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1.
Stem Cells ; 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34224633

RESUMO

Endometrial stem/progenitor cells play a role in postpartum uterine tissue regeneration but the underlying mechanisms are poorly understood. While circulating bone marrow (BM)-derived cells (BMDCs) contribute to nonhematopoietic endometrial cells, the contribution of BMDCs to postpartum uterus remodeling is unknown. We investigated the contribution of BMDCs to the postpartum uterus using 5-fluorouracil-based nongonadotoxic BM transplant from green fluorescent protein (GFP) donors into wild-type C57BL/6J female mice. Flow cytometry showed an influx of GFP+ cells to the uterus immediately postpartum accounting for 28.7% of total uterine cells, followed by a rapid decrease to prepregnancy levels. The majority of uterine GFP+ cells were CD45+ leukocytes and the proportion of nonhematopoietic CD45-GFP+ cells peaked on postpartum day (PPD) 1 (17.5%). Immunofluorescence colocalization of GFP with CD45 pan-leukocyte and F4/80 macrophage markers corroborated these findings. GFP+ cells were found mostly in subepithelial stromal location. Importantly, GFP+ cytokeratin-positive epithelial cells were found within the luminal epithelium exclusively on PPD1, demonstrating direct contribution to postpartum re-epithelialization. A subset (3.2%) of GFP+ cells were CD31+CD45- endothelial cells, and found integrated within blood vessel endothelium. Notably, BM-derived GFP+ cells demonstrated preferential proliferation (PCNA+) and apoptosis (TUNEL+) on PPD1 vs resident GFP- cells, suggesting an active role for BMDCs in rapid tissue turnover. Moreover, GFP+ cells gradually acquired cell senescence together with decreased proliferation throughout the postpartum. In conclusion, BM-derived progenitors were found to have a novel nonhematopoietic cellular contribution to postpartum uterus remodeling. This contribution may have an important functional role in physiological as well as pathological postpartum endometrial regeneration.

2.
Nat Commun ; 12(1): 4502, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301937

RESUMO

Cells in many tissues, such as bone, muscle, and placenta, fuse into syncytia to acquire new functions and transcriptional programs. While it is known that fused cells are specialized, it is unclear whether cell-fusion itself contributes to programmatic-changes that generate the new cellular state. Here, we address this by employing a fusogen-mediated, cell-fusion system to create syncytia from undifferentiated cells. RNA-Seq analysis reveals VSV-G-induced cell fusion precedes transcriptional changes. To gain mechanistic insights, we measure the plasma membrane surface area after cell-fusion and observe it diminishes through increases in endocytosis. Consequently, glucose transporters internalize, and cytoplasmic glucose and ATP transiently decrease. This reduced energetic state activates AMPK, which inhibits YAP1, causing transcriptional-reprogramming and cell-cycle arrest. Impairing either endocytosis or AMPK activity prevents YAP1 inhibition and cell-cycle arrest after fusion. Together, these data demonstrate plasma membrane diminishment upon cell-fusion causes transient nutrient stress that may promote transcriptional-reprogramming independent from extrinsic cues.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Glicoproteínas de Membrana/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética/genética , Proteínas do Envelope Viral/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Transporte Biológico , Fusão Celular , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Células Gigantes/metabolismo , Células HEK293 , Humanos , Glicoproteínas de Membrana/genética , Camundongos , RNA-Seq/métodos , Transdução de Sinais/genética , Fatores de Transcrição/genética , Proteínas do Envelope Viral/genética
3.
Am J Pathol ; 191(7): 1292-1302, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964217

RESUMO

Hyperactivation of the CXCL12-CXCR4 axis occurs in endometriosis; the therapeutic potential of treatments aimed at global inhibition of the axis was recently reported. Because CXCR4 is predominantly expressed on epithelial cells in the uterus, this study explored the effects of targeted disruption of CXCR4 in endometriosis lesions. Uteri derived from adult female mice homozygous for a floxed allele of CXCR4 and co-expressing Cre recombinase under control of progesterone receptor promoter were sutured onto the peritoneum of cycling host mice expressing the green fluorescent protein. Four weeks after endometriosis induction, significantly lower number of lesions developed in Cxcr4-conditional knockout lesions relative to those in controls (37.5% vs. 68.8%, respectively). In lesions that developed in Cxcr4-knockout, reduced epithelial proliferation was associated with a lower ratio of epithelial to total lesion area compared with controls. Furthermore, while CD3+ lymphocytes were largely excluded from the epithelial compartment in control lesions, in Cxcr4-knockout lesions, CD3+ lymphocytes infiltrated the Cxcr4-deficient epithelium in the diestrus and proestrus stages. Current data demonstrate that local CXCR4 expression is necessary for proliferation of the epithelial compartment of endometriosis lesions, that its downregulation compromises lesion numbers, and suggest a role for epithelial CXCR4 in lesion immune evasion.


Assuntos
Endometriose/imunologia , Endometriose/metabolismo , Linfócitos Intraepiteliais/imunologia , Receptores CXCR4/metabolismo , Animais , Proliferação de Células , Células Epiteliais/imunologia , Feminino , Camundongos
4.
Placenta ; 114: 133-138, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33941390

RESUMO

INTRODUCTION: Trophoblast inclusions (TIs) are associated with aneuploidy and pregnancy loss and have thus been considered to be a marker of genetic abnormality. However, to date, no study has specifically explored whether TIs are a manifestation of fetal genetics or, rather, the result of the intrauterine environment. The goal of this study was to compare the frequency of TIs in the placentas of monozygotic (MZ) and dizygotic (DZ) twin pairs in order to determine whether the formation of TIs is genetically driven or not. METHODS: We performed a retrospective case series of placentas from 48 twin pairs. The placentas were grouped based on zygosity: MZ, DZ, or unknown (UZ). The average number of total TIs per slide was calculated for each twin individual and the mean absolute difference in the total TIs per slide between the twin pairs was calculated for each zygosity group and compared. RESULTS: The mean difference in the total TIs per slide for DZ twins was significantly greater than the mean difference in the total TIs per slide for MZ twins (p = 0.003). The mean difference in the total TIs per slide for the UZ group was also significantly greater than the mean difference in total TIs per slide between MZ twin pairs (p = 0.028). DISCUSSION: Our finding that MZ twins were significantly more concordant than DZ twins for the average number of TIs per slide supports the conclusion that TIs are intrinsic to the genetics of the fetus, not the uterine environment.

5.
Med (N Y) ; 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33969332

RESUMO

Background: Pregnant women are at increased risk for severe outcomes from coronavirus disease 2019 (COVID-19), but the pathophysiology underlying this increased morbidity and its potential effect on the developing fetus is not well understood. Methods: We assessed placental histology, ACE2 expression, and viral and immune dynamics at the term placenta in pregnant women with and without respiratory severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Findings: The majority (13 of 15) of placentas analyzed had no detectable viral RNA. ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term, suggesting that low ACE2 expression may protect the term placenta from viral infection. Using immortalized cell lines and primary isolated placental cells, we found that cytotrophoblasts, the trophoblast stem cells and precursors to syncytiotrophoblasts, rather than syncytiotrophoblasts or Hofbauer cells, are most vulnerable to SARS-CoV-2 infection in vitro. To better understand potential immune mechanisms shielding placental cells from infection in vivo, we performed bulk and single-cell transcriptomics analyses and found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited robust immune responses, including increased activation of natural killer (NK) and T cells, increased expression of interferon-related genes, as well as markers associated with pregnancy complications such as preeclampsia. Conclusions: SARS-CoV-2 infection in late pregnancy is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion. Funding: NIH (T32GM007205, F30HD093350, K23MH118999, R01AI157488, U01DA040588) and Fast Grant funding support from Emergent Ventures at the Mercatus Center.

6.
Placenta ; 103: 172-176, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152642

RESUMO

We sought to examine placentas enriched for trophoblast inclusions (TIs) in order to characterize, quantify, and examine the interrelations between subtypes of TIs to better understand their underlying biology. We examined a cohort of 600 placentas from deliveries between 200 and 430 weeks of gestation. Forty-five percent of the placentas had at least one TI in the two slides examined. Four percent of the placentas had 10 or more TIs and two placentas had more than 70 TIs. Four distinct TI subtypes were observed: inclusionoids (early forming inclusions), inclusions, calcified inclusions, and calcified bodies. We suggest this reflects a developmental trajectory of TI maturation, the timing of which might be useful when comparing TI expression to clinical outcomes.

7.
Proc Natl Acad Sci U S A ; 116(41): 20267-20273, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31570579

RESUMO

The ovulatory homolog model of female orgasm posits that the neuro-endocrine mechanisms underlying female orgasm evolved from and are homologous to the mechanisms mediating copulation-induced ovulation in some mammals. This model predicts that pharmacological agents that affect human orgasm, such as fluoxetine, should also affect ovulation in animals with copulation-induced ovulation, such as rabbits. We tested this prediction by treating rabbits with daily doses of fluoxetine for 2 wk and found that fluoxetine treatment reduces the number of ovulations postcopulation by 30%. In a second experiment we tested whether this result was mediated by an effect on the brain or via peripheral serotonin functions. We treated animals with fluoxetine and induced ovulation with a single injection of human chorionic gonadotropin. In this experiment ovulation rate was nominally reduced by only 8%, which is statistically not significant. We conclude that the effect of fluoxetine on copulation-induced ovulation rate supports the ovulatory homolog model of female orgasm, suggesting that female orgasm has very deep evolutionary roots among the early eutherian mammals.


Assuntos
Evolução Biológica , Gonadotropina Coriônica/farmacologia , Fluoxetina/farmacologia , Ovulação/efeitos dos fármacos , Animais , Gonadotropina Coriônica/administração & dosagem , Copulação/fisiologia , Feminino , Fluoxetina/administração & dosagem , Masculino , Ovulação/fisiologia , Coelhos , Substâncias para o Controle da Reprodução/administração & dosagem , Substâncias para o Controle da Reprodução/farmacologia , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia
8.
PLoS Biol ; 17(9): e3000421, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513564

RESUMO

Decidua is a transient uterine tissue shared by mammals with hemochorial placenta and is essential for pregnancy. The decidua is infiltrated by many immune cells promoting pregnancy. Adult bone marrow (BM)-derived cells (BMDCs) differentiate into rare populations of nonhematopoietic endometrial cells in the uterus. However, whether adult BMDCs become nonhematopoietic decidual cells and contribute functionally to pregnancy is unknown. Here, we show that pregnancy mobilizes mesenchymal stem cells (MSCs) to the circulation and that pregnancy induces considerable adult BMDCs recruitment to decidua, where some differentiate into nonhematopoietic prolactin-expressing decidual cells. To explore the functional importance of nonhematopoietic BMDCs to pregnancy, we used Homeobox a11 (Hoxa11)-deficient mice, having endometrial stromal-specific defects precluding decidualization and successful pregnancy. Hoxa11 expression in BM is restricted to nonhematopoietic cells. BM transplant (BMT) from wild-type (WT) to Hoxa11-/- mice results in stromal expansion, gland formation, and marked decidualization otherwise absent in Hoxa11-/- mice. Moreover, in Hoxa11+/- mice, which have increased pregnancy losses, BMT from WT donors leads to normalized uterine expression of numerous decidualization-related genes and rescue of pregnancy loss. Collectively, these findings reveal that adult BMDCs have a previously unrecognized nonhematopoietic physiologic contribution to decidual stroma, thereby playing important roles in decidualization and pregnancy.


Assuntos
Células da Medula Óssea/fisiologia , Decídua/citologia , Implantação do Embrião , Células-Tronco Mesenquimais/fisiologia , Gravidez/fisiologia , Animais , Feminino , Proteínas de Homeodomínio/genética , Masculino , Camundongos Knockout
9.
Fertil Steril ; 111(4): 618-628, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929719

RESUMO

The endometrium is a dynamic, repetitively cycling tissue that mediates the implantation of the blastocyst. Evaluation of this complex tissue necessitates sophisticated methods that can assess its functional potential. Beginning in the 1950s with simple histological endometrial "dating," these methods have crossed into the molecular era with the use of arrays aimed at dating, functional tests that assess for proliferation and differentiation, and tests that screen for inflammatory markers. In addition to these specialized tests, histologic evaluation for pathologic conditions-such as growth disorders (i.e. polyps and hyperplasia), inflammatory lesions, and retained products of conception-are critical for a complete assessment of the patient with recurrent implantation failure. Whatever the means of testing, the goal is to reveal actionable findings that can assist in offering the best options to patients who have failed multiple transfers with high quality embryos.


Assuntos
Aborto Habitual/diagnóstico , Técnicas de Diagnóstico Obstétrico e Ginecológico , Implantação do Embrião/fisiologia , Endométrio/patologia , Infertilidade Feminina/diagnóstico , Aborto Habitual/etiologia , Aborto Habitual/terapia , Técnicas de Diagnóstico Obstétrico e Ginecológico/normas , Prática Clínica Baseada em Evidências , Feminino , Humanos , Infertilidade Feminina/etiologia , Infertilidade Feminina/terapia , Gravidez
10.
J Exp Med ; 215(9): 2339-2353, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30115739

RESUMO

We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein-coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL). Homozygosity results in fetal demise from hydrops fetalis, while heterozygosity in females is associated with spontaneous miscarriage and subfertility. Using molecular dynamic modeling and in vitro biochemical assays, we show that the hCLR(V205del) mutant results in misfolding of the first extracellular loop, reducing association with its requisite receptor chaperone, receptor activity modifying protein (RAMP), translocation to the plasma membrane and signaling. Using three independent genetic mouse models we establish that the adrenomedullin-CLR-RAMP2 axis is both necessary and sufficient for driving lymphatic vascular proliferation. Genetic ablation of either lymphatic endothelial Calcrl or nonendothelial Ramp2 leads to severe NIHF with embryonic demise and placental pathologies, similar to that observed in humans. Our results highlight a novel candidate gene for human congenital NIHF and provide structure-function insights of this signaling axis for human physiology.


Assuntos
Sequência de Aminoácidos , Proteína Semelhante a Receptor de Calcitonina , Anormalidades Craniofaciais , Hidropisia Fetal , Linfangiectasia Intestinal , Linfedema , Camundongos Transgênicos , Deleção de Sequência , Animais , Proteína Semelhante a Receptor de Calcitonina/genética , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Heterozigoto , Homozigoto , Humanos , Hidropisia Fetal/genética , Hidropisia Fetal/metabolismo , Hidropisia Fetal/patologia , Linfangiectasia Intestinal/genética , Linfangiectasia Intestinal/metabolismo , Linfangiectasia Intestinal/patologia , Linfedema/genética , Linfedema/metabolismo , Linfedema/patologia , Masculino , Camundongos , Placenta , Gravidez
11.
Sci Immunol ; 3(19)2018 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-29305462

RESUMO

Zika virus (ZIKV) infection during pregnancy is associated with adverse fetal outcomes, including microcephaly, growth restriction, and fetal demise. Type I interferons (IFNs) are essential for host resistance against ZIKV, and IFN-α/ß receptor (IFNAR)-deficient mice are highly susceptible to ZIKV infection. Severe fetal growth restriction with placental damage and fetal resorption is observed after ZIKV infection of type I IFN receptor knockout (Ifnar1-/-) dams mated with wild-type sires, resulting in fetuses with functional type I IFN signaling. The role of type I IFNs in limiting or mediating ZIKV disease within this congenital infection model remains unknown. In this study, we challenged Ifnar1-/- dams mated with Ifnar1+/- sires with ZIKV. This breeding scheme enabled us to examine pregnant dams that carry a mixture of fetuses that express (Ifnar1+/-) or do not express IFNAR (Ifnar1-/-) within the same uterus. Virus replicated to a higher titer in the placenta of Ifnar1-/- than within the Ifnar1+/- concepti. Yet, rather unexpectedly, we found that only Ifnar1+/- fetuses were resorbed after ZIKV infection during early pregnancy, whereas their Ifnar1-/- littermates continue to develop. Analyses of the fetus and placenta revealed that, after ZIKV infection, IFNAR signaling in the conceptus inhibits development of the placental labyrinth, resulting in abnormal architecture of the maternal-fetal barrier. Exposure of midgestation human chorionic villous explants to type I IFN, but not type III IFNs, altered placental morphology and induced cytoskeletal rearrangements within the villous core. Our results implicate type I IFNs as a possible mediator of pregnancy complications, including spontaneous abortions and growth restriction, in the context of congenital viral infections.


Assuntos
Morte Fetal/etiologia , Interferon Tipo I/imunologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/imunologia , Retardo do Crescimento Fetal/virologia , Feto/imunologia , Feto/virologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placenta/imunologia , Placenta/virologia , Gravidez , Receptor de Interferon alfa e beta/imunologia , Útero/imunologia , Útero/virologia , Infecção por Zika virus/virologia
12.
Endocrinology ; 159(4): 1609-1629, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29381782

RESUMO

Serotonin [5-hydroxytryptamine (5-HT)] is essential to intrauterine development, but its source is debated. We used immunocytochemistry to gauge 5-HT, its biosynthetic enzyme tryptophan hydroxylase 1 (TPH1); an importer (serotonin transporter, 5-HTT/SERT/SLC6A); other transporters [P-glycoprotein 1 (P-gp/ABCB1), OCT3/SLC22A3, and gap junction connexin-43]; and the 5-HT degradative enzyme monoamine oxidase A (MAOA) in sections of placentas. In humans, 5-HT was faintly stained only in first-trimester trophoblasts, whereas TPH1 was not seen at any stage. SERT was expressed in syncytiotrophoblasts and, more strongly, in cytotrophoblasts. MAOA was prominent in syncytiotrophoblasts, OCT3 and gap junctions were stained in cytotrophoblasts, and P-gp was present at the apical surfaces of both epithelia. 5-HT added to cultured placental explants accumulated in the trophoblast epithelium and reached the villus core vessels. Trophoblast uptake was blocked by the SERT inhibitor escitalopram. Inhibition of gap junctions with heptanol prevented the accumulation of 5-HT in cytotrophoblasts, whereas blocking OCT3 with decynium-22 and P-gp with mitotane led to its accumulation in cytotrophoblasts. Reducing 5-HT destruction by inhibiting MAOA with clorgyline increased the accumulation of 5-HT throughout the villus. In the mouse fetus, intravascular platelets stained prominently for 5-HT at day 13.5, whereas the placenta and yolk sac endoderm were both negative. TPH1 was not detected, but SERT was prominent in these mouse tissues. We conclude that serotonin is conveyed from the maternal blood stream through syncytiotrophoblasts, cytotrophoblasts and the villus core to the fetus through a physiological pathway that involves at least SERT, gap junctions, P-gp, OCT3, and MAOA.


Assuntos
Feto/metabolismo , Troca Materno-Fetal/fisiologia , Placenta/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Serotonina/metabolismo , Trofoblastos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Conexina 43/metabolismo , Feminino , Humanos , Camundongos , Monoaminoxidase/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , Segundo Trimestre da Gravidez/metabolismo , Triptofano Hidroxilase/metabolismo
13.
Am J Perinatol ; 35(8): 748-757, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29281842

RESUMO

OBJECTIVE: The objective of this study was to validate estimated placental volume (EPV) across a range of gestational ages (GAs). STUDY DESIGN: Three hundred sixty-six patients from 2009 to 2011 received ultrasound scans between 11 + 0 and 38 + 6 weeks GA to assess EPV. An EPV versus GA best fit curve was generated and compared with published normative curves of EPV versus GA in a different population. A subanalysis was performed to explore the relationship between EPV and birth weight (BW). RESULTS: Analysis of EPV versus GA revealed a parabolic curve with the following best fit equation: EPV = (0.372 GA - 0.00364 GA2)3. EPV was weakly correlated with BW, and patients with an EPV in the bottom 50th percentile had 2.42 times the odds of having a newborn with a BW in the bottom 50th percentile (95% confidence interval: 1.27-4.68). Microscopic evaluation of two placentas corresponding to the smallest EPV outliers revealed significant placental pathology. CONCLUSION: Placental volume increases throughout gestation and follows a predictable parabolic curve, in agreement with the existing literature. Further validation is required, but EPV may have the potential for clinical utility as a screening tool in a variety of settings.


Assuntos
Peso ao Nascer , Idade Gestacional , Placenta/anatomia & histologia , Adolescente , Adulto , Feminino , Humanos , Recém-Nascido , Masculino , Tamanho do Órgão , Placenta/diagnóstico por imagem , Gravidez , Estudos Prospectivos , Ultrassonografia Pré-Natal , Adulto Jovem
14.
Am J Obstet Gynecol ; 218(1): 126.e1-126.e13, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29097177

RESUMO

BACKGROUND: Preeclampsia is a major cause of perinatal morbidity and mortality. First-trimester screening has been shown to be effective in selecting patients at an increased risk for preeclampsia in some studies. OBJECTIVE: We sought to evaluate the feasibility of screening for preeclampsia in the first trimester based on maternal characteristics, medical history, biomarkers, and placental volume. STUDY DESIGN: This is a prospective observational nonintervention cohort study in an unselected US population. Patients who presented for an ultrasound examination between 11-13+6 weeks' gestation were included. The following parameters were assessed and were used to calculate the risk of preeclampsia: maternal characteristics (demographic, anthropometric, and medical history), maternal biomarkers (mean arterial pressure, uterine artery pulsatility index, placental growth factor, pregnancy-associated plasma protein A, and maternal serum alpha-fetoprotein), and estimated placental volume. After delivery, medical records were searched for the diagnosis of preeclampsia. Detection rates for early-onset preeclampsia (<34 weeks' gestation) and later-onset preeclampsia (≥34 weeks' gestation) for 5% and 10% false-positive rates using various combinations of markers were calculated. RESULTS: We screened 1288 patients of whom 1068 (82.99%) were available for analysis. In all, 46 (4.3%) developed preeclampsia, with 13 (1.22%) having early-onset preeclampsia and 33 (3.09%) having late-onset preeclampsia. Using maternal characteristics, serum biomarkers, and uterine artery pulsatility index, the detection rate of early-onset preeclampsia for either 5% or 10% false-positive rate was 85%. With the same protocol, the detection rates for preeclampsia with delivery <37 weeks were 52% and 60% for 5% and 10% false-positive rates, respectively. Based on maternal characteristics, the detection rates for late-onset preeclampsia were 15% and 48% for 5% and 10%, while for preeclampsia at ≥37 weeks' gestation the detection rates were 24% and 43%, respectively. The detection rates for late-onset preeclampsia and preeclampsia with delivery at >37 weeks' gestation were not improved by the addition of biomarkers. CONCLUSION: Screening for preeclampsia at 11-13+6 weeks' gestation using maternal characteristics and biomarkers is associated with a high detection rate for a low false-positive rate. Screening for late-onset preeclampsia yields a much poorer performance. In this study the utility of estimated placental volume and mean arterial pressure was limited but larger studies are needed to ultimately determine the effectiveness of these markers.


Assuntos
Placenta/diagnóstico por imagem , Pré-Eclâmpsia/diagnóstico , Primeiro Trimestre da Gravidez , Adulto , Biomarcadores/sangue , Diagnóstico Precoce , Estudos de Viabilidade , Feminino , Humanos , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/sangue , Gravidez , Proteína Plasmática A Associada à Gravidez/análise , Estudos Prospectivos , Fluxo Pulsátil/fisiologia , Artéria Uterina/fisiologia , alfa-Fetoproteínas/análise
15.
Fertil Steril ; 107(3): 684-690.e2, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28081870

RESUMO

OBJECTIVE: To assess the effectiveness of luteal start vaginal micronized P in a recurrent pregnancy loss (RPL) cohort. DESIGN: Observational cohort study using prospectively collected data. SETTING: Not applicable. PATIENT(S): Women seen between 2004 and 2012 with a history of two or more unexplained pregnancy losses <10 weeks in size; endometrial biopsy (EB) performed 9-11 days after LH surge; and one or more subsequent pregnancy(ies). Women were excluded if concomitant findings, such as endometritis, maturation delay, or glandular-stromal dyssynchrony, were identified on EB. INTERVENTION(S): Vaginal micronized P was prescribed at a dose of 100-200 mg every 12 hours starting 3 days after LH surge (luteal start) if glandular epithelial nuclear cyclin E (nCyclinE) expression was elevated (>20%) in endometrial glands or empirically despite normal nCyclinE (≤20%). Women with normal nCyclinE (≤20%) who did not receive P were used as controls. MAIN OUTCOME MEASURE(S): Pregnancy success was an ongoing pregnancy >10 weeks in size. RESULT(S): One hundred sixteen women met the inclusion criteria, of whom 51% (n = 59) had elevated nCyclinE and 49% (n = 57) had normal nCyclinE. Pregnancy success in the 59 women with elevated nCyclinE significantly improved after intervention: 6% (16/255) in prior pregnancies versus 69% (57/83) in subsequent pregnancies. Pregnancy success in subsequent pregnancies was higher in women prescribed vaginal micronized P compared with controls: 68% (86/126) versus 51% (19/37); odds ratio = 2.1 (95% confidence interval, 1.0-4.4). CONCLUSION(S): In this study, we found that the use of luteal start vaginal micronized P was associated with improved pregnancy success in a strictly defined cohort of women with RPL.


Assuntos
Aborto Habitual/prevenção & controle , Endométrio/efeitos dos fármacos , Fármacos para a Fertilidade Feminina/administração & dosagem , Fase Luteal/efeitos dos fármacos , Progesterona/administração & dosagem , Aborto Habitual/diagnóstico , Aborto Habitual/fisiopatologia , Administração Intravaginal , Adulto , Ciclina E/metabolismo , Composição de Medicamentos , Endométrio/metabolismo , Endométrio/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Humanos , Fase Luteal/metabolismo , Gravidez , Progesterona/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento
16.
J Clin Endocrinol Metab ; 101(7): 2883-91, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27088794

RESUMO

CONTEXT: Type 2 diabetes and obesity are risk factors for endometrial hyperplasia and cancer, suggesting that hyperinsulinemia contributes to pathogenesis. Insulin action through insulin receptor (IR) splice variants IR-A and IR-B regulates cellular mitogenesis and metabolism, respectively. OBJECTIVE: We hypothesized that IR-A and IR-B are differentially regulated in normal endometrium, according to mitogenic and metabolic requirements through the menstrual cycle, as well as in endometrial hyperplasia and cancer. DESIGN: IR-A, IR-B, and IGF-1 receptor (IGF-1R) mRNA was quantified in endometrium, endometrial epithelial and stromal cells, and in vitro after hormone stimulation. SETTING: Academic center. PATIENTS: Endometrium was collected from women with regular cycles (n = 71), complex hyperplasia (n = 5), or endometrioid adenocarcinoma (n = 11). INTERVENTION(S): In vitro sex-steroid treatment. MAIN OUTCOME MEASURE(S): IR-A and IR-B expression Results: IR-A increased dramatically during the early proliferative phase, 20-fold more than IR-B. In early secretory phase, IR-B and IGF-1R expression increased, reaching maximal expression, whereas IR-A decreased. In adenocarcinoma, IR-B and IGF-1R expression was 5- to 6-fold higher than normal endometrium, whereas IR-A expression was similar to IR-B. Receptor expression was unrelated to body mass index. CONCLUSION: IR-A was elevated during the normal proliferative phase, and in endometrial hyperplasia and adenocarcinoma. The dramatic early rise of IR-A in normal endometrium indicates IR-A is the predominant isoform responsible for initial estrogen-independent endometrial proliferation as well as that of cancer. IR-B is elevated during the normal secretory phase when glucose uptake and glycogen synthesis support embryo development. Differing from other cancers, IR-B expression equals mitogenic IR-A in endometrial adenocarcinoma. Differential IR isoform expression suggests a distinct role for each in endometrial physiology and cancer.


Assuntos
Adenocarcinoma/genética , Antígenos CD/genética , Neoplasias do Endométrio/genética , Endométrio/metabolismo , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Transcriptoma , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Antígenos CD/metabolismo , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Células Cultivadas , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/metabolismo , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Ciclo Menstrual/genética , Ciclo Menstrual/metabolismo , Pessoa de Meia-Idade , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo
18.
Am J Perinatol ; 31(8): 683-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24108663

RESUMO

OBJECTIVE: The objective of this study was to use two-dimensional (2D) ultrasound (US) during routine prenatal surveillance to develop normative estimated placental volume (EPV) growth curves. STUDY DESIGN: Patients ≥ 18 years old with singleton pregnancies were prospectively followed from 11 weeks gestational age (GA) until delivery. At routine US visits, placental width, height, and thickness were measured and EPV calculated using a validated mathematical model. RESULTS: In this study, 423 patients were scanned between 9.7 and 39.3 weeks GA to generate a total of 627 EPV calculations. Readings were clustered at 12 and 20 weeks, times of routine scanning. The mean EPV was 73 ± 47 cc at 12.5 ± 1.5 weeks (n = 444) and 276 ± 106 cc at 20 ± 2 weeks (n = 151). The data best fit a parabolic function as follows: EPV = (0.384GA - 0.00366GA(2))(3). Tenth and 90th percentile lines were generated with ± 1.28 SE offset. EPV readings below the 10th or above the 90th percentiles tended to be associated with either small or large newborns, respectively. CONCLUSION: Routine 2D US created EPV growth curves, which may be useful for stratifying patients into prenatal risk groups.


Assuntos
Peso ao Nascer , Placenta/diagnóstico por imagem , Gravidez , Adulto , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Tamanho do Órgão , Placentação , Estudos Prospectivos , Valores de Referência , Ultrassonografia Pré-Natal , Adulto Jovem
19.
Biol Psychiatry ; 74(3): 204-11, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23623455

RESUMO

BACKGROUND: Gestation is a critical window for neurodevelopmental vulnerability. This study examined whether the presence of trophoblast inclusions (TIs) in the placenta could serve as a predictor for children at elevated risk for autism spectrum disorder (ASD). METHODS: Placentas were obtained from 117 births in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) cohort of families who have one or more previous biological children with ASD, placing their newborn at elevated risk for neurodevelopmental compromise. Control samples were obtained from 100 uncomplicated term pregnancies of multiparous women with one or more typically developing biological children. Frequency of TIs was compared across the two groups. RESULTS: Placentas from at-risk pregnancies had an eightfold increased odds of having two or more TIs compared with control samples (odds ratio: 8.0, 95% confidence interval: 3.6-18.0). The presence of≥2 TIs yielded a sensitivity of 41% and a specificity of 92% for predicting ASD risk status, whereas≥4 TIs yielded a sensitivity of 19%, a specificity of 99.9%, and a positive likelihood ratio of 242 and conservatively predicted an infant with a 74% probability of being at risk for ASD. CONCLUSIONS: Our findings suggest that the placentas from women whose fetuses are at elevated risk for autism are markedly different from control placentas. These differences are manifested histologically as TIs. Their identification has the possibility of identifying newborns at risk for ASD who might benefit from targeted early interventions aimed at preventing or ameliorating behavioral symptoms and optimizing developmental outcomes.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/etiologia , Deficiências do Desenvolvimento/diagnóstico , Saúde da Família , Placenta/patologia , Trofoblastos/patologia , Transtornos Globais do Desenvolvimento Infantil/genética , Intervalos de Confiança , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Razão de Chances , Gravidez , Fatores de Risco
20.
Am J Obstet Gynecol ; 206(3): 236.e1-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22264652

RESUMO

OBJECTIVE: Spontaneous labor at term involves the activation of placental corticotropin-releasing hormone and the fetal adrenal axis, but the basis for extreme preterm labor is unknown. Our objective was to determine whether placental corticotropin-releasing hormone is activated in extreme preterm labor. STUDY DESIGN: One thousand five hundred six mothers delivering at less than 28 weeks' gestation were enrolled. Each mother/infant pair was assigned to the category that described the primary reason for hospitalization. Observers who had no knowledge of patient categorization assessed placenta microbiology, histology, and corticotropin-releasing hormone expression. These were correlated with the primary reason for hospitalization. RESULTS: Among infants delivered at less than 28 weeks' gestation, spontaneous (vs induced) delivery was associated with less placental corticotropin-releasing hormone expression and more frequent signs of placental inflammation and infection. CONCLUSION: Inflammation and infection, rather than premature activation of the fetal adrenal axis, should be the major focus of research to prevent extremely preterm human birth.


Assuntos
Corioamnionite/microbiologia , Complicações Infecciosas na Gravidez/microbiologia , Nascimento Prematuro/microbiologia , Glândulas Suprarrenais/metabolismo , Estudos de Coortes , Hormônio Liberador da Corticotropina/análise , Citocinas/sangue , Feminino , Humanos , Recém-Nascido , Masculino , Estudos Multicêntricos como Assunto , Placenta/química , Placenta/citologia , Placenta/microbiologia , Gravidez , Resultado da Gravidez
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