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In vitro secretion of PAPP-A and hCG by villous trophoblast tissues isolated from normal placentas and placentas complicated by aneuploidy. Villous cytototrophoblasts were cultured after being isolated from aneuploid placentas (one trisomy 21 at 20 WG, one trisomy 18 at 19WG, one trisomy 13 at 18WG) and from three age matched normal placentas. PAPP-A was measured in the culture supernatant from 24 hours to 72 hours of culture using the assay developed on the Immulite 2000 analyser® (Siemens, Germany) specific for the heterotetrameric complex (htPAPP-A). hCG was measured with the assay developed on Advia Centaur XP analyser® (Siemens, Germany) to assess the formation of the syncytiotrophoblast.
Source publication
Pregnancy-associated placental protein-A (PAPP-A) is a metalloprotease which circulates as an hetero-tetramer in maternal blood. Its maternal serum concentration in fetal trisomy 21 is decreased during the first trimester, so that PAPP-A is a useful screening biomarker. However, the regulation of PAPP-A placental secretion is unclear. We therefore...
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Citations
... During human pregnancy, serum PAPP-A/proMBP levels continually increase up to parturition [55]. The syncytiotrophoblasts are the main source of PAPP-A and extravillous X cells or cytotrophoblasts are the source of proMBP [4]. ...
Pregnancy associated plasma protein-A (PAPP-A) plays an integral role in breast cancer (BC), especially triple negative breast cancer (TNBC). This subtype accounts for the most aggressive BC, possesses high tumor heterogeneity, is least responsive to standard treatments and has the poorest clinical outcomes. There is a critical need to address the lack of effective targeted therapeutic options available. PAPP-A is a protein that is highly elevated during pregnancy. Frequently, higher PAPP-A expression is detected in tumors than in healthy tissues. The increase in expression coincides with increased rates of aggressive cancers. In BC, PAPP-A has been demonstrated to play a role in tumor initiation, progression, metastasis including epithelial-mesenchymal transition (EMT), as well as acting as a biomarker for predicting patient outcomes. In this review, we present the role of PAPP-A, with specific focus on TNBC. The structure and function of PAPP-A, belonging to the pappalysin subfamily, and its proteolytic activity are assessed. We highlight the link of BC and PAPP-A with respect to the IGFBP/IGF axis, EMT, the window of susceptibility and the impact of pregnancy. Importantly, the relevance of PAPP-A as a TNBC clinical marker is reviewed and its influence on immune-related pathways are explored. The relationship and mechanisms involving PAPP-A reveal the potential for more treatment options that can lead to successful immunotherapeutic targets and the ability to assist with better predicting clinical outcomes in TNBC.
... It cleaves insulin like growth factor binding protein 4 and 5 and decreases its affinity for insulin like growth factors (IGF) at tissue level thereby increasing their availability at the tissue level. 4 Its production starts from 5th week of gestation and continues with a slow rise till 8th week with a doubling time from 9th to 14th week in 2 -3 days. Decreased PAPP-A values in first trimester can predict complications of pregnancy such as IUGR), preterm delivery, pre-eclampsia and miscarriage. ...
Objective: To determine the reference values of beta hCG and PAPP-A among women aged 20-40 years at 9-10 weeks of normal gestation. Methodology: This descriptive observational study was conducted at Pathology Department of PGMI/ Lahore General Hospital, Lahore from May, 2018 to June, 2020 and included 500 women at 9-10 weeks of gestation. Those with molar pregnancy, multiple pregnancies, threatened abortion, abnormal obstetric ultrasound findings, history of chronic diseases and smoking were excluded. Quantitative analysis of PAPP-A and β-hCG was performed on Backman Coulter Access 2 Immunoassay. Data was entered in SPSS version 21. Median and IQR were calculated for β-hCG and PAPP-A for total samples and in various subgroups of this population. Mann-Whitney U test and Kruskal-Wallis test were applied to find association between levels of β-HCG and PAPP-A with parity and age respectively. Results: Out of 500 women, 214 (43%) were primigravida and 286 (57%) multigravidas. Mean age was 27.3 ± 7.5 years. The median (IQR) values for β-hCG and PAPP-A were 53449.5 (33322.5) mIU/ml and 425.10 (262.60) ng/ml, respectively. There was no significant association between levels of β-hCG and PAPP-A and parity. However, significant association was found between value of β-hCG and maternal age. Conclusion: The median values of β-hCG and PAPP-A at 9-10 weeks of normal gestation were 53449.5 mIU/ml and 425.10 ng/ml, respectively. Significant association was found between value of β-hCG and maternal age.
... Pregnancy-associated plasma protein-A 7 PAPP-A, synthesized in the placental syncytiotrophoblast, is a metalloprotease that circulates in the maternal blood. PAPP-A is used for trisomy screening because its maternal serum concentration decreases during the first trimester in fetal trisomy 21 [8,9]. ...
A vanishing twin (VT) is the early demise of a twin fetus. It is estimated to occur in 20-30% of pregnancies associated with assisted reproductive technology. VT becomes increasingly prominent when assisted fertilization is used, because one or more embryos are transferred to the uterus. Maternal serum screening tests during pregnancy can screen for trisomy chromosomes 21, 18, and 13 and are divided into first- and second-trimester tests. In singleton pregnancies, the first trimester screening test is performed at 11-13 weeks and 6 days of gestation. It consists of two serum markers, pregnancy-associated plasma protein A and β-human chorionic gonadotropin (β-hCG), and measures nuchal translucency thickness. The second-trimester screening test was performed at 15-20 weeks and 6 days of gestation. It consists of four serum markers: alpha-fetoprotein, β-hCG, unconjugated estriol, and inhibin A. More effective screening for trisomy 21 in singleton pregnancies is achieved by analyzing cell-free DNA in the maternal blood. A VT includes a demise of the fetus. Although it affects maternal serum markers, it has not been corrected. Five studies examined the effect of VT on maternal serum markers, but the results were controversial. This study aimed to review the patterns of changes in maternal serum markers in VTs, interpret prenatal tests for pregnant women with VTs in clinical practice, and consider what information should be provided.
... During human pregnancy, serum PAPP-A/proMBP levels continually increase up to parturition [49]. The syncytiotrophoblasts are the main source of PAPP-A and extravillous X cells or cytotrophoblasts are the source of proMBP [4]. ...
Pregnancy associated plasma protein-A (PAPP-A) plays an integral role in breast cancer (BC), especially triple negative breast cancer (TNBC). This subtype accounts for the most aggressive BC, possesses high tumor heterogeneity, is least responsive to standard treatments and has the poorest clinical outcomes. There is a critical need to address the lack of effective targeted therapeutic options available. PAPP-A is a protein that is highly elevated during pregnancy. Frequently, higher PAPP-A expression is detected in tumors than in healthy tissues. The increase in expression coincides with increased rates of aggressive cancers. In BC, PAPP-A has been demonstrated to play a role in tumor initiation, progression, metastasis including epithelial-mesenchymal transition (EMT), as well as acting as a biomarker for predicting patient outcomes. In this review, we present the role of PAPP-A, with specific focus on TNBC. The structure and function of PAPP-A, belonging to the pappalysin subfamily, and its proteolytic activity are assessed. We highlight the link of BC and PAPP-A with respect to the IGFBP/IGF axis, EMT, the window of susceptibility and the impact of pregnancy. Importantly, the relevance of PAPP-A as a TNBC clinical marker is reviewed and its influence on immune-related pathways are explored. The relationship and mechanisms involving PAPP-A reveal the potential for more treatment options that can lead to successful immunotherapeutic targets and the ability to assist with better predicting clinical outcomes in TNBC.
... Although (Öztürk, et al. [8] ) showed that the patients with PCOS revealed higher PAPP-A levels than healthy women, other studies suggested that PAPP-A levels increase throughout a normal pregnancy. There is a sharp increase of about 24-fold between the end of the first trimester and the end of the second trimester, followed by a slower, 2-fold increase from the end of the second trimester up to delivery (Leguy, et al. [14] ). These results reveal that the PAPP-A level increases in pregnant more than in nonpregnant women, mainly in the first trimester. ...
Pregnancy-Associated Plasma Protein (PAPP-A) is a zinc metalloproteinase in the insulin growth factor system (IGFs) produced by the syncytiotrophoplast region of the placenta. It plays a critical function in the cleavage of IGFBP4. In the ovary IGFs, it regulates follicular and oocyte maturation, and steroidogenesis. While in polycystic ovarian syndrome (PCOS) Hyperinsulinemia and hyperandrogenemia it causes follicular environment changes and early ovulation resulting in lower oocyte and embryo quality in patients and this will decrease the success of pregnancy in women enrolled in the ICSI cycle. The present study aimed to assess the relationship of PAPP-A levels in serum and follicular fluid in women with PCOS and non-PCOS with oocyte and embryo quality in women undergoing ICSI cycle. 45 infertile Iraqi women were enrolled. Women with PCOS had to meet at least two of the three criteria set by the Rotterdam ESHRE/ASRMS criteria, the age of the included women ranged between 20-45 years. In non-PCOS patients, PAPP-A has higher level in serum and follicular fluid but without a statistically significant difference matching with PCOS group. In addition, there was no significant correlation between PAPP-A levels in serum and follicular fluid with oocytes and embryo characteristics. However, PAPP-A levels are higher in serum and follicular fluid in women with positive pregnancy but without significant differences. PAPP-A had no correlation with oocyte and embryo quality.
... PAPP-A is a zinc-binding matrix metalloproteinase secreted by the trophoblast and can be measured as early as 28 days of pregnancy [281]. PAPP-a has been used as a screening test in the first-trimester of pregnancy for aneuploidy and for identifying certain adverse pregnancy outcomes [282,283]. Through its properties, PAPP-A increases insulin-like growth factor 1 (IGF-1) bioavailability through its cleavage from the IGF binding protein-4, suggesting a possible link between PAPP-A and insulin sensitivity. Pellitero et al. [284] found lower PAPP-A levels in diabetic patients compared to controls with a negative association between PAPP-A levels and HbA1c. ...
Introduction: Gestational diabetes (GDM), defined as hyperglycemia with onset or initial recognition during pregnancy, has a rising prevalence paralleling the rise in type 2 diabetes (T2DM) and obesity. GDM is associated with short-term and long-term consequences for both mother and child. Therefore, it is crucial we efficiently identify all cases and initiate early treatment, reducing fetal exposure to hyperglycemia and reducing GDM-related adverse pregnancy outcomes. For this reason, GDM screening is recommended as part of routine pregnancy care. The current screening method, the oral glucose tolerance test (OGTT), is a lengthy, cumbersome and inconvenient test with poor reproducibility. Newer biomarkers that do not necessitate a fasting sample are needed for the prompt diagnosis of GDM. The aim of this scoping review is to highlight and describe emerging protein biomarkers that fulfill these requirements for the diagnosis of GDM. Materials and Methods: This scoping review was conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for scoping reviews using Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing & Allied Health Literature (CINAHL), PubMed, Embase and Web of Science with a double screening and extraction process. The search included all articles published in the literature to July 2020. Results: Of the 3519 original database citations identified, 385 were eligible for full-text review. Of these, 332 (86.2%) were included in the scoping review providing a total of 589 biomarkers studied in relation to GDM diagnosis. Given the high number of biomarkers identified, three post hoc criteria were introduced to reduce the items set for discussion: we chose only protein biomarkers with at least five citations in the articles identified by our search and published in the years 2017-2020. When applied, these criteria identified a total of 15 biomarkers, which went forward for review and discussion. Conclusions: This review details protein biomarkers that have been studied to find a suitable test for GDM diagnosis with the potential to replace the OGTT used in current GDM screening protocols. Ongoing research efforts will continue to identify more accurate and practical biomarkers to take GDM screening and diagnosis into the 21st century.
... Due to this remarkable decrease, PAPP-A is the best first trimester serum marker for trisomy 21. Its screening performance for trisomy 21 declines rapidly with increasing GA and becomes useless in the second trimester 65,69 . Fetal trisomy 13 and 18 are associated with decreased PAPP-A levels throughout the entire pregnancy 61,69 . ...
... Its screening performance for trisomy 21 declines rapidly with increasing GA and becomes useless in the second trimester 65,69 . Fetal trisomy 13 and 18 are associated with decreased PAPP-A levels throughout the entire pregnancy 61,69 . ...
... Elle est codée par le gène PAPPA situé sur le chromosome 9. Elle est majoritairement synthétisée par les CT, le ST et les CTEV (Guibourdenche et al., 2003;Handschuh et al., 2006). Les taux de PAPP-A augmentent tout au long de la grossesse et chutent après la délivrance (Leguy et al., 2014;Sutcliffe et al., 1982). Très peu de données sont connues concernant les facteurs régulant l'expression de cette protéine. ...
L’obésité se définit par une accumulation excessive de masse grasse et une inflammation systémique chronique. Elle se mesure par un indice de masse corporelle supérieur à 30 kg/m². L’obésité maternelle est associée à de nombreux troubles de la santé et en particulier à un risque accru de développer des pathologies de la grossesse (pré éclampsie, diabète gestationnel). D’autre part, l’obésité maternelle impacte la descendance avec une augmentation des risques d’apparition de maladies métaboliques à l’âge adulte.Le placenta est un organe présent à l’interface entre la mère et le fœtus. Il assure des fonctions endocrines, d’échanges et de protection immunitaire.La leptine et l’adiponectine sont des adipokines majoritairement produites par le tissu adipeux. La leptine joue un rôle satiétogène et l’adiponectine exerce des effets insulino-sensibilisateurs. Elles sont donc impliquées dans l’homéostasie énergétique.Le placenta exprime la leptine et les récepteurs spécifiques de ces deux hormones. Il est bien établi que la leptine et l’adiponectine participent au contrôle des fonctions placentaires.Au cours de ce travail, nous nous sommes intéressés à l’impact de l’obésité maternelle (sans diabète gestationnel) sur les principales fonctions du placenta humain.Dans une première partie, nous avons montré que l’obésité maternelle entraîne i) une diminution de l’expression des transporteurs de nutriments, ii) une diminution du nombre de cellules immunitaires, iii) une altération des capillaires fœtaux et iv) une diminution de la production de cytokines pro-inflammatoires et de l’hormone chorionique gonadotrope (hCG) dans le placenta à terme.Dans une deuxième partie, nous avons montré que l’obésité maternelle altère l’expression des systèmes leptine et adiponectine (ligand et récepteurs) dans le placenta humain. En effet, l’obésité maternelle conduit à une diminution de l’expression des récepteurs des deux hormones et à une modification de la méthylation des régions promotrices des gènes codant pour les deux adipokines et leurs récepteurs.L’ensemble de ces résultats montre que l’obésité maternelle altère les fonctions endocrines, d’échanges et immunitaires du placenta. Cet organe transitoire semble s’adapter à un environnement maternel délétère.
... The isolated cells were plated in DMEM containing 10% FCS, 1% Penicillin-Streptomycin and 1% L-Glutamin and were incubated at 37°C with 5% CO 2 . Purified VCTs aggregate and fuse to form ST at 72 h of culture (Leguy et al., 2014). Cells were incubated or not with FSK (10 μM) for 6 h/24 h of culture or for 48 h/72 h of culture to stimulate cytotrophoblasts fusion. ...
... In our in vitro culture model, VCTs isolated from human placenta aggregate and fuse to form ST within 72 h of culture mimicking their in vivo physiological differentiation (Kliman et al., 1986;Alsat et al., 1993). This morphological differentiation is associated with a functional differentiation as stated by the significant increase in hCG secretion (Kudo et al., 2003;Leguy et al., 2014). In this work, we showed that VCT secretes significant amounts of P4 increasing as it turns into ST. ...
Placental syncytiotrophoblast (ST) is considered as the main placental endocrine tissue secreting progesterone, a steroid essential for maintenance of pregnancy. However, each step of progestins production has been poorly investigated in villous cytotrophoblast (VCT) regarding ST formation. We aimed to characterize progestins production during human differentiation of VCT into ST. VCTs were isolated from term placenta and cultivated, with or without forskolin (FSK), to stimulate trophoblast differentiation. Secreted progestins concentrations were determined by immuno-assay and Gas Chromatography-tandem mass spectrometry. Intracellular expression of cholesterol transporter and enzymes involved in steroidogenesis were studied by immunofluorescence, western-blot, and RT-qPCR. Progesterone and pregnenolone are produced by VCT and their secretion increases with VCT differentiation while 17-hydroxyprogesterone concentration remains undetectable. HSD3B1 enzyme expression increases whereas MLN64, the cholesterol placental mitochondrial transporter and P450SCC expressions do not. FSK induces progestins production. Progestins placental synthesis is effective since VCT and increases with ST formation thanks to mitochondria.
... PAPP-A circulates at very low levels in non-pregnant women. Like β-hCG, it is produced at high levels by the placenta during pregnancy (29). We could not find any differences in the temporal relation of β-hCG and PAPP-A with each other and gestational age between natural and IVF conceptions. ...
Objective:We aimed to compare the first trimester screening profiles of spontaneous (n=972) and in in vitro fertilization (IVF) pregnancies (n=339) in a population of patients who had uncomplicated singleton pregnancies comparable for maternal age, gestation, body mass index, and ethnicity.Material and Methods:A non-interventional analysis of retrospective cohort data and review of the literature.Results:All IVF pregnancies were achieved via intracytoplasmic sperm injection using the same ovarian stimulation protocol with recombinant follicle-stimulating hormone and a gonadotropin-releasing hormone antagonist, cetrorelix acetate. The means of the multiple of median (MoM) of pregnancy-associated plasma protein-A (PAPP-A) were slightly lower in the fresh (1.19±0.6 vs 1.33±0.7, respectively; p=0.056) and frozen embryo transfer (1.03±0.5 vs 1.33±0.7, respectively; p=0.036) IVF pregnancies compared with natural conceptions. However, when the medians of the MoMs of PAPP-A and beta-human chorionic gonadotrophin (β-hCG), and their distributions were compared across the mode of conception, there were no differences between IVF pregnancies spontaneous pregnancies. Furthermore, the scatterplot diagram and curve fitting regression analyses revealed no difference in the temporal relations of β-hCG and PAPP-A with each other and gestational age between spontaneous and IVF pregnancies.Conclusion:These results support the notion that uncomplicated singleton IVF pregnancies have similar first trimester screening profiles to spontaneous onceptions.
