnant mice from E7.5 onwards resulted in PE-like symptoms, along with elevated T production and reduced E and melatonin production. Notably, supplementation with melatonin (10 mg/kg/day) in TP-treated mice had detrimental effects on fetal and placental development and compromised hormone synthesis. Importantly, E , but not T , actively enhanced melatonin synthetase AANAT expression and melatonin production in primary human trophoblast (PHT) cells through GPER1-PKA-CREB signaling pathway. On the other hand, melatonin suppressed the level of estrogen synthetase aromatase while promoting the expressions of androgen synthetic enzymes including 17β-HSD3 and 3β-HSD1 in PHT cells. These findings reveal an orchestrated feedback mechanism that maintains homeostasis of placental sex hormones and melatonin. It is implied that abnormal elevation of T synthesis likely serves as the primary cause of placental endocrine disturbances associated with PE. The suppression of melatonin may represent an adaptive strategy to correct the imbalance in sex hormone levels within preeclamptic placentas. The findings of this study offer novel evidence that identifies potential targets for the development of innovative therapeutic strategies for PE.
PubMed: 37746893
DOI: 10.1111/jpi.12913 -
Molecular and Cellular Endocrinology Dec 2023Human exposures to pyrethroid pesticides have increased in recent years following the bans and sanctions placed on other families of pesticides. Although pyrethroids are...
Human exposures to pyrethroid pesticides have increased in recent years following the bans and sanctions placed on other families of pesticides. Although pyrethroids are currently widely used across the United States and throughout the world, and their overt neurological toxicity classified, the extent of their toxicity through low dose and chronic exposures on humans is less well characterized, particularly when it comes to prenatal exposures, their impacts on neurodevelopment, and any role for the placenta in those effects. In this review, we assess the state of research on pyrethroid pesticide exposure and placental effects. These studies presented hormone disrupting, genotoxic, neurodevelopmental and neurobehavioral effects, among others, following prenatal pyrethroid exposures, and highlights a need for future research to assess gaps relating to effects in the human placenta and mechanisms of toxicity as well as shortcomings in the reproducibility and standardization of the methodologies presented.
PubMed: 37722502
DOI: 10.1016/j.mce.2023.112070 -
BMJ Case Reports Sep 2023An ectopic pregnancy (EP) accounts for 1-2% of all pregnancies, of which 90% implant in the fallopian tube. An abdominal ectopic pregnancy (AEP) is defined as an ectopic...
An ectopic pregnancy (EP) accounts for 1-2% of all pregnancies, of which 90% implant in the fallopian tube. An abdominal ectopic pregnancy (AEP) is defined as an ectopic pregnancy occurring when the gestational sac is implanted in the peritoneal cavity outside the uterine cavity or the fallopian tube. Implantation sites may include the omentum, peritoneum of the pelvic and abdominal cavity, the uterine surface and abdominal organs such as the spleen, intestine, liver and blood vessels. Primary abdominal pregnancy results from fertilisation of the ovum in the abdominal cavity and secondary occurs from an aborted or ruptured tubal pregnancy. It represents a very rare form of an EP, occurring in <1% of cases. At early gestations, it can be challenging to render the diagnosis, and it can be misdiagnosed as a tubal ectopic pregnancy. An AEP diagnosed >20 weeks' gestation, caused by the implantation of an abnormal placenta, is an important cause of maternal-fetal mortality due to the high risk of a major obstetric haemorrhage and coagulopathy following partial or total placental separation. Management options include surgical therapy (laparoscopy±laparotomy), medical therapy with intramuscular or intralesional methotrexate and/or intracardiac potassium chloride or a combination of medical and surgical management. The authors present the case of a multiparous woman in her early 30s presenting with heavy vaginal bleeding and abdominal pain at 8 weeks' gestation. Her beta-human chorionic gonadotropin (bHCG) was 5760 IU/L (range: 0-5), consistent with a viable pregnancy. Her transvaginal ultrasound scan suggested an ectopic pregnancy. Laparoscopy confirmed an AEP involving the pelvic lateral sidewall. Her postoperative 48-hour bHCG was 374 IU/L. Due to the rarity of this presentation, a high index of clinical suspicion correlated with the woman's symptoms; bHCG and ultrasound scan is required to establish the diagnosis to prevent morbidity and mortality.
Topics: Pregnancy; Female; Humans; Pregnancy, Abdominal; Placenta; Chorionic Gonadotropin, beta Subunit, Human; Pregnancy, Tubal; Methotrexate
PubMed: 37775278
DOI: 10.1136/bcr-2022-252960 -
Frontiers in Endocrinology 2023Gestational diabetes mellitus (GDM) is the most frequent pathophysiological state of pregnancy, which in many cases produces fetuses with macrosomia, requiring increased... (Review)
Review
Gestational diabetes mellitus (GDM) is the most frequent pathophysiological state of pregnancy, which in many cases produces fetuses with macrosomia, requiring increased nutrient transport in the placenta. Recent studies by our group have demonstrated that leptin is a key hormone in placental physiology, and its expression is increased in placentas affected by GDM. However, the effect of leptin on placental nutrient transport, such as transport of glucose, amino acids, and lipids, is not fully understood. Thus, we aimed to review literature on the leptin effect involved in placental nutrient transport as well as activated leptin signaling pathways involved in the expression of placental transporters, which may contribute to an increase in placental nutrient transport in human pregnancies complicated by GDM. Leptin appears to be a relevant key hormone that regulates placental transport, and this regulation is altered in pathophysiological conditions such as gestational diabetes. Adaptations in the placental capacity to transport glucose, amino acids, and lipids may underlie both under- or overgrowth of the fetus when maternal nutrient and hormone levels are altered due to changes in maternal nutrition or metabolic disease. Implementing new strategies to modulate placental transport may improve maternal health and prove effective in normalizing fetal growth in cases of intrauterine growth restriction and fetal overgrowth. However, further studies are needed to confirm this hypothesis.
Topics: Female; Humans; Pregnancy; Amino Acids; Diabetes, Gestational; Fetal Macrosomia; Glucose; Leptin; Lipids; Membrane Transport Proteins; Nutrients; Placenta
PubMed: 37497352
DOI: 10.3389/fendo.2023.1172831 -
JAMA Dec 2023Cannabis use is increasing among reproductive-age individuals and the risks associated with cannabis exposure during pregnancy remain uncertain.
IMPORTANCE
Cannabis use is increasing among reproductive-age individuals and the risks associated with cannabis exposure during pregnancy remain uncertain.
OBJECTIVE
To evaluate the association between maternal cannabis use and adverse pregnancy outcomes known to be related to placental function.
DESIGN, SETTING, AND PARTICIPANTS
Ancillary analysis of nulliparous individuals treated at 8 US medical centers with stored urine samples and abstracted pregnancy outcome data available. Participants in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort were recruited from 2010 through 2013; the drug assays and analyses for this ancillary project were completed from June 2020 through April 2023.
EXPOSURE
Cannabis exposure was ascertained by urine immunoassay for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol using frozen stored urine samples from study visits during the pregnancy gestational age windows of 6 weeks and 0 days to 13 weeks and 6 days (visit 1); 16 weeks and 0 days to 21 weeks and 6 days (visit 2); and 22 weeks and 0 days to 29 weeks and 6 days (visit 3). Positive results were confirmed with liquid chromatography tandem mass spectrometry. The timing of cannabis exposure was defined as only during the first trimester or ongoing exposure beyond the first trimester.
MAIN OUTCOME AND MEASURE
The dichotomous primary composite outcome included small-for-gestational-age birth, medically indicated preterm birth, stillbirth, or hypertensive disorders of pregnancy ascertained by medical record abstraction by trained perinatal research staff with adjudication of outcomes by site investigators.
RESULTS
Of 10 038 participants, 9257 were eligible for this analysis. Of the 610 participants (6.6%) with cannabis use, 32.4% (n = 197) had cannabis exposure only during the first trimester and 67.6% (n = 413) had ongoing exposure beyond the first trimester. Cannabis exposure was associated with the primary composite outcome (25.9% in the cannabis exposure group vs 17.4% in the no exposure group; adjusted relative risk, 1.27 [95% CI, 1.07-1.49]) in the propensity score-weighted analyses after adjustment for sociodemographic characteristics, body mass index, medical comorbidities, and active nicotine use ascertained via urine cotinine assays. In a 3-category cannabis exposure model (no exposure, exposure only during the first trimester, or ongoing exposure), cannabis use during the first trimester only was not associated with the primary composite outcome; however, ongoing cannabis use was associated with the primary composite outcome (adjusted relative risk, 1.32 [95% CI, 1.09-1.60]).
CONCLUSIONS AND RELEVANCE
In this multicenter cohort, maternal cannabis use ascertained by biological sampling was associated with adverse pregnancy outcomes related to placental dysfunction.
Topics: Female; Humans; Infant; Infant, Newborn; Pregnancy; Cannabis; Cohort Studies; Dronabinol; Hallucinogens; Marijuana Abuse; Maternal Exposure; Placenta; Placenta Diseases; Pregnancy Outcome; Premature Birth; Stillbirth; Pregnancy Complications
PubMed: 38085313
DOI: 10.1001/jama.2023.21146 -
International Journal of Molecular... Aug 2023Endometrial decidualization is a uterine process essential for spiral artery remodeling, embryo implantation, and trophoblast invasion. Defects in endometrial... (Review)
Review
Endometrial decidualization is a uterine process essential for spiral artery remodeling, embryo implantation, and trophoblast invasion. Defects in endometrial decidualization and spiral artery remodeling are important contributing factors in preeclampsia, a major disorder in pregnancy. Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood volume and pressure. ANP is also generated in non-cardiac tissues, such as the uterus and placenta. In recent human genome-wide association studies, multiple loci with genes involved in natriuretic peptide signaling are associated with gestational hypertension and preeclampsia. In cellular experiments and mouse models, uterine ANP has been shown to stimulate endometrial decidualization, increase TNF-related apoptosis-inducing ligand expression and secretion, and enhance apoptosis in arterial smooth muscle cells and endothelial cells. In placental trophoblasts, ANP stimulates adenosine 5'-monophosphate-activated protein kinase and the mammalian target of rapamycin complex 1 signaling, leading to autophagy inhibition and protein kinase N3 upregulation, thereby increasing trophoblast invasiveness. ANP deficiency impairs endometrial decidualization and spiral artery remodeling, causing a preeclampsia-like phenotype in mice. These findings indicate the importance of natriuretic peptide signaling in pregnancy. This review discusses the role of ANP in uterine biology and potential implications of impaired ANP signaling in preeclampsia.
Topics: Humans; Animals; Signal Transduction; Natriuretic Peptides; Pre-Eclampsia; Uterus; Hypertension, Pregnancy-Induced; Placenta; Serine Endopeptidases
PubMed: 37569683
DOI: 10.3390/ijms241512309 -
Frontiers in Nutrition 2023Conditions influence intrauterine and postnatal infant growth and a few studies indicate that maternal inflammation and insulin resistance might affect birth and...
BACKGROUND
Conditions influence intrauterine and postnatal infant growth and a few studies indicate that maternal inflammation and insulin resistance might affect birth and breastfeeding outcomes. Furthermore, hormones in human milk (HM) may influence infant appetite-regulation and thereby milk intake, but the associations are less understood.
OBJECTIVE
(1) To investigate associations between maternal inflammatory, lipid and metabolic markers and birth and breastfeeding outcomes, and (2) to assess predictors of maternal inflammatory, lipid and metabolic markers in pregnancy.
METHODS
Seventy-one mother-infant dyads participating in the Mothers, Infants and Lactation Quality (MILQ) study were included in the present study. Fasting blood samples were collected around 28th gestational week, and HM samples at three time points from 1.0 to 8.5 months, where milk intake was assessed using 24-h test weighing. Maternal plasma inflammatory, lipid and metabolic markers included high-sensitive C-reactive protein (hs-CRP), tumor-necrosis factor-α (TNFα), interferon-γ (IFNγ), Interleukin (IL)-6, IL-8, high-, low-, and very-low-density lipoprotein (HDL, LDL, VLDL), total-cholesterol, triglycerides, leptin, adiponectin, insulin, C-peptide, the homeostasis model assessment of insulin resistance (HOMA-IR) and glucose concentration at = 120 min following an oral glucose tolerance test. Of these, TNFα, IFNγ, IL-6, IL-8, leptin, adiponectin and insulin were also measured in HM samples.
RESULTS
HDL in pregnancy was inversely associated with gestational age (GA) at birth and GA-adjusted birthweight z-score, whereas triglycerides and glucose ( = 120) were positively associated with GA-adjusted birthweight z-score. Higher hs-CRP, VLDL and triglycerides were associated with a higher placental weight. Furthermore, higher HDL, insulin, leptin and HOMA-IR were associated with longer duration of exclusive breastfeeding (EBF). Higher pre-pregnancy BMI was the main predictor of higher levels of hs-CRP, log-TNFα, leptin, insulin, C-peptide, and HOMA-IR.
CONCLUSION
Maternal lipid and metabolic markers influenced birthweight z-score and placental weight as well as duration of EBF. Furthermore, pre-pregnancy BMI and maternal age predicted levels of several inflammatory and metabolic markers during pregnancy. Our findings indicate that maternal lipid and metabolic profiles in pregnancy may influence fetal growth and breastfeeding, possibly explained by overweight and/or higher placental weight.
CLINICAL TRIAL REGISTRATION
https://clinicaltrials.gov/, identifier NCT03254329.
PubMed: 37731394
DOI: 10.3389/fnut.2023.1223753 -
International Journal of Molecular... Nov 2023Transforming growth factor beta (TGF-β), a multifunctional cytokine, is one of the most important inflammatory cytokines closely related to pregnancy. It plays... (Review)
Review
Transforming growth factor beta (TGF-β), a multifunctional cytokine, is one of the most important inflammatory cytokines closely related to pregnancy. It plays significant roles in hormone secretion, placental development, and embryonic growth during pregnancy. TGF-β is implicated in embryo implantation and inhibits the invasion of extraepithelial trophoblast cells. It also moderates the mother-fetus interaction by adjusting the secretion pattern of immunomodulatory factors in the placenta, consequently influencing the mother's immune cells. The TGF-β family regulates the development of the nervous, respiratory, and cardiovascular systems by regulating gene expression. Furthermore, TGF-β has been associated with various pregnancy complications. An increase in TGF-β levels can induce the occurrences of pre-eclampsia and gestational diabetes mellitus, while a decrease can lead to recurrent miscarriage due to the interference of the immune tolerance environment. This review focuses on the role of TGF-β in embryo implantation and development, providing new insights for the clinical prevention and treatment of pregnancy complications.
Topics: Pregnancy; Female; Humans; Placenta; Transforming Growth Factor beta; Trophoblasts; Placentation; Cytokines; Pre-Eclampsia
PubMed: 38069201
DOI: 10.3390/ijms242316882