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It is now well established that maternal serum markers are often abnormal in fetal trisomy 21. Their determination is recommended for prenatal screening and pregnancy follow-up. However, mechanisms leading to abnormal maternal serum levels of such markers are still debated. Our objective was to help clinicians and scientists unravel the pathophysiology of these markers via a review of the main studies published in this field, both in vivo and in vitro, focusing on the six most widely used markers (hCG, its free subunit hCGβ, PAPP-A, AFP, uE3, and inhibin A) as well as cell-free feto-placental DNA. Analysis of the literature shows that mechanisms underlying each marker's regulation are multiple and not necessarily directly linked with the supernumerary chromosome 21. The crucial involvement of the placenta is also highlighted, which could be defective in one or several of its functions (turnover and apoptosis, endocrine production, and feto-maternal exchanges and transfer). These defects were neither constant nor specific for trisomy 21, and might be more or less pronounced, reflecting a high variability in placental immaturity and alteration. This explains why maternal serum markers can lack both specificity and sensitivity, and are thus restricted to screening.

In a three-dimensional (3D) representation, each protein molecule displays a specific pattern of chemical and topological features, which are altered during its misfolding and aggregation pathway. Generating a recognizable fingerprint from such features could provide an enticing approach not only to identify these biomolecules but also to gain clues regarding their folding state and the occurrence of pathologically lethal misfolded aggregates. We report here a universal strategy to generate a fluorescent fingerprint from biomolecules by employing the pan-selective molecular recognition feature of a cucurbit[7]uril (CB[7]) macrocyclic receptor. We implemented a direct sensing strategy by covalently tethering CB[7] with a library of fluorescent reporters. When CB[7] recognizes the chemical and geometrical features of a biomolecule, it brings the tethered fluorophore into the vicinity, concomitantly reporting the nature of its binding microenvironment through a change in their optical signature. The photophysical properties of the fluorophores allow a multitude of probing modes, while their structural features provide additional binding diversity, generating a distinct fluorescence fingerprint from the biomolecule. We first used this strategy to rapidly discriminate a diverse range of protein analytes. The macrocyclic sensor was then applied to probe conformational changes in the protein structure and identify the formation of oligomeric and fibrillar species from misfolded proteins. Notably, the sensor system allowed us to differentiate between different self-assembled forms of the disease-specific amyloid-β (Aβ) aggregates and segregated them from other generic amyloid structures with a 100% identification accuracy. Ultimately, this sensor system predicted clinically relevant changes by fingerprinting serum samples from a cohort of pregnant women.

Objective: Large response of steroid precursors, including 17-hydroxyprogesterone, to adrenocorticotropic hormone (ACTH) has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in the basal state and after ACTH 1-24 stimulation., Design and Methods: A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in the basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio, whereas enzymatic activity was assessed by the downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method., Results: For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 (43.1-199.4)) in comparison to both UL (122.7 (13.8-228.4), P = 0.0002) and CT (186.8 (42.1-1236.3), P < 0.0001). On mineralocorticoids and androgens pathways, the enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT., Conclusions: Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass., Significance Statement: Activity of distal steroidogenesis enzymes (CYP11B1, CYP11B2 and CYP17A1 on glucocorticoids, mineralocorticoids and androgens pathways, respectively) is decreased in adrenocortical benign tumors. This decrease is more pronounced in bilateral lesions and seems to depend more on the nature of the lesion than on the increase in adrenal volume. It is responsible for the explosive response to ACTH of steroid precursors located upstream of these enzymes. It probably allows bioactive steroids, particularly cortisol, to stay in the normal range for a long time despite the increase in adrenal mass.

Polyhydramnios is a common feature diagnosed by ultrasound in the second half of pregnancy. Biochemical analysis of amniotic fluid can be useful when suspecting Bartter syndrome or digestive atresia but in most of cases, no etiology of polyhydramnios is found because of the complex regulation of amniotic fluid. Aquaporins (AQP) are transmembrane channel proteins contributing to water transfers. Some of them are expressed in fetal membranes and placenta. Their expression has been shown to be disrupted in some pathological conditions such as maternal diabetes, often associated with polyhydramnios. AQP-1, 3 and 8 levels in amniotic fluid were retrospectively measured in patients suffering from polyhydramnios (n=21) from 23 weeks of gestation (WG). They were compared to the levels observed in control subjects (n=96) and their relationship with maternal factors and neonatal issues was analyzed. AQP-1, 3, 8 levels were physiologically fluctuating, AQP-1 levels always being the lowest and AQP-3 the highest, with a significant decrease at the end of pregnancy. AQPs/AFP ratios increased about 8 folds during pregnancy, their kinetic profiles reflecting physiological dynamic evolution of amniotic fluid volume. In polyhydramnios, AQP-3 level tended to be decreased whereas AQP-8 level was decreased from mid-gestation whatever the etiology of polyhydramnios. No significant relationship was found between AQPs levels and either the fetal prematurity degree or macrosomia. No specific pattern was observed in idiopathic polyhydramnios, limiting the interest of AQPs dosage in amniotic fluid in the management of those complicated pregnancies., (© 2021. Society for Reproductive Investigation.)

Background & Aims: Gestational diabetes mellitus (GDM) is one of the most frequent medical complications during pregnancy. It has been associated with many adverse pregnancy, fetal and neonatal outcomes, as well as with an increased risk for mothers and children in the long term. There is a growing interest in vitamin D and its potential role in the development of metabolic disorders. However, the medical literature is not consensual. The aim of this study was to assess the risk of GDM according to vitamin D status during the first trimester., Methods: This study is a nested case-control study performed from a multicenter prospective observational cohort of pregnant women assessed for 25-hydroxyvitamin D levels (25OHD). Three hundred ninety-three patients were included in the initial cohort. After applying exclusion criteria, a total of 1191 pregnant women were included. Two hundred fifty women with GDM (cases) were matched to 941 women without GDM (controls) for parity, age, body mass index before pregnancy, the season of conception, and phototype. This study was funded by a grant from the "Programme Hospitalier de Recherche Publique 2010"., Results: The GDM risk was significantly greater for patients with 25OHD levels <20 ng/mL (OR = 1∙42, 95% CI 1∙06-1∙91; p = 0∙021). However, there was no significant relationship with other thresholds. The study of 25OHD levels with the more precise cutting of 5 units intervals showed a variable relationship with GDM risk, as the risk was low for very low 25OHD levels, increased for moderated levels, decreased for normal levels, and finally increased for higher levels., Conclusion: According to our study, there seems to be no linear relationship between GDM and 25OHD levels in the first trimester of pregnancy since GDM risk does not continuously decrease as 25OHD concentrations increase. Our results most probably highlight the absence of an association between 25OHD levels and GDM risk., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Preeclampsia (PE) is a hypertensive disease of pregnancy associated with substantial maternal and fetal morbidity and mortality. CORIN is a transmembrane type II serine protease expressed in cardiomyocytes that converts pro-atrial natriuretic peptide into atrial natriuretic peptide, a cardiac hormone that regulates blood pressure. High levels of soluble CORIN have been reported in PE and are supposed to be cardiac in origin. We hypothesized that during pregnancy soluble CORIN is released by the syncytiotrophoblast and that increased levels of soluble CORIN in preeclampsia originate from placenta. A total of 375 patients (181 PE patients and 194 controls) were analyzed. High levels of soluble CORIN were confirmed in maternal blood from preeclamptic pregnancies compared with controls. Differentiated primary villous cytotrophoblasts showed that CORIN was expressed (mRNA and protein levels) and secreted by trophoblastic cells, mostly by the syncytiotrophoblast. Finally, placental explants showed a significant increase in CORIN production and secretion in PE cases compared with controls. This study showed that CORIN is secreted by trophoblastic cells and that high levels of soluble CORIN in preeclampsia have a placental origin., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Vitamin D is thought to be involved in the pathogenesis of preeclampsia. To evaluate the relationship between vitamin D insufficiency in the first trimester of pregnancy and preeclampsia., Methods: Nested case-control study (FEPED study) in type 3 obstetrical units. Pregnant women from 10 to 15 WA. For each patient with preeclampsia, 4 controls were selected from the cohort and matched by parity, skin color, maternal age, season and BMI. The main outcome measure was serum 25(OH)D status in the first trimester., Results: 83 cases of preeclampsia were matched with 319 controls. Mean 25(OH)D levels in the first trimester were 20.1 ± 9.3 ng/mL in cases and 22.3 ± 11.1 ng/mL in controls (p = 0.09). The risk for preeclampsia with 25(OH)D level ≥30 ng/mL in the first trimester was decreased, but did not achieve statistical significance (OR, 0.57; 95% CI, 0.30-1.01; p = 0.09). High 25(OH)D during the 3rd trimester was associated with a significantly decreased risk of preeclampsia (OR, 0.43; 95%CI, 0.23-0.80; p = 0.008). When women with 25(OH)D levels <30 ng/mL both in the first and 3rd trimesters ("low-low") were taken as references, OR for preeclampsia was 0.59 (95% CI, 0.31-1.14; p = 0.12) for "low-high" or "high-low" women and 0.34 (95% CI, 0.13-0.86; p = 0.02) for "high-high" women., Conclusions: No significant association between preeclampsia and vitamin D insufficiency in the first trimester was evidenced. However, women with vitamin D sufficiency during the 3rd trimester and both in the first and 3rd trimesters had a significantly lower risk of preeclampsia., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objectives: Angiogenic factors may be involved in lung development. To evaluate the relations between maternal and cord blood angiogenic factors (sFlt-1, placental growth factor [PlGF], soluble endogline [sEng], transforming growth factor β [TGF-beta]) and their association with moderate and severe bronchopulmonary dysplasia (BPD) in very preterm growth-restricted infants., Study Design: Prospective monocentric cohort study. Twenty-four mother-child dyads featuring antepartum preeclampsia, intra-uterine growth restriction (IUGR) and birth before 30 weeks' gestation were included. This ensured a 80% power to test whether sFlt-1 maternal levels would be twice as high in cases of BPD as in the absence of BPD., Main Outcome Measures: Four pro/anti-angiogenic factors from two pathways (sFlt-1, PlGF and sEng, TGF-beta) were measured in maternal serum before delivery (at the time of hospitalization or the day of birth) and in neonates' cord blood. Neonatal outcome was moderate to severe BPD, defined as oxygen requirement for at least 28 days and persistent need for oxygen or ventilatory support at 36 weeks' postmenstrual age., Results: sFlt-1 levels were positively correlated in maternal serum and cord blood (r s  = 0.83, p < .001) but levels of PlGF and TGF-beta and its receptor sEng were not. Among all the factors studied in cord and maternal blood, none was associated with BPD., Conclusions: In IUGR preterm babies born before 30 weeks' gestation from preeclamptic mothers, serum sFlt-1, PlGF and sEng, TGF-β levels were not correlated with BPD. The increased BPD risk in preterm neonates born from preeclamptic mothers cannot be related to high sFlt-1 levels., (Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Vitamin D status during pregnancy and in newborns has never been studied in France. This study aims at determining the vitamin D status during the first and third trimesters of pregnancy (T1, T3) and in cord blood (CB) in the middle-north of France., Methods: We conducted a prospective cohort study in five French centers (latitude 47.22 to 48.86°N). Serum 25(OH)-vitamin D (25(OH)D) concentrations were measured using a radioimmunoassay during T1, T3 and in CB. According to the French guidelines, pregnant women received cholecalciferol, 100,000 IU, in the seventh month., Results: Between April 2012 and July 2014, 2832 women were included, of whom 2803 were analyzed (mean ± SD age: 31.5 ± 5.0 years; phototypes 5-6: 21.8%). Three and 88.6% of participants received supplementation during the month before inclusion and in the seventh month, respectively. At T1, T3, and CB, mean 25(OH)D concentrations were 21.9 ± 10.4, 31.8 ± 11.5, and 17.0 ± 7.2 ng/mL, respectively, and 25(OH)D was <20 ng/mL in 46.5%, 14.0%, and 68.5%, respectively. At T1, body mass index ≥25 kg/m 2 , dark phototypes, sampling outside summer, and no supplementation before inclusion were independently associated with vitamin D insufficiency (25(OH)D < 20 ng/mL). Women who received cholecalciferol supplementation in month 7 had higher 25(OH)D at T3 than non-supplemented women (32.5 ± 11.4 versus 25.8 ± 11.4 ng/mL, p = <0.001) and marginally higher 25(OH)D in CB (17.2 ± 7.2 versus 15.5 ± 7.1 ng/mL, p = 0.004)., Conclusions: Despite the recommended supplementation, vitamin D insufficiency is frequent during pregnancy and in newborns in France., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction The use of paclitaxel in pregnant cancer patients is feasible in terms of fetal safety, but little is known about the effects of paclitaxel on the placenta. Using three experimental models, we aimed to assess the effects of paclitaxel on the expression of placental drug transporters. Methods In the in vitro model (human primary trophoblast culture), trophoblasts were isolated from normal term placentas and subsequently exposed to paclitaxel. The transcriptional regulation of 84 genes encoding for drug transporters, and the protein expression of ABCB1/P-gp and ABCG2/BCRP were assessed. In the in vivo model, placental tissues isolated from pregnant cancer patients treated with paclitaxel were analyzed to assess the protein expression of ABCB1/P-gp and ABCG2/BCRP. The same parameters were assessed in extracts from human placental cotyledons perfused ex vivo with paclitaxel. Results In the in vitro model, the expression of twelve drug-transporters genes was found to be significantly down-regulated after exposure to paclitaxel, including ABCC10, SLC28A3, SLC29A2, and ATP7B (involved in the transport of taxanes, antimetabolites, and cisplatin, respectively). The protein expression of ABCB1/P-gp increased by 1.3-fold after paclitaxel administration. Finally, the protein expression of ABCB1/P-gp and ABCG2/BCRP was higher in cotyledons from mothers treated with multiple doses of paclitaxel during pregnancy than in cotyledons perfused with a single dose of paclitaxel. Discussion Paclitaxel modulates the expression of placental drug transporters involved in the disposition of various anticancer agents. Further studies will be needed to assess the impact of repeated or prolonged exposure to paclitaxel on the expression and function of placental drug transporters.

Background: parturition involves multiple signalling pathways and most advances in research underline the importance of fetal development and maturation in the timing of labour, especially the fetal pituitary-adrenal axis. But, there is currently no consensual hypothesis on all the physiological processes responsible for human parturition., Methods: sixty low-risk pregnant women were enrolled in a prospective cohort. Maternal blood was sampled regularly during consultations each week in last trimester, at delivery and at postnatal consultation. Cord blood was collected at delivery. We used proteomic analysis to identify maternal blood biomarkers of potential interest, focusing on serum proteins from 39 W G in pregnancies to delivery and postpartum., Results: among 56 peaks we identified variation in the N-terminal part of fetuin-A in maternal serum. Fetuin-A is a natural antagonist of TGF-beta and is able to bind calcium. We found a significant decrease in maternal serum fetuin-A in the days preceding delivery, independently of the mode of delivery. Also, there does not appear to be significant influence of the different fetal parameters (sex, Z-score) on maternal serum variations at delivery., Conclusion: fetuin-A is described by the literature as a potential biomarker for organ dysfunction and metabolic syndrome disorders. The protein mineral homeostasis would be an interesting pathway to explore during pregnancy and particularly parturition., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Preeclampsia is a hypertensive pregnancy disease associated with a massive increase in sFlt-1 (soluble form of the vascular endothelial growth factor 1) in the maternal circulation, responsible for angiogenic imbalance and endothelial dysfunction. Pilot studies suggest that extracorporeal apheresis may reduce circulating sFlt-1 and prolong pregnancy. Nonspecific apheresis systems have potential adverse effects because of the capture of many other molecules. Our concept is based on a specific and competitive apheresis approach using VEGF (vascular endothelial growth factor) functionalized magnetic beads to capture sFlt-1 while releasing endogenous PlGF (placental growth factor) to restore a physiological angiogenic balance. Magnetic beads were functionalized with VEGF to capture sFlt-1. Experiments were performed using PBS, conditioned media from human trophoblastic cells, and human plasma. The proof of concept was validated in dynamic conditions in a microfluidic device as an approach mimicking real apheresis. Magnetic beads were functionalized with VEGF and characterized to evaluate their surface ligand density and recognition capabilities. VEGF-coated magnetic beads proved to be an efficient support in capturing sFlt-1 and releasing PlGF. In static conditions, sFlt-1 concentration decreased by 33±13%, whereas PlGF concentration increased by 27±10%. In dynamic conditions, the performances were improved, with 40% reduction of sFlt-1 and up to 2-fold increase of free PlGF. The sFlt-1/PlGF ratio was reduced by 63% in the plasma of preeclamptic patients. Apheresis was also associated with VEGF release. A ligand-based approach using VEGF-coated beads is an effective approach to the capture of sFlt-1 and the release of endogenous PlGF. It offers new perspectives for the treatment of preeclampsia.

Background: HIV-infected transwomen face multiple specific issues. Economic and social marginalization, sex work, substance abuse, hormonal consumption and silicone injection may affect the course of HIV infection and lead to metabolic and endocrine complications., Methods: A matched case-control study was performed between 2013 and 2015 in a University Hospital and compared metabolic syndrome (MetS), thyroid and adrenal functions in HIV-infected transwomen (i.e. cases) and cisgender HIV-infected men (i.e. controls) matched for age and antiretroviral therapy. The interaction between hormonal consumption, the course of HIV infection and antiretroviral therapy was also studied. Clinical and biological data (CD4 cell count, HIV RNA load, antiretroviral plasma drug concentration, HDL, triglycerides, glucose, cortisol, thyroid stimulating hormone, free thyroxine, prolactine) were measured., Results: A total of 292 HIV-infected patients (100 cases and 192 controls) were prospectively included. There was no difference between the two populations in terms of frequency of MetS, but subclinical hypothyroidism and adrenal insufficiency were more frequent in cases than in controls with, respectively, 12 vs. 3% (P < 0.002) for hypothyroidism and 20 vs. 8% (P < 0.001) for adrenal insufficiency. Prolactinemia, only performed in transwomen, was often elevated (21%) but rarely confirmed as true active hyperprolactinemia (monomeric form) (3%). Although hormonal intake was frequent among transwomen (31%), no impact on antiretroviral bioavailability and efficacy was detected., Conclusion: In this study, no increase in the prevalence of MetS was detected in HIV-infected transwomen patients. In contrast, adrenal and thyroid functions abnormalities were frequent and should be systematically assessed in this population. No impact of hormonal intake on antiretroviral bioavailability and efficacy was detected.

Objective: To evaluate the association of active renin concentration (ARC), plasma aldosterone concentration (PAC) and aldosterone-to-renin ratio (ARR) with the risk of preeclampsia (PE), in particular according to the status of obesity., Design: This retrospective case-control study involved 90 women with PE (mean gestation 35.6 ± 3.6 weeks) and 90 age-matched control women with uncomplicated pregnancies (mean gestation 38.5 ± 2.5 weeks). ARC and PAC were measured by radioimmunoassay; ARR calculated as PAC to ARC ratio. PE cases were stratified into 5 percentiles groups, and analyzed in multivariate logistic regression., Results: Women with PE had significantly lower median ARC and PAC than control women, which were confirmed by percentiles analysis. Spearman correlation demonstrated negative correlation of ARC with body mass index, systolic/diastolic blood pressure. PAC correlated negatively with systolic/diastolic blood pressure, but positively with baby weight, ARC and ARR. On the other hand, ARR positively correlated with BMI and PAC, but negatively with ARC. Lower PAC was associated with PE, irrespective of body weight, while ARC levels were significantly lower in non-obese PE cases vs. control women. ARR was not significantly different between PE cases and control women, when stratified according to obesity., Conclusion: Low ARC and PAC in third trimester are more strongly associated with preeclampsia respectively in non-obese and obese women., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Preeclampsia is a hypertensive disease of pregnancy due to abnormal utero-placental circulation. Hypoperfusion of the placenta and hypoxia/reoxygenation of the intervillous space are responsible of placental dysfunction. Trophoblastic factors are released in the maternal circulation and are responsible of the maternal endothelial dysfunction that characterize preeclampsia. Among those factors, the PlGF/sFlt-1 couple plays a major pathophysiologic role., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Placental development is markedly abnormal in trisomy 21 (T21) pregnancies. We hypothesized that abnormal paracrine cross talk between the fetal mesenchymal core and the trophoblast might be involved in the defect of syncytiotrophoblast formation and function. In a large series of primary cultured human cytotrophoblasts isolated from second-trimester control (n = 44) and T21 placentae (n = 71), abnormal trophoblast fusion and differentiation was observed in more than 90% of T21 cases. We then isolated and cultured villous mesenchymal cells from control (n = 10) and T21 placentae (n = 8) and confirmed their fetal origin. Conditioned medium of control mesenchymal cells overcame the abnormal trophoblast fusion of T21 cytotrophoblasts by activating the TGFβ signaling pathway, as shown by the phosphospecific protein microarray analysis and the use of TGFβ signaling pathway antagonists. Using protein arrays, we further analyzed the cytokines present in the conditioned medium from control and T21 mesenchymal cells. Activin-A was identified as strongly secreted by cells from both sources, but at a significantly (P < 0.01) lower level in the case of T21 mesenchymal cells. Recombinant activin-A stimulated T21 trophoblast fusion. Blocking activin-A antibody inhibited the fusion induced by conditioned medium and exogenous activin-A. Furthermore, follistatin, an activin-A binding protein largely secreted by T21 mesenchymal cells, inhibited the conditioned medium fusogenic activity. These results show that the defective trophoblast fusion and differentiation associated with T21 can be overcome in vitro and reveal the key role of the fetal mesenchymal core in human trophoblast differentiation.

Deep infiltrating endometriosis (DIE) is a particular clinical and histological entity of endometriosis responsible for chronic pelvic pain and infertility. Here we characterize the proliferative phenotype of DIE cells, to explore the cellular and molecular mechanisms that could explain their aggressive potential. In addition, the inhibition of mTOR/AKT pathway was tested, as a potential treatment of DIE. Included were 22 patients with DIE and 12 control patients without endometriosis. Epithelial and stromal cells were extracted from biopsies of eutopic endometrium and deep infiltrating endometriotic nodules from patients with DIE. Cell proliferation was determined by thymidine incorporation. Oxidative stress was assayed by spectrofluorometry. The ERK and mTOR/AKT pathways were analyzed in vitro by Western blot and for AKT in vivo in a mouse model of DIE. The proliferation rate of eutopic endometrial cells and of deep infiltrating endometriotic cells from DIE patients was higher than that of endometrial cells from controls. The hyperproliferative phenotype of endometriotic cells was associated with an increase in endogenous oxidative stress, and with activation of the ERK and mTOR/AKT pathways. mTOR/AKT inhibition by temsirolimus decreased endometriotic cell proliferation both in vitro and in vivo in a mouse model of DIE. Blocking the mTOR/AKT pathway offers new prospects for the treatment of DIE., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily that controls in a ligand-dependent manner the expression of a large array of genes involved in the control of energy homeostasis and in cell differentiation, proliferation, apoptosis, and the inflammatory process. Unexpectedly, genetic studies performed in mice established that PPARγ is essential for placental development. In the human placenta, PPARγ is specifically expressed in the trophoblast, both endocrine villous and invasive extravillous cytotrophoblasts (EVCT). Activation of PPARγ induces accumulation of lipids, villous trophoblast differentiation and inhibits trophoblast invasiveness. Oxidized LDLs that contain potential PPARγ ligands, but not native LDL, induce PPARγ transcriptional activity and inhibit trophoblast invasion in vitro. Recently, human cytomegalovirus (HCMV) was shown to activate trophoblastic PPARγ for its own replication and consequently inhibits invasiveness of infected cytotrophoblasts. Analysis of PPARγ target genes revealed trophoblastic factors described to control trophoblast invasiveness and surprisingly chorionic gonadotropin hormone (hCG), known to be mainly produced by the endocrine villous trophoblast. Analysis of hCG gene expression revealed opposite regulation by PPARγ in the two trophoblast subtypes. Finally, a hyperglycosylated form of hCG (hCG-H) only produced by invasive EVCT was shown to promote trophoblast invasion. Together, these data underscore the major role of PPARγ and its target genes, such as hCG, in the control of human trophoblast differentiation and invasion, and suggest that over-activation of this nuclear receptor following HCMV infection or by excess of ligands at the maternal-fetal interface could impair implantation and placentation and therefore embryonic development., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Deep infiltrating endometriosis (DIE) is characterized by chronic pain, hyperproliferation of endometriotic cells and fibrosis. Since cannabinoids are endowed with antiproliferative and antifibrotic properties, in addition to their psychogenic and analgesic effects, cannabinoid agonists have been evaluated in DIE both in vitro and in vivo. The in vitro effects of the cannabinoid agonist WIN 55212-2 were evaluated on primary endometriotic and endometrial stromal and epithelial cell lines extracted from patients with or without DIE. Cell proliferation was determined by thymidine incorporation and production of reactive oxygen species by spectrofluorometry. ERK and Akt pathways were studied by immunoblotting. Immunoblotting of α-smooth muscle actin was studied as evidence of myofibroblastic transformation. The in vivo effects of WIN 55212-2 were evaluated on Nude mice implanted with human deep infiltrating endometriotic nodules. The in vitro treatment of stromal endometriotic cells by WIN 55212-2 decreased cell proliferation, reactive oxygen species production, and α-smooth muscle actin expression. The decrease in cell proliferation induced by WIN 55212-2 was not associated with a decrease in ERK activation, but was associated with the inhibition of Akt activation. WIN 55212-2 abrogated the growth of endometriotic tissue implanted in Nude mice. Cannabinoid agonists exert anti-proliferative effects on stromal endometriotic cells linked to the inhibition of the Akt pathway. These beneficial effects of cannabinoid agonists on DIE have been confirmed in vivo.

Context: Nonimmune fetal goitrous hypothyroidism is a rare condition that can induce obstetrical and/or neonatal complications and neurodevelopmental impairments such as those still seen in some patients with congenital hypothyroidism. Prenatal treatment to prevent these adverse outcomes is appealing, but experience is limited and the risk to benefit ratio controversial., Objective: The objective of the study was to evaluate the feasibility, safety, and effectiveness of intrauterine l-thyroxine treatment in a large cohort with nonimmune fetal goitrous hypothyroidism., Design: This was a retrospective study of 12 prenatally treated fetuses diagnosed between 1991 and 2005 in France., Methods: During pregnancy, goiter size and thyroid hormone levels were compared before and after prenatal treatment. At birth, clinical, laboratory, and ultrasound data were evaluated., Results: Prenatal treatment varied widely in terms of l-thyroxine dosage (200-800 microg/injection), number of injections (one to six), and frequency (every 1-4 wk). No adverse events were recorded. During pregnancy, thyroid size decreased in eight of nine cases and amniotic-fluid TSH levels decreased in the six investigated cases, returning to normal in four. However, at birth, all babies had hypothyroidism, indicating that intraamniotic TSH levels did not reliably reflect fetal thyroid function., Conclusion: Our data confirm the feasibility and safety of intraamniotic l-thyroxine treatment for nonimmune fetal goitrous hypothyroidism. Although goiter size reduction is usually obtained, thyroid hormone status remains deficient at birth. Amniocentesis seems inadequate for monitoring fetal thyroid function. Further studies are needed to determine the optimal management of this disorder.

The role of the placenta in normal and pathological pregnancy is poorly understood, but important new insights into trophoblast biology have been obtained in recent years. The oxygen environment and retroviral envelope proteins are now known to play a role in morphological and functional differentiation of the human trophoblast. The qualitative and quantitative development of trophoblast hormonal functions during pregnancy, from a paracrine role during the first trimester to an endocrine role in placentation and uterine quiescence, is becoming increasingly clear. These findings are offering new perspectives in the diagnosis and treatment of disorders of placental origin.

Objective: To evaluate anti-Müllerian hormone (AMH) as a marker of reproductive outcome after IVF/intracytoplasmic sperm injection (ICSI)., Design: Longitudinal study., Setting: University hospital., Patient(s): Two hundred seventy-six consecutive women undergoing IVF/ICSI., Intervention(s): Ovarian stimulation, oocyte retrieval, IVF, ICSI, embryo transfer, AMH, and inhibin B determinations in serum and follicular fluid (FF)., Main Outcome Measure(s): The AMH and inhibin B concentrations in 276 matched FF/serum pairs have been determined. Different outcome groups have been compared and set in relation to the oocyte count, morphological parameters, and steroid hormone levels., Result(s): The concentrations of AMH and inhibin B in both serum and FF were significantly higher in the group of women who became pregnant in the corresponding treatment cycle than in those who did not conceive. Positive correlations were observed between serum inhibin B concentrations and embryo morphology (r = 0.126, 95% confidence interval 0.026-0.284). Serum and FF AMH or inhibin B correlated positively with the oocyte count and negatively with the pretreatment cycle day 3 FSH level and the total administered gonadotropin dose., Conclusion(s): The AMH and inhibin B levels on the day of oocyte retrieval are correlated to reproductive outcome.

A critical step in the establishment of human pregnancy is the invasion of the uterus wall by extravillous cytotrophoblasts (EVCTs) during the first trimester. It is well established that human chorionic gonadotropin hormone (hCG) is secreted by the endocrine syncytiotrophoblast (ST) into the maternal compartment. We recently reported that invasive EVCTs also produce hCG, suggesting an autocrine role in the modulation of trophoblast invasion. Here we analyzed the role of hCG secreted in vitro by primary cultures of invasive EVCT and noninvasive ST. We first demonstrated that LH/CG receptor was present in EVCTs in situ and in vitro as well as in an EVCT cell line (HIPEC65). We next showed that hCG secreted by EVCTs stimulated progesterone secretion by MA10 cells in a concentration-dependent manner. Incubation of HIPEC65 with EVCT supernatants induced a 10-fold increase in cell invasion, whereas ST supernatants had no effect. This stimulating effect was strongly decreased when hCG was depleted from EVCT supernatants containing a large amount of the hyperglycosylated form of hCG, which is almost undetectable in ST supernatants. Finally, we investigated the regulation of hCG expression by peroxisome proliferator-activated receptor (PPAR)-gamma, a nuclear receptor shown to inhibit trophoblast invasion. Activation of PPARgamma decreased alpha- and beta-subunit transcript levels and total hCG secretion in primary EVCTs. Our results offer the first evidence that hCG secreted by the invasive trophoblast, likely the hyperglycosylated form of hCG, but not by the syncytiotrophoblast, promotes trophoblast invasion and may be a PPARgamma target gene in trophoblast invasion process.