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The Journal of Physiology Apr 2023Maternal obesity and gestational diabetes mellitus (GDM) are associated with insulin resistance and health risks for mother and offspring. Obesity is also characterized...
Obesity and gestational diabetes independently and collectively induce specific effects on placental structure, inflammation and endocrine function in a cohort of South African women.
Maternal obesity and gestational diabetes mellitus (GDM) are associated with insulin resistance and health risks for mother and offspring. Obesity is also characterized by low-grade inflammation, which in turn, impacts insulin sensitivity. The placenta secretes inflammatory cytokines and hormones that influence maternal glucose and insulin handling. However, little is known about the effect of maternal obesity, GDM and their interaction, on placental morphology, hormones and inflammatory cytokines. In a South African cohort of non-obese and obese pregnant women with and without GDM, this study examined placental morphology using stereology, placental hormone and cytokine expression using real-time PCR, western blotting and immunohistochemistry, and circulating TNFα and IL-6 concentrations using ELISA. Placental expression of endocrine and growth factor genes was not altered by obesity or GDM. However, LEPTIN gene expression was diminished, syncytiotrophoblast TNFα immunostaining elevated and stromal and fetal vessel IL-6 staining reduced in the placenta of obese women in a manner that was partly influenced by GDM status. Placental TNFα protein abundance and maternal circulating TNFα concentrations were reduced in GDM. Both maternal obesity and, to a lesser extent, GDM were accompanied by specific changes in placental morphometry. Maternal blood pressure and weight gain and infant ponderal index were also modified by obesity and/or GDM. Thus, obesity and GDM have specific impacts on placental morphology and endocrine and inflammatory states that may relate to pregnancy outcomes. These findings may contribute to developing placenta-targeted treatments that improve mother and offspring outcomes, which is particularly relevant given increasing rates of obesity and GDM worldwide. KEY POINTS: Rates of maternal obesity and gestational diabetes (GDM) are increasing worldwide, including in low-middle income countries (LMIC). Despite this, much of the work in the field is conducted in higher-income countries. In a well-characterised cohort of South African women, this study shows that obesity and GDM have specific impacts on placental structure, hormone production and inflammatory profile. Moreover, such placental changes were associated with pregnancy and neonatal outcomes in women who were obese and/or with GDM. The identification of specific changes in the placenta may help in the design of diagnostic and therapeutic approaches to improve pregnancy and neonatal outcomes with particular significant benefit in LMICs.
Topics: Infant, Newborn; Female; Humans; Pregnancy; Diabetes, Gestational; Placenta; Tumor Necrosis Factor-alpha; Interleukin-6; Obesity, Maternal; South Africa; Obesity; Inflammation; Cytokines; Insulin Resistance
PubMed: 36849131
DOI: 10.1113/JP284139 -
Frontiers in Endocrinology 2021The glycoprotein hormones (GPH) are heterodimers composed of a common α subunit and a specific β subunit. They act by activating specific leucine-rich repeat G... (Review)
Review
The glycoprotein hormones (GPH) are heterodimers composed of a common α subunit and a specific β subunit. They act by activating specific leucine-rich repeat G protein-coupled receptors. However, individual subunits have been shown to elicit responses in cells devoid of the receptor for the dimeric hormones. The α subunit is involved in prolactin production from different tissues. The human chorionic gonadotropin β subunit (βhCG) plays determinant roles in placentation and in cancer development and metastasis. A truncated form of the thyrotropin (TSH) β subunit is also reported to have biological effects. The GPH α- and β subunits are derived from precursor genes ( and , respectively), which are expressed in most invertebrate species and are still represented in vertebrates as GPH subunit paralogs ( and , respectively). No specific receptor has been found for the vertebrate GPA2 and GPB5 even if their heterodimeric form is able to activate the TSH receptor in mammals. Interestingly, GPA and GPB are phylogenetically and structurally related to cysteine-knot growth factors (CKGF) and particularly to a group of antagonists that act independently on any receptor. This review article summarizes the observed actions of individual GPH subunits and presents the current hypotheses of how these actions might be induced. New approaches are also proposed in light of the evolutionary relatedness with antagonists of the CKGF family of proteins.
Topics: Amino Acid Sequence; Animals; Glycoprotein Hormones, alpha Subunit; Glycoproteins; Humans; Peptide Hormones; Protein Subunits; Receptors, G-Protein-Coupled
PubMed: 34671318
DOI: 10.3389/fendo.2021.731966 -
BioRxiv : the Preprint Server For... Aug 2023Maternal prenatal stress is associated with adverse pregnancy outcomes and predisposition to long-term adverse health outcomes in children. While the molecular...
INTRODUCTION
Maternal prenatal stress is associated with adverse pregnancy outcomes and predisposition to long-term adverse health outcomes in children. While the molecular mechanisms that govern these associations has not been fully teased apart, stress-induced changes in placental function can drive sex-specific phenotypes in offspring. We sought to identify and examine molecular pathways in the placenta that are altered in response to maternal prenatal stress.
METHODS
Using a mouse model of maternal prenatal stress, we conducted RNA-seq analysis of whole placenta at E18.5. We used qRT-PCR to validate gene expression changes in the placenta and in a trophoblast cell line. ELISAs were used to measure the abundance of thyroid hormones in maternal and fetal serum and in the placenta.
RESULTS
was amongst the top differentially expressed genes in response to elevated maternal stress hormone. expression was more downregulated in female placenta from stressed dams than both female control and male placenta. Consistent with Dio2's role in production of bioactive thyroid hormone (T3), we found that there was a reduction of T3 in placenta and serum of female embryos from stressed dams at E18.5. Both T3 and T4 were reduced in the fetal compartment of the female placenta from stressed dams at E16.5. Stress hormone induced reduction in thyroid hormone in females was independent of circulating levels of TH in the dams.
DISCUSSION
The placental thyroid hormone synthesis pathway may be a target of maternal stress and modulate fetal programming of health and disease of offspring in a sex-specific fashion.
PubMed: 37461599
DOI: 10.1101/2023.07.05.547278 -
EBioMedicine Dec 2022Physiological shifts during pregnancy predispose women to a higher risk of developing sepsis resulting from a maladapted host-response to infection. Insightful studies... (Review)
Review
Physiological shifts during pregnancy predispose women to a higher risk of developing sepsis resulting from a maladapted host-response to infection. Insightful studies have delineated subtle point-changes to the immune system during pregnancy. Here, we present an overlay of these point-changes, asking what changes and when, at a physiological, cellular, and molecular systems-level in the context of sepsis. We identify distinct immune phases in pregnancy delineated by placental hormone-driven changes in homeostasis setpoints of the immune and metabolic systems that subtly mirrors changes observed in sepsis. We propose that pregnancy immune-metabolic setpoint changes impact feedback thresholds that increase risk for a maladapted host-response to infection and thus act as a stepping-stone to sepsis. Defining maternal immune-metabolic setpoint changes is not only vital for tailoring the right diagnostic tools for early management of maternal sepsis but will facilitate an unravelling of the pathophysiological pathways that predispose an individual to sepsis.
Topics: Humans; Pregnancy; Female; Placenta; Sepsis; Pregnancy Complications, Infectious; Adaptation, Physiological; Homeostasis
PubMed: 36470829
DOI: 10.1016/j.ebiom.2022.104337 -
Environment International Aug 2019Per- and polyfluoroalkyl substances (PFASs) are widely used in China, but little is known about the association between prenatal PFASs exposure and fetal reproductive...
BACKGROUND
Per- and polyfluoroalkyl substances (PFASs) are widely used in China, but little is known about the association between prenatal PFASs exposure and fetal reproductive development as well as its potential mechanism.
OBJECTIVE
We investigated the effects of cord blood PFASs on fetal reproductive hormones and its potential mechanism in relation to steroidogenic enzymes.
METHODS
Ten selected PFASs (n = 351) including PFOS, PFOA, PFBS, PFDA, PFDoA, PFHpA, PFHxS, PFNA, PFOSA, and PFUA, and two reproductive hormones estradiol (E2) (n = 351) and testosterone (T) (n = 349) were measured in 351 cord blood serum samples from a Chinese birth cohort between 2010 and 2013. Three steroidogenic enzymes including P450arom (n = 125), 3β-HSD1 (n = 123), and 17β-HSD1 (n = 116) were measured in 125 placental tissue samples. Linear regression tested the associations between cord blood PFASs and reproductive hormones in cord blood. Mediation analysis assessed the role of placental steroidogenic enzymes between cord blood PFASs and reproductive hormones.
RESULTS
The positive associations between PFOA, PFHxS and E2 levels, PFOS, PFUA, PFNA and T levels, and PFOS, PFUA and T/E2 ratio were significant. PFUA, PFNA, PFDA, PFHxS, and ∑PFASs were associated with higher P450arom levels. PFHxS was also associated with increased 3β-HSD1 and 17β-HSD1 levels. These associations were more pronounced in females than males when stratified by gender. Furthermore, 17β-HSD1 demonstrated mediating effects in the positive association between cord blood PFHxS and E2 levels in females.
CONCLUSION
Our findings suggested the potential impacts of cord blood PFASs on fetal reproductive hormones, in which steroidogenic enzymes may play important roles. These associations were more pronounced in females than males.
Topics: China; Cytochrome P-450 Enzyme System; Environmental Pollutants; Estradiol; Female; Fetal Blood; Fluorocarbons; Humans; Male; Placenta; Pregnancy; Testosterone
PubMed: 31174145
DOI: 10.1016/j.envint.2019.03.047 -
International Journal of Molecular... Feb 2024Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of...
Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-β-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL ( = 14) and controls undergoing elective termination of pregnancy ( = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free β-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free β-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-β-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks.
Topics: Pregnancy; Female; Humans; Pregnancy-Associated Plasma Protein-A; Placenta Growth Factor; Pregnancy Trimester, First; Placenta; Pregnancy Proteins; Chorionic Gonadotropin, beta Subunit, Human; Biomarkers; Abortion, Habitual; Blood Proteins
PubMed: 38339143
DOI: 10.3390/ijms25031865 -
Methods in Molecular Biology (Clifton,... 2024The human placenta is a transient organ that functions to support the needs of the fetus throughout gestation. Trophoblasts are the major epithelial cells found within...
The human placenta is a transient organ that functions to support the needs of the fetus throughout gestation. Trophoblasts are the major epithelial cells found within the placenta and comprise a variety of distinct cell types with specialized roles in fetal-maternal communication. Our understanding of human trophoblast development remains limited due to ethical and legal restrictions on accessing first-trimester placental tissues, as well as the inability of common animal models to replicate primate placental development. It is therefore important to advance in vitro models of human trophoblast development as a basis for studying pregnancy-associated complications and diseases. In this chapter, we describe a protocol for generating 3D trophoblast organoids from naïve human pluripotent stem cells (hPSCs). The resulting stem-cell-derived trophoblast organoids (SC-TOs) contain distinct cytotrophoblast (CTB), syncytiotrophoblast (STB), and extravillous trophoblast (EVT) cell types, which closely correspond to trophoblast identities in the human post-implantation embryo. We discuss methods for characterizing SC-TOs by immunofluorescence, flow cytometry, mRNA and microRNA expression profiling, and placental hormone secretion. Furthermore, SC-TOs can undergo differentiation into specialized 3D EVT organoids, which display robust invasion when co-cultured with human endometrial cells. Thus, the protocol described herein offers an accessible 3D model system of human placental development and trophoblast invasion.
Topics: Pregnancy; Humans; Female; Placenta; Trophoblasts; Pluripotent Stem Cells; Pregnancy Trimester, First; Cell Differentiation; Organoids
PubMed: 37402094
DOI: 10.1007/7651_2023_496 -
Reproductive Biology and Endocrinology... Jul 2023To explore whether prolonged hCG-ovum pickup interval improves assisted reproductive technology outcomes. (Meta-Analysis)
Meta-Analysis Review
RESEARCH QUESTION
To explore whether prolonged hCG-ovum pickup interval improves assisted reproductive technology outcomes.
DESIGN
CENTRAL, CNKI, Cochrane Systematic Reviews, EMBASE, MEDLINE, PUBMED, and Web of Science up to May 13 2023 were searched for studies reporting associations between hCG-ovum pickup intervals and assisted reproductive technology outcomes. Intervention types included short (≤ 36 h) and long (> 36 h) hCG-ovum pickup intervals in assisted reproductive technology cycles. All outcomes were based upon only fresh embryo transfers. Primary outcome is defined as the clinical pregnancy rate. Data were pooled using random-effects models. Heterogeneity was assessed using the I 2 statistics.
RESULTS
Twelve studies were included in the meta-analysis, including five retrospective cohort studies, one prospective cohort study, and six randomized or quasi-randomized controlled trials. The short and long interval groups had similar oocyte maturation rates, fertilization rate and high-quality embryo rate (OR, 0.69; 95% CI, 0.45-1.06; I 2 = 91.1%, OR, 0.88; 95% CI, 0.77-1.0; I 2 = 44.4% and OR, 1.05; 95% CI, 0.95-1.17; I 2 = 8.6%, respectively). The clinical pregnancy rates in the long retrieval group were significantly higher than in the short retrieval group (OR, 0.66; 95% CI, 0.45-0.95; I 2 = 35.4%). The groups had similar miscarriage and live birth rates (OR, 1.92; 95% CI, 0.66-5.60; I 2 = 0.0% and OR, 0.50; 95% CI, 0.24-1.04; I 2 = 0.0%, respectively).
CONCLUSIONS
The clinical pregnancy rates can be increased by prolonging the hCG-ovum pickup interval, which would help us develop more reasonable time schedules for fertility centers and patients.
META-ANALYSIS REGISTRATION
PROSPERO CRD42022310006 (28 Apr 2022).
Topics: Pregnancy; Female; Humans; Oocyte Retrieval; Retrospective Studies; Prospective Studies; Pregnancy Rate; Chorionic Gonadotropin; Live Birth; Fertilization in Vitro
PubMed: 37400840
DOI: 10.1186/s12958-023-01110-9 -
ESMO Open Aug 2023Oocytes/embryo cryopreservation and ovarian function suppression with gonadotropin-releasing hormone (GnRH) agonists (GnRHas) are two established strategies for...
BACKGROUND
Oocytes/embryo cryopreservation and ovarian function suppression with gonadotropin-releasing hormone (GnRH) agonists (GnRHas) are two established strategies for preserving fertility in patients with cancer, frequently both being offered to the same woman. As the first injection of GnRHa should be administered before chemotherapy, it is usually performed in the luteal phase of the urgent controlled ovarian stimulation (COS) cycle. The GnRHa flare-up effect on recently stimulated ovaries may cause ovarian hyperstimulation syndrome (OHSS) and this risk may discourage some oncologists to offer an ovarian function preservation method with proven efficacy. We suggest the long-acting GnRHa as an option to trigger ovulation for egg retrieval in oncological patients, whenever ovarian suppression during chemotherapy is planned.
PATIENTS AND METHODS
We retrospectively analyzed prospectively collected data from all consecutive ovarian stimulation cases in oncological patients for oocyte cryopreservation from 2016 to 2021 in a single academic referral center. The COS was performed according to good clinical practice standards. Since 2020 long-acting GnRHa trigger was offered to all patients for whom ovarian suppression after cryopreservation was planned. All other patients served as controls, stratified for the triggering method used: highly purified chorionic gonadotrophin 10 000 UI or short-acting GnRHa 0.2 mg.
RESULTS
Mature oocytes were collected, with the expected maturation rate, in all the 22 cycles triggered with GnRHa. The mean number of cryopreserved oocytes was 11.1 ± 4, with a maturation rate of 80% (57%-100%), versus 8.8 ± 5.8, 74% (33%-100%) with highly purified chorionic gonadotrophin and 14 ± 8.4, 80% (44%-100%) with short-acting GnRHa. No case of OHSS was observed after long-acting GnRHa triggering and by 5 days after egg retrieval most patients had reached luteinizing hormone levels showing suppression.
CONCLUSIONS
Our preliminary data show that long-acting GnRHa is efficacious in inducing the final oocytes' maturation, reducing OHSS risk and suppressing ovarian function by the start of chemotherapy.
Topics: Female; Humans; Fertility Preservation; Retrospective Studies; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Chorionic Gonadotropin; Gonadotropin-Releasing Hormone
PubMed: 37421801
DOI: 10.1016/j.esmoop.2023.101597 -
Acta Bio-medica : Atenei Parmensis Mar 2022The aim of the study is to show the relationship between oxidative stress and ectopic pregnancy.
PURPOSE
The aim of the study is to show the relationship between oxidative stress and ectopic pregnancy.
MATERIALS AND METHODS
A total of 62 patients, 31 in the ectopic pregnancy group (study group) and 31 in the first-trimester pregnancy (control group) were included in the study. Patients between 18-45 years of age who had tubal ectopic pregnancy diagnosed by transvaginal ultrasonography and serum β-HCG values were included in the study group. Serum thiol- disulfide hemostasis were measured from venous blood.
RESULTS
Between the control group and the ectopic pregnant group; there was no statistically significant difference in terms of age, total thiol, albumin, disulfide, index 1 (disulfide / total thiol), index 2 (disulfide / native thiol), and index 3 levels (p> 0.05). The area under the ROC curve for native thiol measurements was statistically significant in distinguishing the control group and the ectopic pregnant group [AUC = 0.657, 95% CI: 0.521-0.793, p = 0.034] Conclusion: This study shows that ectopic pregnancies may be associated with the presence of high oxidative stress. Especially in early stage suspected patients, demonstrating the presence of oxidative stress together with serial β-HCG follow-up may be helpful in diagnosis.
Topics: Chorionic Gonadotropin, beta Subunit, Human; Disulfides; Female; Humans; Oxidative Stress; Pregnancy; Pregnancy, Ectopic; Sulfhydryl Compounds
PubMed: 35315421
DOI: 10.23750/abm.v93i1.11097