Beta-Estradiol Regulates Voltage-Gated Calcium Channels and Estrogen Receptors in Telocytes from Human Myometrium.

PubMed

Banciu, Adela; Banciu, Daniel Dumitru; Mustaciosu, Cosmin Catalin; Radu, Mihai; Cretoiu, Dragos; Xiao, Junjie; Cretoiu, Sanda Maria; Suciu, Nicolae; Radu, Beatrice Mihaela

2018-05-09

Voltage-gated calcium channels and estrogen receptors are essential players in uterine physiology, and their association with different calcium signaling pathways contributes to healthy and pathological conditions of the uterine myometrium. Among the properties of the various cell subtypes present in human uterine myometrium, there is increasing evidence that calcium oscillations in telocytes (TCs) contribute to contractile activity and pregnancy. Our study aimed to evaluate the effects of beta-estradiol on voltage-gated calcium channels and estrogen receptors in TCs from human uterine myometrium and to understand their role in pregnancy. For this purpose, we employed patch-clamp recordings, ratiometric Fura-2-based calcium imaging analysis, and qRT-PCR techniques for the analysis of cultured human myometrial TCs derived from pregnant and non-pregnant uterine samples. In human myometrial TCs from both non-pregnant and pregnant uterus, we evidenced by qRT-PCR the presence of genes encoding for voltage-gated calcium channels (Cav3.1, Ca3.2, Cav3.3, Cav2.1), estrogen receptors (ESR1, ESR2, GPR30), and nuclear receptor coactivator 3 (NCOA3). Pregnancy significantly upregulated Cav3.1 and downregulated Cav3.2, Cav3.3, ESR1, ESR2, and NCOA3, compared to the non-pregnant condition. Beta-estradiol treatment (24 h, 10, 100, 1000 nM) downregulated Cav3.2, Cav3.3, Cav1.2, ESR1, ESR2, GRP30, and NCOA3 in TCs from human pregnant uterine myometrium. We also confirmed the functional expression of voltage-gated calcium channels by patch-clamp recordings and calcium imaging analysis of TCs from pregnant human myometrium by perfusing with BAY K8644, which induced calcium influx through these channels. Additionally, we demonstrated that beta-estradiol (1000 nM) antagonized the effect of BAY K8644 (2.5 or 5 µM) in the same preparations. In conclusion, we evidenced the presence of voltage-gated calcium channels and estrogen receptors in TCs from non-pregnant and pregnant human uterine myometrium and their gene expression regulation by beta-estradiol in pregnant conditions. Further exploration of the calcium signaling in TCs and its modulation by estrogen hormones will contribute to the understanding of labor and pregnancy mechanisms and to the development of effective strategies to reduce the risk of premature birth.

Decreased expression of microRNA-29 family in leiomyoma contributes to increased major fibrillar collagen production.

PubMed

Marsh, Erica E; Steinberg, Marissa L; Parker, J Brandon; Wu, Ju; Chakravarti, Debabrata; Bulun, Serdar E

2016-09-01

To determine the expression and function of the microRNA-29 family (miRNA-29a, miRNA-29b, miRNA-29c) in human leiomyoma and myometrium. Basic science experimental design. Academic medical center. Women undergoing surgery for symptomatic uterine fibroids. Overexpression and knockdown of miRNA-29a, miRNA-29b, and miRNA-29c in primary leiomyoma and myometrial cells. [1] Expression of the miRNA-29 family members in vivo in leiomyoma versus myometrium; [2] Major fibrillar collagen (I, II, III) expression in leiomyoma and myometrial cells with manipulation of miRNA-29 species. Members of the miRNA-29 family (29a, 29b, 29c) are all down-regulated in leiomyoma versus myometrium in vivo. The expression of the miRNA-29 family can be successfully modulated in primary leiomyoma and myometrial cells. Overexpression of the miRNA-29 family in leiomyoma cells results in down-regulation of the major fibrillar collagens. Down-regulation of the miRNA-29 species in myometrium results in an increase in collagen type III deposition. The miRNA-29 family is consistently down-regulated in leiomyoma compared to matched myometrial tissue. This down-regulation contributes to the increased collagen seen in leiomyomas versus myometrium. When miRNA-29 members are overexpressed in leiomyoma cells, protein levels of all of the major fibrillar collagens decrease. The miRNA-29 members are potential therapeutic targets in this highly prevalent condition. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Expression and organization of basement membranes and focal adhesion proteins in pregnant myometrium is regulated by uterine stretch.

PubMed

Shynlova, Oksana; Chow, Michelle; Lye, Stephen J

2009-10-01

The mechanisms underlying the preparation of the uterus for labor are not fully understood. We have previously found a significant increase in the expression of messenger RNA (mRNAs) encoding extracellular basement membrane (BM) proteins of the smooth muscle cells (SMCs) in late pregnant rat myometrium. At term, the myometrium is stretched by growing fetuses and these mechanical signals are transmitted from extracellular matrix into SMCs through focal adhesions (FA). The aim of this study was to investigate the effect of gravidity on the expression and spatiotemporal distribution of major BM proteins, laminin-gamma2 and collagen IV, as well as typical FA constituents, vinculin and paxillin, in the myometrium during gestation and parturition, using a unilaterally pregnant rat model. We found that the expression of laminin-gamma2 and collagen IV proteins increased significantly with gestational age (P < .05) and was dependent on gravidity whereas vinculin and paxillin proteins were not affected. Near term, BM proteins from gravid horn myometrium demonstrated increased extracellular immunostaining and major rearrangement from sporadic protein distribution to organized, continuous, and regular structures surrounding the plasma membrane of each myocyte. Examination of FA proteins revealed that paxillin was translocated from the cytoplasm to the cell periphery, while vinculin was sequestered specifically to FAs. At labor, BM and FA proteins, organized in similar bead-like structures, were localized on opposing sides of SMC plasma membrane into 2 different compartments. We suggest that these stretch-induced changes facilitate formation of stable cell-matrix adhesions and provide the molecular basis for optimal force transduction during labor contractions.

Alterations in gap junction connexin43/connexin45 ratio mediate a transition from quiescence to excitation in a mathematical model of the myometrium

PubMed Central

Sheldon, Rachel E.; Mashayamombe, Chipo; Shi, Shao-Qing; Garfield, Robert E.; Shmygol, Anatoly; Blanks, Andrew M.; van den Berg, Hugo A.

2014-01-01

The smooth muscle cells of the uterus contract in unison during delivery. These cells achieve coordinated activity via electrical connections called gap junctions which consist of aggregated connexin proteins such as connexin43 and connexin45. The density of gap junctions governs the excitability of the myometrium (among other factors). An increase in gap junction density occurs immediately prior to parturition. We extend a mathematical model of the myometrium by incorporating the voltage-dependence of gap junctions that has been demonstrated in the experimental literature. Two functional subtypes exist, corresponding to systems with predominantly connexin43 and predominantly connexin45, respectively. Our simulation results indicate that the gap junction protein connexin45 acts as a negative modulator of uterine excitability, and hence, activity. A network with a higher proportion of connexin45 relative to connexin43 is unable to excite every cell. Connexin45 has much more rapid gating kinetics than connexin43 which we show limits the maximum duration of a local burst of activity. We propose that this effect regulates the degree of synchronous excitation attained during a contraction. Our results support the hypothesis that as labour approaches, connexin45 is downregulated to allow action potentials to spread more readily through the myometrium. PMID:25401181

[Resistance of the functional systems of the smooth muscle cells of isolated myometrium to long-term incubation in Ringer-Locke solution at 4 degrees C].

PubMed

Peshikov, V L; Tsirkin, V I; Burmistrova, T D; Bordunovskaia, V P

1977-09-01

Contractile effects of adrenaline, acethylcholine and hyperpotassium solution on the isolated myometrium strips (non-pregnent rats, and women; pregnant rabbits, cats, and women) are studied. The amplitudes of these contractile effects were seen decreasing if the strips were previously immersed in the Ringer-Lokk solution at 4 degrees C 5--9 days prior to observation.

The activity of thymidine phosphorylase in the uterine myomas and the myometrium in perimenopausal women.

PubMed

Miszczak-Zaborska, E; Greger, J; Wozniak, K; Kowalska-Koprek, U; Pajszczyk-Kieszkiewicz, T

1997-01-01

The activity of thymidine phosphorylase (dThdPase) in the myometrium and uterine myomas has been investigated in perimenopausal women. Differences in the activity of dThdPase have been found depending on the myoma type, menopause stage and the phase of the menstrual cycle in which the surgery was performed. The enzyme in the cytoplasmatic soluble fraction obtained at 50,000 x g was the most active in cellular leiomyomas of the follicular phase, the least in adenomyomas of the luteal phase of the menstrual cycle, whereas its activity in myometrium was always unchanged. Greater differences can be observed in the activity of dThdPase after a partial purification of the enzyme from myomas. It seems that the increase in dThdPase activity may point to its correlation with transient, premalignant tumor which may later transform into malignant forms.

Placenta accreta spectrum: pathophysiology and evidence-based anatomy for prenatal ultrasound imaging.

PubMed

Jauniaux, Eric; Collins, Sally; Burton, Graham J

2018-01-01

Placenta accreta spectrum is a complex obstetric complication associated with high maternal morbidity. It is a relatively new disorder of placentation, and is the consequence of damage to the endometrium-myometrial interface of the uterine wall. When first described 80 years ago, it mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Superficial damage leads primarily to an abnormally adherent placenta, and is diagnosed as the complete or partial absence of the decidua on histology. Today, the main cause of placenta accreta spectrum is uterine surgery and, in particular, uterine scar secondary to cesarean delivery. In the absence of endometrial reepithelialization of the scar area the trophoblast and villous tissue can invade deeply within the myometrium, including its circulation, and reach the surrounding pelvic organs. The cellular changes in the trophoblast observed in placenta accreta spectrum are probably secondary to the unusual myometrial environment in which it develops, and not a primary defect of trophoblast biology leading to excessive invasion of the myometrium. Placenta accreta spectrum was separated by pathologists into 3 categories: placenta creta when the villi simply adhere to the myometrium, placenta increta when the villi invade the myometrium, and placenta percreta where the villi invade the full thickness of the myometrium. Several prenatal ultrasound signs of placenta accreta spectrum were reported over the last 35 years, principally the disappearance of the normal uteroplacental interface (clear zone), extreme thinning of the underlying myometrium, and vascular changes within the placenta (lacunae) and placental bed (hypervascularity). The pathophysiological basis of these signs is due to permanent damage of the uterine wall as far as the serosa, with placental tissue reaching the deep uterine circulation. Adherent and invasive placentation may coexist in the same placental bed and evolve with advancing gestation. This may explain why no single, or set combination of, ultrasound sign(s) was found to be specific for the depth of abnormal placentation, and accurate for the differential diagnosis between adherent and invasive placentation. Correlation of pathological and clinical findings with prenatal imaging is essential to improve screening, diagnosis, and management of placenta accreta spectrum, and standardized protocols need to be developed. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene Expression Profiling of Multiple Leiomyomata Uteri and Matched Normal Tissue from a Single Patient

PubMed Central

Dimitrova, Irina K.; Richer, Jennifer K.; Rudolph, Michael C.; Spoelstra, Nicole S.; Reno, Elaine M.; Medina, Theresa M.; Bradford, Andrew P.

2009-01-01

Objective To identify differentially expressed genes between fibroid and adjacent normal myometrium in an identical hormonal and genetic background. Design Array analysis of 3 leiomyomata and matched adjacent normal myometrium in a single patient. Setting University of Colorado Hospital. Patient(s) A single female undergoing medically indicated hysterectomy for symptomatic fibroids. Interventions(s) mRNA isolation and microarray analysis, reverse-transcriptase polymerase chain reaction, western blotting and immunohistochemistry. Main Outcome Measure(s) Changes in mRNA and protein levels in leiomyomata and matched normal myometrium. Result(s) Expression of 197 genes was increased and 619 decreased, significantly by at least 2 fold, in leiomyomata relative to normal myometrium. Expression profiles between tumors were similar and normal myometrial samples showed minimal variation. Changes in, and variation of, expression of selected genes were confirmed in additional normal and leiomyoma samples from multiple patients. Conclusion(s) Analysis of multiple tumors from a single patient confirmed changes in expression of genes described in previous, apparently disparate, studies and identified novel targets. Gene expression profiles in leiomyomata are consistent with increased activation of mitogenic pathways and inhibition of apoptosis. Down-regulation of genes implicated in invasion and metastasis, of cancers, was observed in fibroids. This expression pattern may underlie the benign nature of uterine leiomyomata and may aid in the differential diagnosis of leiomyosarcoma. PMID:18672237

Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications

PubMed Central

Ciarmela, Pasquapina; Islam, Md. Soriful; Reis, Fernando M.; Gray, Peter C.; Bloise, Enrrico; Petraglia, Felice; Vale, Wylie; Castellucci, Mario

2011-01-01

BACKGROUND Growth factors are proteins secreted by a number of cell types that are capable of modulating cellular growth, proliferation and cellular differentiation. It is well accepted that uterine cellular events such as proliferation and differentiation are regulated by sex steroids and their actions in target tissues are mediated by local production of growth factors acting through paracrine and/or autocrine mechanisms. Myometrial mass is ultimately modified in pregnancy as well as in tumour conditions such as leiomyoma and leiomyosarcoma. Leiomyomas, also known as fibroids, are benign tumours of the uterus, considered to be one of the most frequent causes of infertility in reproductive years in women. METHODS For this review, we searched the database MEDLINE and Google Scholar for articles with content related to growth factors acting on myometrium; the findings are hereby reviewed and discussed. RESULTS Different growth factors such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and TGF-β perform actions in myometrium and in leiomyomas. In addition to these growth factors, activin and myostatin have been recently identified in myometrium and leiomyoma. CONCLUSIONS Growth factors play an important role in the mechanisms involved in myometrial patho-physiology. PMID:21788281

Near-infrared optical properties of ex vivo human uterus determined by the Monte Carlo inversion technique

NASA Astrophysics Data System (ADS)

Ripley, P. M.; Laufer, J. G.; Gordon, A. D.; Connell, R. J.; Bown, S. G.

1999-10-01

The optical properties, absorption (µa) and reduced scattering coefficient (µs´), of ex vivo human myometrium and leiomyoma (fibroid) have been determined by the Monte Carlo inversion technique over the wavelength range 600 - 1000 nm. This region is currently of interest for new, minimal-access, surgical laser procedures such as photodynamic therapy (PDT) for abnormalities of the uterus, and interstitial laser photocoagulation (ILP) for the thermal ablation of fibroids. In the region 630 - 675 nm (corresponding to PDT), the optical coefficients of myometrium are µa = 0.041±0.012 mm-1 and µs´ = 1.37±0.19 mm-1. For the wavelength range 800-1000 nm (associated with infrared lasers for ILP), the optical coefficients of fibroid were found to be µa = 0.020±0.003 mm-1 and µs´ = 0.56±0.03 mm-1. Overall, the optical properties of fibroid were found to be lower than myometrium, and this was attributed to the differences in both anatomy and vascularity. The results show that PDT for ablation of the uterine endometrium is most unlikely to affect any tissues beyond the myometrium, and that the region around 800 nm is the most effective for ablation of fibroids using ILP as the penetration depth of light is greatest at this wavelength.

Distribution, expression and functional effects of small conductance Ca-activated potassium (SK) channels in rat myometrium.

PubMed

Noble, Karen; Floyd, Rachel; Shmygol, Andre; Shmygol, Anatoly; Mobasheri, A; Wray, Susan

2010-01-01

Calcium-activated potassium channels are important in a variety of smooth muscles, contributing to excitability and contractility. In the myometrium previous work has focussed on the large conductance channels (BK), and the role of small conductance channels (SK) has received scant attention, despite the finding that over-expression of an SK channel isoform (SK3) results in uterine dysfunction and delayed parturition. This study therefore characterises the expression of the three SK channel isoforms (SK1-3) in rat myometrium throughout pregnancy and investigates their effect on cytosolic [Ca] and force and compares this with that of BK channels. Consistent expression of all SK isoform transcripts and clear immunostaining of SK1-3 was found. Inhibition of SK1-3 channels (apamin, scyllatoxin) significantly inhibited outward current, caused membrane depolarisation and elicited action potentials in previously quiescent cells. Apamin or scyllatoxin increased the amplitude of [Ca] and force in spontaneously contracting myometrial strips throughout gestation. The functional effect of SK inhibition was larger than that of BK channel inhibition. Thus we show for the first time that SK1-3 channels are expressed and translated throughout pregnancy and contribute to outward current, regulate membrane potential and hence Ca signals in pregnant rat myometrium. They contribute more to quiescence that BK channels. 2009 Elsevier Ltd. All rights reserved.

ANTHROPOMORPHIC PHANTOMS FOR ASSESSMENT OF STRAIN IMAGING METHODS INVOLVING SALINE-INFUSED SONOHYSTEROGRAPHY

PubMed Central

Hobson, Maritza A.; Madsen, Ernest L.; Frank, Gary R.; Jiang, Jingfeng; Shi, Hairong; Hall, Timothy J.; Varghese, Tomy

2008-01-01

Two anthropomorphic uterine phantoms were developed which allow assessment and comparison of strain imaging systems adapted for use with saline-infused sonohysterography (SIS). Tissue-mimicking (TM) materials consist of dispersions of safflower oil in gelatin. TM fibroids are stiffer than the TM myometrium/cervix and TM polyps are softer. The first uterine phantom has 3-mm diameter TM fibroids randomly distributed in TM myometrium. The second uterine phantom has a 5-mm and an 8-mm spherical TM fibroid in addition to a 5-mm spherical and a 12.5-mm long (medicine-capsule-shaped) TM endometrial polyp protruding into the endometrial cavity; also, a 10-mm spherical TM fibroid projects from the serosal surface. Strain images using the first phantom show the stiffer 3-mm TM fibroids in the myometrium. Results from the second uterine phantom show that, as expected, parts of inclusions projecting into the uterine cavity will appear very stiff, whether they are stiff or soft. Results from both phantoms show that even though there is a five-fold difference in the Young’s moduli values, there is not a significant difference in the strain in the transition from the TM myometrium to the TM fat. These phantoms allow for realistic comparison and evolution of SIS strain imaging techniques and can aid clinical personnel to develop skills for SIS strain imaging. PMID:18514999

A novel role for GSK3 in the regulation of the processes of human labour.

PubMed

Lim, Ratana; Lappas, Martha

2015-02-01

Preterm birth remains the largest single cause of neonatal death and morbidity. Infection and/or inflammation are strongly associated with preterm delivery. Glycogen synthase kinase 3 (GSK3) is known to be a crucial mediator of inflammation homeostasis. The aims of this study were to determine the effect of spontaneous human labour in foetal membranes and myometrium on GSK3α/β expression, and the effect of inhibition of GSK3α/β on pro-labour mediators in foetal membranes and myometrium stimulated with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines. Term and preterm labour in foetal membranes was associated with significantly decreased serine phosphorylated GSK3α and β expression, and thus increased GSK3 activity. There was no effect of term labour on serine phosphorylated GSK3β expression in myometrium. The specific GSK3α/β inhibitor CHIR99021 significantly decreased lipopolysaccharide (ligand to TLR4)-stimulated pro-inflammatory cytokine gene expression and release; COX2 gene expression and prostaglandin release; and MMP9 gene expression and pro MMP9 release in foetal membranes and/or myometrium. CHIR99021 also decreased FSL1 (TLR2 ligand) and flagellin (TLR5 ligand)-induced pro-inflammatory cytokine gene expression and release and COX2 mRNA expression and prostaglandin release. GSK3β siRNA knockdown in primary myometrial cells was associated with a significant decrease in IL1β and TNFα-induced pro-inflammatory cytokine and prostaglandin release. In conclusion, GSK3α/β activity is increased in foetal membranes after term and preterm labour. Pharmacological blockade of the kinase GSK3 markedly reduced pro-inflammatory and pro-labour mediators in human foetal membranes and myometrium, providing a possible therapeutics for the management of preterm labour. © 2015 Society for Reproduction and Fertility.

A Novel Role for SIRT3 in Regulating Mediators Involved in the Terminal Pathways of Human Labor and Delivery.

PubMed

Lim, Ratana; Barker, Gillian; Menon, Ramkumar; Lappas, Martha

2016-11-01

Preterm birth remains the major cause of neonatal mortality and morbidity, mediated largely by an inflammatory process. The sirtuin (SIRT) family of cellular regulators has been implicated as key inhibitors of inflammation. We have previously reported a role for SIRT1, SIRT2, and SIRT6 in regulating inflammation-induced prolabor mediators. In this study, we determined the effect of term labor and pro-inflammatory cytokines on SIRT3, SIRT4, SIRT5, and SIRT7 expression in human myometrium. Functional studies were also used to investigate the effect of small interfering RNA (siRNA) knockdown of SIRTs in regulating inflammation-induced prolabor mediators. Western blot analysis and qRT-PCR were used to determine SIRT3, SIRT4, SIRT5, and SIRT7 mRNA and protein expression in human myometrium. Small interfering RNA knockdown of SIRT3 in myometrial primary cells determined its role in response to inflammatory stimuli IL1B and TNF. SIRT3 mRNA and protein expression levels were significantly lower in term laboring myometrium compared with term nonlaboring myometrium. There was no effect of labor on SIRT4, SIRT5 or SIRT7 protein expression. The pro-inflammatory cytokines IL1B and TNF significantly decreased levels of SIRT3 mRNA and protein expression. SIRT3 knockdown by siRNA significantly augmented IL1B- and TNF-stimulated IL6, CXCL8, and CCL2 mRNA expression and release; PTGS2 mRNA expression and subsequent PGF 2alpha release; the mRNA expression and secretion of the adhesion molecule ICAM1 and the extracellular matrix remodeling enzyme MMP9; and nuclear factor kappa B1 (NFkappaB1) transcriptional activity. In human myometrium, SIRT3 expression decreases with term labor and regulates the mediators involved in the terminal effector pathways of human labor and delivery through the NFkappaB1 pathway. © 2016 by the Society for the Study of Reproduction, Inc.

Effects of ovarian steroids upon responses mediated by adrenoceptors in separated layers of the myometrium and in the costo-uterine muscle of the guinea-pig

PubMed Central

Hartley, Margaret L.; Pennefather, Jocelyn N.; Story, Margot E.

1983-01-01

1 This study describes the effects of ovarian steroid hormones upon the responses to adrenoceptor agonists of isolated myometrium, separated into its longitudinal and circular layers, and of costo-uterine muscle from guinea-pigs. The preparations were field-stimulated at 100 s intervals, and the adrenoceptor agonists phenylephrine and isoprenaline produced enhancement or inhibition of the evoked contractions. 2 Isoprenaline produced propranolol-sensitive inhibitory effects in longitudinal and circular myometrium and costo-uterine muscle preparations from animals from all experimental groups: i.e. from nonsteroid-treated animals (ovariectomized and intact); intact animals treated with either oestrogen or progesterone alone; ovariectomized animals treated with oestrogen; ovariectomized and intact animals treated with progesterone following oestrogen priming; and from animals 1-4 days post-partum. Longitudinal myometrial preparations from progesterone-treated oestrogen-primed and from post-partum animals were most sensitive to this agonist. 3 Phenylephrine produced phentolamine-sensitive excitatory effects in circular myometrial and costo-uterine muscle preparations from animals from all the experimental groups. In contrast, propranolol-sensitive inhibitory responses to phenylephrine occurred in longitudinal myometrial preparations taken from animals treated with progesterone following oestrogen priming, and from post-partum animals. Longitudinal myometrium from animals from the remaining experimental groups exhibited phentolamine-sensitive excitatory responses to phenylephrine. 4 The basis for the selective effect upon the longitudinal myometrium of exposure to progesterone following a period of oestrogen priming, is discussed. The results described are consistent with the possibility that in the longitudinal layer of guinea-pig uterus exposed to progesterone following oestrogen priming there is an increase in the proportion of β-adrenoceptors in this layer. This increase may reduce the likelihood of contractions arising via direct stimulation of α-adrenoceptors in this layer in response to sympathetic activation during pregnancy. PMID:6871558

Immunohistochemical localization of constitutive and inducible cyclo-oxygenases in rat uterus during the oestrous cycle and pregnancy.

PubMed

Fang, L; Chatterjee, S; Dong, Y L; Gangula, P R; Yallampalli, C

1998-06-01

The uterus is a rich source of eicosanoids synthesized from arachidonic acid metabolism through the cyclo-oxygenase pathway. Two isoforms of cyclo-oxygenase, constitutive (COX-I) and inducible (COX-II) enzyme, have been reported. In the present study, we have immunohistochemically mapped the distribution of both COX-I and COX-II during various physiological states of the rat uterus. Uterine tissue was collected from female rats (a) during different stages of the oestrous cycle, (b) on days 1, 4, 8 and 18 of gestation, (c) after spontaneous delivery and (d) post partum, and fixed in Bouin's fixative. After paraffin wax embedding, 5-microm-thick sections were immunohistochemically stained by the ABC technique. Observation of the stained sections under the light microscope revealed that, in non-pregnant rat uterus, both COX-I and COX-II were abundantly expressed in the endometrium, with minimal staining observed in the myometrium. Staining was more prominent in epithelial cells than in stromal cells. The intensity of staining in epithelial cells was highest at pro-oestrus and oestrus and lowest at dioestrus. In pregnant rats, although the expression of both COX-I and COX-II was localized primarily to the endometrium with very little staining in the myometrium on day 1 of gestation, both of these enzymes were also apparent in myometrial cells by day 4 of gestation. The staining intensity of endometrial and myometrial cells increased further with the progression of gestation, being maximal at the time of spontaneous delivery. During the post-partum period, however, the staining intensity for both of the enzymes in endometrium and myometrium was decreased. Thus, our studies show that the expression of cyclo-oxygenases in various uterine cells vary with the oestrous cycle and with pregnancy. Furthermore, prominent increases in the expression of cyclo-oxygenases in the myometrium during pregnancy and parturition imply that the cyclo-oxygenase system in the myometrium may play a major role in modulating uterine contractility during pregnancy and labour.

[Morphological features of the myometrium in connective tissue dysplasia in women with uterine inertia].

PubMed

Konovalov, P V; Mitrofanova, L B; Gorshkov, A N; Ovsyannikov, F A

2015-01-01

to reveal the morphological features of the lower uterine segment myometrium in connective tissue dysplasia (CTD) in women with uterine inertia. Histological, immunohistochemical (with antibodies against collagen types I and III, matrix metalloproteinases 1 and 9 (MMR-1, MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), fibronectin; fibulin-5, connexin-43), electron microscopic, and electron immunocytochemical studies with morphometry of myometrial fragments from 15 parturient women with CTD and uterine inertia (a study group) and those from 10 women without CTD (a control group). The myometrium in CTD exhibited the decreased expression of connextin-43, fibulin-5, TIMP-1, collagens types I and III with collagen type III predominance and the unchanged levels of fibronectin and MMP-1 and MMP-9. Electron microscopy and immunocytochemistry showed fewer intercellular contacts and the dramatically lower expression of connexin-43 than in the control. A set of found myometrial changes in women with uterine inertia is a manifestation of CTD.

Transcriptome interrogation of human myometrium identifies differentially expressed sense-antisense pairs of protein-coding and long non-coding RNA genes in spontaneous labor at term.

PubMed

Romero, Roberto; Tarca, Adi L; Chaemsaithong, Piya; Miranda, Jezid; Chaiworapongsa, Tinnakorn; Jia, Hui; Hassan, Sonia S; Kalita, Cynthia A; Cai, Juan; Yeo, Lami; Lipovich, Leonard

2014-09-01

To identify differentially expressed long non-coding RNA (lncRNA) genes in human myometrium in women with spontaneous labor at term. Myometrium was obtained from women undergoing cesarean deliveries who were not in labor (n = 19) and women in spontaneous labor at term (n = 20). RNA was extracted and profiled using an Illumina® microarray platform. We have used computational approaches to bound the extent of long non-coding RNA representation on this platform, and to identify co-differentially expressed and correlated pairs of long non-coding RNA genes and protein-coding genes sharing the same genomic loci. We identified co-differential expression and correlation at two genomic loci that contain coding-lncRNA gene pairs: SOCS2-AK054607 and LMCD1-NR_024065 in women in spontaneous labor at term. This co-differential expression and correlation was validated by qRT-PCR, an experimental method completely independent of the microarray analysis. Intriguingly, one of the two lncRNA genes differentially expressed in term labor had a key genomic structure element, a splice site, that lacked evolutionary conservation beyond primates. We provide, for the first time, evidence for coordinated differential expression and correlation of cis-encoded antisense lncRNAs and protein-coding genes with known as well as novel roles in pregnancy in the myometrium of women in spontaneous labor at term.

A Dominant Loss-of-Function GJA1 (Cx43) Mutant Impairs Parturition in the Mouse1

PubMed Central

Tong, Dan; Lu, Xuerong; Wang, Hong-Xing; Plante, Isabelle; Lui, Ed; Laird, Dale W.; Bai, Donglin; Kidder, Gerald M.

2009-01-01

Expression of GJA1 (commonly known as connexin43 or Cx43), a major myometrial gap junction protein, is upregulated before the onset of delivery, suggesting an essential role for Cx43-mediated gap junctional intercellular communication (GJIC) in normal uterine contraction during parturition. To determine how a disease-linked Cx43 mutation affects myometrial function, we studied a mutant mouse model carrying an autosomal dominant mutation (Gja1Jrt) in the gene encoding Cx43 that displays features of the human genetic disease oculodentodigital dysplasia. We found that Cx43 level, specifically the phosphorylated species of the protein, is significantly reduced in the myometrium of the mutant mice (Gja1Jrt/+), as revealed by Western blotting and immunostaining. Patch-clamp electrophysiological measurements demonstrated that coupling between myometrial smooth muscle cells is reduced to <15% of wild-type, indicating that the mutant protein acts dominantly on its wild-type counterpart. The phosphorylated species of Cx43 in the mutant myometrium failed to increase prior to parturition as well as in response to exogenous estrogen. Correspondingly, in vitro experiments with uterine strips revealed weaker contraction of the mutant myometrium and reduced responsiveness to oxytocin, providing an explanation for the prolonged gestation and presence of suffocated fetuses in the uteri that were observed in some of the mutant mice. We conclude that the Gja1Jrt mutation has a dominant-negative effect on Cx43 function in the myometrium, severely reducing GJIC, leading to impaired parturition. PMID:19176884

Tachykinins and tachykinin receptors in human uterus

PubMed Central

Patak, Eva; Luz Candenas, M; Pennefather, Jocelyn N; Ziccone, Sebastian; Lilley, Alison; Martín, Julio D; Flores, Carlos; Mantecón, Antonio G; Story, Margot E; Pinto, Francisco M

2003-01-01

Studies were undertaken to determine the nature of the receptors mediating contractile effects of tachykinins in the uteri of nonpregnant women, and to analyse the expression of preprotachykinins (PPT), tachykinin receptors and the cell-surface peptidase, neprilysin (NEP), in the myometrium from pregnant and nonpregnant women. The neurokinin B (NKB) precursor PPT-B was expressed in higher levels in the myometrium from nonpregnant than from pregnant women. Faint expression of PPT-A mRNA was detectable in the myometrium from nonpregnant but not pregnant women. PPT-C, the gene encoding the novel tachykinin peptide hemokinin-1 (HK-1), was present in trace amounts in the uteri from both pregnant and nonpregnant women. Tachykinin NK2 receptors were more strongly expressed in tissues from nonpregnant than from pregnant women. NK1 receptor mRNA was present in low levels in tissues from both pregnant and nonpregnant women. A low abundance transcript corresponding to the NK3 receptor was present only in tissues from nonpregnant women. The mRNA expression of the tachykinin-degrading enzyme NEP was lower in tissues from nonpregnant than from pregnant women. Substance P (SP), neurokinin A (NKA) and NKB, in the presence of the peptidase inhibitors thiorphan, captopril and bestatin, produced contractions of myometrium from nonpregnant women. The order of potency was NKA≫SP≥NKB. The potency of NKA was unchanged in the absence of peptidase inhibitors. The tachykinin NK2 receptor-selective agonist [Lys5MeLeu9Nle10]NKA(4–l0) was approximately equipotent with NKA, but the tachykinin NK1 and NK3 receptor-selective agonists [Sar9Met(O2)11]SP and [MePhe7]NKB were ineffective in the myometrium from nonpregnant women. The uterotonic effects of [Lys5MeLeu9Nle10]NKA(4–10) were antagonized by the tachykinin NK2 receptor-selective antagonist SR48968. Neither atropine, nor phentolamine nor tetrodotoxin affected responses to [Lys5MeLeu9Nle10]NKA(4–10). These data are consistent with a role of tachykinins in the regulation of human uterine function, and reinforce the importance of NK2 receptors in the regulation of myometrial contraction. PMID:12788812

Tachykinins and tachykinin receptors in human uterus.

PubMed

Patak, Eva; Candenas, M Luz; Pennefather, Jocelyn N; Ziccone, Sebastian; Lilley, Alison; Martín, Julio D; Flores, Carlos; Mantecón, Antonio G; Story, Margot E; Pinto, Francisco M

2003-06-01

(1) Studies were undertaken to determine the nature of the receptors mediating contractile effects of tachykinins in the uteri of nonpregnant women, and to analyse the expression of preprotachykinins (PPT), tachykinin receptors and the cell-surface peptidase, neprilysin (NEP), in the myometrium from pregnant and nonpregnant women. (2) The neurokinin B (NKB) precursor PPT-B was expressed in higher levels in the myometrium from nonpregnant than from pregnant women. Faint expression of PPT-A mRNA was detectable in the myometrium from nonpregnant but not pregnant women. PPT-C, the gene encoding the novel tachykinin peptide hemokinin-1 (HK-1), was present in trace amounts in the uteri from both pregnant and nonpregnant women. (3) Tachykinin NK(2) receptors were more strongly expressed in tissues from nonpregnant than from pregnant women. NK(1) receptor mRNA was present in low levels in tissues from both pregnant and nonpregnant women. A low abundance transcript corresponding to the NK(3) receptor was present only in tissues from nonpregnant women. (4) The mRNA expression of the tachykinin-degrading enzyme NEP was lower in tissues from nonpregnant than from pregnant women. (5) Substance P (SP), neurokinin A (NKA) and NKB, in the presence of the peptidase inhibitors thiorphan, captopril and bestatin, produced contractions of myometrium from nonpregnant women. The order of potency was NKA>SP>/=NKB. The potency of NKA was unchanged in the absence of peptidase inhibitors. (6) The tachykinin NK(2) receptor-selective agonist [Lys(5)MeLeu(9)Nle(10)]NKA(4-l0) was approximately equipotent with NKA, but the tachykinin NK(1) and NK(3) receptor-selective agonists [Sar(9)Met(O(2))(11)]SP and [MePhe(7)]NKB were ineffective in the myometrium from nonpregnant women. (7) The uterotonic effects of [Lys(5)MeLeu(9)Nle(10)]NKA(4-10) were antagonized by the tachykinin NK(2) receptor-selective antagonist SR48968. Neither atropine, nor phentolamine nor tetrodotoxin affected responses to [Lys(5)MeLeu(9)Nle(10)]NKA(4-10). (8) These data are consistent with a role of tachykinins in the regulation of human uterine function, and reinforce the importance of NK(2) receptors in the regulation of myometrial contraction.

Long-term type 1 diabetes alters the deposition of collagens and proteoglycans in the early pregnant myometrium of mice.

PubMed

Favaro, Rodolfo R; Raspantini, Priscila R; Salgado, Renato M; Fortes, Zuleica B; Zorn, Telma M T

2015-04-01

We have previously shown that long-term type 1 diabetes affects the structural organization, contractile apparatus and extracellular matrix (ECM) of the myometrium during early pregnancy in mice. This study aimed to identify which myometrial ECM components are affected by diabetes, including fibril-forming collagen types I, III and V, as well as proteoglycans, decorin, lumican, fibromodulin and biglycan. Alloxan-induced type 1 diabetic female mice were divided into subgroups D1 and D2, formed by females that bred 90-100 and 100-110 days after diabetes induction, respectively. The deposition of ECM components in the myometrium was evaluated by immunohistochemistry/immunofluorescence. The subgroup D1 showed decreased deposition of collagen types I and III in the external muscle layer (EML) and decreased collagen types III and V in the internal muscle layer (IML). Collagen types I and III were decreased in both muscle layers of the subgroup D2. In addition, increased deposition of collagen types I and III and lumican as well as decreased collagen type V were observed in the connective tissue between muscle layers of D2. Lumican was decreased in the EML of the subgroups D1 and D2. Fibromodulin was repressed in the IML and EML of both D1 and D2. In contrast, decorin deposition diminished only in muscle layers of D2. No changes were noticed for biglycan. Subgroups D1 and D2 showed distinct stages of progression of diabetic complications in the myometrium, characterized by both common and specific sets of changes in the ECM composition.

Uterine Perforation with Intra-Abdominal Clostridium perfringens Gas Gangrene: A Rare and Fatal Infection.

PubMed

Kashan, David; Muthu, Nagarajan; Chaucer, Benjamin; Davalos, Fidencio; Bernstein, Michael; Chendrasekhar, Akella

2016-06-01

Background: Clostridium perfringens gas gangrene is an extremely rare and fatal infection. Necrosis of the myometrium is rarely seen and has only been recorded in 18 cases to date. Of these 18 reported cases, only 5 have occurred in nonpregnant women. This article presents the 6th case of myometrium necrosis from C. perfringens. Case: A 72-year-old woman, gravida 2, para 2, presented with abdominal pain and vaginal bleeding. After examinations, laboratory testing, and several surgical interventions, she was found to have C. perfringens infection and advanced high-grade serous adenocarcinoma of the endometrium with >50% invasion into the myometrium. Results: Despite the surgical interventions and use of several antibiotics, this patient did not improve. She was weaned from treatment per her advance directive and died after weaning. Conclusions: Awareness of the many etiologies for peritonitis is of great importance when a fatal infection may be the cause of the condition. Correct diagnosis and proper treatment is essential for the survival of patients infected with C. perfringens . (J GYNECOL SURG 32:182).

Proangiogenic features in chronic pelvic pain caused by adenomyosis.

PubMed

Orazov, M R; Nosenko, E N; Radzinsky, V E; Khamoshina, M B; Lebedeva, M G; Sounov, M A

2016-10-01

The study of peculiarities of expression of vascular endothelial growth factor (VEGF) in the tissues of the endometrium and myometrium in patients with adenomyosis, associated with chronic pelvic pain syndrome. Uterus macro-preparations obtained after hysterectomy in 60 patients with pelvic pain on a background of diffuse adenomyosis II-III degree were used for morphological examination, and macro-preparations received from 30 women with adenomyosis without pain syndrome. The diagnosis of adenomyosis was confirmed by sonography and magnetic resonance imaging. The expression of VEGF in tissues of the endometrium and myometrium was determined using the immune-histochemical method. The significance of differences of the compared parameters was determined using the criterion of Wilcoxon and Mann-Whitney. The differences were considered statistically significant when p < 0.05. It was found that a higher expression of VEGF is characteristic for patients with pelvic pain associated with adenomyosis, compared to women with adenomyosis and abnormal uterine bleeding, both in epithelial cells of ectopic endometrium (14.7 ± 1.6% against 10.7 ± 1.6%, p < 0.01), and in smooth myocytes of the myometrium (12.6 ± 1.4% against 9.6 ± 1.2%, p < 0.01) and in the stromal cells of the myometrium (10.1 ± 1.9% versus 7.4 ± 1.8%, p < 0.01). An increased expression of VEGF in the tissues of the uterus is one of the most important pathogenetic mechanisms of algogenesis with adenomyosis, associated syndrome of chronic pelvic pain, compared to the silent form of the disease.

Basic study of healing of injuries to the myometrium and amniotic membrane using photocrosslinkable chitosan.

PubMed

Suzuki, Keitaro; Shinya, Masaru; Kitagawa, Michihiro

2006-04-01

We performed in vivo and in vitro adhesion experiments on the use of photocrosslinkable chitosan (PC) for healing of the myometrium and the amniotic membrane to test its usefulness in the perinatal field. To determine the adhesion conditions of PC in the healing of the myometrium and amniotic membrane, we applied two concentrations (30 and 50 mg/mL) of PC to the postpartum amniotic membrane, and radiated it with ultraviolet (UV) light for 10, 20, 30 or 60 s. Next, we created incisions of three sizes (pinhole, 5 mm and 10 mm), and performed PC adhesion followed by pressure application experiments. Subsequently, we laparotomized 12-day-pregnant rats under anesthesia, created a 5-mm incision, applied PC and closed the abdomen. We removed the uterus at 20 days of pregnancy, and histologically examined the site of PC application. The optimal adhesion conditions of PC were 50 mg/mL, and the optimal time of UV irradiation was 30 s or longer. In pressure application experiments, the bonding strength of PC was so high that even 10-mm incisions withstood a mean pressure of 92 mmH2O. The bonding strength of PC was significantly higher than that of fibrin glue that was tested in parallel. Histological examination of the rat myometrium showed a mild foreign body reaction with no inflammatory findings, confirming the usefulness of PC. PC is a wound-healing drug, an improvement on the naturally occurring polysaccharide chitosan, and is safer and has a higher bonding strength than biological adhesives including fibrin, making it promising for fetal surgical and perinatal applications.

History of adenomyosis.

PubMed

Benagiano, Giuseppe; Brosens, Ivo

2006-08-01

Although the claim has been made that there are early descriptions of what today we call endometriosis and adenomyosis in theses presented in Europe in the late 17(th) and during the 18(th) centuries, the first description of the condition initially named 'adenomyoma' is that provided in 1860 by the German pathologist Carl von Rokitansky, who found endometrial glands in the myometrium and designated this finding as 'cystosarcoma adenoids uterinum'. Over the following 50 years 'adenomyoma' (and endometriosis) were considered pathologies separate from the so-called 'haemorrhagic ovarian cysts', and it was not until 1921 that this condition was recognized to be of endometriotic origin. The first systematic description of what is today known as adenomyosis was the work of Thomas Stephen Cullen who, at the turn of the 19(th) century, fully researched the 'mucosal invasion' already observed by a number of investigators in several parts of the lower abdominal cavity. Cullen clearly identified the epithelial tissue invasion as being made of 'uterine mucosa' and defined the mechanism through which the mucosa invades the underlying tissue. In 1925, 2 years before Sampson created the term 'endometriosis', Frankl created a name for the mucosal invasion of the myometrium and clearly described its anatomical picture; he called it 'adenomyosis uteri' and explained that 'I have chosen the name of adenomyosis, which does not suggest any inflammatory genesis as do terms like adenometritis, adenomyositis, adenomyometritis, still employed'. The current definition of adenomyosis was finally provided in 1972 by Bird who stated: 'Adenomyosis may be defined as the benign invasion of endometrium into the myometrium, producing a diffusely enlarged uterus which microscopically exhibits ectopic non-neoplastic, endometrial glands and stroma surrounded by the hypertrophic and hyperplastic myometrium'.

Endometrial expression of the insulin-like growth factor system during uterine involution in the postpartum dairy cow.

PubMed

Llewellyn, S; Fitzpatrick, R; Kenny, D A; Patton, J; Wathes, D C

2008-05-01

Rapid uterine involution in the postpartum period of dairy cows is important to achieve a short interval to conception. Expression patterns for members of the insulin-like growth factor (IGF) family were determined by in situ hybridisation at day 14+/-0.4 postpartum (n=12 cows) to investigate a potential role for IGFs in modulating uterine involution. Expression in each uterine tissue region was measured as optical density units and data were analysed according to region and horn. IGF-I mRNA was localized to the sub-epithelial stroma (SES) of inter-caruncular and caruncular endometrium. Both IGF-II and IGF-1R expression was detected in the deep endometrial stroma (DES), the caruncular stroma and myometrium. IGFBP-2, IGFBP-4 and IGFBP-6 mRNAs were all localised to the SES of inter-caruncular and caruncular uterine tissue, and in the DES and caruncular stroma, with IGFBP-4 mRNA additionally expressed in myometrium. IGFBP-3 mRNA was only detectable in luminal epithelium. IGFBP-5 mRNA was found in myometrium, inter-caruncular and caruncular SES and caruncular stroma. These data support a role for IGF-I and IGF-II in the extensive tissue remodelling and repair which the postpartum uterus undergoes to return to its non-pregnant state. The differential expression of binding proteins between tissues (IGFBP-3 in epithelium, IGFBP-2, -4, -5 and -6 in stroma and IGFBP-4 and -5 in myometrium) suggest tight control of IGF activity within each compartment. Differential expression of many members of the IGF family between the significantly larger previously gravid horn and the previously non-gravid horn may relate to differences in their rate of tissue remodelling.

Endometrial expression of the insulin-like growth factor system during uterine involution in the postpartum dairy cow☆

PubMed Central

Llewellyn, S.; Fitzpatrick, R.; Kenny, D.A.; Patton, J.; Wathes, D.C.

2008-01-01

Rapid uterine involution in the postpartum period of dairy cows is important to achieve a short interval to conception. Expression patterns for members of the insulin-like growth factor (IGF) family were determined by in situ hybridisation at day 14 ± 0.4 postpartum (n = 12 cows) to investigate a potential role for IGFs in modulating uterine involution. Expression in each uterine tissue region was measured as optical density units and data were analysed according to region and horn. IGF-I mRNA was localized to the sub-epithelial stroma (SES) of inter-caruncular and caruncular endometrium. Both IGF-II and IGF-1R expression was detected in the deep endometrial stroma (DES), the caruncular stroma and myometrium. IGFBP-2, IGFBP-4 and IGFBP-6 mRNAs were all localised to the SES of inter-caruncular and caruncular uterine tissue, and in the DES and caruncular stroma, with IGFBP-4 mRNA additionally expressed in myometrium. IGFBP-3 mRNA was only detectable in luminal epithelium. IGFBP-5 mRNA was found in myometrium, inter-caruncular and caruncular SES and caruncular stroma. These data support a role for IGF-I and IGF-II in the extensive tissue remodelling and repair which the postpartum uterus undergoes to return to its non-pregnant state. The differential expression of binding proteins between tissues (IGFBP-3 in epithelium, IGFBP-2, -4, -5 and -6 in stroma and IGFBP-4 and -5 in myometrium) suggest tight control of IGF activity within each compartment. Differential expression of many members of the IGF family between the significantly larger previously gravid horn and the previously non-gravid horn may relate to differences in their rate of tissue remodelling. PMID:18258405

KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium.

PubMed

Lappas, Martha

2015-05-01

The transcription factor Kruppel-like factor 5 (KLF5) has been shown to associate with nuclear factor kappa B (NFκB) to regulate genes involved in inflammation. However, there are no studies on the expression and regulation of KLF5 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour on KLF5 expression in both foetal membranes and myometrium; ii) the pro-inflammatory cytokine interleukin 1 beta (IL1β), bacterial product flagellin and the viral dsRNA analogue poly(I:C) on KLF5 expression and iii) KLF5 knockdown by siRNA in human myometrial primary cells on pro-inflammatory and pro-labour mediators. In foetal membranes, there was no effect of term or preterm labour on KLF5 expression. In myometrium, the term labour was associated with an increase in nuclear KLF5 protein expression. Moreover, KLF5 expression was also increased in myometrial cells treated with IL1β, flagellin or poly(IC), likely factors contributing to preterm birth. KLF5 silencing in myometrial cells significantly decreased IL1β-induced cytokine expression (IL6 and IL8 mRNA expression and release), COX2 mRNA expression, and subsequent release of prostaglandins PGE2 and PGF2 α. KLF5 silencing also significantly reduced flagellin- and poly(I:C)-induced IL6 and IL8 mRNA expression. Lastly, IL1β-, flagellin- and poly(I:C)-stimulated NFκB transcriptional activity was significantly suppressed in KLF5-knockout myometrial cells. In conclusion, this study describes novel data in which KLF5 is increased in labouring myometrium, and KLF5 silencing decreased inflammation- and infection-induced pro-labour mediators. © 2015 Society for Reproduction and Fertility.

HSPB8 and the Cochaperone BAG3 Are Highly Expressed During the Synthetic Phase of Rat Myometrium Programming During Pregnancy.

PubMed

Marsh, Noelle M; Wareham, Angela; White, Bryan G; Miskiewicz, Ewa I; Landry, Jacques; MacPhee, Daniel J

2015-05-01

The small heat shock protein (HSP) B family of proteins are a group of molecular chaperones that enable tissues to adapt to changes in their local environments during differentiation, stress, or disease conditions. The objective of this research was to characterize the expression of HSPB8 and its cochaperone Bcl2-associated athanogene 3 (BAG3) in nonpregnant (NP) and pregnant rat myometrium during myometrial programming. Rat myometrium was collected from NP and pregnant rats as well as 1 day postpartum (PP) and samples prepared for immunoblot and immunofluorescence analysis. Immunoblot analysis determined that HSPB8 protein expression was significantly elevated at Day (D) 15, D17, and D19 compared to expression at NP and D6, while BAG3 expression was significantly elevated at D15 compared to NP, and D17 compared to NP, D6, D23, and PP time points (P < 0.05). In situ, HSPB8 and BAG3 were predominantly localized to myometrial cells throughout pregnancy, with intense cytoplasmic HSPB8 and BAG3 detection on D15 and D17 in both longitudinal and circular muscle layers. Immunoblot analysis of HSPB8 and BAG3 protein expression in myometrium from unilateral pregnancies also revealed that expression of both proteins was significantly increased at D15 in gravid compared to nongravid horns. Thus, HSPB8 and BAG3 are highly expressed during the synthetic phase of myometrial differentiation marked by initiation of uterine distension and myometrial hypertrophy. HSPB8 and BAG3 could be regulators of the protein quality control required for this process. © 2015 by the Society for the Study of Reproduction, Inc.

The expression of transforming growth factor beta in pregnant rat myometrium is hormone and stretch dependent.

PubMed

Shynlova, Oksana; Tsui, Prudence; Dorogin, Anna; Langille, B Lowell; Lye, Stephen J

2007-09-01

From a quiescent state in early pregnancy to a highly contractile state in labor, the myometrium displays tremendous growth and remodeling. We hypothesize that the transforming growth factor beta (TGFbeta) system is involved in the differentiation of pregnant myometrium throughout gestation and labor. Furthermore, we propose that during pregnancy the mechanical and hormonal stimuli play a role in regulating myometrial TGFbetas. The expression of TGFbeta1-3 mRNAs and proteins was examined by real-time PCR, Western immunoblot, and localized with immunohistochemistry in the rat uterus throughout pregnancy and labor. Tgfbeta1-3 genes were expressed differentially in pregnant myometrium. Tgfbeta2 gene was not affected by pregnancy, whereas the Tgfbeta1 gene showed a threefold increase during the second half of gestation. In contrast, we observed a dramatic bimodal change in Tgfbeta3 gene expression throughout pregnancy. Tgfbeta3 mRNA levels first transiently increased at mid-gestation (11-fold on day 14) and later at term (45-fold at labor, day 23). Protein expression levels paralleled the changes in mRNA. Treatment of pregnant rats with the progesterone (P4) receptor antagonist RU486 induced premature labor on day 19 and increased Tgfbeta3 mRNA, whereas artificial maintenance of elevated P4 levels at late gestation (days 20-23) caused a significant decrease in the expression of Tgfbeta3 gene. In addition, Tgfbeta3 was up-regulated specifically in the gravid horn of unilaterally pregnant rats subjected to a passive biological stretch imposed by the growing fetuses, but not in the empty horn. Collectively, these data indicate that the TGFbeta family contributes in the regulation of myometrial activation at term integrating mechanical and endocrine signals for successful labor contraction.

Loss of functional K+ channels encoded by ether-à-go-go-related genes in mouse myometrium prior to labour onset

PubMed Central

Greenwood, I A; Yeung, S Y; Tribe, R M; Ohya, S

2009-01-01

There is a growing appreciation that ion channels encoded by the ether-à-go-go-related gene family have a functional impact in smooth muscle in addition to their accepted role in cardiac myocytes and neurones. This study aimed to assess the expression of ERG1–3 (KCNH1–3) genes in the murine myometrium (smooth muscle layer of the uterus) and determine the functional impact of the ion channels encoded by these genes in pregnant and non-pregnant animals. Quantitative RT-PCR did not detect message for ERG2 and 3 in whole myometrial tissue extracts. In contrast, message for two isoforms of mERG1 were readily detected with mERG1a more abundant than mERG1b. In isometric tension studies of non-pregnant myometrium, the ERG channel blockers dofetilide (1 μm), E4031 (1 μm) and Be-KM1 (100 nm) increased spontaneous contractility and ERG activators (PD118057 and NS1643) inhibited spontaneous contractility. In contrast, neither ERG blockade nor activation had any effect on the inherent contractility in myometrium from late pregnant (19 days gestation) animals. Moreover, dofetilide-sensitive K+ currents with distinctive ‘hooked’ kinetics were considerably smaller in uterine myocytes from late pregnant compared to non-pregnant animals. Expression of mERG1 isoforms did not alter throughout gestation or upon delivery, but the expression of genes encoding auxillary subunits (KCNE) were up-regulated considerably. This study provides the first evidence for a regulation of ERG-encoded K+ channels as a precursor to late pregnancy physiological activity. PMID:19332483

MRI of placental adhesive disorder

PubMed Central

Prapaisilp, P; Bangchokdee, S

2014-01-01

Placental adhesive disorder (PAD) is a serious pregnancy complication that occurs when the chorionic villi invade the myometrium. Placenta praevia and prior caesarean section are the two important risk factors. PAD is classified on the basis of the depth of myometrial invasion (placenta accreta, placenta increta and placenta percreta). MRI is the preferred image modality for pre-natal diagnosis of PAD and as complementary technique when ultrasonography is inconclusive. Imaging findings that are helpful for the diagnosis include dark intraplacental bands, direct invasion of adjacent structures by placental tissue, interruption of normal trilayered myometrium and uterine bulging. Clinicians should be aware of imaging features of PAD to facilitate optimal patient management. PMID:25060799

Ovarian steroid hormones modulate the expression of progesterone receptors and histone acetylation patterns in uterine leiomyoma cells.

PubMed

Sant'Anna, Gabriela Dos Santos; Brum, Ilma Simoni; Branchini, Gisele; Pizzolato, Lolita Schneider; Capp, Edison; Corleta, Helena von Eye

2017-08-01

Uterine leiomyomas are the most common benign smooth muscle cell tumors in women. Estrogen (E2), progesterone (P4) and environmental factors play important roles in the development of these tumors. New treatments, such as mifepristone, have been proposed. We evaluated the gene expression of total (PRT) and B (PRB) progesterone receptors, and the histone acetyltransferase (HAT) and deacetylase (HDAC) activity after treatment with E2, P4 and mifepristone (RU486) in primary cell cultures from uterine leiomyoma and normal myometrium. Compared to myometrium, uterine leiomyoma cells showed an increase in PRT mRNA expression when treated with E2, and increase in PRB mRNA expression when treated with E2 and P4. Treatment with mifepristone had no significant impact on mRNA expression in these cells. The HDAC activity was higher in uterine leiomyoma compared to myometrial cells after treatment with E2 and E2 + P4 + mifepristone. HAT activity was barely detectable. Our results suggest that ovarian steroid hormones modulate PR, and mifepristone was unable to decrease PRT and PRB mRNA. The higher activity of HDAC leiomyoma cells could be involved in transcriptional repression of genes implicated in normal myometrium cell function, contributing to the maintenance and growth of uterine leiomyoma.

A Proteomic Approach for the Identification of Up-Regulated Proteins Involved in the Metabolic Process of the Leiomyoma.

PubMed

Ura, Blendi; Scrimin, Federica; Arrigoni, Giorgio; Franchin, Cinzia; Monasta, Lorenzo; Ricci, Giuseppe

2016-04-09

Uterine leiomyoma is the most common benign smooth muscle cell tumor of the uterus. Proteomics is a powerful tool for the analysis of complex mixtures of proteins. In our study, we focused on proteins that were upregulated in the leiomyoma compared to the myometrium. Paired samples of eight leiomyomas and adjacent myometrium were obtained and submitted to two-dimensional gel electrophoresis (2-DE) and mass spectrometry for protein identification and to Western blotting for 2-DE data validation. The comparison between the patterns revealed 24 significantly upregulated (p < 0.05) protein spots, 12 of which were found to be associated with the metabolic processes of the leiomyoma and not with the normal myometrium. The overexpression of seven proteins involved in the metabolic processes of the leiomyoma was further validated by Western blotting and 2D Western blotting. Four of these proteins have never been associated with the leiomyoma before. The 2-DE approach coupled with mass spectrometry, which is among the methods of choice for comparative proteomic studies, identified a number of proteins overexpressed in the leiomyoma and involved in several biological processes, including metabolic processes. A better understanding of the mechanism underlying the overexpression of these proteins may be important for therapeutic purposes.

A Proteomic Approach for the Identification of Up-Regulated Proteins Involved in the Metabolic Process of the Leiomyoma

PubMed Central

Ura, Blendi; Scrimin, Federica; Arrigoni, Giorgio; Franchin, Cinzia; Monasta, Lorenzo; Ricci, Giuseppe

2016-01-01

Uterine leiomyoma is the most common benign smooth muscle cell tumor of the uterus. Proteomics is a powerful tool for the analysis of complex mixtures of proteins. In our study, we focused on proteins that were upregulated in the leiomyoma compared to the myometrium. Paired samples of eight leiomyomas and adjacent myometrium were obtained and submitted to two-dimensional gel electrophoresis (2-DE) and mass spectrometry for protein identification and to Western blotting for 2-DE data validation. The comparison between the patterns revealed 24 significantly upregulated (p < 0.05) protein spots, 12 of which were found to be associated with the metabolic processes of the leiomyoma and not with the normal myometrium. The overexpression of seven proteins involved in the metabolic processes of the leiomyoma was further validated by Western blotting and 2D Western blotting. Four of these proteins have never been associated with the leiomyoma before. The 2-DE approach coupled with mass spectrometry, which is among the methods of choice for comparative proteomic studies, identified a number of proteins overexpressed in the leiomyoma and involved in several biological processes, including metabolic processes. A better understanding of the mechanism underlying the overexpression of these proteins may be important for therapeutic purposes. PMID:27070597

Early embryonic demise: no evidence of abnormal spiral artery transformation or trophoblast invasion.

PubMed

Ball, E; Robson, S C; Ayis, S; Lyall, F; Bulmer, J N

2006-03-01

Invasion by extravillous trophoblast of uterine decidua and myometrium and the associated spiral artery 'transformation' are essential for the development of normal pregnancy. Small pilot studies of placental bed and basal plate tissues from miscarriages have suggested that impaired interstitial and endovascular trophoblast invasion may play a role in the pathogenesis of miscarriage. The hypothesis that early miscarriage is associated with reduced extravillous trophoblast invasion and spiral artery transformation was tested in a large series of placental bed biopsies containing decidua and myometrium and at least one spiral artery from early, karyotyped embryonic miscarriages (

A New Slow Releasing, H2S Generating Compound, GYY4137 Relaxes Spontaneous and Oxytocin-Stimulated Contractions of Human and Rat Pregnant Myometrium

PubMed Central

Robinson, Hayley; Wray, Susan

2012-01-01

Better tocolytics are required to help prevent preterm labour. The gaseotransmitter Hydrogen sulphide (H2S) has been shown to reduce myometrial contractility and thus is of potential interest. However previous studies used NaHS, which is toxic and releases H2S as a non-physiological bolus and thus alternative H2S donors are sought. GYY4137 has been developed to slowly release H2S and hence better reflect endogenous physiological release. We have examined its effects on spontaneous and oxytocin-stimulated contractility and compared them to NaHS, in human and rat myometrium, throughout gestation. The effects on contractility in response to GYY4137 (1 nM–1 mM) and NaHS (1 mM) were examined on myometrial strips from, biopsies of women undergoing elective caesarean section or hysterectomy, and from non-pregnant, 14, 18, 22 day (term) gestation or labouring rats. In pregnant rat and human myometrium dose-dependent and significant decreases in spontaneous contractions were seen with increasing concentrations of GYY4137, which also reduced underlying Ca transients. GYY4137 and NaHS significantly reduced oxytocin-stimulated and high-K depolarised contractions as well as spontaneous activity. Their inhibitory effects increased as gestation advanced, but were abruptly reversed in labour. Glibenclamide, an inhibitor of ATP-sensitive potassium (KATP) channels, abolished the inhibitory effect of GYY4137. These data suggest (i) H2S contributes to uterine quiescence from mid-gestation until labor, (ii) that H2S affects L-type calcium channels and KATP channels reducing Ca entry and thereby myometrial contractions, (iii) add to the evidence that H2S plays a physiological role in relaxing myometrium, and thus (iv) H2S is an attractive target for therapeutic manipulation of human myometrial contractility. PMID:23029460

AKR1C1 and SRD5A1 messenger RNA expression at term in the human myometrium and chorioamniotic membranes.

PubMed

Lee, Richard H; Stanczyk, Frank Z; Stolz, Andrew; Ji, Qing; Yang, Gloria; Goodwin, T Murphy

2008-10-01

We sought to determine relative mRNA expression of AKR1C1 and SRD5A1, which respectively encode for the key progesterone metabolizing enzymes, 20alpha-hydroxysteroid dehydrogenase and 5alpha-reductase type 1, in the myometrium and chorioamniotic membranes during human spontaneous or induced labor and nonlabor. Quantitative real-time reverse-transcriptase polymerase chain reaction was used to compare relative mRNA expression of AKR1C1 and SRD5A1 in the myometrium and chorioamniotic membranes from 20 subjects during three different states of labor: not in labor ( N = 10), spontaneous labor ( N = 5), or induced labor ( N = 5). Labor was defined as regular uterine contractions that resulted in cervical dilation. Myometrial AKR1C1 mRNA expression was significantly greater in spontaneously laboring subjects compared with those not in labor (2.4-fold [1.97 to 2.98], P = 0.02). There was no difference in myometrial AKR1C1 mRNA expression between those with induced labor compared with those not in labor. Regardless of labor status, no differences were observed in the chorioamniotic membrane AKR1C1 mRNA expression between the groups. SRD5A1 mRNA expression was significantly lower in the membranes of both laboring groups when compared with those not in labor (spontaneous: 0.10-fold [0.06 to 0.18], P = 0.007; induced: 0.09-fold [0.03 to 0.25], P = 0.013). Regardless of labor status, there was no difference in SRD5A1 mRNA expression in the myometrium. Our study demonstrated tissue-specific changes in progesterone metabolizing enzyme mRNA expression in human intrauterine tissue at term associated with labor status. These observed changes in mRNA expression may have important implications for progesterone metabolism at those specific sites and thereby may differentially regulate the tissue-specific progesterone concentration and/or the level of specific progesterone metabolites.

Reciprocal Feedback Between miR-181a and E2/ERα in Myometrium Enhances Inflammation Leading to Labor

PubMed Central

Wang, Gang; Liu, Wei-Na; Kinser, Holly; Franco, Hector L.

2016-01-01

Context: The initiation of term and preterm labor is associated with an up-regulated inflammatory response in myometrium; however, the underlying signaling pathways remain incompletely defined. Objective: To define the regulatory mechanisms that mediate the increased myometrial inflammatory response leading to labor, we investigated the roles of microRNAs (miRNA/miR). Design and Setting: Human myometrial tissues, isolated smooth muscle cells, and animal models were used to study miR-181a regulation of uterine inflammatory pathways and contractility. Patients: Myometrial tissues from 15 term pregnant women undergoing elective cesarean section (not in labor) and 10 term pregnant women undergoing emergency cesarean section (in labor) were used. Results: Expression of the highly conserved microRNA, miR-181a, was significantly decreased in mouse and human myometrium during late gestation. By contrast, the putative miR-181a targets, TNF-α, and estrogen receptor (ER)-α, and the validated target, c-Fos, key factors in the inflammatory response leading to parturition, were coordinately up-regulated. In studies using human myometrial cells, overexpression of miR-181a mimics repressed basal as well as IL-1β-induced TNF-α, C-C motif chemokine ligand 2 and 8 expression, whereas the expression of the antiinflammatory cytokine, IL-10, was increased. Overexpression of miR-181a dramatically inhibited both spontaneous and IL-1β-induced contraction of human myometrial cells. Notably, miR-181a directly targeted ERα and decreased its expression, whereas estradiol-17β reciprocally inhibited expression of mature miR-181a in myometrial cells. Conclusions: Thus, increased estradiol-17β/ERα signaling in myometrium near term inhibits miR-181a, resulting in a further increase in ERα and proinflammatory signaling. This escalating feedback loop provides novel targets and therapeutic strategies for the prevention of preterm labor and its consequences. PMID:27459534

The antiprogesterone steroid RU 486: a short pharmacological and clinical review, with emphasis on the interruption of pregnancy.

PubMed

Garfield, R E; Baulieu, E E

1987-02-01

In this review we have briefly outlined the clinical applications and mechanism of action of the progesterone antagonist RU 486. RU 486 has been successfully used in a variety of conditions to regulate the reproductive cycle and to control fertility in women. We suggest that the mechanism by which RU 486 acts during the cycle and early pregnancy is probably by affecting mainly the endometrium. During late pregnancy, the compound has significant effects on the myometrium including the induction of gap junctions between myometrium cells, which is required for muscle contractility during labour. The use of RU 486 has helped to demonstrate that progesterone is required for maintenance of the late stages of pregnancy in women.

Differential expression of G-protein-coupled estrogen receptor-30 in human myometrial and uterine leiomyoma smooth muscle.

PubMed

Tian, Ruijuan; Wang, Zengyong; Shi, Zhan; Li, Dong; Wang, Yuebing; Zhu, Yingjun; Lin, Wanjun; Gui, Yu; Zheng, Xi-Long

2013-01-01

To determine differential expression of G-protein-coupled receptor 30 (GPR30) in uterine leiomyoma and its matched myometrium. GPR30 expression examined in both tissues and cultured cells. Research laboratories. Women 35 to 50 years old with uterine leiomyomas. Hysterectomy. GPR30 expression profile. Using Western blot and real-time quantitative polymerase chain reaction analyses, we found that GPR30 was highly expressed in uterine leiomyomas compared with their matched myometrium. In only three out of nine patients examined was GPR30 protein detectable by Western blot analysis in myometrial tissues, but at statistically significantly lower levels than in their leiomyomas. Confocal microscopy revealed the nuclear localization of GPR30 in leiomyoma tissues and cultured leiomyoma smooth muscle cells (SMCs). Treatment with 0.1 μM 17β-estradiol increased mRNA expression of GPR30 in leiomyoma SMCs but decreased expression in myometrial SMCs. Treatment with G-1, a GPR30 agonist, stimulated phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) in both SMC types. PD98059, the MEK inhibitor, completely inhibited G-1-induced phosphorylation of p44/42 in myometrium SMCs, but not in SMCs from leiomyoma. GPR30 is abundantly expressed in uterine leiomyomas, likely resulting from estrogen stimulation. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Gynecological and obstetrical outcomes after laparoscopic repair of a cesarean scar defect in a series of 38 women.

PubMed

Donnez, Olivier; Donnez, Jacques; Orellana, Renan; Dolmans, Marie-Madeleine

2017-01-01

To evaluate gynecological and obstetrical outcomes, as well as remaining myometrial thickness, after laparoscopic repair of a cesarean scar. Observational study and prospective evaluation of the remaining myometrium before and after repair. Academic department in a university hospital. A series of 38 symptomatic women with cesarean scar defects and remaining myometrial thickness of less than 3 mm, according to magnetic resonance imaging. Laparoscopic repair of the defect. Increase in myometrial thickness at the site of cesarean section, gynecological and obstetrical outcomes, and histological analysis of the defect after excision. The mean thickness of the myometrium increased significantly from 1.43 ± 0.7 mm before surgery to 9.62 ± 1.8 mm after surgery. All but three patients were free of symptoms. Among the 18 women with infertility, eight (44%) became pregnant and delivered healthy babies by cesarean section at 38-39 weeks of gestation. Histological analysis, performed in all 38 cases, revealed the presence of endometriosis in eight women (21.1%). Muscle fiber density was significantly lower compared with adjacent myometrium. In symptomatic women with residual myometrial thickness of less than 3 mm who wish to conceive, laparoscopic repair could be considered an appropriate approach. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

[MRI evaluation of placenta accreta treated by embolization. Apropos of a case. Review of the literature].

PubMed

Lemercier, E; Genevois, A; Descargue, G; Clavier, E; Benozio, M

1999-04-01

Placenta accreta results from an abnormal attachment of the placenta to the uterine myometrium. The reported incidence in literature is variable, with an average of 1/7000 pregnancies. This condition is associated with a significant risk of bleeding at the time of delivery, usually requiring hysterectomy. Sonography associated with color Doppler is useful for diagnosis, but MRI can be used successfully to evaluate the degree of placental tissue invading into the myometrium, the serosa, and for follow-up after conservative management. To our knowledge, only two cases of placenta accreta evaluated with MR and six cases of placenta accreta treated by embolization have been reported in the literature. The authors report one case of placenta accreta treated successfully by embolization, and followed-up by MRI.

Stretch-induced uterine myocyte differentiation during rat pregnancy: involvement of caspase activation.

PubMed

Shynlova, Oksana; Dorogin, Anna; Lye, Stephen J

2010-06-01

Proliferation, differentiation, and apoptosis are three major processes by which the pregnant uterus maintains homeostasis to accommodate the growing fetus. We demonstrated previously that caspase activation in the pregnant rat myometrium at midgestation coincides with the transition from uterine hyperplasia to hypertrophy. We hypothesized that this transition was induced by stasis of myometrial blood flow (and subsequent hypoxia/ischaemia insult) resulting from acute myometrial stretch induced by a growing embryo. Therefore, we measured the expression of active caspase 3 and two hypoxia markers (transcription factor HIF1A and pimonidazole hydrochloride) in pregnant rat myometrium. To investigate the effect of gravidity we used unilaterally pregnant rats. Caspase 3 was activated only in the gravid horn of the unilaterally pregnant animals on Gestational Days 12-15. This activation was associated with high levels of HIF1A and pimonidazole immunostaining, which were limited to the circular myometrial layer of the gravid horn, indicative of hypoxia within this tissue. To isolate the effect of myometrial stretch applied by the growing fetus, we inserted an expandable polymer tube (intra-uterine expandable tube [IUET]) into the empty horn of Day 13 and Day 20 unilaterally pregnant rats. Tissue was collected 2, 14, and 24 h later. In the IUET-stretched empty horn, cleaved caspase 3 was activated at midgestation (Day 14), but not at late gestation (Day 21). We speculate that hypoxia resulting from mechanical stretch may activate caspase 3 within the pregnant myometrium only in the context of a specific endocrine environment.

Oxytocin and vasopressin: distinct receptors in myometrium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guillon, G.; Balestre, M.N.; Roberts, J.M.

1987-06-01

The binding characteristics of (/sup 3/H)oxytocin (( /sup 3/H)OT) and (/sup 3/H)lysine vasopressin (( /sup 3/H)LVP) to nonpregnant human myometrium were investigated. Binding of both radioligands was saturable, time dependent, and reversible. Whereas (/sup 3/H)OT was found to bind to a single class of sites with high affinity (Kd, 1.5 +/- 0.4 (+/- SEM) nM) and low capacity (maximum binding (Bmax), 34 +/- 6 fmol/mg protein), (/sup 3/H)LVP bound to two classes of sites, one with high affinity (Kd, 2.2 +/- 0.1 nM) and low capacity (Bmax, 198 +/- 7 fmol/mg protein) and another with low affinity (Kd, 655 +/-more » 209 nM) and high capacity (Bmax, 5794 +/- 1616 fmol/mg protein). The binding of the labeled peptides also displayed a marked difference in sensitivity to Mg2+ and guanine nucleotides. These differences in binding characteristics as well as the differences in potency of analogs in competing for (/sup 3/H)OT and (/sup 3/H)LVP binding indicate the presence of distinct receptors for OT and vasopressin in human myometrium. Pharmacological characterization of the high affinity binding sites for (/sup 3/H)LVP indicated that these are of the V1 subtype. Although, as suggested by others, vasopressin and OT can bind to the same sites, the presence of distinct receptors for both peptides provides an explanation for the previously reported difference in myometrial responsiveness to OT and vasopressin.« less

Modulation of Progesterone Receptor Isoform Expression in Pregnant Human Myometrium

PubMed Central

2017-01-01

Background. Regulation of myometrial progesterone receptor (PR) expression is an unresolved issue central to understanding the mechanism of functional progesterone withdrawal and initiation of labor in women. Objectives. To determine whether pregnant human myometrium undergoes culture-induced changes in PR isoform expression ex situ and, further, to determine if conditions approaching the in vivo environment stabilise PR isoform expression in culture. Methods. Term nonlaboring human myometrial tissues were cultured under specific conditions: serum supplementation, steroids, stretch, cAMP, PMA, PGF2α, NF-κB inhibitors, or TSA. Following 48 h culture, PR-T, PR-A, and PR-B mRNA levels were determined using qRT-PCR. PR-A/PR-B ratios were calculated. Results. PR-T and PR-A expression and the PR-A/PR-B ratio significantly increased in culture. Steroids prevented the culture-induced increase in PR-T and PR-A expression. Stretch blocked the effects of steroids on PR-T and PR-A expression. PMA further increased the PR-A/PR-B ratio, while TSA blocked culture-induced increases of PR-A expression and the PR-A/PR-B ratio. Conclusion. Human myometrial tissue in culture undergoes changes in PR gene expression consistent with transition toward a laboring phenotype. TSA maintained the nonlaboring PR isoform expression pattern. This suggests that preserving histone and/or nonhistone protein acetylation is critical for maintaining the progesterone dependent quiescent phenotype of human myometrium in culture. PMID:28540297

Elastin distribution in the normal uterus, uterine leiomyomas, adenomyosis and adenomyomas: a comparison.

PubMed

Zheng, Wei-Qiang; Ma, Rong; Zheng, Jian-Ming; Gong, Zhi-Jing

2006-04-01

To describe the histologic distribution of elastin in the nonpregnant human uterus, uterine leiomyomas, adenomyosis and adenomyomas. Uteri were obtained from women undergoing hysterectomy for benign conditions, including 26 cases of uterine leiomyomas, 24 cases of adenomyosis, 18 adenomyomas and 6 cases of autopsy specimens. Specific histochemical staining techniques were employed in order to demonstrate the distribution of elastin. The distribution of elastin components in the uterus was markedly uneven and showed a decreasing gradient from outer to inner myometrium. No elastin was present within leiomyomas, adenomyomas or adenomyosis. The distribution of elastin may help explain the normal function of the myometrium in labor. It implies that the uneven distribution of elastin components and absence of elastin within leiomyomas, adenomyomas and adenomyosis could be of some clinical significance. The altered elastin distribution in disease states may help explain such symptoms as dysmenorrhea in uterine endometriosis.

Effect of Bryophyllum pinnatum versus fenoterol on uterine contractility.

PubMed

Gwehenberger, Birgit; Rist, Lukas; Huch, Renate; von Mandach, Ursula

2004-04-15

To characterise the phytotherapeutic tocolytic Bryophyllum pinnatum in vitro versus the conventional betamimetic, fenoterol, in human myometrium. Contractility (endpoints: area under the curve (AUC), amplitude and frequency of isometric force development) was measured in strips of term myometrium biopsied at caesarean section in 14 women and exposed to increasing concentrations of B. pinnatum versus +/- oxytocin 1 U/l. Inhibition of spontaneous contraction by B. pinnatum was concentration-dependent: 16% at maximum concentration (10(4) mg/l), or 53% that with fenoterol 5 x 10(-8)mol/l. B. pinnatum increased contraction frequency by 91% at constant amplitude and inhibited oxytocin-stimulated contractions by 20% (AUC) at constant amplitude with slightly decreased frequency. Fenoterol decreased contraction AUC by 50% with a significant decrease in frequency. Our in vitro data confirm the tocolytic activity of B. pinnatum observed in alternative medicine centres and may justify further clinical studies.

Determination of the functional size of oxytocin receptors in plasma membranes from mammary gland and uterine myometrium of the rat by radiation inactivation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soloff, M.S.; Beauregard, G.; Potier, M.

1988-05-01

Gel filtration of detergent-solubilized oxytocin (OT) receptors in plasma membrane fractions from both regressed mammary gland and labor myometrium of the rat, showed that specific (/sup 3/H)OT binding was associated with a heterogeneously sized population of macromolecules. As radiation inactivation is the only method available to measure the apparent molecular weights of membrane proteins in situ, we used this approach to define the functional sizes of OT receptors. The results indicate that both mammary and myometrial receptors are uniform in size and of similar molecular mass. Mammary and myometrial receptors were estimated to be 57.5 +/- 3.8 (SD) and 58.8more » +/- 1.6 kilodaltons, respectively. Knowledge of the functional size of OT receptors will be useful in studies involving the purification and characterization of the receptor and associated membrane components.« less

Matrix Metalloproteinase Expression in the Rat Myometrium During Pregnancy, Term Labor, and Postpartum1

PubMed Central

Nguyen, Tina Tu-Thu Ngoc; Shynlova, Oksana; Lye, Stephen J.

2016-01-01

Pregnancy, spontaneous term labor (TL), and postpartum (PP) involution are associated with changes in the cellular and extracellular matrix composition of the uterus. Both the uterine smooth muscle (myometrium) and the infiltrating peripheral blood leukocytes involved in the activation of labor secrete extracellular matrix-degrading enzymes (matrix metalloproteinases, MMPs) that can modulate cellular behavior and barrier function. MMP expression is induced by mechanical stretch in several tissues. We hypothesized that the expression and activity of myometrial MMPs and their tissue inhibitors (TIMPs) are modulated in preparation for TL and PP involution and are regulated by mechanical stretch of uterine walls imposed by the growing fetus. Myometrial tissues were collected from bilaterally and unilaterally pregnant rats across gestation, TL, and PP. Total RNA and proteins were subjected to real-time PCR and immunoblotting, respectively, and tissue localization and activity was examined by immunohistochemistry and in situ zymography. We found that Mmp7, Mmp11, and Mmp12 mRNA levels were upregulated during TL and PP, while Mmp2, Mmp3, Mmp8, Mmp9, Mmp10, and Mmp13 mRNAs were only upregulated during PP. Timp1–Timp4 were stably expressed throughout gestation with some fluctuations PP. Active MMP2 was induced in the empty uterine horn during gestation and in the gravid PP uterus, suggesting negative regulation by biological mechanical stretch. We conclude that specific subsets of uterine MMPs are differentially regulated in the rat myometrium in preparation for two major events: TL and PP uterine involution. PMID:27251092

Solubilization of adenylyl cyclase from human myometrium in a alphas-coupled form.

PubMed

Bajo, Ana M; Prieto, Juan C; Valenzuela, Pedro; Martinez, Pilar; Guijarro, Luis G

2003-08-01

Adenylyl cyclase (AC) was extracted from human myometrium with either non-ionic (Lubrol-PX or Triton X-100) or zwitterionic (3-[3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, CHAPS) detergents. The soluble enzyme was stimulated by forskolin, a hydrophobic activator, in the presence of Mg2+ indicating that the catalytic subunit had not been damaged after solubilization. The enzyme was also activated by 5'-guanylyl imidodiphosphate (Gpp(NH)p) showing that the catalytic unit was not separated from stimulatory guanine nucleotide binding protein (Gs) during the extraction. Both activators showed different effects on the stimulatory efficacy and potency of AC activity solobulized with detergents. Gel filtration of Lubrol-PX and CHAPS extracts over a Sepharose CL-2B column partially resolved AC and its complexes. The chromatographic profile for Lubrol-solubilized AC presented a main peak of about 200 kDa whereas CHAPS-solubilized AC showed a dominant peak of about 1100 kDa. The heterodisperse peaks obtained revealed that the catalytic AC subunit was not separated from Gs proteins after gel filtration, and that AC could be associated with other cellular proteins. When Lubrol extract was submitted to anionic-exchange chromatography, the enzyme was purified about 7.5 fold (enzymatic activity of 48.1 pmol/min/mg of protein). The catalytic subunit was co-eluted with both AC-activating proteins Galphas large (52.2 kDa) and Galphas small (48.7 kDa). This is the first demonstration of the stable physical association of AC with both alphas subunits of G proteins in human myometrium.

Immunohistochemical characteristics of atypical polypoid adenomyoma with special reference to h-caldesmon.

PubMed

Horita, Ayako; Kurata, Atsushi; Maeda, Daichi; Fukayama, Masashi; Sakamoto, Atsuhiko

2011-01-01

Atypical polypoid adenomyoma (APA) is a relatively rare benign uterine tumor, histologically characterized by proliferation of irregular endometrioid glands accompanied by stromal cells of smooth muscle origin. As the epithelial components of APA usually show cytological atypia, a differential diagnosis between this tumor and endometrioid carcinoma invading myometrium is often difficult, especially in curettage material. This distinction is clinically very important to avoid unnecessary hysterectomy. However, only a few immunohistochemical studies of APA that differentiate it from malignancy have been published. Therefore, we have investigated the expression of several antigens in APA and compared them with those present in myoinvasive carcinoma. Six specimens of APA were studied, along with controls of endometrioid carcinoma invading myometrium. Antibodies to p53, Ki-67, CD10, and h-caldesmon reacted positively using immunohistochemistry. Variable positive expressions of p53 and Ki-67 were observed in both epithelial and stromal components of APA, and in myoinvasive endometrioid carcinoma. CD10 was negative or partially and weakly positive whereas h-caldesmon was completely negative in the stromal cells of all 6 specimens of APA. However, in the myometrium in which endometrioid carcinoma invaded, a fringe-like positive staining pattern was occasionally observed for CD10, whereas a diffuse positive signal was obtained for h-caldesmon. The results of this study indicate that immunohistochemically, p53, and Ki-67 are not reliable markers but that h-caldesmon is useful in distinguishing APA from myoinvasive endometrioid carcinoma. Further, our data suggest that the stromal cells of APA are mainly immature smooth muscle cells, and thus APA may be a mixed tumor.

Myometrial cavernous hemangioma with pulmonary thromboembolism in a post-partum woman: a case report and review of the literature.

PubMed

Bhavsar, Tapan; Wurzel, John; Duker, Nahum

2012-11-23

Cavernous hemangiomas of the uterus are rare benign vascular lesions. Nine cases of diffuse cavernous hemangioma of the gravid uterus have been reported, most of which diffusely involved the myometrium. These vascular malformations are clinically significant, and may cause pronounced bleeding resulting in maternal or fetal demise. Thrombosis of cavernous hemangiomas of the uterus has been previously reported. We here report the first case in which a thrombosed cavernous hemangioma of the myometrium resulted in a fatal pulmonary embolism in a post-partum woman. A 25-year-old obese African-American woman who had one pregnancy and was delivered of twins by cesarean section was admitted 1 week after the successful delivery. The 12-day clinical course included ventilator-dependent respiratory failure, systemic hypertension, methicillin-resistant Staphylococcus aureus in the sputum, leukocytosis and asystole. A transabdominal ultrasound examination showed heterogeneous thickened and irregular products in the endometrial canal. The laboratory values were relevant for an increased prothrombin time, activated partial thromboplastin time, ferritin and a decrease in hemoglobin. The clinical cause of death was cited as acute respiratory distress syndrome. At autopsy, a 400g spongy, hemorrhagic uterus with multiple cystic spaces measuring approximately 0.5 × 0.4cm filled with thrombi within the myometrium was identified. Immunohistological examination with a CD31 stain for vascular endothelium associated antigen confirmed several endothelium-lined vessels, some of which contained thrombi. These histological features were consistent with cavernous hemangioma of the myometrium. A histological examination of the lungs revealed multiple fresh thromboemboli in small- and medium-sized pulmonary arteries in the right upper and lower lobes without organization, but with adjacent areas of fresh hemorrhagic infarction. This case underscores the importance of a high index of suspicion in a pregnant or post-partum woman presenting with respiratory symptoms. Thrombosis of the cavernous hemangiomas of the gravid or post-partum uterus is a rare entity. This case is of interest because it indicates that this condition can be fatally complicated by embolization of the thrombi in the cavernous myometrial hemangiomas. Although delivery by conservative methods, as well as cesarean section, is possible without resorting to hysterectomy, occasionally, the consequences could be fatal as in this case.

Transcriptome interrogation of human myometrium identifies differentially expressed sense-antisense pairs of protein-coding and long non-coding RNA genes in spontaneous labor at term

PubMed Central

Romero, Roberto; Tarca, Adi; Chaemsaithong, Piya; Miranda, Jezid; Chaiworapongsa, Tinnakorn; Jia, Hui; Hassan, Sonia S.; Kalita, Cynthia A.; Cai, Juan; Yeo, Lami; Lipovich, Leonard

2014-01-01

Objective The mechanisms responsible for normal and abnormal parturition are poorly understood. Myometrial activation leading to regular uterine contractions is a key component of labor. Dysfunctional labor (arrest of dilatation and/or descent) is a leading indication for cesarean delivery. Compelling evidence suggests that most of these disorders are functional in nature, and not the result of cephalopelvic disproportion. The methodology and the datasets afforded by the post-genomic era provide novel opportunities to understand and target gene functions in these disorders. In 2012, the ENCODE Consortium elucidated the extraordinary abundance and functional complexity of long non-coding RNA genes in the human genome. The purpose of the study was to identify differentially expressed long non-coding RNA genes in human myometrium in women in spontaneous labor at term. Materials and Methods Myometrium was obtained from women undergoing cesarean deliveries who were not in labor (n=19) and women in spontaneous labor at term (n=20). RNA was extracted and profiled using an Illumina® microarray platform. The analysis of the protein coding genes from this study has been previously reported. Here, we have used computational approaches to bound the extent of long non-coding RNA representation on this platform, and to identify co-differentially expressed and correlated pairs of long non-coding RNA genes and protein-coding genes sharing the same genomic loci. Results Upon considering more than 18,498 distinct lncRNA genes compiled nonredundantly from public experimental data sources, and interrogating 2,634 that matched Illumina microarray probes, we identified co-differential expression and correlation at two genomic loci that contain coding-lncRNA gene pairs: SOCS2-AK054607 and LMCD1-NR_024065 in women in spontaneous labor at term. This co-differential expression and correlation was validated by qRT-PCR, an independent experimental method. Intriguingly, one of the two lncRNA genes differentially expressed in term labor had a key genomic structure element, a splice site that lacked evolutionary conservation beyond primates. Conclusions We provide for the first time evidence for coordinated differential expression and correlation of cis-encoded antisense lncRNAs and protein-coding genes with known, as well as novel roles in pregnancy in the myometrium of women in spontaneous labor at term. PMID:24168098

Differences in uterine immunoexpression of PR, ERα and OTR when comparing prostaglandin- to progestagen-based protocols for ovine estrus synchronization.

PubMed

Ruiz-González, I; Sánchez, M A; García-Palencia, P; Sánchez, B; García-Fernández, R A; González-Bulnes, A; Flores, J M

2012-07-01

The aim of this work was to compare PR, ERα and OTR uterine expression between days 9 and 21 of pregnancy in ewes whose estrus had been synchronized with two different protocols. Sixty-four adult Manchega ewes were synchronized with either conventional progestagens (P) or prostaglandin analogues (PG), and mated. Uterine samples were obtained from pregnant animals (group P, n=24; group PG, n=25) on days 9 post coitus (pc), 13pc, 15pc, 17pc and 21pc. Immunohistochemical detection of progesterone receptor (PR), estrogen receptor-α (ERα) and oxytocin receptor (OTR) was assessed in different uterine cell compartments including luminal and glandular epithelium, stroma and myometrium. Interaction day × treatment was obtained when assessing PR expression in the caruncular stroma (P=0.027) and myometrium (P=0.000), as well as for ERα in the superficial stroma (P=0.05). Significant "day post coitus" effect was found regarding to PR (P<0.01, with the exception of the superficial stroma, deep stroma and myometrium), ERα (P<0.01), and OTR (P<0.05, except in the deep compartments). No significant "treatment" effect was found for PR, ERα or OTR protein immunoexpression. This study supports the implication of PR, ERα and OTR within days 9-21 of the ovine pregnancy. Moreover, different expression pattern of PR and ERα proteins has been found between treatments in various compartments studied. Collectively, these results indicate that PR, ERα and OTR expression during early pregnancy is similar between ewes treated with either progestagens or prostaglandin analogues-based protocols for estrus synchronization. Copyright © 2012 Elsevier B.V. All rights reserved.

Primary Uterine Peripheral T-cell Lymphoma

PubMed Central

Gong, Jing; Dong, Aisheng; Wang, Yang; Zhang, Xuefeng; Yang, Panpan; Wang, Li; Jing, Wei

2016-01-01

Abstract Primary uterine non-Hodgkin's lymphoma is extremely rare accounting for <1% of all extranodal non-Hodgkin's lymphomas. Imaging findings of primary uterine lymphoma have rarely been reported before. We present magnetic resonance imaging (MRI) and fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT findings in a patient with primary uterine peripheral T-cell lymphoma. A 27-year-old female presented with intermittent fever with neutropenia for 7 months. MRI showed an ill-defined mass involved both the uterine corpus and cervix, resulting in diffuse enlargement of the uterus. This mass showed inhomogeneous hypointensity on unenhanced T1-weighted images, hyperintensity on diffusion-weighted imaging, relative hypointensity compared to the surrounding myometrium on T2-weighted images and lower enhancement than the surrounding myometrium on enhanced T1-weighted images. FDG PET/CT showed intense FDG uptake in the thickened wall of the uterine corpus and cervix with SUVmax of 26.9. There were multiple hypermetabolic lymph nodes in the pelvis and retroperitoneum. Uterine curettage and CT-guided biopsy of the uterine mass revealed peripheral T-cell lymphoma. Bone marrow biopsy revealed no evidence of lymphomatous involvement. The imaging and pathologic findings were consistent with primary uterine lymphoma. After 3 circles of chemotherapy, follow-up enhanced MRI showed decreased thickness of the uterine wall. Despite its rarity, primary uterine non-Hodgkin's lymphoma should be taken into consideration when a uterine tumor shows large size, relative hypointesity on both T2-weighted images and enhanced T1-weighted images compared to the surrounding myometrium, and intense FDG uptake on PET/CT. MRI may be helpful for describing the relationship between the tumor and adjacent structures. FDG PET/CT may be useful for tumor detection and staging. PMID:27124063

An unusual case of uterine cotyledonoid dissecting leiomyoma with adenomyosis.

PubMed

Shimizu, Ai; Tanaka, Hoshihito; Iwasaki, Sari; Wakui, Yukio; Ikeda, Hitoshi; Suzuki, Akira

2016-08-04

Cotyledonoid dissecting leiomyoma is a rare variant of uterine smooth muscle tumor with an unusual growth pattern that shows intramural dissection within uterine myometrium and often a placenta-like appearance in its extrauterine components. We present a unique case of cotyledonoid dissecting leiomyoma with adenomyosis. A 40-year-old Japanese female presented with prolonged menorrhagia and severe anemia. She had a pelvic mass followed-up for 6 years with a diagnosis of leiomyoma. However, increase in tumor size and cystic changes with hemorrhage were found by magnetic resonance imaging, and total abdominal hysterectomy with bilateral salpingectomy was performed. Macroscopically, the placenta-like exophytic mass protruding from the posterior uterine wall was composed of multiple nodules containing numerous hemorrhagic cysts. The mass showed continuity as a white multinodular dissecting mass infiltrating the posterolateral myometrium. Microscopically, both extra-and intrauterine portions of the mass were composed of nodules that contained swirled neoplastic smooth muscle cells with marked hyalinized degeneration, as observed in cotyledonoid dissecting leiomyomas of conventional type. In addition, numerous non-neoplastic glands of endometrial type surrounded by abundant endometrium-like stromal cells and non-neoplastic smooth muscle cells were found in the tumor, suggesting that it involved a part of concomitant adenomyosis originating from the nontumoral myometrium. Thus far, over 30 cases of cotyledonoid dissecting leiomyoma have been reported, none of which have described the presence of adenomyosis within the tumor. The present case suggested that cotyledonoid dissecting leiomyoma might have a unique clinical presentation involving concomitant uterine adenomyosis. It is critical for pathologists, gynecologists, and radiologists to be cognizant of cotyledonoid dissecting leiomyoma variants for timely and appropriate diagnosis and treatment.

Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms.

PubMed

Tsigkou, Anastasia; Reis, Fernando M; Lee, Meng H; Jiang, Bingjie; Tosti, Claudia; Centini, Gabriele; Shen, Fang-Rong; Chen, You-Guo; Petraglia, Felice

2015-07-01

To investigate the possible correlation between progesterone receptor (PR) expression in uterine leiomyoma or adjacent myometrium and patient's age, size/number of leiomyomas, or clinical symptoms such as dysmenorrhea, acyclic pelvic pain, or menstrual and intermenstrual uterine bleeding. Cross-sectional study. Referral center. Sixty-two Chinese women undergoing elective hysterectomy for uterine leiomyomata. None. Evaluation of PR-total and PR-B mRNA with real-time polymerase chain reaction; PR-A and PR-B proteins quantified by Western blot in leiomyoma tissue and myometrium; symptoms rated by the patients using visual analog scores. The PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium. A direct correlation between PR-B mRNA levels in leiomyoma and age (r = 0.347) and number of tumors (r = 0.295) was found. Conversely, there was an inverse correlation between PR-B mRNA levels in leiomyoma and dysmenorrhea (r = -0.260) and intermenstrual bleeding (r = -0.266). Multiple regression analysis indicated that age (β = 0.363) and the number of myomas (β = 0.296) were independently associated with PR-B mRNA levels in leiomyoma tissue. The levels of PR-B mRNA in leiomyoma tissue are directly associated with the number of tumors and inversely correlated with the intensity of intermenstrual bleeding and dysmenorrhea, suggesting that PR signaling may favor leiomyoma growth while attenuating clinical symptoms. This duality should be taken into account in the clinical management of patients with symptomatic uterine leiomyoma. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Uterine sarcoma vs adenocarcinoma: can MRI distinguish between them?

PubMed

Hernández Mateo, P; Méndez Fernández, R; Serrano Tamayo, E

2016-01-01

To analyze the MRI characteristics of uterine sarcomas (mainly carcinosarcomas) and to compare them with those of adenocarcinomas to define the findings that would be useful for the differential diagnosis. We retrospectively reviewed the MRI studies of 13 patients with histologically diagnosed uterine sarcoma. We analyzed tumor size, signal in T2-weighted, unenhanced and gadolinium-enhanced T1-weighted, and diffusion-weighted sequences. We compared the data obtained with those of another series of 30 consecutive cases of adenocarcinomas studied with MRI. The sarcomas (> 9cm in 77% of cases) were considerably larger than the adenocarcinomas (p<0.001). There were no differences in FIGO staging by MRI or surgery: both tumor types were diagnosed in early stages. The signal intensity in T2-weighted images differed significantly between the two tumor types: all the sarcomas were heterogeneous and predominantly hyperintense with respect to the myometrium in T2-weighted sequences (p<0.001). In postcontrast studies, all the sarcomas showed enhancement greater than or equal to the myometrium; this finding was significantly different from the adenocarcinomas (p<0.001). In diffusion-weighted sequences, we found no significant differences in ADC values in the areas with greatest restriction, but the ADC map was more heterogeneous in the sarcomas. Uterine sarcomas do not have specific characteristics on MRI, but some findings can indicate the diagnosis. In our study, we found significant differences between sarcomas and adenocarcinomas. Sarcomas were larger, had more hyperintense and heterogeneous signal intensity in T2-weighted sequences, and enhanced more than or at least as much as the myometrium. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

The role of T1 perfusion-based classification in magnetic resonance-guided high-intensity focused ultrasound ablation of uterine fibroids.

PubMed

Keserci, Bilgin; Duc, Nguyen Minh

2017-12-01

To comparatively evaluate the role of magnetic resonance (MR) T1 perfusion-based time-signal intensity (SI) curves of fibroid tissue and the myometrium in classification of fibroids for predicting treatment outcomes of high-intensity focused ultrasound (HIFU) treatment. The fibroids of 74 women who underwent MR-HIFU treatment were classified into group A (time-SI curve of fibroid lower than that of the myometrium) and group B (time-SI curve of fibroid equal to or higher than that of the myometrium). Non-perfused volume (NPV) ratios immediately after treatment and fibroid volume reduction ratios and symptom severity scores (SSS) at the 6-month follow-up were retrospectively assessed. The immediate NPV ratios in groups A and B were 95.3 ± 6.3% (n = 62) and 63.8 ± 11% (n = 12), respectively. At the 6-month follow-up, the fibroid volume reduction ratios in groups A and B were 0.52 ± 0.14 (n = 50) and 0.07 ± 0.14 (n = 11), with the corresponding improvement in mean transformed SSS being 0.86 ± 0.14 and 0.19 ± 0.3, respectively. No serious adverse effects were reported. Our novel classification method could play an important role in classifying fibroids for predicting the immediate outcomes of HIFU treatment. • MRI is an important modality for outcome prediction in HIFU treatment • Patient selection is a significant factor for achieving high NPV ratio • NPV ratio is very strongly correlated with T1 perfusion-based classification • T1 perfusion-based classification is a strong predictor of treatment outcome.

Porcine calbindin-D9k gene: expression in endometrium, myometrium, and placenta in the absence of a functional estrogen response element in intron A.

PubMed

Krisinger, J; Jeung, E B; Simmen, R C; Leung, P C

1995-01-01

The expression of Calbindin-D9k (CaBP-9k) in the pig uterus and placenta was measured by Northern blot analysis and reverse transcription polymerase chain reaction (PCR), respectively. Progesterone (P4) administration to ovariectomized pigs decreased CaBP-9k mRNA levels. Expression of endometrial CaBP-9k mRNA was high on pregnancy Days 10-12 and below the detection limit on Days 15 and 18. On Day 60, expression could be detected at low levels. In myometrium and placenta, CaBP-9k mRNA expression was not detectable by Northern analysis using total RNA. Reverse-transcribed RNA from both tissues demonstrated the presence of CaBP-9k transcripts by means of PCR. The partial CaBP-9k gene was amplified by PCR and cloned to determine the sequence of intron A. In contrast to the rat CaBP-9k gene, the pig gene does not contain a functional estrogen response element (ERE) within this region. A similar ERE-like sequence located at the identical location was examined by gel retardation analysis and failed to bind the estradiol receptor. A similar disruption of this ERE-like sequence has been described in the human CaBP-9k gene, which is not expressed at any level in placenta, myometrium, or endometrium. It is concluded that the pig CaBP-9k gene is regulated in these reproductive tissues in a manner distinct from that in rat and human tissues. The regulation is probably due to a regulatory region outside of intron A, which in the rat gene contains the key cis element for uterine expression of the CaBP-9k gene.

G protein-coupled estrogen receptor 1-mediated effects in the rat myometrium.

PubMed

Tica, Andrei A; Dun, Erica C; Tica, Oana S; Gao, Xin; Arterburn, Jeffrey B; Brailoiu, G Cristina; Oprea, Tudor I; Brailoiu, Eugen

2011-11-01

G protein-coupled estrogen receptor 1 (GPER), also named GPR30, has been previously identified in the female reproductive system. In this study, GPER expression was found in the female rat myometrium by reverse transcriptase-polymerase chain reaction and immunocytochemistry. Using GPER-selective ligands, we assessed the effects of the GPER activation on resting membrane potential and cytosolic Ca(2+) concentration ([Ca(2+)](i)) in rat myometrial cells, as well as on contractility of rat uterine strips. G-1, a specific GPER agonist, induced a concentration-dependent depolarization and increase in [Ca(2+)](i) in myometrial cells. The depolarization was abolished in Na(+)-free saline. G-1-induced [Ca(2+)](i) increase was markedly decreased by nifedipine, a L-type Ca(2+) channel blocker, by Ca(2+)-free or Na(+)-free saline. Intracellular administration of G-1 produced a faster and transitory increase in [Ca(2+)](i), with a higher amplitude than that induced by extracellular application, supporting an intracellular localization of the functional GPER in myometrial cells. Depletion of internal Ca(2+) stores with thapsigargin produced a robust store-activated Ca(2+) entry; the Ca(2+) response to G-1 was similar to the constitutive Ca(2+) entry and did not seem to involve store-operated Ca(2+) entry. In rat uterine strips, administration of G-1 increased the frequency and amplitude of contractions and the area under the contractility curve. The effects of G-1 on membrane potential, [Ca(2+)](i), and uterine contractility were prevented by pretreatment with G-15, a GPER antagonist, further supporting the involvement of GPER in these responses. Taken together, our results indicate that GPER is expressed and functional in rat myometrium. GPER activation produces depolarization, elevates [Ca(2+)](i) and increases contractility in myometrial cells.

Effect of Silibinin in Reducing Inflammatory Pathways in In Vitro and In Vivo Models of Infection-Induced Preterm Birth

PubMed Central

Lim, Ratana; Morwood, Carrington J.; Barker, Gillian; Lappas, Martha

2014-01-01

Infection-induced preterm birth is the largest cause of infant death and of neurological disabilities in survivors. Silibinin, from milk thistle, exerts potent anti-inflammatory activities in non-gestational tissues. The aims of this study were to determine the effect of silibinin on pro-inflammatory mediators in (i) human fetal membranes and myometrium treated with bacterial endotoxin lipopolysaccharide (LPS) or the pro-inflammatory cytokine IL-1β, and (ii) in preterm fetal membranes with active infection. The effect of silibinin on infection induced inflammation and brain injury in pregnant mice was also assessed. Fetal membranes and myometrium (tissue explants and primary cells) were treated with 200 μM silibinin in the presence or absence of 10 μg/ml LPS or 1 ng/ml IL-1β. C57BL/6 mice were injected with 70 mg/kg silibinin with or without 50 μg LPS on embryonic day 16. Fetal brains were collected after 6 h. In human fetal membranes, silibinin significantly decreased LPS-stimulated expression of IL-6 and IL-8, COX-2, and prostaglandins PGE2 and PGF2α. In primary amnion and myometrial cells, silibinin also decreased IL-1β-induced MMP-9 expression. Preterm fetal membranes with active infection treated with silibinin showed a decrease in IL-6, IL-8 and MMP-9 expression. Fetal brains from mice treated with silibinin showed a significant decrease in LPS-induced IL-8 and ninjurin, a marker of brain injury. Our study demonstrates that silibinin can reduce infection and inflammation-induced pro-labour mediators in human fetal membranes and myometrium. Excitingly, the in vivo results indicate a protective effect of silibinin on infection-induced brain injury in a mouse model of preterm birth. PMID:24647589

Prevalence and clinical significance of mediator complex subunit 12 mutations in 362 Han Chinese samples with uterine leiomyoma.

PubMed

Wu, Juan; Zou, Yang; Luo, Yong; Guo, Jiu-Bai; Liu, Fa-Ying; Zhou, Jiang-Yan; Zhang, Zi-Yu; Wan, Lei; Huang, Ou-Ping

2017-07-01

Uterine leiomyomas (ULs) are the most common gynecological benign tumors originating from the myometrium. Prevalent mutations in the mediator complex subunit 12 (MED12) gene have been identified in ULs, and functional evidence has revealed that these mutations may promote the development of ULs. However, whether MED12 mutations are associated with certain clinical characteristics in ULs remains largely unknown. In the present study, the potential mutations of MED12 and its paralogous gene, mediator complex subunit 12-like (MED12L), were screened in 362 UL tumors from Han Chinese patients. A total of 158 out of 362 UL tumors (43.6%) were identified as harboring MED12 somatic mutations, and the majority of these mutations were restricted to the 44th residue. MED12 mutations were also observed in 2 out of 145 (1.4%) adjacent control myometrium. Furthermore, the mutation spectrum of MED12 in the concurrent leiomyomas was noticeably different. Correlation analysis of MED12 mutations with the available clinical features indicated that patients with mutated MED12 tended to have smaller cervical diameters. By contrast, no MED12L mutation was identified in the present samples. In summary, the present study demonstrated the presence of prevalent MED12 somatic mutations in UL samples, and the MED12 mutation was associated with smaller cervical diameters. The low mutation frequency of MED12 in adjacent control myometrium indicated that MED12 mutation may be an early event in the pathogenesis of ULs. Furthermore, MED12 mutation status in concurrent tumors from multiple leiomyomas supported several prior observations that the majority of these tumors arose independently.

Reduced Dermatopontin Expression Is a Molecular Link Between Uterine Leiomyomas and Keloids

PubMed Central

Catherino, William H.; Leppert, Phyllis C.; Stenmark, Matthew H.; Payson, Mark; Potlog-Nahari, Clariss; Nieman, Lynnette K.; Segars, James H.

2014-01-01

Uterine leiomyomas are prevalent estrogen-responsive clonal tumors, but the specific genetic alterations that contribute to their development have not been elucidated. To identify genes involved in the formation of leiomyomas, we used global expression profiling to compare clonal tumors with normal myometrium. Contrary to expectation, genes involved in estrogen action were not differentially expressed between leiomyoma and normal myometrium. Genes encoding extracellular-matrix proteins were prominently featured, suggesting their involvement in formation of a myofibroblast phenotype. Analysis of the extracellular matrix in the leiomyomas revealed a disordered collagen fibril orientation. Expression of the collagen-binding protein dermatopontin was found to be consistently decreased in leiomyoma by both reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR (mean underexpression = 9.41-fold) regardless of leiomyoma size, leiomyoma location, patient race, and patient age. This expression pattern was observed in 11 subjects and a total of 23 leiomyoma: myometrium pairs. Decreased expression of dermatopontin was also associated with keloid formation, a fibrotic disease that shares epidemiologic similarities with leiomyoma. Immunohistochemical studies of leiomyomas and keloids demonstrated reduced levels of dermatopontin in both tissues. In addition, ultrastructural analysis revealed that the orientation of the collagen fibrils in the keloid tissues strongly resembled that in the leiomyomas. Reduction in dermatopontin was associated with an increase in transforming growth factor–β3 (TGFB3) mRNA levels in leiomyomas, whereas other genes involved in dermatopontin signaling were not differentially expressed. These findings suggest that leiomyoma development involves a myofibroblast cell phenotype characterized by dysregulation of genes encoding extracellular-matrix proteins. In particular, decreased expression of dermatopontin represents a molecular link between the leiomyoma and keloid phenotypes. PMID:15139000

The HysNiche trial: hysteroscopic resection of uterine caesarean scar defect (niche) in patients with abnormal bleeding, a randomised controlled trial.

PubMed

Vervoort, A J M W; Van der Voet, L F; Witmer, M; Thurkow, A L; Radder, C M; van Kesteren, P J M; Quartero, H W P; Kuchenbecker, W K H; Bongers, M Y; Geomini, P M A J; de Vleeschouwer, L H M; van Hooff, M H A; van Vliet, H A A M; Veersema, S; Renes, W B; van Meurs, H S; Bosmans, J; Oude Rengerink, K; Brölmann, H A M; Mol, B W J; Huirne, J A F

2015-11-12

A caesarean section (CS) can cause a defect or disruption of the myometrium at the site of the uterine scar, called a niche. In recent years, an association between a niche and postmenstrual spotting after a CS has been demonstrated. Hysteroscopic resection of these niches is thought to reduce spotting and menstrual pain. However, there are no randomised trials assessing the effectiveness of a hysteroscopic niche resection. We planned a multicentre randomised trial comparing hysteroscopic niche resection to no intervention. We study women with postmenstrual spotting after a CS and a niche with a residual myometrium of at least 3 mm during sonohysterography. After informed consent is obtained, eligible women will be randomly allocated to hysteroscopic resection of the niche or expectant management for 6 months. The primary outcome is the number of days with postmenstrual spotting during one menstrual cycle 6 months after randomisation. Secondary outcomes are menstrual characteristics, menstruation related pain and experienced discomfort due to spotting or menstrual pain, quality of life, patient satisfaction, sexual function, urological symptoms, medical consultations, medication use, complications, lost productivity and medical costs. Measurements will be performed at baseline and at 3 and 6 months after randomisation. A cost-effectiveness analysis will be performed from a societal perspective at 6 months after randomisation. This trial will provide insight in the (cost)effectiveness of hysteroscopic resection of a niche versus expectant management in women who have postmenstrual spotting and a niche with sufficient residual myometrium to perform a hysteroscopic niche resection. Dutch Trial Register NTR3269 . Registered 1 February 2012. ZonMw Grant number 80-82305-97-12030.

Adenomyosis and Endometrial Cancer: Literature Review.

PubMed

Habiba, Marwan; Pluchino, Nicola; Petignat, Patrick; Bianchi, Paola; Brosens, Ivo A; Benagiano, Giuseppe

2018-06-06

To confirm the origin of cancer found in both the endometrium and the myometrium is difficult. Cancer may spread from the endometrium into adenomyotic foci or vice versa. Also, premalignant changes may arise at either or both sites. Investigating disease origin enhances our understanding of pathophysiology and prognosis. Additional critical questions are whether women with adenomyosis have a higher risk of endometrial cancer; whether the invasive properties and prognosis of cancer in adenomyosis differ from those arising in the eutopic endometrium and whether the ectopic glandular tissue in adenomyosis becomes altered in the presence of eutopic endometrial cancer. A final question is whether cancer arising within adenomyosis carries a worse prognosis because of its location within the myometrium and the possibility that the presence of adenomyosis facilitates invasion of cancer arising in the eutopic endometrium. The present review explores currently available literature in an attempt to answer these questions and to examine clinical presentations, diagnostic criteria, pathogenesis and prognosis. © 2018 S. Karger AG, Basel.

A molecular signature of an arrest of descent in human parturition

PubMed Central

MITTAL, Pooja; ROMERO, Roberto; TARCA, Adi L.; DRAGHICI, Sorin; NHAN-CHANG, Chia-Ling; CHAIWORAPONGSA, Tinnakorn; HOTRA, John; GOMEZ, Ricardo; KUSANOVIC, Juan Pedro; LEE, Deug-Chan; KIM, Chong Jai; HASSAN, Sonia S.

2010-01-01

Objective This study was undertaken to identify the molecular basis of an arrest of descent. Study Design Human myometrium was obtained from women in term labor (TL; n=29) and arrest of descent (AODes, n=21). Gene expression was characterized using Illumina® HumanHT-12 microarrays. A moderated t-test and false discovery rate adjustment were applied for analysis. Confirmatory qRT-PCR and immunoblot was performed in an independent sample set. Results 400 genes were differentially expressed between women with an AODes compared to those with TL. Gene Ontology analysis indicated enrichment of biological processes and molecular functions related to inflammation and muscle function. Impacted pathways included inflammation and the actin cytoskeleton. Overexpression of HIF1A, IL-6, and PTGS2 in AODES was confirmed. Conclusion We have identified a stereotypic pattern of gene expression in the myometrium of women with an arrest of descent. This represents the first study examining the molecular basis of an arrest of descent using a genome-wide approach. PMID:21284969

Differential effects of tumor necrosis factor-α on matrix metalloproteinase-2 expression in human myometrial and uterine leiomyoma smooth muscle cells.

PubMed

Wang, Yuebing; Feng, Guowei; Wang, Jiyuan; Zhou, Yu; Liu, Yixin; Shi, Yiquan; Zhu, Yingjun; Lin, Wanjun; Xu, Yang; Li, Zongjin

2015-01-01

Does tumor necrosis factor-α (TNF-α) differentially regulate matrix metalloproteinase-2 (MMP-2) expression in leiomyomas compared with normal myometrium? TNF-α up-regulates MMP-2 expression and stimulates cell migration through the activation of extracellular signal-regulated kinase (ERK) signaling pathway in leiomyoma smooth muscle cells (SMCs), but not in normal myometrial SMCs. Uterine leiomyoma, the benign smooth muscle cell tumor, is the single most common indication for hysterectomy. High expression of MMPs or TNF-α has been reported in uterine leiomyomas; however, the molecular mechanism underlying these observations remains unknown. Samples were obtained between 2009 and 2013 from 12 women of reproductive age at the proliferative phase of the menstrual cycle by hysterectomy. Leiomyomas and matched normal myometrium from each woman were analyzed in vitro. Western blot, RT-qPCR and a wound-healing assay were used to investigate the effects of TNF-α on MMP-2 expression and intracellular signal transduction in cultured SMCs from leiomyomas and matched myometrium. Western blot and RT-qPCR analyses using tissues from clinical patients showed that the levels of MMP-2 protein (P = 0.008) and mRNA (P = 0.009) were significantly higher in uterine leiomyomas compared with their matched myometrium. Treatment with TNF-α significantly up-regulated the protein (P = 0.039) and mRNA (P = 0.037) levels of MMP-2 in cultured leiomyoma SMCs but not in matched myometrial SMCs. The extracellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways were activated by TNF-α in leiomyoma SMCs. Specific inhibitors of the ERK or NF-κB pathway (PD98059 or Bay11-7082) suppressed TNF-α-induced MMP-2 expression in leiomyoma SMCs. The wound-healing assay revealed that TNF-α promoted the migration of cultured leiomyoma SMCs (P = 0.036); however, PD98059 compromised the cell migration triggered by TNF-α. This study is descriptive and although we observed clear differential regulation of MMP-2 by TNF-α at mRNA and protein levels in leiomyoma, future studies are needed to identify why the difference in TNF-α response exists between human leiomyoma tissue and normal myometrium. Including some of the experiments such as transfection studies for TNF-α and MMP-2 promoter mapping could have added more insight as to why this difference exists. In addition, further studies in vivo are needed to verify the results obtained from primary cultured SMCs. Considering the positive effect of TNF-α on leiomyoma SMC migration, strategies targeting TNF-α, in parallel with the production of more specific inhibitors of MMPs, may provide alternative therapeutic approaches for the treatment of leiomyoma. This work was partially supported by grants from the Program for New Century Excellent Talents in University (NCET-12-0282), National Natural Science Foundation of China (81371620) and Tianjin Natural Science Foundation (12JCZDJC24900). The authors have no conflicts of interest to declare. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Retained placenta: will medical treatment ever be possible?

PubMed

Akol, Achier D; Weeks, Andrew D

2016-05-01

The standard treatment for retained placenta is manual removal whatever its subtype (adherens, trapped or partial accreta). Although medical treatment should reduce the risk of anesthetic and surgical complications, they have not been found to be effective. This may be due to the contrasting uterotonic needs of the different underlying pathologies. In placenta adherens, oxytocics have been used to contract the retro-placental myometrium. However, if injected locally through the umbilical vein, they bypass the myometrium and perfuse directly into the venous system. Intravenous injection is an alternative but exacerbates a trapped placenta. Conversely, for trapped placentas, a relaxant could help by resolving cervical constriction, but would worsen the situation for placenta adherens. This confusion over medical treatment will continue unless we can find a way to diagnose the underlying pathology. This will allow us to stop treating the retained placenta as a single entity and to deliver targeted treatments. © 2016 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).

Mechanisms leading to increased risk of preterm birth in growth-restricted guinea pig pregnancies.

PubMed

Palliser, Hannah K; Kelleher, Meredith A; Welsh, Toni N; Zakar, Tamas; Hirst, Jonathan J

2014-02-01

Intrauterine growth restriction (IUGR) is a risk factor for preterm labor; however, the mechanisms of the relationship remain unknown. Prostaglandin (PG), key stimulants of labor, availability is regulated by the synthetic enzymes, prostaglandin endoperoxidases 1 and 2 (PTGS1 and 2), and the metabolizing enzyme, 15-hydroxyprostaglandin dehydrogenase (HPGD). We hypothesized that IUGR increases susceptibility to preterm labor due to the changing balance of synthetic and metabolizing enzymes and hence greater PG availability. We have tested this hypothesis using a surgically induced IUGR model in guinea pigs, which results in significantly shorter gestation. Myometrium, amnion, chorion, and placentas were collected from sham operated or IUGR pregnancies, and PTGS1 and HPGD protein expression were quantified throughout late gestation (>62 days) and labor. The PTGS1 expression was significantly upregulated in the myometrium of IUGR animals, and chorionic HPGD expression was markedly decreased (P < .01 and P < .001, respectively). These findings suggest a shift in the balance of PG production over metabolism in IUGR pregnancies leads to a greater susceptibility to preterm birth.

Placenta accreta: pathogenesis of a 20th century iatrogenic uterine disease.

PubMed

Jauniaux, E; Jurkovic, D

2012-04-01

Placenta accreta refers to different grades of abnormal placental attachment to the uterine wall, which are characterised by invasion of trophoblast into the myometrium. Placenta accreta has only been described and studied by pathologists for less than a century. The fact that the first detailed description of a placenta accreta happened within a couple of decades of major changes in the caesarean surgical techniques is highly suggestive of a direct relationship between prior uterine surgery and abnormal placenta adherence. Several concepts have been proposed to explain the abnormal placentation in placenta accreta including a primary defect of the trophoblast function, a secondary basalis defect due to a failure of normal decidualization and more recently an abnormal vascularisation and tissue oxygenation of the scar area. The vast majority of placenta accreta are found in women presenting with a previous history of caesarean section and a placenta praevia. Recent epidemiological studies have also found that the strongest risk factor for placenta praevia is a prior caesarean section suggesting that a failure of decidualization in the area of a previous uterine scar can have an impact on both implantation and placentation. Ultrasound studies of uterine caesarean section scar have shown that large and deep myometrial defects are often associated with absence of re-epithelialisation of the scar area. These findings support the concept of a primary deciduo-myometrium defect in placenta accreta, exposing the myometrium and its vasculature below the junctional zone to the migrating trophoblast. The loss of this normal plane of cleavage and the excessive vascular remodelling of the radial and arcuate arteries can explain the in-vivo findings and the clinical consequence of placenta accreta. Overall these data support the concept that abnormal decidualization and trophoblastic changes of the placental bed in placenta accreta are secondary to the uterine scar and thus entirely iatrogenic. Copyright © 2011 Elsevier Ltd. All rights reserved.

Altered expression of histone deacetylases, inflammatory cytokines and contractile-associated factors in uterine myometrium of Long Evans rats gestationally exposed to benzo[a]pyrene

PubMed Central

Laknaur, Archana; Foster, Terri-Lee; Bobb, Lesley E.; Ramesh, Aramandla; Ladson, Gwinnett M.; Hood, Darryl B.; Al-Hendy, Ayman; Thota, Chandrasekhar

2017-01-01

Etiology of preterm birth (PTB) is multifactorial; therefore, decreasing the incidence of PTB is a major challenge in the field of obstetrics. Epidemiological studies have reported an association between toxicants and PTB. However, there are no studies on the role of benzo[a]pyrene (BaP), an environmental toxicant, in the incidence of PTB. We first assessed the effects of BaP (150 and 300 μg kg−1 body weight) dosed via gavage from day 14 to 17 of pregnancy on gestation length in Long Evans rats. We further assessed the histopathology of the uterus, expression of inflammatory cytokines, contractile-associated factors, histone deacetylases (HDACs) and NFқB-p65 in myometrium collected on day 22 postpartum versus vehicle-treated controls. In our study, rats exposed to BaP delivered prematurely (P < 0.05) compared to control. Hematoxylin and eosin staining of uterus showed squamous metaplasia, glandular and stromal hyperplasia in BaP-exposed rats versus control. The concentrations of BaP metabolites measured by high-pressure liquid chromatography were higher in uterine myometrium of BaP-exposed rats while they were undetectable in controls. Quantitative real-time polymerase chain reaction showed significant increases in mRNA expression of interleukin-1β and -8, tumor necrosis factor-α, connexin 43, cyclo-oxygenase-2 and prostaglandin F2α receptor as compared to controls (P < 0.05). Western blot analysis revealed that BaP exposure caused decreases in class I HDACs 1 and 3 and increases in class II HDAC 5, cyclo-oxygenase-2 and nuclear translocation of NFκB-p65 relative to controls. Our results suggest that gestational exposure to BaP increases incidence of PTB through epigenetic changes that causes increases in the expression of contractile-associated factors through the NFκB pathway. PMID:26358852

Titanium Dioxide Modulation of the Contractibility of Visceral Smooth Muscles In Vivo

NASA Astrophysics Data System (ADS)

Tsymbalyuk, Olga V.; Naumenko, Anna M.; Rohovtsov, Oleksandr O.; Skoryk, Mykola A.; Voiteshenko, Ivan S.; Skryshevsky, Valeriy A.; Davydovska, Tamara L.

2017-02-01

Electronic scanning microscopy was used in the work to obtain the image and to identify the sizes of titanium dioxide (TiO2) nanoparticles 21 ± 5 nm. The qualitative and quantitative elemental analysis of the preparations of the caecum, antrum, myometrium, kidneys, and lungs of the rats, burdened with titanium dioxide, was also performed. It was established using the tenzometric method in the isometric mode that the accumulation of titanium dioxide in smooth muscles of the caecum resulted in the considerable, compared to the control, increase in the frequency of their spontaneous contractions, the decrease in the duration of the contraction-relaxation cycle, and the decrease in the indices of muscle functioning efficiency (the index of contractions in Montevideo units (MU) and the index of contractions in Alexandria units (AU)). In the same experimental conditions, there was not the increase, but the decrease in the frequency of spontaneous contractions, the duration of the contraction-relaxation cycle, and the increase in MU and AU indices in the smooth muscles of myometrium (in the group of rats, burdened with TiO2 for 30 days). It was also determined that TiO2 modulates both the mechanisms of the input of extracellular Ca2+ ions and the mechanisms of decreasing the concentration of these cations in smooth muscle cells of the caecum during the generation of the high potassium contraction. In these conditions, there is a considerable increase in the normalized maximal velocity of the contraction phase and the relaxation phase. It was demonstrated in the work that titanium dioxide also changes the cholinergic excitation in these muscles. The impact of titanium dioxide in the group of rats, burdened with TiO2, was accompanied with a considerable impairment of the kinetics of forming the tonic component of the oxytocin-induced contraction of the smooth muscles of myometrium.

Endometrial cancer: correlation of apparent diffusion coefficient with tumor grade, depth of myometrial invasion, and presence of lymph node metastases.

PubMed

Rechichi, Gilda; Galimberti, Stefania; Signorelli, Mauro; Franzesi, Cammillo Talei; Perego, Patrizia; Valsecchi, Maria Grazia; Sironi, Sandro

2011-07-01

The objective of our study was to investigate whether apparent diffusion coefficient (ADC) values of endometrial cancer differ from those of normal endometrium and myometrium and whether they vary according to histologic tumor grade, the depth of myometrial invasion, or lymph node status. Seventy patients with histologically proved endometrial cancer and 36 control subjects with normal endometrium were enrolled in this prospective study. T2-weighted, dynamic T1-weighted, and diffusion-weighted images with b values of 0 and 1000 s/mm(2) were obtained of all patients. The ADC values of endometrial cancer, normal endometrium, and normal myometrium were recorded. Tumor grade, the depth of myometrial invasion, and lymph node status were assessed at postoperative histopathologic analysis. The mean (± SD) ADC value (10(-3) mm(2)/s) of endometrial cancer (0.77 ± 0.12) was significantly lower than that of normal endometrium (1.31 ± 0.11, p < 0.0001) and normal myometrium (1.52 ± 0.21, p < 0.0001), with no overlap between the two former distributions. There was no significant difference between ADC values of endometrial cancer tissue in patients with tumor grade 1 (0.79 ± 0.08, n = 14), grade 2 (0.76 ± 0.14, n = 40), or grade 3 (0.75 ± 0.12, n = 16) (p = 0.67); in patients with deep (0.77 ± 0.13, n = 18) and those with superficial (0.76 ± 0.12, n = 52) myometrial invasion (p = 0.87); and in patients with (0.78 ± 0.10, n = 6) and those without (0.75 ± 0.14, n = 39) lymph node metastases (p = 0.64). ADC values allow normal endometrium to be differentiated from endometrial carcinoma; however, they do not correlate with histologic tumor grade, the depth of myometrial invasion, or whether lymph node metastases are present.

Sodium leak channel, non-selective contributes to the leak current in human myometrial smooth muscle cells from pregnant women.

PubMed

Reinl, Erin L; Cabeza, Rafael; Gregory, Ismail A; Cahill, Alison G; England, Sarah K

2015-10-01

Uterine contractions are tightly regulated by the electrical activity of myometrial smooth muscle cells (MSMCs). These cells require a depolarizing current to initiate Ca(2+) influx and induce contraction. Cationic leak channels, which permit a steady flow of cations into a cell, are known to cause membrane depolarization in many tissue types. Previously, a Gd(3+)-sensitive, Na(+)-dependent leak current was identified in the rat myometrium, but the presence of such a current in human MSMCs and the specific ion channel conducting this current was unknown. Here, we report the presence of a Na(+)-dependent leak current in human myometrium and demonstrate that the Na(+)-leak channel, NALCN, contributes to this current. We performed whole-cell voltage-clamp on fresh and cultured MSMCs from uterine biopsies of term, non-laboring women and isolated the leak currents by using Ca(2+) and K(+) channel blockers in the bath solution. Ohmic leak currents were identified in freshly isolated and cultured MSMCs with normalized conductances of 14.6 pS/pF and 10.0 pS/pF, respectively. The myometrial leak current was significantly reduced (P < 0.01) by treating cells with 10 μM Gd(3+) or by superfusing the cells with a Na(+)-free extracellular solution. Reverse transcriptase PCR and immunoblot analysis of uterine biopsies from term, non-laboring women revealed NALCN messenger RNA and protein expression in the myometrium. Notably, ∼90% knockdown of NALCN protein expression with lentivirus-delivered shRNA reduced the Gd(3+)-sensitive leak current density by 42% (P < 0.05). Our results reveal that NALCN, in part, generates the leak current in MSMCs and provide the basis for future research assessing NALCN as a potential molecular target for modulating uterine excitability. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Treatment with eCG decreases the vascular density and increases the glandular density of the bovine uterus.

PubMed

Mona e Pinto, J; Pavanelo, V; Alves de Fátima, L; Medeiros de Carvalho Sousa, L M; Pacheco Mendes, G; Machado Ferreira, R; Ayres, H; Sampaio Baruselli, P; Palma Rennó, F; de Carvallo Papa, P

2014-06-01

The uterus plays an essential role in mammalian reproduction and is a target of several hormonal protocols used to improve fertility in cattle. Many studies highlighted the importance of eCG treatment following fixed-time artificial insemination in improving follicular growth, ovulation and pregnancy rates in cattle. Moreover, eCG has been implicated in angiogenesis, leading to important changes in uterine blood flow and vascularisation. However, there is still a lack of information regarding the specific alterations induced by eCG upon glandular and vascular characteristics of bovine uterus. To investigate the influence of eCG on: uterine thickness and area; uterine artery diameter and area; uterine vascular and gland density; and the expression of the VEGFA-system, the uteri of crossbred beef cows were collected. All cows were submitted to follicular wave emergence synchronization. On day four of protocol, cows submitted to superovulation (n = 6) received 2000 IU eCG, on day eight, after expected follicular deviation, cows submitted to stimulatory treatment (n = 5) received 400 IU eCG. Control cows (n = 5) did not receive eCG. On day five po cows were subjected to ultrassonographic evaluation and slaughtered for uterine tissue sampling on day six po. Uterine vessels and glands were quantified by the counting point stereological method. The VEGFA-system was localized in different cellular types, showing no qualitative or quantitative differences in the site of expression or the intensity of the positive signal among the groups. Vascular density was decreased in the endometrium of stimulated and myometrium of superovulated cows compared with the control ones, which showed higher vascular density in the myometrium and endometrium of the ipsilateral uterine horn. The uterine gland density was higher in superovulated compared with stimulated and control cows. Thus, we can infer that stimulatory or superovulatory treatments with eCG influence the vascular density in the endometrium and myometrium in cattle. © 2014 Blackwell Verlag GmbH.

Identification of myoelectric signals of pregnant rat uterus: new method to detect myometrial contraction

PubMed Central

Szűcs, Kálmán F.; Grosz, György; Süle, Miklós; Nagy, Anikó; Tiszai, Zita; Samavati, Reza; Gáspár, Róbert

2017-01-01

Aim To develop an electromyography method for pregnant rat uterus in vivo and to separate myometrial signals from the gastrointestinal tract signals. Methods Pregnant Sprague-Dawley rats (n = 8) were anaesthetized and their stomach, small intestine, and large intestine were removed from the abdomen. A pair of thread electrodes was inserted into the uterus, while a pair of disk electrodes was placed subcutaneously above the myometrium. Additionally, a strain gauge sensor was fixed on the surface of the myometrium and cecum for the parallel detection of mechanical contractions in rats (n = 18) with intact gastrointestinal tract. The filtered electric signals were amplified and recorded by an online computer system and analyzed by fast Fourier transformation. The frequency of the electric activity was characterized by cycle per minute (cpm), the magnitude of the activity was described as power spectrum density maximum (PsDmax). Results The frequency of the pregnant uterine activity was 1-3 cpm, which falls within the same range as that of cecum. Measuring by both electrodes, oxytocin (1 µg/kg) increased and terbutaline (50 µg/kg) decreased the PsDmax by 25%-50% (P < 0.001) and 25%-40% (P < 0.01), respectively. We found a strong positive correlation between the alterations of PsDmax values and the strain gauge sensor-detected mechanical contractions (area under curve). The GI specific compounds (neostigmine, atropine) mainly affected the cecal activity, while myometrium specific drugs (oxytocin, terbutaline) influenced the myometrial signals only. Conclusion Our method proved to be able to detect the myoelectric activity that reflects the mechanical contraction. The overlapping myometrial and cecal signals are not separable, but they can be distinguished based on the much higher activity and different pharmacological reactivity of the pregnant uterus. Thus, the early signs of contractions can be detected and labor may be predicted in a fast and sensitive way. PMID:28409497

Enterobius vermicularis infestation of a hysterectomy specimen in a patient with a colonic reservoir.

PubMed

Worley, Michael J; Slomovitz, Brian M; Pirog, Edyta C; Caputo, Thomas A; Ledger, William J

2009-06-01

A 43-year-old woman (gravida 2, para 1011) with a history of uterine leiomyomata and a Barnett colonic reservoir underwent a supracervical hysterectomy. Final pathology revealed Enterobius vermicularis within the myometrium and adnexal vasculature. Infection may have occurred through a modified mode given the presence of a Barnett colonic reservoir and absence of an anus.

The Role of Hysteroscopy in the Diagnosis and Treatment of Adenomyosis.

PubMed

Di Spiezio Sardo, Attilio; Calagna, Gloria; Santangelo, Fabrizia; Zizolfi, Brunella; Tanos, Vasilis; Perino, Antonino; De Wilde, Rudy Leon

2017-01-01

Uterine adenomyosis is a common gynecologic disorder in women of reproductive age, characterized by the presence of ectopic endometrial glands and stroma within the myometrium. Dysmenorrhea, abnormal uterine bleeding, chronic pelvic pain, and deep dyspareunia are common symptoms of this pathological condition. However, adenomyosis is often an incidental finding in specimens obtained from hysterectomy or uterine biopsies. The recent evolution of diagnostic imaging techniques, such as transvaginal sonography, hysterosalpingography, and magnetic resonance imaging, has contributed to improving accuracy in the identification of this pathology. Hysteroscopy offers the advantage of direct visualization of the uterine cavity while giving the option of collecting histological biopsy samples under visual control. Hysteroscopy is not a first-line treatment approach for adenomyosis and it represents a viable option only in selected cases of focal or diffuse "superficial" forms. During office hysteroscopy, it is possible to enucleate superficial focal adenomyomas or to evacuate cystic haemorrhagic lesions of less than 1.5 cm in diameter. Instead, resectoscopic treatment is indicated in cases of superficial adenomyotic nodules > 1.5 cm in size and for diffuse superficial adenomyosis. Finally, endometrial ablation may be performed with the additional removal of the underlying myometrium.

Molecular Regulation of Parturition: A Myometrial Perspective

PubMed Central

Renthal, Nora E.; Williams, Koriand’r C.; Montalbano, Alina P.; Chen, Chien-Cheng; Gao, Lu; Mendelson, Carole R.

2015-01-01

The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P4) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called “contractile” genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17β (E2) and/or increased estrogen receptor α (ERα) activity and a sharp decline in circulating P4 levels. However, in women, circulating levels of P4 and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P4 and estradiol-17β. The integrative roles of microRNAs also are considered. PMID:26337112

Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth.

PubMed

Asano, Ryoko; Asai-Sato, Mikiko; Miyagi, Yohei; Mizushima, Taichi; Koyama-Sato, Makiko; Nagashima, Yoji; Taguri, Masataka; Sakakibara, Hideya; Hirahara, Fumiki; Miyagi, Etsuko

2015-08-01

Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth. Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry. EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test). This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas. Copyright © 2015 Elsevier Inc. All rights reserved.

Integrated microRNA and mRNA network analysis of the human myometrial transcriptome in the transition from quiescence to labor.

PubMed

Ackerman, William E; Buhimschi, Irina A; Brubaker, Douglas; Maxwell, Sean; Rood, Kara M; Chance, Mark R; Jing, Hongwu; Mesiano, Sam; Buhimschi, Catalin S

2018-02-13

We conducted integrated transcriptomics network analyses of miRNA and mRNA interactions in human myometrium to identify novel molecular candidates potentially involved in human parturition. Myometrial biopsies were collected from women undergoing primary Cesarean deliveries in well-characterized clinical scenarios: 1) spontaneous term labor (TL, n = 5); 2) term non-labor (TNL, n = 5); 3) spontaneous preterm birth (PTB) with histologic chorioamnionitis (PTB-HCA, n = 5); and 4) indicated PTB non-labor (PTB-NL, n = 5). MicroRNAs and long RNAs were profiled using RNA sequencing, and miRNA-target interaction networks were mined for key discriminatory subnetworks. Forty miRNAs differed between TL and TNL myometrium while seven miRNAs differed between PTB-HCA vs. PTB-NL specimens; six of these miRNAs were cross-validated using quantitative PCR. Based on the combined sequencing data, unsupervised clustering revealed two non-overlapping cohorts that differed primarily by absence or presence of uterine quiescence, rather than gestational age or original clinical cohort. The intersection of differentially expressed miRNAs and their mRNA targets predicted 22 subnetworks with enriched representation of miR-146b-5p, miR-223-3p, and miR-150-5p among miRNAs, and of myocyte enhancer factor-2C (MEF2C) among mRNAs. Of four known MEF2 transcription factors, decreased MEF2A and MEF2C expression in women with uterine non-quiescence was observed in the transcriptome profiling data, and validated in a second cohort by quantitative PCR. Immunohistochemistry localized MEF2A and MEF2C to myometrial smooth muscle cells and confirmed decreased abundance with labor. Collectively, these results suggest that repression of MEF2 expression may represent a previously unrecognized process through which miRNAs contribute to the phenotypic switch from quiescence to labor in human myometrium. © The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Phorbol 12,13-dibutyrate-induced protein kinase C activation triggers sustained contracture in human myometrium in vitro.

PubMed

Massenavette, Laurence; Paul, Wilène; Corriveau, Stéphanie; Pasquier, Jean-Charles; Rousseau, Éric

2017-09-01

Although physiologic transition from rhythmic contractions to uterine retraction postpartum remains a poorly understood process, it has been shown that the latter is essential in the prevention of hemorrhage and its negative consequences. To investigate the transition from oscillatory contractions to tonic contracture in human myometrium after delivery, a mechanism purported to facilitate postpartum hemostasis. Protein kinase C (PKC) plays a key regulatory role in human uterine contractions because it can prevent dephosphorylation of regulatory proteins and sensitize the contractile machinery to low Ca 2+ . Thus, activation of PKC by phorbol 12,13-dibutyrate (PDBu) may act as a strong uterotonic agent. Uterine biopsies were obtained from consenting women undergoing elective caesarian delivery at term without labor (N = 19). Isometric tension measurements were performed on uterine strips (n = 114). The amplitudes and area under the curve of phasic contractions and tonic responses were measured and compared. A total of 1 μM PDBu was added to the isolated organ baths, and maximal tension of the uterine contracture was determined in the absence and presence of either 1 μM of staurosporine, 100 nM nifedipine, or 10 μM cyclopiazonic acid to assess the role of PKC and calcium sensitivity on uterine contractility. On the addition of PDBu on either basal or oxytocin-induced activity, consistent contractures were obtained concomitant with complete inhibition of phasic contractions. After a 30-minute incubation period, the mean amplitude of the PDBu-induced tone represented 65.3% of the amplitude of spontaneous contraction. Staurosporine, a protein kinase inhibitor, induced a 91.9% inhibition of PDBu contractures, a process not affected by nifedipine or cyclopiazonic acid, thus indicating that this mechanism is largely Ca 2+ independent. Pharmacologic activation of PKC leads to a significant contracture of the myometrium. Together, these data suggest that the up-regulation of PKC plays a physiologic role in the modulation of uterine contracture after delivery. A switch from phasic to strong tonic contractions potentially may facilitate postpartum hemostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

Abnormal expression of leiomyoma cytoskeletal proteins involved in cell migration.

PubMed

Ura, Blendi; Scrimin, Federica; Arrigoni, Giorgio; Athanasakis, Emmanouil; Aloisio, Michelangelo; Monasta, Lorenzo; Ricci, Giuseppe

2016-05-01

Uterine leiomyomas are monoclonal tumors. Several factors are involved in the neoplastic transformation of the myometrium. In our study we focused on dysregulated cytoskeletal proteins in the leiomyoma as compared to the myometrium. Paired tissue samples of ten leiomyomas and adjacent myometria were obtained and analyzed by two‑dimensional gel electrophoresis (2-DE). Mass spectrometry was used for protein identification, and western blotting for 2-DE data validation. The values of ten cytoskeletal proteins were found to be significantly different: eight proteins were upregulated in the leiomyoma and two proteins were downregulated. Three of the upregulated proteins (myosin regulatory light polypeptide 9, four and a half LIM domains protein 1 and LIM and SH3 domain protein 1) are involved in cell migration, while downregulated protein transgelin is involved in replicative senescence. Myosin regulatory light polypeptide 9 (MYL9) was further validated by western blotting because it is considered to be a cell migration marker in several cancers and could play a key role in leiomyoma development. Our data demonstrate significant alterations in the expression of cytoskeletal proteins involved in leiomyoma growth. A better understanding of the involvement of cytoskeletal proteins in leiomyoma pathogenesis may contribute to the identification of new therapeutic targets and the development of new pharmacological approaches.

Perioperative Internal Iliac Artery Balloon Occlusion, In the Setting of Placenta Accreta and Its Variants: The Role of the Interventional Radiologist.

PubMed

Petrov, David A; Karlberg, Benjamin; Singh, Kamalpreet; Hartman, Matthew; Mittal, Pardeep K

2017-11-10

Placenta accreta and its variants (increta and percreta) are conditions of abnormal placentation that are encountered with increasing frequency. The spectrum of placenta accreta (including placenta increta and percreta) involves an abnormal attachment of the placental chorionic villi to the uterine myometrium. This abnormal attachment leads to increased adherence of the placenta to the uterus and abnormal placental-uterine separation at the time of delivery. Placental invasion into, or through the myometrium is associated with increased postpartum morbidity and mortality as a result of uterine hemorrhage during and following cesarean section. A multidisciplinary clinical approach to the treatment of patients with placenta accreta is recommended by the American College of Obstetricians and Gynecologists. As potential members of an interdisciplinary team, interventional radiologists can perform prophylactic internal iliac arterial balloon occlusion as an adjunctive therapy for reducing potentially life-threatening postpartum hemorrhage. The procedure involves placement of a balloon catheter into the internal iliac or common iliac arteries bilaterally prior to cesarean section. Following delivery, and prior to placental separation, the catheter balloons are inflated with a pre-determined volume of saline leading to transient occlusion of the internal iliac arteries and reduced uterine blood flow. Copyright © 2017 Elsevier Inc. All rights reserved.

Value of in vitro acoustic radiation force impulse application on uterine adenomyosis.

PubMed

Bildaci, Tevfik Berk; Cevik, Halime; Yilmaz, Birnur; Desteli, Guldeniz Aksan

2017-11-24

Adenomyosis is the presence of endometrial glandular and stromal tissue in the myometrium. This phenomenon can be the cause of excessive bleeding and menstrual pain in premenopausal women. Diagnosis of adenomyosis may present difficulty with conventional methods such as ultrasound and magnetic resonance imaging. Frequently, diagnosis is accomplished retrospectively based on the hysterectomy specimen. This is a prospective case control study done in vitro on 90 patients' hysterectomy specimens. Acoustic radiation force impulse (ARFI) and color elastography were used to determine the elasticity of hysterectomy specimens of patients undergoing indicated surgeries. Based on histopathological examinations, two groups were formed: a study group (n = 28-with adenomyosis) and a control group (n = 62-without adenomyosis). Elasticity measurements of tissue with adenomyosis were observed to be significantly higher than measurements of normal myometrial tissue (p < 0.01). Uterine fibroids were found to have higher values on ARFI study compared to normal myometrial tissues (p < 0.01). The findings lead to the conclusion that adenomyosis tissue is significantly softer than the normal myometrium. ARFI was found to be beneficial in differentiating myometrial tissue with adenomyosis from normal myometrial tissue. It was found to be feasible and beneficial to implement ARFI in daily gynecology practice for diagnosis of adenomyosis.

Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates

PubMed Central

Waldorf, Kristina M. Adams; Singh, Natasha; Mohan, Aarthi R.; Young, Roger C.; Ngo, Lisa; Das, Ananya; Tsai, Jesse; Bansal, Aasthaa; Paolella, Louis; Herbert, Bronwen R.; Sooranna, Suren R.; Gough, G. Michael; Astley, Cliff; Vogel, Keith; Baldessari, Audrey E.; Bammler, Theodor K.; MacDonald, James; Gravett, Michael G.; Rajagopal, Lakshmi; Johnson, Mark R.

2015-01-01

OBJECTIVE Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. STUDY DESIGN A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace. RESULTS Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an “inflammatory pulse” that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth. CONCLUSION Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension. PMID:26284599

Identification of interactive gene networks: a novel approach in gene array profiling of myometrial events during guinea pig pregnancy.

PubMed

Mason, Clifford W; Swaan, Peter W; Weiner, Carl P

2006-06-01

The transition from myometrial quiescence to activation is poorly understood, and the analysis of array data is limited by the available data mining tools. We applied functional analysis and logical operations along regulatory gene networks to identify molecular processes and pathways underlying quiescence and activation. We analyzed some 18,400 transcripts and variants in guinea pig myometrium at stages corresponding to quiescence and activation, and compared them to the nonpregnant (control) counterpart using a functional mapping tool, MetaCore (GeneGo, St Joseph, MI) to identify novel gene networks composed of biological pathways during mid (MP) and late (LP) pregnancy. Genes altered during quiescence and or activation were identified following gene specific comparisons with myometrium from nonpregnant animals, and then linked to curated pathways and formulated networks. The MP and LP networks were subtracted from each other to identify unique genomic events during those periods. For example, changes 2-fold or greater in genes mediating protein biosynthesis, programmed cell death, microtubule polymerization, and microtubule based movement were noted during the transition to LP. We describe a novel approach combining microarrays and genetic data to identify networks associated with normal myometrial events. The resulting insights help identify potential biomarkers and permit future targeted investigations of these pathways or networks to confirm or refute their importance.

The potential role of elastography in differentiating between endometrial polyps and submucosal fibroids: a preliminary study

PubMed Central

2015-01-01

Endometrial polyps and submucosal fibroids are common causes of abnormal uterine bleeding (AUB) and less commonly infertility. The prevalence of such intrauterine lesions increases with age during the reproductive years, and usually decreases after menopause. The first-line imaging examination in the diagnosis of endometrial polyps as well as submucosal fibroidsis ultrasound, but its accuracy is not obvious. Elastography is an ultrasound-based imaging modality that is used to assess the stiffness of examined tissues. Considering the fact that endometrial polyps derive from soft endometrial tissue and submucosal fibroids are made of hard muscle tissue, elastography seems a perfect tool to differentiate between such lesions. I present two groups of patients with AUB and intrauterine lesions suspected on ultrasound. In the first group of patients, elastography showed that the stiffness of the lesion was similar to the endometrium and softer than the myometrium. During hysteroscopies endometrial polyps were removed. In the second group of patients, elastography showed that the stiffness of the lesion was similar to the myometrium and harder than the endometrium. During hysteroscopies submucosal fibroids were removed. In both groups, the diagnosis was confirmed by the pathological examination in all cases. It was demonstrated that with the use of elastography it is possible to assess the stiffness of intrauterine lesions, which may be useful in differentiating between endometrial polyps and submucosal fibroids. PMID:26327901

The potential role of elastography in differentiating between endometrial polyps and submucosal fibroids: a preliminary study.

PubMed

Woźniak, Sławomir

2015-06-01

Endometrial polyps and submucosal fibroids are common causes of abnormal uterine bleeding (AUB) and less commonly infertility. The prevalence of such intrauterine lesions increases with age during the reproductive years, and usually decreases after menopause. The first-line imaging examination in the diagnosis of endometrial polyps as well as submucosal fibroidsis ultrasound, but its accuracy is not obvious. Elastography is an ultrasound-based imaging modality that is used to assess the stiffness of examined tissues. Considering the fact that endometrial polyps derive from soft endometrial tissue and submucosal fibroids are made of hard muscle tissue, elastography seems a perfect tool to differentiate between such lesions. I present two groups of patients with AUB and intrauterine lesions suspected on ultrasound. In the first group of patients, elastography showed that the stiffness of the lesion was similar to the endometrium and softer than the myometrium. During hysteroscopies endometrial polyps were removed. In the second group of patients, elastography showed that the stiffness of the lesion was similar to the myometrium and harder than the endometrium. During hysteroscopies submucosal fibroids were removed. In both groups, the diagnosis was confirmed by the pathological examination in all cases. It was demonstrated that with the use of elastography it is possible to assess the stiffness of intrauterine lesions, which may be useful in differentiating between endometrial polyps and submucosal fibroids.

Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition

PubMed Central

Fetalvero, Kristina M.; Zhang, Peisheng; Shyu, Maureen; Young, Benjamin T.; Hwa, John; Young, Roger C.; Martin, Kathleen A.

2008-01-01

An incomplete understanding of the molecular events that regulate the myometrial transition from the quiescent pregnant state to the active contractile state during labor has hindered the development of improved therapies for preterm labor. During myometrial activation, proteins that prime the smooth muscle for contraction are upregulated, allowing maximal responsiveness to contractile agonists and thereby producing strong phasic contractions. Upregulation of one such protein, COX-2, generates PGs that induce contractions. Intriguingly, the predominant myometrial PG produced just prior to labor is prostacyclin (PGI2), a smooth muscle relaxant. However, here we have shown that activation of PGI2 receptor (IP) upregulated the expression of several contractile proteins and the gap junction protein connexin 43 through cAMP/PKA signaling in human myometrial tissue in organ and cell culture. Functionally, these IP-dependent changes in gene expression promoted an enhanced contractile response to oxytocin in pregnant human myometrial tissue strips, which was inhibited by the IP antagonist RO3244794. Furthermore, contractile protein induction was dependent on the concentration and time of exposure to the PGI2 analog iloprost and was blocked by both RO3244794 and PKA knockdown. We therefore propose that PGI2-mediated upregulation of contractile proteins and connexin 43 is a critical step in myometrial activation, allowing for a maximal contractile response. Our observations have important implications regarding activation of the myometrium prior to the onset of labor. PMID:19033666

Deep trophoblast invasion and spiral artery remodelling in the placental bed of the lowland gorilla.

PubMed

Pijnenborg, R; Vercruysse, L; Carter, A M

2011-08-01

In contrast to baboon or rhesus macaque, trophoblast invasion in the human placental bed occurs by the interstitial as well as the endovascular route and reaches as deep as the inner myometrium. We here describe two rare specimens of gorilla placenta. In the light of recent findings in the chimpanzee, we postulated the occurrence of deep invasion in gorilla pregnancy. Tissues were processed for histology (PAS, orcein), lectin staining (Ulex europaeus agglutinin 1) and immunohistochemistry (cytokeratin 7/17, α-actin). A specimen of young but undetermined gestational age included deep placental bed tissue, showing interstitial and spiral artery invasion of the inner myometrium as well as the decidua. The cell density and depth of trophoblast invasion was equivalent to a human placental bed of 10-14 weeks. Intraluminal trophoblasts were not seen in any of the invaded vessels, allowing no definite conclusions about the origin of the intramural trophoblast and the time-course of spiral artery invasion. A different late second trimester placenta specimen showed scattered extravillous trophoblast in the basal plate and underlying decidua, as well as a remodelled spiral artery containing intramural trophoblast. Absence of inner myometrial tissue precluded assessment of invasion depth in this later specimen. Despite the limited material we can conclude that key aspects of trophoblast invasion are shared by the three hominid species: gorilla, chimpanzee and human. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Activity of tissue cathepsin-L-like proteinases of women with womb body oncopathology].

PubMed

Vovchuk, I L; Chernadchuk, S S

2004-01-01

Activity and optimal pH of cathepsin-L-like proteinases was studied in benign and malignant tumours of the womb body. In the benign tumors activity of cathepsin-L-like proteinases changes depending on the expansion and depth of extension benign tumour and is defined by proliferative potential of tumour cells of myometrium and endometrium. Activity of cathepsin-L-like proteinases in malignant epithelial tumour of endometrium--adenocarcinoma is inversely proportional to the level of differentiation of the tumour cells.

[Adenomyosis - diagnostic and therapeutic challenge].

PubMed

Seikkula, Jaana; Niinimäki, Maarit; Suvitie, Pia

2016-01-01

In adenomyosis, endometrial glandular and stromal cells grow inside the myometrium, and form localized or diffusely expanding islets. Smooth muscle cells of the uterus surrounding the adenomyosis colonies become hypertrophic, which may lead to abnormal contractions of the uterine wall. Adenomyosis is an estrogen-dependent disease with abnormal uterine bleeding and dysmenorrhea as typical symptoms. The disease may even be asymptomate. The diagnosis is made by histologically or ultrasonic or MRI imaging. Adenomyosis can be treated with hormonal medications. Fertility-sparing radiologic and surgical techniques are also available.

Venous Intravasation: A Potential Pitfall of Confirmatory Hysterosalpingogram Following Essure Hysteroscopic Sterilization

PubMed Central

Chang, Michael C.; Shim, John J.

2012-01-01

Indications for hysterosalpingography (HSG) include evaluation of infertility, spontaneous abortions, postoperative evaluation of tubal ligation, pre-myomectomy evaluation, and more recently, evaluation of tubal occlusion after placement of the Essure Permanent Birth Control System. Here we report a case of venous intravasation during a routine post-Essure HSG, a phenomenon in which contrast transits from the uterine cavity, through the myometrium, and directly into draining pelvic veins. Venous intravasation is a potential pitfall in interpretation of HSGs. PMID:23378884

Endometrial cancer: magnetic resonance imaging.

PubMed

Manfredi, R; Gui, B; Maresca, G; Fanfani, F; Bonomo, L

2005-01-01

Carcinoma of the endometrium is the most common invasive gynecologic malignancy of the female genital tract. Clinically, patients with endometrial carcinoma present with abnormal uterine bleeding. The role of magnetic resonance imaging (MRI) in endometrial carcinoma is disease staging and treatment planning. MRI has been shown to be the most valuable imaging mod-ality in this task, compared with endovaginal ultrasound and computed tomography, because of its intrinsic contrast resolution and multiplanar capability. MRI protocol includes axial T1-weighted images; axial, sagittal, and coronal T2-weighted images; and dynamic gadolinium-enhanced T1-weighted imaging. MR examination is usually performed in the supine position with a phased array multicoil using a four-coil configuration. Endometrial carcinoma is isointense with the normal endometrium and myometrium on noncontrast T1-weighted images and has a variable appearance on T2-weighted images demonstrating heterogeneous signal intensity. The appearance of noninvasive endometrial carcinoma on MRI is characterized by a normal or thickened endometrium, with an intact junctional zone and a sharp tumor-myometrium interface. Invasive endometrial carcinoma is characterized disruption or irregularity of the junctional zone by intermediate signal intensity mass on T2-weighted images. Invasion of the cervical stroma is diagnosed when the low signal intensity cervical stroma is disrupted by the higher signal intensity endometrial carcinoma. MRI in endometrial carcinoma performs better than other imaging modalities in disease staging and treatment planning. Further, the accuracy and the cost of MRI are equivalent to those of surgical staging.

The stretch-dependent potassium channel TREK-1 and its function in murine myometrium

PubMed Central

Monaghan, Kevin; Baker, Salah A; Dwyer, Laura; Hatton, William C; Sik Park, Kyung; Sanders, Kenton M; Koh, Sang Don

2011-01-01

Smooth muscle of the uterus stays remarkably quiescent during normal pregnancy to allow sufficient time for development of the fetus. At present the mechanisms leading to uterine quiescence during pregnancy and how the suppression of activity is relieved at term are poorly understood. Myometrial excitability is governed by ion channels, and a major hypothesis regarding the regulation of contractility during pregnancy has been that expression of certain channels is regulated by hormonal influences. We have explored the expression and function of stretch-dependent K+ (SDK) channels, which are likely to be due to TREK channels, in murine myometrial tissues and myocytes using PCR, Western blots, patch clamp, intracellular microelectrode and isometric force measurements. TREK-1 is more highly expressed than TREK-2 in myometrium, and there was no detectable expression of TRAAK. Expression of TREK-1 transcripts and protein was regulated during pregnancy and delivery. SDK channels were activated in response to negative pressure applied to patches. SDK channels were insensitive to a broad-spectrum of K+ channel blockers, including tetraethylammonium and 4-aminopyridine, and insensitive to intracellular Ca2+. SDK channels were activated by stretch and arachidonic acid and inhibited by reagents that block TREK-1 channels, l-methionine and/or methioninol. Our data suggest that uterine excitability and contractility during pregnancy is regulated by the expression of SDK/TREK-1 channels. Up-regulation of these channels stabilizes membrane potential and controls contraction during pregnancy and down-regulation of these channels induces the onset of delivery. PMID:21224218

11β-hydroxysteroid dehydrogenase type 1 and pregnancy: Role in the timing of labour onset and in myometrial contraction.

PubMed

Damiani, Francesco; Makieva, Sofia; Rinaldi, Sara F; Hua, Lei; Marcolongo, Paola; Petraglia, Felice; Norman, Jane E

2017-05-15

Glucocorticoids play a primary role in the maturation of fetal organs and may contribute to the onset of labour. Glucocorticoid activity depends on the 11β-hydroxysteroid dehydrogenase family (11β-HSDs), catalysing the interconversion between "active" cortisol into inactive cortisone. No definitive study exists on 11β-HSD expression profile in human decidua and myometrium during pregnancy. We investigated the implications of 11β-HSD1 in the regulation of uterine activity in pregnancy, examining its role on contraction of a myocyte cell line and murine 11β-hsd1 levels in utero. Murine 11β-hsd1 mRNA and protein levels in utero progressively increased until the last day of gestation and significantly decreased at the onset of labour (P < 0.0001) (n = 3 to 5 in the various gestational days analysed). Experiments on human myometrial samples confirm the significant fall in 11β-hsd1 mRNA levels at labour, compared to end pregnancy samples (n = 5 to 8). In vitro experiments showed that human myometrial contraction is inhibited by using a non-selective inhibitor of 11β-HSD1. The present study shows the temporal localisation of 11β-HSD1 in uterus, highlighting its importance in the timing of gestation and suggesting its contribution in the myometrium contraction. Copyright © 2017 Elsevier B.V. All rights reserved.

Activation of the MAPK/ERK Cell-Signaling Pathway in Uterine Smooth Muscle Cells of Women With Adenomyosis.

PubMed

Streuli, Isabelle; Santulli, Pietro; Chouzenoux, Sandrine; Chapron, Charles; Batteux, Frédéric

2015-12-01

We investigated whether the myometrium might be intrinsically different in women with adenomyosis. We studied whether the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs) and phosphoinositide 3-kinase/mammalian target of rapamycin/AKT (PI3K/mTOR/AKT) cell-signaling pathways, implicated in the pathogenesis of endometriosis, might also be activated in uterine smooth muscle cells (uSMCs) of women with adenomyosis and measured the production of reactive oxygen species (ROS), proinflammatory mediators that modulate cell proliferation and have been shown to activate the MAPK/ERK pathway in endometriosis. The uSMC cultures were derived from myometrium biopsies obtained during hysterectomy or myomectomy in women with adenomyosis and controls with leiomyoma. Proliferation of uSMCs and in vitro activation of the MAPK/ERK cell-signaling pathway were increased in women with adenomyosis compared to controls. The activation of the PI3K/mTOR/AKT pathway was not significant. The ROS production and ROS detoxification pathways were not different between uSMCs of women with adenomyosis and controls suggesting an ROS-independent activation of the MAPK/ERK pathway. Our results also provide evidence that protein kinase inhibitors and the rapanalogue temsirolimus can control proliferation of uSMCs in vitro suggesting an implication of the MAPK/ERK and the PI3K/mTOR/AKT pathways in proliferation of uSMCs in women with adenomyosis and leiomyomas. © The Author(s) 2015.

Why do niches develop in Caesarean uterine scars? Hypotheses on the aetiology of niche development

PubMed Central

Vervoort, A.J.M.W.; Uittenbogaard, L.B.; Hehenkamp, W.J.K.; Brölmann, H.A.M.; Mol, B.W.J.; Huirne, J.A.F.

2015-01-01

Caesarean section (CS) results in the occurrence of the phenomenon ‘niche’. A ‘niche’ describes the presence of a hypoechoic area within the myometrium of the lower uterine segment, reflecting a discontinuation of the myometrium at the site of a previous CS. Using gel or saline instillation sonohysterography, a niche is identified in the scar in more than half of the women who had had a CS, most with the uterus closed in one single layer, without closure of the peritoneum. An incompletely healed scar is a long-term complication of the CS and is associated with more gynaecological symptoms than is commonly acknowledged. Approximately 30% of women with a niche report spotting at 6–12 months after their CS. Other reported symptoms in women with a niche are dysmenorrhoea, chronic pelvic pain and dyspareunia. Given the association between a niche and gynaecological symptoms, obstetric complications and potentially with subfertility, it is important to elucidate the aetiology of niche development after CS in order to develop preventive strategies. Based on current published data and our observations during sonographic, hysteroscopic and laparoscopic evaluations of niches we postulate some hypotheses on niche development. Possible factors that could play a role in niche development include a very low incision through cervical tissue, inadequate suturing technique during closure of the uterine scar, surgical interventions that increase adhesion formation or patient-related factors that impair wound healing or increase inflammation or adhesion formation. PMID:26409016

Uterine Wound Healing: A Complex Process Mediated by Proteins and Peptides.

PubMed

Lofrumento, Dario D; Di Nardo, Maria A; De Falco, Marianna; Di Lieto, Andrea

2017-01-01

Wound healing is the process by which a complex cascade of biochemical events is responsible of the repair the damage. In vivo, studies in humans and mice suggest that healing and post-healing heterogeneous behavior of the surgically wounded myometrium is both phenotype and genotype dependent. Uterine wound healing process involves many cells: endothelial cells, neutrophils, monocytes/macrophages, lymphocytes, fibroblasts, myometrial cells as well a stem cell population found in the myometrium, myoSP (side population of myometrial cells). Transforming growth factor beta (TGF-β) isoforms, connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNF-β) are involved in the wound healing mechanisms. The increased TGF- β1/β3 ratio reduces scarring and fibrosis. The CTGF altered expression may be a factor involved in the abnormal scars formation of low uterine segment after cesarean section and of the formation of uterine dehiscence. The lack of bFGF is involved in the reduction of collagen deposition in the wound site and thicker scabs. The altered expression of TNF-β, VEGF, and PDGF in human myometrial smooth muscle cells in case of uterine dehiscence, it is implicated in the uterine healing process. The over-and under-expressions of growth factors genes involved in uterine scarring process could represent patient's specific features, increasing the risk of cesarean scar complications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity

PubMed Central

Brauer, M. Mónica; Smith, Peter G.

2014-01-01

The female reproductive tract undergoes remarkable functional and structural changes associated with cycling, conception and pregnancy, and it is likely advantageous to both individual and species to alter relationships between reproductive tissues and innervation. For several decades, it has been appreciated that the mammalian uterus undergoes massive sympathetic axon depletion in late pregnancy, possibly representing an adaptation to promote smooth muscle quiescence and sustained blood flow. Innervation to other structures such as cervix and vagina also undergo pregnancy-related changes in innervation that may facilitate parturition. These tissues provide highly tractable models for examining cellular and molecular mechanisms underlying peripheral nervous system plasticity. Studies show that estrogen elicits rapid degeneration of sympathetic terminal axons in myometrium, which regenerate under low-estrogen conditions. Degeneration is mediated by the target tissue: under estrogen's influence, the myometrium produces proteins repulsive to sympathetic axons including BDNF, neurotrimin, semaphorins, and pro-NGF, and extracellular matrix components are remodeled. Interestingly, nerve depletion does not involve diminished levels of classical sympathetic neurotrophins that promote axon growth. Estrogen also affects sympathetic neuron neurotrophin receptor expression in ways that appear to favor pro-degenerative effects of the target tissue. In contrast to the uterus, estrogen depletes vaginal autonomic and nociceptive axons, with the latter driven in part by estrogen-induced suppression BMP4 synthesis. These findings illustrate that hormonally mediated physiological plasticity is a highly complex phenomenon involving multiple, predominantly repulsive target-derived factors acting in concert to achieve rapid and selective reductions in innervation. PMID:25530517

Seasonal Variation of Dystocia in a Large Danish Cohort

PubMed Central

Rohr Thomsen, Christine; Uldbjerg, Niels; Hvidman, Lone; Atladóttir, Hjördís Ósk; Henriksen, Tine Brink; Milidou, Ioanna

2014-01-01

Background Dystocia is one of the most frequent causes of cesarean delivery in nulliparous women. Despite this, its causes are largely unknown. Vitamin D receptor (VDR) has been found in the myometrium. Thus, it is possible that vitamin D affects the contractility of the myometrium and may be involved in the pathogenesis of dystocia. Seasonal variation of dystocia in areas with distinct seasonal variation in sunlight exposure, like Denmark, could imply that vitamin D may play a role. This study examined whether there was seasonal variation in the incidence of dystocia in a Danish population. Method We used information from a cohort of 34,261 nulliparous women with singleton pregnancies, spontaneous onset of labor between 37 and 42 completed gestational weeks, and vertex fetal presentation. All women gave birth between 1992 and 2010 at the Department of Obstetrics and Gynecology, Aarhus University Hospital, Skejby. Logistic regression combined with cubic spline was used to estimate the seasonal variation for each outcome after adjusting for calendar time. Results No evidence for seasonal variation was found for any of the outcomes: acute cesarean delivery due to dystocia (p = 0.44); instrumental vaginal delivery due to dystocia (p = 0.69); oxytocin augmentation due to dystocia (p = 0.46); and overall dystocia (p = 0.91). Conclusion No seasonal variation in the incidence of dystocia was observed in a large cohort of Danish women. This may reflect no association between vitamin D and dystocia, or alternatively that other factors with seasonal variation and influence on the occurrence of dystocia attenuate such an association. PMID:24736600

Seasonal variation of dystocia in a large Danish cohort.

PubMed

Rohr Thomsen, Christine; Uldbjerg, Niels; Hvidman, Lone; Atladóttir, Hjördís Ósk; Henriksen, Tine Brink; Milidou, Ioanna

2014-01-01

Dystocia is one of the most frequent causes of cesarean delivery in nulliparous women. Despite this, its causes are largely unknown. Vitamin D receptor (VDR) has been found in the myometrium. Thus, it is possible that vitamin D affects the contractility of the myometrium and may be involved in the pathogenesis of dystocia. Seasonal variation of dystocia in areas with distinct seasonal variation in sunlight exposure, like Denmark, could imply that vitamin D may play a role. This study examined whether there was seasonal variation in the incidence of dystocia in a Danish population. We used information from a cohort of 34,261 nulliparous women with singleton pregnancies, spontaneous onset of labor between 37 and 42 completed gestational weeks, and vertex fetal presentation. All women gave birth between 1992 and 2010 at the Department of Obstetrics and Gynecology, Aarhus University Hospital, Skejby. Logistic regression combined with cubic spline was used to estimate the seasonal variation for each outcome after adjusting for calendar time. No evidence for seasonal variation was found for any of the outcomes: acute cesarean delivery due to dystocia (p = 0.44); instrumental vaginal delivery due to dystocia (p = 0.69); oxytocin augmentation due to dystocia (p = 0.46); and overall dystocia (p = 0.91). No seasonal variation in the incidence of dystocia was observed in a large cohort of Danish women. This may reflect no association between vitamin D and dystocia, or alternatively that other factors with seasonal variation and influence on the occurrence of dystocia attenuate such an association.

Why do niches develop in Caesarean uterine scars? Hypotheses on the aetiology of niche development.

PubMed

Vervoort, A J M W; Uittenbogaard, L B; Hehenkamp, W J K; Brölmann, H A M; Mol, B W J; Huirne, J A F

2015-12-01

Caesarean section (CS) results in the occurrence of the phenomenon 'niche'. A 'niche' describes the presence of a hypoechoic area within the myometrium of the lower uterine segment, reflecting a discontinuation of the myometrium at the site of a previous CS. Using gel or saline instillation sonohysterography, a niche is identified in the scar in more than half of the women who had had a CS, most with the uterus closed in one single layer, without closure of the peritoneum. An incompletely healed scar is a long-term complication of the CS and is associated with more gynaecological symptoms than is commonly acknowledged. Approximately 30% of women with a niche report spotting at 6-12 months after their CS. Other reported symptoms in women with a niche are dysmenorrhoea, chronic pelvic pain and dyspareunia. Given the association between a niche and gynaecological symptoms, obstetric complications and potentially with subfertility, it is important to elucidate the aetiology of niche development after CS in order to develop preventive strategies. Based on current published data and our observations during sonographic, hysteroscopic and laparoscopic evaluations of niches we postulate some hypotheses on niche development. Possible factors that could play a role in niche development include a very low incision through cervical tissue, inadequate suturing technique during closure of the uterine scar, surgical interventions that increase adhesion formation or patient-related factors that impair wound healing or increase inflammation or adhesion formation. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

[Features of cytotrophoblast invasion in complete placenta previa and increta].

PubMed

Milovanov, A P; Bushtarev, A V; Fokina, T V

to investigate the characteristics of cytotrophoblast invasion in complete placenta previa and increta. Three groups of placentas and amputated uteri were examined. These were: 1) 10 placentas at 20-22 weeks' gestation after drug-induced abortion; 2) 4 uteri with typical placentation at 34-36 weeks and wall ruptures; 3) 12 uteri with ultrasound-confirmed complete placenta previa and subsequent hysterectomy (at 34-36 weeks.) due to massive bleeding. In all cases, the sections were stained with hematoxylin and eosin, azan by the Mallory's method; immunovisualization of invasive cells with the marker cytokeratin 8 was also used. In Groups 2 and 3, the uterine distribution density of invasive cells was compared in a standard slice area (×200) separately, within the endometrium and myometrium. Complete placenta previa was found to have the following characteristics: 1) all the uteri exhibited focal or diffuse friable, or thick scars after cesarean section; 2) multiple active anchor villi with villous cytotrophoblast layers, which were characteristic of Group 1 placentas and absent in the uteri women of Group 2; 3) bays diagnosed in the basal endometrium with ingrown villi (placenta increta); 4) a morphometrically significant increase in the distribution density of interstitial cytotrophoblast in the endometrium and only a similar trend in the myometrium. Invasive cells did not penetrate into the area of scars. Failure of the second wave of cytotrophoblast invasion was confirmed by incomplete gestational restructuring and partial obliteration of the myometrial radial arteries. Real risks for severe clinical forms of abnormal placentation declare more stringent indications for surgical delivery.

Are 3D ultrasound and office hysteroscopy useful for the assessment of uterine cavity after late foetal loss?

PubMed

Thellier, E; Levaillant, J-M; Pourcelot, A-G; Houllier, M; Fernandez, H; Capmas, P

2018-05-01

To assess the efficacy of office hysteroscopy and 3D ultrasound for the diagnostic of uterine anomalies after late foetal loss. This retrospective observational study took place in the gynaecologic unit of a teaching hospital from 2009 to 2014. Women with late foetal loss (<22 weeks of gestation) had an office hysteroscopy and 3D ultrasound within three months after delivery. The results of the ultrasound and hysteroscopy were recorded and compared. Eighty women were included with a mean age of 29.8 years (28.2-31.4). Forty-seven women had both hysteroscopy and 3D ultrasound, and a uterine cavity's anomaly (bicornuate uterus, T-Shape uterus and septate uterus) was found in ten women (21%) at 3D sonography and in 13 women (28%) at office hysteroscopy. Concordance between the two exams was very good with a kappa at 0.83. In three cases, a uterine cavity's anomaly was found at hysteroscopy whereas sonography was normal. Anomalies at ultrasound (uterine cavity's anomaly, myometrium anomaly or ovarian anomaly) were found in 27.6% of cases. Both 3D ultrasound and office hysteroscopy are useful for assessment of the uterine cavity after late foetal loss. The application of these two exams is important, as hysteroscopy is generally used for assessment of the uterine cavity and endometrium, while 3D ultrasound is generally used to identify the precise type of uterine malformation and for the examination of the myometrium and annexes. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Distension of the uterus induces HspB1 expression in rat uterine smooth muscle.

PubMed

White, B G; MacPhee, D J

2011-11-01

The uterine musculature, or myometrium, demonstrates tremendous plasticity during pregnancy under the influences of the endocrine environment and mechanical stresses. Expression of the small stress protein heat shock protein B1 (HspB1) has been reported to increase dramatically during late pregnancy, a period marked by myometrial hypertrophy caused by fetal growth-induced uterine distension. Thus, using unilaterally pregnant rat models and ovariectomized nonpregnant rats with uteri containing laminaria tents to induce uterine distension, we examined the effect of uterine distension on myometrial HspB1 expression. In unilaterally pregnant rats, HspB1 mRNA and Ser(15)-phosphorylated HspB1 (pSer(15) HspB1) protein expression were significantly elevated in distended gravid uterine horns at days 19 and 23 (labor) of gestation compared with nongravid horns. Similarly, pSer(15) HspB1 protein in situ was only readily detectable in the distended horns compared with the nongravid horns at days 19 and 23; however, pSer(15) HspB1 was primarily detectable in situ at day 19 in membrane-associated regions, while it had primarily a cytoplasmic localization in myometrial cells at day 23. HspB1 mRNA and pSer(15) HspB1 protein expression were also markedly increased in ovariectomized nonpregnant rat myometrium distended for 24 h with laminaria tents compared with empty horns. Therefore, uterine distension plays a major role in the stimulation of myometrial HspB1 expression, and increased expression of this small stress protein could be a mechanoadaptive response to the increasing uterine distension that occurs during pregnancy.

Inflammatory Stimuli Increase Progesterone Receptor-A Stability and Transrepressive Activity in Myometrial Cells

PubMed Central

Peters, Gregory A.; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Patel, Bansari; Amini, Peyvand; Tan, Huiqing

2017-01-01

The steroid hormone progesterone acting via the nuclear progesterone receptor (PR) isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), is essential for the maintenance of uterine quiescence during pregnancy. Inhibition of PR signaling augments uterine contractility and induces labor. Human parturition is thought to be triggered by modulation of PR signaling in myometrial cells to induce a functional progesterone withdrawal. One mechanism for functional progesterone withdrawal is increased abundance of PR-A, which decreases progesterone responsiveness by inhibiting the transcriptional activity of PR-B. Human parturition also involves tissue-level inflammation within the myometrium. This study examined the control of PR-A abundance and transrepressive activity in myometrial cells and the role of the inflammatory stimuli in the form of interleukin-1β (IL-1β) and lipopolysaccharide (LPS) in these processes. We found that abundance of PR-A was markedly increased by progesterone and by exposure to IL-1β and LPS via posttranslational mechanisms involving increased PR-A protein stability. In contrast, progesterone decreased abundance of PR-B by increasing its rate of degradation. Together, progesterone and proinflammatory stimuli induced a PR-A–dominant state in myometrial cells similar to that observed in term laboring myometrium. IL-1β and LPS also increased the capacity for PR-A to inhibit the transcriptional activity of PR-B. Taken together, our data suggest that proinflammatory stimuli increase the steady-state levels of PR-A and its transrepressive activity in myometrial cells and support the hypothesis that tissue-level inflammation triggers parturition by inducing PR-A–mediated functional progesterone withdrawal. PMID:27886516

Endometrial carcinoma in a single horn of a bicornuate uterus: A case report.

PubMed

Gaballa, Khaled; Cicero, Carla; Gallotta, Valerio; Zannoni, Gianfranco; Scambia, Giovanni

2018-06-01

We discuss the diagnosis and the management of endometrial carcinoma in a single horn of bicornuate uterus in a 64-year-old woman as a case report. The case underwent laparoscopic radical hysterectomy and bilateral iliac lymphadenectomy. The gross examination of the uterus revealed a bicornuate uterus with a greater horn of 12 × 9 × 8 cm and a smaller horn of 10 × 3 cm. The cavity of the greater horn showed a neoplastic growth of 10 cm with infiltration of about 1,8 cm of the myometrium from whole thickness of 1.9 cm. while the other horn was free of tumor tissue. The microscopic examination of the uterus revealed G2 endometrioid adenocarcinoma of the endometrium of the greater horn with infiltration of more than 50% of the myometrium. In the presence of bicornuate uterus, a bilateral endometrial biopsy should be performed in order to reduce the risk of delayed or missed diagnosis. The management of a case of bicornuate unicollis uterus with endometrial carcinoma in only one horn is the same as patients with endometrial cancer in single uterus and depends mainly on stage and histological grade of the tumor. The possibility of existence of a separate uterine cavity should always be considered when endometrial cancer is clinically suspected but pathology fails to confirm the diagnosis. This points out the importance of a careful physical examination and radiographic evaluation in such cases. Copyright © 2018. Production and hosting by Elsevier B.V.

Acquired Uterine Arteriovenous Malformation and Retained Placenta Increta.

PubMed

Roach, Michelle K; Thomassee, May S

2015-09-01

Uterine arteriovenous malformations are rare and have been reported to occur after uterine trauma (eg, surgery, gestational trophoblastic disease, malignancy). A 33-year-old woman, gravida 3 para 3, presented 4 weeks post-cesarean delivery with episodic profuse vaginal bleeding. Pelvic ultrasonography and magnetic resonance imaging revealed a left uterine arteriovenous malformation. After consideration of all treatment options, total laparoscopic hysterectomy was performed. Acquired uterine arteriovenous malformations and placental ingrowth into the myometrium are increasingly reported after surgical uterine procedures. This case of a postpartum patient with both uterine arteriovenous malformation and retained placenta increta suggests a correlation between the two complications.

Extensive uterine arteriovenous malformation with hemodynamic instability: Embolization for whole myometrium affection.

PubMed

El Agwany, Ahmed Samy; Elshafei, Mohamed

2018-03-01

Uterine arteriovenous malformation is abnormal and nonfunctional connections between the uterine arteries and veins. Patients typically present with vaginal bleeding which may be life-threatening. Treatment depends on the symptoms, age, desire for future fertility, localization and size of the lesion. Embolization of the uterine artery is the first choice in symptomatic AVM in patients in the reproductive age. We report a case of acquired AVM with an extensive lesion on ultrasound and MRI, which was successfully treated with uterine artery embolization for severe bleeding (UAE). Copyright © 2018 Elsevier B.V. All rights reserved.

Cesarean section scar as a cause of abnormal vaginal bleeding: diagnosis by sonohysterography.

PubMed

Thurmond, A S; Harvey, W J; Smith, S A

1999-01-01

A previously undescribed cause of abnormal uterine bleeding is presented. Nine of 310 women evaluated by sonohysterography for abnormal bleeding demonstrated an 8 to 17 mm gap in the anterior lower uterine segment myometrium at the site of prior cesarean deliveries. All women were premenopausal and had a history of 2 to 12 days of postmenstrual spotting. Presumably a lack of coordinated muscular contractions occurs around the cesarean scar, allowing the defect to collect menstrual debris. Subsequently, the debris leaches out through the cervix for several days after the majority of menstrual flow has ceased.

Bitter taste receptors as targets for tocolytics in preterm labor therapy.

PubMed

Zheng, Kaizhi; Lu, Ping; Delpapa, Ellen; Bellve, Karl; Deng, Ruitang; Condon, Jennifer C; Fogarty, Kevin; Lifshitz, Lawrence M; Simas, Tiffany A Moore; Shi, Fangxiong; ZhuGe, Ronghua

2017-09-01

Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity, with few prevention and treatment options. Uterine contraction is a central feature of PTB, so gaining new insights into the mechanisms of this contraction and consequently identifying novel targets for tocolytics are essential for more successful management of PTB. Here we report that myometrial cells from human and mouse express bitter taste receptors (TAS2Rs) and their canonical signaling components ( i.e., G-protein gustducin and phospholipase C β2). Bitter tastants can completely relax myometrium precontracted by different uterotonics. In isolated single mouse myometrial cells, a phenotypical bitter tastant (chloroquine, ChQ) reverses the rise in intracellular Ca 2+ concentration ([Ca 2+ ] i ) and cell shortening induced by uterotonics, and this reversal effect is inhibited by pertussis toxin and by genetic deletion of α-gustducin. In human myometrial cells, knockdown of TAS2R14 but not TAS2R10 inhibits ChQ's reversal effect on an oxytocin-induced rise in [Ca 2+ ] i Finally, ChQ prevents mouse PTBs induced by bacterial endotoxin LPS or progesterone receptor antagonist mifepristone more often than current commonly used tocolytics, and this prevention is largely lost in α-gustducin-knockout mice. Collectively, our results reveal that activation of the canonical TAS2R signaling system in myometrial cells produces profound relaxation of myometrium precontracted by a broad spectrum of contractile agonists, and that targeting TAS2Rs is an attractive approach to developing effective tocolytics for PTB management.-Zheng, K., Lu, P., Delpapa, E., Bellve, K., Deng, R., Condon, J. C., Fogarty, K., Lifshitz, L. M., Simas, T. A. M., Shi, F., ZhuGe, R. Bitter taste receptors as targets for tocolytics in preterm labor therapy. © FASEB.

World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue collection, processing, and storage in endometriosis research

PubMed Central

Fassbender, Amelie; Rahmioglu, Nilufer; Vitonis, Allison F.; Viganò, Paola; Giudice, Linda C.; D’Hooghe, Thomas M.; Hummelshoj, Lone; Adamson, G. David; Becker, Christian M.; Missmer, Stacey A.; Zondervan, Krina T.; Adamson, G.D.; Allaire, C.; Anchan, R.; Becker, C.M.; Bedaiwy, M.A.; Buck Louis, G.M.; Calhaz-Jorge, C.; Chwalisz, K.; D'Hooghe, T.M.; Fassbender, A.; Faustmann, T.; Fazleabas, A.T.; Flores, I.; Forman, A.; Fraser, I.; Giudice, L.C.; Gotte, M.; Gregersen, P.; Guo, S.-W.; Harada, T.; Hartwell, D.; Horne, A.W.; Hull, M.L.; Hummelshoj, L.; Ibrahim, M.G.; Kiesel, L.; Laufer, M.R.; Machens, K.; Mechsner, S.; Missmer, S.A.; Montgomery, G.W.; Nap, A.; Nyegaard, M.; Osteen, K.G.; Petta, C.A.; Rahmioglu, N.; Renner, S.P.; Riedlinger, J.; Roehrich, S.; Rogers, P.A.; Rombauts, L.; Salumets, A.; Saridogan, E.; Seckin, T.; Stratton, P.; Sharpe-Timms, K.L.; Tworoger, S.; Vigano, P.; Vincent, K.; Vitonis, A.F.; Wienhues-Thelen, U.-H.; Yeung, P.P.; Yong, P.; Zondervan, K.T.

2014-01-01

Objective To harmonize standard operating procedures (SOPs) and standardize the recording of associated data for collection, processing, and storage of human tissues relevant to endometriosis. Design An international collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries on five continents. Setting In 2013, two workshops were conducted followed by global consultation, bringing together 54 leaders in endometriosis research and sample processing from around the world. Patient(s) None. Intervention(s) Consensus SOPs were based on: 1) systematic comparison of SOPs from 24 global centers collecting tissue samples from women with and without endometriosis on a medium or large scale (publication on >100 cases); 2) literature evidence where available, or consultation with laboratory experts otherwise; and 3) several global consultation rounds. Main Outcome Measure(s) Standard recommended and minimum required SOPs for tissue collection, processing, and storage in endometriosis research. Result(s) We developed “recommended standard” and “minimum required” SOPs for the collection, processing, and storage of ectopic and eutopic endometrium, peritoneum, and myometrium, and a biospecimen data collection form necessary for interpretation of sample-derived results. Conclusion(s) The EPHect SOPs allow endometriosis research centers to decrease variability in tissue-based results, facilitating between-center comparisons and collaborations. The procedures are also relevant to research into other gynecologic conditions involving endometrium, myometrium, and peritoneum. The consensus SOPs are based on the best available evidence; areas with limited evidence are identified as requiring further pilot studies. The SOPs will be reviewed based on investigator feedback and through systematic triannual follow-up. Updated versions will be made available at: http://endometriosisfoundation.org/ephect. PMID:25256928

Maximum Peak Systolic Velocity and Management of Highly Vascularized Retained Products of Conception.

PubMed

Van den Bosch, Thierry; Van Schoubroeck, Dominique; Timmerman, Dirk

2015-09-01

The purpose of this study was to evaluate blood loss and procedure-related complications during and after surgical removal of retained products of conception with high-velocity enhanced myometrial vascularity. We conducted a prospective study of 18 consecutive women with a diagnosis of retained products of conception and enhanced myometrial vascularity, with a peak systolic velocity (PSV) higher than 60 cm/s. All underwent ultrasound-guided surgical removal of the retained products under general anesthesia. Blood loss during the procedure was collected and recorded. The removed tissue was sent for histologic examination. An ultrasound examination was repeated within 24 hours. Five patients had retained products of conception after a term delivery, 1 after a second-trimester termination of pregnancy, 7 after a spontaneous first-trimester miscarriage, and 5 after a first-trimester termination elsewhere. The PSV in the area of enhanced myometrial vascularity at diagnosis ranged from 61.0 to 152.6 cm/s (mean, 104.9 cm/s). The estimated blood loss at surgery ranged from 20 to 1000 mL (mean, 200 mL). After surgery, the PSV in the myometrium dropped dramatically (≤30 cm/s in all but 1 case). In all cases, trophoblastic tissue was confirmed at histologic examination. Although surgical removal of retained products of conception was uneventful in most cases, heavy bleeding has to be anticipated in cases of high-velocity flow in the myometrium underlying residual trophoblastic tissue. Accordingly, in cases of high-velocity enhanced myometrial vascularity, we advocate surgical removal of the residual tissue under ultrasound guidance by an experienced surgeon and in the presence of a fully informed anesthetist. © 2015 by the American Institute of Ultrasound in Medicine.

Gene Expression in Uterine Leiomyoma from Tumors Likely to Be Growing (from Black Women over 35) and Tumors Likely to Be Non-Growing (from White Women over 35)

PubMed Central

Davis, Barbara J.; Risinger, John I.; Chandramouli, Gadisetti V. R.; Bushel, Pierre R.; Baird, Donna Day; Peddada, Shyamal D.

2013-01-01

The study of uterine leiomyomata (fibroids) provides a unique opportunity to investigate the physiological and molecular determinants of hormone dependent tumor growth and spontaneous tumor regression. We conducted a longitudinal clinical study of premenopausal women with leiomyoma that showed significantly different growth rates between white and black women depending on their age. Growth rates for leiomyoma were on average much higher from older black women than for older white women, and we now report gene expression pattern differences in tumors from these two groups of study participants. Total RNA from 52 leiomyoma and 8 myometrial samples were analyzed using Affymetrix Gene Chip expression arrays. Gene expression data was first compared between all leiomyoma and normal myometrium and then between leiomyoma from older black women (age 35 or older) and from older white women. Genes that were found significant in pairwise comparisons were further analyzed for canonical pathways, networks and biological functions using the Ingenuity Pathway Analysis (IPA) software. Whereas our comparison of leiomyoma to myometrium produced a very large list of genes highly similar to numerous previous studies, distinct sets of genes and signaling pathways were identified in comparisons of older black and white women whose tumors were likely to be growing and non-growing, respectively. Key among these were genes associated with regulation of apoptosis. To our knowledge, this is the first study to compare two groups of tumors that are likely to have different growth rates in order to reveal molecular signals likely to be influential in tumor growth. PMID:23785396

Locostatin, a disrupter of Raf kinase inhibitor protein, inhibits extracellular matrix production, proliferation, and migration in human uterine leiomyoma and myometrial cells.

PubMed

Janjusevic, Milijana; Greco, Stefania; Islam, Md Soriful; Castellucci, Clara; Ciavattini, Andrea; Toti, Paolo; Petraglia, Felice; Ciarmela, Pasquapina

2016-11-01

To investigate the presence of Raf kinase inhibitor protein (RKIP) in human myometrium and leiomyoma as well as to determine the effect of locostatin (RKIP inhibitor) on extracellular matrix (ECM) production, proliferation, and migration in human myometrial and leiomyoma cells. Laboratory study. Human myometrium and leiomyoma. Thirty premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Myometrial and leiomyoma tissues were used to investigate the localization and the expression level of RKIP through immunohistochemistry and Western blotting. Myometrial and leiomyoma cells were treated with locostatin (10 μM) to measure ECM expression by real-time polymerase chain reaction, GSK3β expression by Western blotting, cell migration by wound-healing assay, and cell proliferation by MTT assay and immunocytochemistry. The expression of RKIP in human myometrial and leiomyoma tissue; ECM components and GSK3β expression, migration, and proliferation in myometrial and leiomyoma cells. RKIP is expressed in human myometrial and leiomyoma tissue. Locostatin treatment resulted in the activation of the mitogen-activated protein kinase (MAPK) signal pathway (ERK phosphorylation), providing a powerful validation of our targeting protocol. Further, RKIP inhibition by locostatin reduces ECM components. Moreover, the inhibition of RKIP by locostatin impaired cell proliferation and migration in both leiomyoma and myometrial cells. Finally, locostatin treatment reduced GSK3β expression. Therefore, even if the activation of MAPK pathway should increase proliferation and migration, the destabilization of GSK3β leads to the reduction of proliferation and migration of myometrial and leiomyoma cells. Our results indicate that RKIP may be involved in leiomyoma pathophysiology. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Differential expression of caveolin-1 in human myometrial and uterine leiomyoma smooth muscle.

PubMed

Zhou, Yu; Ren, Yuanyuan; Cui, Lihua; Li, Zongjin; Zhu, Yingjun; Lin, Wanjun; Wang, Yuebing

2014-11-01

Uterine leiomyomas, the most common neoplasms of the female genital tract, are benign tumors of the uterus arising from the smooth muscle cells (SMCs) of the myometrium with an involvement of estrogen. Caveolin-1 (Cav-1), a major protein component in caveolae membrane lipid rafts, is down-regulated in several estrogen-related cancer cells, and overexpression of Cav-1 inhibits proliferation of cancer cells and vascular SMCs as well. Therefore, we hypothesize that Cav-1 is down-regulated in human uterine leiomyoma. Western blot using tissues from clinical patients showed that Cav-1 expression was significantly lower or undetectable in uterine leiomyoma compared with their matched myometrium (P < .001). This finding was confirmed by immunohistochemistry and confocal microscopy. The cav-1 mRNA level in uterine leiomyomas was also significantly lower as detected by reverse transcription-quantitative polymerase chain reaction analysis (P = .001). To further study the underlying mechanism, we performed primary cell culture, and found that the expression of Cav-1 remained low in cultured leiomyoma SMCs (P = .009). Serum withdrawal did not change Cav-1 expression in leiomyoma SMCs, but increased expression in myometrial SMCs (P = .006). 17-β estradiol inhibited the expression of Cav-1 protein (P = .047) and mRNA (P = .007) in leiomyoma SMCs, whereas it stimulated expression in myometrial SMCs (P = .043). 17-β estradiol, although activating the mitogen-activated protein kinase pathway in both SMCs, did not stimulate their proliferation. We conclude that human uterine leiomyomas in vitro express low levels of Cav-1, which may result from estrogen inhibition. This effect of estrogen may contribute to the pathogenesis of uterine leiomyoma. Further studies in vivo are needed to verify these results. Copyright © 2014 Elsevier Inc. All rights reserved.

The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy

PubMed Central

Tal, Reshef; Segars, James H.

2014-01-01

Background It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology. Methods Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed. Results Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms. Conclusions Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroid's abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess the potential of anti-angiogenic treatment strategies for uterine fibroids. PMID:24077979

MK-2206, an AKT Inhibitor, Promotes Caspase-Independent Cell Death and Inhibits Leiomyoma Growth

PubMed Central

Sefton, Elizabeth C.; Qiang, Wenan; Serna, Vanida; Kurita, Takeshi; Wei, Jian-Jun; Chakravarti, Debabrata

2013-01-01

Uterine leiomyomas (ULs), benign tumors of the myometrium, are the number one indication for hysterectomies in the United States due to a lack of an effective alternative therapy. ULs show activation of the pro-survival AKT pathway compared with normal myometrium; however, substantial data directly linking AKT to UL cell survival are lacking. We hypothesized that AKT promotes UL cell survival and that it is a viable target for inhibiting UL growth. We used the investigational AKT inhibitor MK-2206, currently in phase II trials, on cultured primary human UL and myometrial cells, immortalized leiomyoma cells, and in leiomyoma grafts grown under the kidney capsule in mice. MK-2206 inhibited AKT and PRAS40 phosphorylation but did not regulate serum- and glucocorticoid-induced kinase and ERK1/2, demonstrating its specificity for AKT. MK-2206 reduced UL cell viability and decreased UL tumor volumes. UL cells exhibited disruption of mitochondrial structures and underwent cell death that was independent of caspases. Additionally, mammalian target of rapamycin and p70S6K phosphorylation were reduced, indicating that mammalian target of rapamycin complex 1 signaling was compromised by AKT inhibition in UL cells. MK-2206 also induced autophagy in UL cells. Pretreatment of primary UL cells with 3-methyladenine enhanced MK-2206-mediated UL cell death, whereas knockdown of ATG5 and/or ATG7 did not significantly influence UL cell viability in the presence of MK-2206. Our data provide molecular evidence for the involvement of AKT in UL cell survival and suggest that AKT inhibition by MK-2206 may be a viable option to consider for the treatment of ULs. PMID:24002033

Alpha-tocopherol succinate increases cyclooxygenase-2 activity: Tissue-specific action in pregnant rat uterus in vitro.

PubMed

Kothencz, Anna; Hajagos-Tóth, Judit; Csányi, Adrienn; Gáspár, Róbert

2018-01-01

Lipid soluble vitamin E plays a role in several physiological mechanisms, however, the mechanism of this action is controversial. We investigated how tocopherol (α-tocopherol acid succinate) influences the effects of cyclooxygenase inhibitors (COXi) in the smooth muscles. The contractility of the samples from 22-day-pregnant myometrium and non-pregnant myometrium and trachea was determined in an isolated organ bath in vitro. The activity of cyclooxygenase enzymes (COX) was also measured in the tissues. Diclofenac (10 -9 -10 -5 M) and rofecoxib (10 -10 -10 -5 M) decreased the contractions in non-pregnant and 22-day-pregnant uteri. Tocopherol (10 -7 M) increased the relaxant effect only in pregnant uteri. Both diclofenac (10 -9 -10 -5 M) and rofecoxib (10 -10 -10 -5 M) reduced the tracheal tones, while they were slightly intensified by pretreatment with tocopherol (10 -7 M). Tocopherol enhanced the contractions of pregnant uteri. Tocopherol (10 -7 M) itself can induce the cyclooxygenase activity and shift the COX-1 and COX-2 ratio to COX-2. The lowest COX activity was found in non-pregnant uteri, while the highest one was in the trachea. The COX enzymes, especially COX-2, play an important role in the contraction of pregnant uteri in rat. Tocopherol has a tissue specific COX-2 activity increasing effect in pregnant rat uterus but has no such action in non-pregnant uteri or tracheal tissue. Hereby, tocopherol may intensify selectively the uterine relaxing effect of COX-2 inhibitors in preterm contractions. However, tocopherol can enhance the contractile response of pregnant uterus that may increase the risk of premature contractions. Copyright © 2017 Elsevier Inc. All rights reserved.

Tocopherol inhibits the relaxing effect of terbutaline in the respiratory and reproductive tracts of the rat: the role of the oxidative stress index.

PubMed

Hódi, A; Földesi, I; Ducza, E; Hajagos-Tóth, J; Seres, A B; Klukovits, A; Gáspár, R

2014-06-06

Reactive oxygen species play a role in the signal transduction of beta-adrenergic receptors. We investigated whether an antioxidant (tocopherol) can reduce the effect of terbutaline in beta-2-adrenergic receptor (β2-AR)-regulated smooth muscles. Contractility of the tissues from nonpregnant (trachea) and 22-day-pregnant (myometrium and cervix) rats was investigated in an isolated organ bath. The tracheal and uterine β2-AR expressions were increased by 17-beta-estradiol valerate (E2) and progesterone (P4), respectively. The accumulation of cyclic-AMP (cAMP), and the total oxidant (TOS) and total antioxidant status (TAS) were also measured. The oxidative stress index (OSI) was defined as the ratio of TOS and TAS. Terbutaline (10(-10)-10(-5)M) decreased the contractions in the nontreated and the P4-pretreated myometria, but tocopherol (10(-7)M) did not alter these actions. Terbutaline (10(-6)M) increased the cervical resistance both in the nontreated and in the P4-treated samples, while tocopherol reduced this action only in the P4-treated cervices. Terbutaline (10(-9)-10(-4)M) reduced the tracheal tones both in the nontreated and in the E2-treated tissues, while tocopherol reduced these effects. The changes in the intracellular cAMP levels of the tissues were in harmony with the isolated organ results. The OSI was highest in the trachea and lowest in the pregnant myometrium. A higher OSI is linked to a higher tocopherol sensitivity of beta-mimetic-induced relaxation. Our results suggest that the antiasthmatic effect of beta-mimetics may worsen, while their tocolytic effect may remain unchanged during parallel tocopherol administration. Copyright © 2014 Elsevier Inc. All rights reserved.

Environmental Estrogens Differentially Engage the Histone Methyltransferase EZH2 to Increase Risk of Uterine Tumorigenesis

PubMed Central

Greathouse, K. Leigh; Bredfeldt, Tiffany; Everitt, Jeffrey I.; Lin, Kevin; Berry, Tia; Kannan, Kurunthachalam; Mittelstadt, Megan L.; Ho, Shuk-mei; Walker, Cheryl L.

2013-01-01

Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol (DES) during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyper-responsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein (GEN), a soy phytoestrogen, and the plasticizer bisphenol A (BPA), differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. While both GEN and BPA induce genomic estrogen receptor (ER) signaling in the developing uterus, only GEN induced PI3K/AKT non-genomic ER signaling to the histone methyltransferase Enhancer of Zeste homolog 2 (EZH2). As a result, this “pre-genomic” signaling phosphorylates and represses EZH2, and reduces levels of H3K27 repressive mark in chromatin. Furthermore, only GEN caused estrogen-responsive genes in the adult myometrium to become hyper-responsive to hormone; estrogen-responsive genes were repressed in BPA exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by GEN promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, while BPA did not. These data demonstrate that environmental estrogens have distinct non-genomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis. PMID:22504913

Comparative studies of placentation and immunology in non-human primates suggest a scenario for the evolution of deep trophoblast invasion and an explanation for human pregnancy disorders.

PubMed

Carter, Anthony M

2011-04-01

Deep trophoblast invasion in the placental bed has been considered the hallmark of human pregnancy. It occurs by two routes, interstitial and endovascular, and results in transformation of the walls of the spiral arteries as they traverse the decidua and the inner third of the myometrium. Disturbances in this process are associated with reproductive disorders such preeclampsia. In contrast, trophoblast invasion in Old World monkeys occurs only by the endovascular route and seldom reaches the myometrium. Recently, it was shown that this pattern is maintained in gibbons, but that the human arrangement also occurs in chimpanzee and gorilla. There is an interesting parallel with results from placental immunology regarding the evolution of the major histocompatability complex class I antigen HLA-C and its cognate receptors. HLA-C is not present in Old World monkeys or gibbons. It emerged in the orangutan and became polymorphic in the lineage leading to gorilla, bonobo, chimpanzee, and human. Interaction between HLA-C1 and HLA-C2 on the surface of trophoblast and killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer cells are important regulators of trophoblast invasion. Evolution of this system in great apes may have been one prerequisite for deep trophoblast invasion but seems to have come at a price. The evidence now suggests that certain combinations of maternal genotype for KIRs and fetal genotype for HLA-C imply an increased risk of preeclampsia, fetal growth restriction, and recurrent abortion. The fetal genotype is in part derived from the father providing an explanation for the paternal contribution to reproductive disorders.

Adherent basal plate myometrial fibers in the delivered placenta as a risk factor for development of subsequent placenta accreta.

PubMed

Linn, Rebecca L; Miller, Emily S; Lim, Grace; Ernst, Linda M

2015-12-01

Placenta accreta is implantation of chorionic tissue directly upon the myometrium without normal intervening decidua. The clinical significance of myometrial fibers attached to the basal plate (BPMYO) has yet to be fully elucidated. To determine the importance of depth and quantity of BPMYO in predicting subsequent accreta in the next pregnancy. Women with placentas from two successive pregnancies submitted for pathologic evaluation were included. 50 cases had clinical and/or pathologic diagnosis of accreta in an index pregnancy. 100 controls had no evidence of accreta in an index pregnancy. H&E slides were re-reviewed and stage of accreta/BPMYO was determined. The stages were defined as: Stage 0-no BPMYO; Stage 1-BPMYO with intervening decidua; Stage 2 < 2 decidual cells separating myometrium from chorionic tissue; Stage 3-accreta; Stage 4-increta; Stage 5-percreta. The amount of BPMYO for each placenta was quantified. Prior placentas of cases were twice as likely to have BPMYO compared to controls (84%vs42%, P < 0.001). The frequency of stage 1 BPMYO was not significantly different between the two groups (46%v40%, P = 0.489), but cases were more likely to have higher stages of BPMYO (stage 2-3) in a prior placenta (38%vs2%, P < 0.001). A significantly higher number of BPMYO foci and a larger proportion of BPMYO on the basal plate (6.2%vs0.7%, P < 0.001) in cases compared to controls. Small amounts and low stage BPMYO (stage 1) may be common; however, higher stages of BPMYO (stage 2-3) and greater quantities of BPMYO in a delivered placenta are significantly associated with the subsequent development of accreta. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identification of Differentially Expressed K-Ras Transcript Variants in Patients With Leiomyoma.

PubMed

Zolfaghari, Nooshin; Shahbazi, Shirin; Torfeh, Mahnaz; Khorasani, Maryam; Hashemi, Mehrdad; Mahdian, Reza

2017-10-01

Molecular studies have demonstrated a wide range of gene expression variations in uterine leiomyoma. The rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase (RAS/RAF/MAPK) is the crucial cellular pathway in transmitting external signals into nucleus. Deregulation of this pathway contributes to excessive cell proliferation and tumorigenesis. The present study aims to investigate the expression profile of the K-Ras transcripts in tissue samples from patients with leiomyoma. The patients were leiomyoma cases who had no mutation in mediator complex subunit 12 ( MED12) gene. A quantitative approach has been applied to determine the difference in the expression of the 2 main K-Ras messenger RNA (mRNA) variants. The comparison between gene expression levels in leiomyoma and normal myometrium group was performed using relative expression software tool. The expression of K-Ras4B gene was upregulated in leiomyoma group ( P = .016), suggesting the involvement of K-Ras4B in the disease pathogenesis. Pairwise comparison of the K-Ras4B expression between each leiomyoma tissue and its matched adjacent normal myometrium revealed gene upregulation in 68% of the cases. The expression of K-Ras4A mRNA was relatively upregulated in leiomyoma group ( P = .030). In addition, the mean expression of K-Ras4A gene in leiomyoma tissues relative to normal samples was 4.475 (95% confidence interval: 0.10-20.42; standard error: 0.53-12.67). In total, 58% of the cases showed more than 2-fold increase in K-Ras4A gene expression. Our results demonstrated increased expression of both K-Ras mRNA splicing variants in leiomyoma tissue. However, the ultimate result of KRAS expression on leiomyoma development depends on the overall KRAS isoform balance and, consequently, on activated signaling pathways.

Loss of CDH1 and Pten accelerates cellular invasiveness and angiogenesis in the mouse uterus.

PubMed

Lindberg, Mallory E; Stodden, Genna R; King, Mandy L; MacLean, James A; Mann, Jordan L; DeMayo, Francesco J; Lydon, John P; Hayashi, Kanako

2013-07-01

E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1(d/d) Pten(d/d)) in the mouse uterus. We observed that Cdh1(d/d) Pten(d/d) mice died at Postnatal Days 15-19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1(d/d) Pten(d/d) mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1(d/d) Pten(d/d) mice. However, complex hyperplasia was not found in the uteri of Cdh1(d/d) Pten(d/d) mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death.

Loss of Cdh1 and Pten Accelerates Cellular Invasiveness and Angiogenesis in the Mouse Uterus1

PubMed Central

Lindberg, Mallory E.; Stodden, Genna R.; King, Mandy L.; MacLean, James A.; Mann, Jordan L.; DeMayo, Francesco J.; Lydon, John P.; Hayashi, Kanako

2013-01-01

ABSTRACT E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1d/d Ptend/d) in the mouse uterus. We observed that Cdh1d/d Ptend/d mice died at Postnatal Days 15–19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1d/d Ptend/d mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1d/d Ptend/d mice. However, complex hyperplasia was not found in the uteri of Cdh1d/d Ptend/d mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death. PMID:23740945

Activation of neurokinin NK(2) receptors by tachykinin peptides causes contraction of uterus in pregnant women near term.

PubMed

Patak, E N; Ziccone, S; Story, M E; Fleming, A J; Lilley, A; Pennefather, J N

2000-06-01

The aim of this study was firstly to elucidate whether the mammalian tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB)-regulated contractility of myometrium obtained from near-term pregnant women, and secondly to investigate the receptor subtype(s) responsible. In the presence of peptidase inhibitors, i.e. thiorphan (3 micromol/l; endopeptidase 24.11 inhibitor), captopril (10 micromol/l; angiotensin converting enzyme inhibitor) and bestatin (10 micromol/l; aminopeptidase inhibitor); all three mammalian tachykinins elicited concentration-related contractions of isolated myometrial preparations. The rank order of agonist potency of the mammalian tachykinins in the presence of the peptidase inhibitors was NKA > SP = NKB, indicating that the contractile effects were mediated by activation of an NK(2) receptor. The NK(2) receptor-selective agonist, [Lys(5), MeLeu(9), Nle(10)]NKA(4-10), produced concentration-related contractile responses, while the respective NK(1) and NK(3) receptor-selective agonists, [Sar(9), Met(O(2))(11)]SP and [N-MePhe(7)]NKB, had no effect either in the absence or presence of the peptidase inhibitors. The NK(2) receptor-selective antagonist, SR48968, produced concentration-related rightward shift in the log concentration curve to [Lys(5), MeLeu(9), Nle(10)]NKA(4-10). This study shows that tachykinins elicit contractile effects on human myometrium obtained from pregnant women near term, and that these effects are mediated by an NK(2) receptor. An excitatory effect of the tachykinins on these preparations could indicate a physiological role for these peptides in enhancing contractility of the uterus in women at term.

Kinetics of oxytocin and deaminooxytocin displacement from the OXTR-receptor compartment in rat uterus ex vivo.

PubMed

Pliska, Vladimir; Jutz, Guido

2018-02-01

The oil immersion method suggested earlier by Kalsner and Nickerson for analysing actions of sympathomimetic drugs upon smooth muscle tissues was applied to isometric preparations of rat myometrium stimulated by oxytocin and deaminooxytocin. An exchange of the aqueous medium by mineral oil allows monitoring the displacement of the peptides from their receptor compartment in absence of free diffusion transport between tissue and organ medium. Exponential analysis of the data from the uterotonic decay phase allows several inferences to be drawn: 1) Transport rate constants (roughly equal for the two peptides) are higher than rate constants of (irreversible) elimination from the receptor compartment. 2) The response decay rate in the oil immersion phase is proportional solely to the peptide elimination and thus offers estimates of elimination rate constants. 3) Peptide elimination kinetics in the receptor compartment is only insignificantly influenced by the kinetics of ligand-receptor binding. 4) As expected, the elimination rate constant of deaminooxytocin is considerably lower than for oxytocin. The apparent concentration of receptors in the paracellular space of the myometrium ("apparent", since receptor molecules are embedded in the cell membrane and hence not exposed to a diffusive flux), estimated from histometric parameters, appears rather high: 7 and 120 μM for high and low affinity receptors, respectively. Concentration-response curves for rat uterus stimulated by oxytocin or deaminooxytocin indicate that only about 0.25 to 5 per cent of the available receptors are involved in eliciting a maximal uterus contraction. The remnant receptor pool is likely to behave as a receptor reserve ("spare receptors"). Copyright © 2018 Elsevier Inc. All rights reserved.

Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata.

PubMed

Sozen, Ibrahim; Arici, Aydin

2002-07-01

To review the available information regarding the role of cytokines, growth factors, and the extracellular matrix in the pathophysiology of uterine leiomyomata and to integrate this information in a suggested model of disease at the cellular level. A thorough literature and MEDLINE search was conducted to identify the relevant studies in the English literature published between January, 1966 and October, 2001. A model of disease at the cellular level was developed using the most likely cytokines to be involved in the pathogenesis of leiomyomata as determined by our assessment of the available literature. A number of cytokines and growth factors, including transforming growth factor-beta (TGF-beta), epidermal growth factor, monocyte chemotactic protein-1, insulin-like growth factors 1 and 2, prolactin, parathyroid-hormone-related peptide, basic fibroblast growth factor, platelet-derived growth factor, interleukin-8, and endothelin, have been investigated in myometrium and leiomyoma. Among these cytokines, TGF-beta appears to be the only growth factor that has been shown to be overexpressed in leiomyoma vs. myometrium, be hormonally-regulated both in vivo and in vitro, and be both mitogenic and fibrogenic in these tissues. In addition to the cytokines, extracellular matrix components such as collagen, fibronectin, proteoglycans, matrix metalloproteinases, and tissue inhibitors of metalloproteinases seem to play pivotal roles in the pathogenesis of leiomyomata. We believe that, given the extent and depth of the current research on the cellular biology of leiomyomata, the cellular mechanisms responsible in the pathogenesis of leiomyomata will be identified clearly within the foreseeable future. This will enable researchers to develop therapy directed against the molecules and mechanisms at the cellular level.

Magnetic Resonance Imaging Parameters in Predicting the Treatment Outcome of High-intensity Focused Ultrasound Ablation of Uterine Fibroids With an Immediate Nonperfused Volume Ratio of at Least 90.

PubMed

Keserci, Bilgin; Duc, Nguyen Minh

2018-03-07

We aimed to investigate the role of magnetic resonance imaging parameters in predicting the treatment outcome of high-intensity focused ultrasound (HIFU) ablation of uterine fibroids with a nonperfused volume (NPV) ratio of at least 90%. A total of 120 women who underwent HIFU treatment were divided into groups 1 (n = 72) and 2 (n = 48), comprising patients with an NPV ratio of at least 90% and less than 90%, respectively. Multivariate logistic regression analyses were carried out to investigate the potential predictors of the NPV ratio of at least 90%. The NPV ratios immediately post-treatment, therapeutic efficacy at 6 months' follow-up, and safety in terms of adverse effects and changes in anti-Mullerian hormone level were assessed. By introducing multiple predictors obtained from multivariate analyses into a generalized estimating equation model, the results showed that the thickness of the subcutaneous fat layer in the anterior abdominal wall, peak enhancement of fibroid, time to peak of fibroid, and the ratio of area under the curve of fibroid to myometrium were statistically significant, except T2 signal intensity ratio of fibroid to myometrium, hence predicting an NPV ratio of at least 90%. No serious adverse effects and no significant difference between the anti-Mullerian hormone levels before or 6 months post-treatment were reported. The findings in this study suggest that the achievement of NPV ratio of at least 90% in magnetic resonance imaging-guided HIFU treatment of uterine fibroids based on prediction model appears clinically possible without compromising the safety of patients. Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells.

PubMed

Amini, Peyvand; Michniuk, Daniel; Kuo, Kelly; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Peters, Gregory A; Tan, Huiqing; Wang, Junye; Malemud, Charles J; Mesiano, Sam

2016-11-01

The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1β and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HM A/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC 50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition.

Isthmocervical labelling and SPECT/CT for optimized sentinel detection in endometrial cancer: technique, experience and results.

PubMed

Mücke, J; Klapdor, R; Schneider, M; Länger, F; Gratz, K F; Hillemanns, P; Hertel, H

2014-08-01

We evaluated the clinical feasibility of a new injection technique for sentinel detection in endometrial carcinoma (EC), transcervical subepithelial injection into the isthmocervical region of the myometrium. We compared detection of sentinel lymph nodes (SLN) by single photon emission computed tomography with CT (SPECT/CT) with planar lymphoscintigraphy. This is a unicentric prospective study. In all patients, transcervical injection of 10 MBq Technetium-99m-nanocolloid was performed into the isthmocervical myometrium without anaesthesia. After 40 (30-60) min, lymphoscintigraphy and SPECT/CT were performed. Patent blue was administered before surgery. The number and localisation of SLN detected in SPECT/CT and lymphoscintigraphy were recorded and compared to the SLN and non-SLN dissected intra-operatively. Between August 2008 and March 2012, 31 patients with EC were enrolled. The new transcervical injection of labelling substances led to high intra-operative (90.3%) detection rates, pelvic bilateral (57%), para-aortic (25%). SPECT/CT significantly identified more SLN than lymphoscintigraphy (mean 2.2 (1-8) to 1.3 (1-7)) in more patients (29/31 (93.5%) to 21/31 (68%), p<0.01). If SLN were identified in one hemi-pelvis, the histological evaluation of the SLN correctly predicted lymph node (LN) metastases for this basin which led to sensitivity 100%, negative predictive value (NPV) 100%, and false negative results 0%. Transcervical SLN marking in combination with SPECT/CT is easily applicable and leads to high physiologic detection rates in pelvic and para-aortic lymphatic drainage areas. Non-affected SLN truly predicted a non-affected LN basin. Combining both methods SLN dissection may be a safe and feasible staging technique for clinical routine in EC. Copyright © 2014 Elsevier Inc. All rights reserved.

Fine spatiotemporal activity in contracting myometrium revealed by motion-corrected calcium imaging.

PubMed

Loftus, Fiona C; Shmygol, Anatoly; Richardson, Magnus J E

2014-10-15

Successful childbirth depends on the occurrence of precisely coordinated uterine contractions during labour. Calcium indicator fluorescence imaging is one of the main techniques for investigating the mechanisms governing this physiological process and its pathologies. The effective spatiotemporal resolution of calcium signals is, however, limited by the motion of contracting tissue: structures of interest in the order of microns can move over a hundred times their width during a contraction. The simultaneous changes in local intensity and tissue configuration make motion tracking a non-trivial problem in image analysis and confound many of the standard techniques. This paper presents a method that tracks local motion throughout the tissue and allows for the almost complete removal of motion artefacts. This provides a stabilized calcium signal down to a pixel resolution, which, for the data examined, is in the order of a few microns. As a byproduct of image stabilization, a complete kinematic description of the contraction-relaxation cycle is also obtained. This contains novel information about the mechanical response of the tissue, such as the identification of a characteristic length scale, in the order of 40-50 μm, below which tissue motion is homogeneous. Applied to our data, we illustrate that the method allows for analyses of calcium dynamics in contracting myometrium in unprecedented spatiotemporal detail. Additionally, we use the kinematics of tissue motion to compare calcium signals at the subcellular level and local contractile motion. The computer code used is provided in a freely modifiable form and has potential applicability to in vivo calcium imaging of neural tissue, as well as other smooth muscle tissue. © 2014 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Fine spatiotemporal activity in contracting myometrium revealed by motion-corrected calcium imaging

PubMed Central

Loftus, Fiona C; Shmygol, Anatoly; Richardson, Magnus J E

2014-01-01

Successful childbirth depends on the occurrence of precisely coordinated uterine contractions during labour. Calcium indicator fluorescence imaging is one of the main techniques for investigating the mechanisms governing this physiological process and its pathologies. The effective spatiotemporal resolution of calcium signals is, however, limited by the motion of contracting tissue: structures of interest in the order of microns can move over a hundred times their width during a contraction. The simultaneous changes in local intensity and tissue configuration make motion tracking a non-trivial problem in image analysis and confound many of the standard techniques. This paper presents a method that tracks local motion throughout the tissue and allows for the almost complete removal of motion artefacts. This provides a stabilized calcium signal down to a pixel resolution, which, for the data examined, is in the order of a few microns. As a byproduct of image stabilization, a complete kinematic description of the contraction–relaxation cycle is also obtained. This contains novel information about the mechanical response of the tissue, such as the identification of a characteristic length scale, in the order of 40–50 μm, below which tissue motion is homogeneous. Applied to our data, we illustrate that the method allows for analyses of calcium dynamics in contracting myometrium in unprecedented spatiotemporal detail. Additionally, we use the kinematics of tissue motion to compare calcium signals at the subcellular level and local contractile motion. The computer code used is provided in a freely modifiable form and has potential applicability to in vivo calcium imaging of neural tissue, as well as other smooth muscle tissue. PMID:25085893

THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation

PubMed Central

Doheny, Helen C; O'Reilly, Michael J; Sexton, Donal J; Morrison, John J

2007-01-01

Background PGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. The BKCa channel is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate potential BKCa channel involvement in the response of human myometrium to THG113.31. Methods Single and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin. Results Single channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions. Conclusion These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31. PMID:17367527

Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells

PubMed Central

Amini, Peyvand; Michniuk, Daniel; Kuo, Kelly; Yi, Lijuan; Skomorovska-Prokvolit, Yelenna; Peters, Gregory A.; Tan, Huiqing; Wang, Junye; Malemud, Charles J.

2016-01-01

The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1β and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HMA/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition. PMID:27653036

Functional coupling of rat myometrial alpha 1-adrenergic receptors to Gh alpha/tissue transglutaminase 2 during pregnancy.

PubMed

Dupuis, Morgan; Lévy, Arlette; Mhaouty-Kodja, Sakina

2004-04-30

Gh alpha protein, which exhibits both transglutaminase and GTPase activities, represents a new class of GTP-binding proteins. In the present study, we characterized Gh alpha in rat uterine smooth muscle (myometrium) and followed its expression during pregnancy by reverse transcription-PCR and Western blot. We also measured transglutaminase and GTP binding functions and used a smooth muscle cell line to evaluate the role of Gh alpha in cell proliferation. The results show that pregnancy is associated with an up-regulation of Gh alpha expression at both the mRNA and protein level. Gh alpha induced during pregnancy is preferentially localized to the plasma membrane. This was found associated with an increased ability of plasma membrane preparations to catalyze Ca(2+)-dependent incorporation of [(3)H]putrescine into casein in vitro. In the cytosol, significant changes in the level of immunodetected Gh alpha and transglutaminase activity were seen only at term. Activation of alpha1-adrenergic receptors (alpha1-AR) enhanced photoaffinity labeling of plasma membrane Gh alpha. Moreover, the level of alpha1-AR-coupled Gh alpha increased progressively with pregnancy, which parallels the active period of myometrial cell proliferation. Overexpression of wild type Gh alpha in smooth muscle cell line DDT1-MF2 increased alpha1-AR-induced [(3)H]thymidine incorporation. A similar response was obtained in cells expressing the transglutaminase inactive mutant (C277S) of Gh alpha. Together, these findings underscore the role of Gh alpha as signal transducer of alpha1-AR-induced smooth muscle cell proliferation. In this context, pregnant rat myometrium provides an interesting physiological model to study the mechanisms underlying the regulation of the GTPase function of Gh alpha

Increased expression of electron transport chain genes in uterine leiomyoma.

PubMed

Tuncal, Akile; Aydin, Hikmet Hakan; Askar, Niyazi; Ozkaya, Ali Burak; Ergenoglu, Ahmet Mete; Yeniel, Ahmet Ozgur; Akdemir, Ali; Ak, Handan

2014-01-01

The etiology and pathophysiology of uterine leiomyomas, benign smooth muscle tumors of the uterus, are not well understood. To evaluate the role of mitochondria in uterine leiomyoma, we compared electron transport gene expressions of uterine leiomyoma tissue with myometrium tissue in six uterine leiomyoma patients by RT-PCR array. Our results showed an average of 1.562 (±0.445) fold increase in nuclear-encoded electron transport genes. These results might suggest an increase in size, number, or activity of mitochondria in uterine leiomyoma that, to our knowledge, has not been previously reported. © 2014 by the Association of Clinical Scientists, Inc.

Massive multicystic dilatation of the uterine wall with myometrial venous thrombosis during pregnancy.

PubMed

Uotila, J; Dastidar, P; Martikainen, P; Kirkinen, P

2004-09-01

We present a pregnancy complicated by multicystic dilatation of the uterine wall during the second trimester, leading to massive uterine distension, anemia and preterm Cesarean section. The cystic changes detected by ultrasound and magnetic resonance imaging involved the whole uterine wall surrounding the entire amniotic cavity. Histopathological examination revealed the benign nature of the cystic changes, which represented dilated and thrombosed venous lacunae. Disturbed venous drainage, combined with local thrombosis, was likely to have led to the collection of a large volume of blood in the uterine wall and the subsequent multicystic change of the myometrium. Copyright 2004 ISUOG

The Polarized Multilayer Theory of Cell Water and Other Facets of the Association-Induction Hypothesis Concerning the Distribution of Ions and Other Solutes in Living Cells,

DTIC Science & Technology

1983-12-16

first demonstrated cooperative K+ uptake by frog muscles (see Fig. 2 ; also Eq. 3 ), extensive confirmation of the theory of cooperative adsorption of K...8217 sz 22 UL K + 20 60 0 ) 02 04 6 08 20 4 . 2 A ATP CinCT10T/9 N TP ERATURE FIGURE 3 Plot of ATP vs. Kconcentration in rat myometrium. !:Variations...1907). 26. H. E. Roaf and E. Alderson, Biochem. J., 2 : 412 (1907). 27. B. Moore and H. E. Roaf, Biochem. J., 3 : 55 (1908). 28. B. Moore and H. E. Roaf

Copper metabolism domain-containing 1 represses the mediators involved in the terminal effector pathways of human labour and delivery.

PubMed

Lappas, Martha

2016-04-01

Does Copper Metabolism MURR1 Domain 1 (COMMD1) play a role in regulating the mediators involved in the terminal processes of human labour and delivery? COMMD1 plays a critical role in the termination of nuclear factor-κB (NF-κB) activity and the control of pro-inflammatory and pro-labour mediators. Inflammation and infection are the biggest aetiological factors associated with preterm birth. NF-κB drives the transcription of pro-inflammatory mediators involved in the terminal effector pathways of human labour and delivery. In non-gestational tissues, COMMD1 is a negative regulator of NF-κB-induced inflammation. The mRNA and/or protein level of COMMD1 was assessed in myometrium (n = 8 per group) and fetal membranes (n = 8 per group) obtained from term non-labouring and labouring women at term, and fetal membranes (n = 8 per group) at preterm with and without histological chorioamnionitis. Primary human myometrial cells were used to determine the effect of pro-inflammatory mediators on COMMD1 level, and the effect of COMMD1 small interfering RNA (siRNA) on pro-labour mediators. Statistical significance was ascribed to a P < 0.05. COMMD1 expression was significantly decreased with spontaneous term labour in myometrium; in fetal membranes with histologically confirmed chorioamnionitis and in myometrial cells treated with pro-inflammatory cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α, the bacterial product fibroblast-stimulating lipopeptide and the viral double stranded RNA analogue polyinosinic polycytidilic acid. Loss-of-function studies revealed an increase in inflammation- and infection-induced TNF-α, IL-1α, IL-1β, IL-6, IL-8 and/or monocyte chemoattractant protein-1 mRNA abundance and/or release; and cyclo-oxygenase-2 mRNA level, release of prostaglandin (PG) F2α and mRNA level of the PGF2α receptor FP. In addition, siRNA knockdown of COMMD1 was associated with significantly increased NF-κB activation as evidenced by increased IL-1β-induced IκB-α protein degradation and NF-κB DNA binding activity. The conclusions are based on in vitro experiments with cells isolated from myometrium. Animal models, however, will be required to establish whether COMMD1 activators can prevent spontaneous preterm birth in vivo. The control of COMMD1 activation may provide an alternative therapeutic strategy for reducing the release of pro-labour mediators in spontaneous preterm labour. Not applicable. Associate Professor Martha Lappas is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; grant no. 1047025). Additional funding was provided by the Medical Research Foundation for Women and Babies and the Mercy Research Foundation. The author has no conflict of interest. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

M-cholinoreactivity of erythrocytes of non-pregnant and pregnant women evaluated by changes in the rate of erythrocyte agglutination under the influence of acetylcholine.

PubMed

Strelnikova, A I; Tsirkin, V I; Krysova, A V; Hlybova, S V; Dmitrieva, S L

2012-12-01

Acetylcholine (5.5×10(-10)-5.5×10(-6)M) accelerated erythrocyte agglutination in men, non-pregnant women in follicular phase of the menstrual cycle, and pregnant women in the first trimester. The effect was blocked with atropine (5.5×10(-6)M). Acetylcholine had no effect on the rate of erythrocyte agglutination in non-pregnant women in the luteal phase and pregnant women in the second and third trimesters, which coincided with the development of myometrium refractoriness to acetylcholine in pregnant women. The results indicate that erythrocytes can reflect M-cholinoreactivity of internal organs.

Management and results of endometrial carcinoma treated at Instituto Português de Oncologia de Francisco Gentil.

PubMed

Tavares, M A; Patricio, M B; Vilhena, M; Da Silva, J N

1977-02-01

The experience of 260 patients with endometrial carcinoma was reviewed. The influence of factors such as age, stage of disease, grade and degree of myometrial penetration on the survival was presented, showing that survival decreases in elderly patients, in patients with advanced stage of disease, when the tumor is undifferentiated, and when the tumor deeply penetrates the myometrium. The methods of therapy, fall into three main groups: surgery, radiotherapy, and combined therapy, the latter yielding the best 5-year survival rate, in all stages. The incidence of vaginal recurrences was low, probably due to the fact that 68.8% of the patients were treated by a combined therapeutic modality.

Hysteroscopy and the treatment of uterine fibroids.

PubMed

Emanuel, Mark Hans

2015-10-01

Fibroids or (leio)myomas are benign tumours that very commonly derive from smooth muscle cells of the myometrium. They are the most common indication for a hysterectomy. However, in women desirous of preservation of their uterus or of their fertility, a myomectomy may be a more appropriate form of surgical therapy. The submucous variant is often associated with heavy menstrual bleeding or subfertility. It can be removed with hysteroscopic surgery. Refinements of hysteroscopic surgical techniques have resulted in a better ability to remove submucous myomas. The state of the art of such hysteroscopical techniques and instrumentation to treat submucous myomas and what has been proven is discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Store-operated Ca²⁺ entry and depolarization explain the anomalous behaviour of myometrial SR: effects of SERCA inhibition on electrical activity, Ca²⁺ and force.

PubMed

Noble, Debbie; Borysova, Lyudmyla; Wray, Susan; Burdyga, Theodor

2014-09-01

In the myometrium SR Ca(2+) depletion promotes an increase in force but unlike several other smooth muscles, there is no Ca(2+) sparks-STOCs coupling mechanism to explain this. Given the importance of the control of contractility for successful parturition, we have examined, in pregnant rat myometrium, the effects of SR Ca(2+)-ATPase (SERCA) inhibition on the temporal relationship between action potentials, Ca(2+) transients and force. Simultaneous recording of electrical activity, calcium and force showed that SERCA inhibition, by cyclopiazonic acid (CPA 20 μM), caused time-dependent changes in excitability, most noticeably depolarization and elevations of baseline [Ca(2+)]i and force. At the onset of these changes there was a prolongation of the bursts of action potentials and a corresponding series of Ca(2+) spikes, which increased the amplitude and duration of contractions. As the rise of baseline Ca(2+) and depolarization continued a point was reached when electrical and Ca(2+) spikes and phasic contractions ceased, and a maintained, tonic force and Ca(2+) was produced. Lanthanum, a non-selective blocker of store-operated Ca(2+) entry, but not the L-type Ca(2+) channel blocker nifedipine (1-10 μM), could abolish the maintained force and calcium. Application of the agonist, carbachol, produced similar effects to CPA, i.e. depolarization, elevation of force and calcium. A brief, high concentration of carbachol, to cause SR Ca(2+) depletion without eliciting receptor-operated channel opening, also produced these results. The data obtained suggest that in pregnant rats SR Ca(2+) release is coupled to marked Ca(2+) entry, via store operated Ca(2+) channels, leading to depolarization and enhanced electrical and mechanical activity. Copyright © 2014. Published by Elsevier Ltd.

[The establishment of environmental endocrine disruptors induced precocious puberty Macaca fascicularis model and the intervention of yin nourishing fire purging Chinese materia medica].

PubMed

Zhu, Lin; Cai, De-pei

2012-12-01

To establish the environmental endocrine disruptors (EEDs) induced precocious puberty macaca fascicularis model, thus verifying the antagonism of yin nourishing fire purging Chinese materia medica (YNFPCMM) against the estrogenic effects. (1) The female prepubescent monkeys at different months old were fed with high dose and low dose EEDs. By observing EEDs' estrogenic effects, the optimal age, the optimal exposure dose, and the optimal exposure time were determined. (2) Fifteen female prepubescent monkeys were randomly divided into the exposure group, the treatment group, and the control group, 5 in each group. Those in the exposure group were fed with EEDs such as nonylphenol (4-NP) and bisphenol A (BPA). Those in the treatment group were fed with EEDs and YNFPCMM. Those in the control group were fed with dissolvent such as corn oil. The therapeutic course was 4 weeks. By the end of the treatment, the serum estrogen level was measured and the maturation index of the vaginal keratinocytes was calculated. The uterus was extracted to measure the wet weight, the endometrial thickness, the ring-shaped myometrium thickness, the endometrial epithelial cells, and the glandular epithelium height. (1) Twenty month was the optimal exposure age. The low dose EEDs was the best exposure dose, and 4 weeks was the optimal exposure time. (2) Compared with the control group, the serum estrogen level obviously increased, the maturation index of the vaginal keratinocytes significantly increased, the wet uterus weight, the endometrial thickness, the ring-shaped myometrium thickness, the endometrial epithelial cells, and the glandular epithelium height significantly increased in the exposure group (P<0.05). Compared with the exposure group, the aforesaid indices significantly decreased in the treatment group (P<0.05). The EEDs induced precocious puberty macaca fascicularis model was successfully established in this study. The EEDs were proved to have estrogenic-like activities. YNFPC-MM was proved to have significant antagonism like estrogenic activities.

Elevated utero/placental GR/NR3C1 is not required for the induction of parturition in the dog.

PubMed

Gram, Aykut; Trachsel, Alexandra; Boos, Alois; Kowalewski, Mariusz P

2016-10-01

The endocrine mechanisms that lead to initiation of parturition in dogs are still not fully understood. The prepartum luteolysis is associated with increased prostaglandin (PG) F2α secretion; however, there is no pregnancy- or parturition-related increase in estrogens. Moreover, unlike in other mammalian species, in the dog, increased peripartum levels of cortisol measured sporadically in maternal peripheral blood are not mandatory for normal parturition. Nevertheless, auto/paracrine effects of cortisol at the placental feto-maternal level cannot be excluded. Therefore, the aim of this study was to investigate the expression and localization of glucocorticoid receptor (GR/NR3C1) in canine utero/placental (Ut/Pl) units and uterine interplacental sites at selected time points during pregnancy (pre-implantation, post-implantation and mid-gestation), and at normal and antigestagen-induced parturition. The Ut/Pl expression of GR/NR3C1 did not change significantly from pre-implantation until mid-gestation; however, it was strongly induced during the prepartum luteolysis. Within the interplacental samples, expression of GR/NR3C1-mRNA was greater post-implantation than pre-implantation and did not change afterward, i.e. toward mid-gestation. Compartmentalization studies within the Ut/Pl units, involving placenta, endometrium and myometrium separately, performed at the prepartum luteolysis revealed the highest GR/NR3C1-mRNA levels in placenta compared with endometrium and myometrium. Interestingly, in antigestagen-treated mid-pregnancy dogs, Ut/Pl and interplacental GR/NR3C1-mRNA expression remained unaffected. At the cellular level, placental GR/NR3C1 was clearly detectable in placenta fetalis, i.e. in trophoblast cells. In conclusion, increased expression of GR/NR3C1 during normal parturition, but not following antigestagen-treatment, suggest that it is not required for initiating the signaling cascade of PG synthesis leading to the induction of parturition in the dog. © 2016 Society for Reproduction and Fertility.

Hysteroscopic resection of a uterine caesarean scar defect (niche) in women with postmenstrual spotting: a randomised controlled trial.

PubMed

Vervoort, Ajmw; van der Voet, L F; Hehenkamp, Wjk; Thurkow, A L; van Kesteren, Pjm; Quartero, H; Kuchenbecker, W; Bongers, M; Geomini, P; de Vleeschouwer, Lhm; van Hooff, Mha; van Vliet, H; Veersema, S; Renes, W B; Oude Rengerink, K; Zwolsman, S E; Brölmann, Ham; Mol, Bwj; Huirne, Jaf

2018-02-01

To compare the effectiveness of a hysteroscopic niche resection versus no treatment in women with postmenstrual spotting and a uterine caesarean scar defect. Multicentre randomised controlled trial. Eleven hospitals collaborating in a consortium for women's health research in the Netherlands. Women reporting postmenstrual spotting after a caesarean section who had a niche with a residual myometrium of ≥3 mm, measured during sonohysterography. Women were randomly allocated to hysteroscopic niche resection or expectant management for 6 months. The primary outcome was the number of days of postmenstrual spotting 6 months after randomisation. Secondary outcomes were spotting at the end of menstruation, intermenstrual spotting, dysuria, sonographic niche measurements, surgical parameters, quality of life, women's satisfaction, sexual function, and additional therapy. Outcomes were measured at 3 months and, except for niche measurements, also at 6 months after randomisation. We randomised 52 women to hysteroscopic niche resection and 51 women to expectant management. The median number of days of postmenstrual spotting at baseline was 8 days in both groups. At 6 months after randomisation, the median number of days of postmenstrual spotting was 4 days (interquartile range, IQR 2-7 days) in the intervention group and 7 days (IQR 3-10 days) in the control group (P = 0.04); on a scale of 0-10, discomfort as a result of spotting had a median score of 2 (IQR 0-7) in the intervention group, compared with 7 (IQR 0-8) in the control group (P = 0.02). In women with a niche with a residual myometrium of ≥3 mm, hysteroscopic niche resection reduced postmenstrual spotting and spotting-related discomfort. A hysteroscopic niche resection is an effective treatment to reduce niche-related spotting. © 2017 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.

Luteal deficiency and embryo mortality in the mare.

PubMed

Allen, W R

2001-08-01

Four separate components combine to produce the progesterone and biologically active 5 alpha-reduced pregnanes needed to maintain pregnancy in the mare. The primary corpus luteum (CL) is prolonged beyond its cyclical lifespan by the down-regulation of endometrial oxytocin receptors to prevent activation of the luteolytic pathway and its waning progesterone production is supplemented from day 40 of gestation by the formation of a series of accessory CL which develop in the maternal ovaries as a result of the gonadotrophic actions of pituitary FSH and the equine chorionic gonadotrophin (eCG). From around day 100 the allantochorion secretes progesterone and progestagens directly to the endometrium and underlying myometrium and, in the last month of gestation, the enlarging foetal adrenal gland secretes appreciable quantities of pregnenelone which is also utilized by the placenta to synthesize progestagens. Between 10 and 15% of mares undergo foetal death and abortion at some time in gestation and the majority of these losses occur during the first 40 days of gestation when the primary CL is the sole source of progesterone. Yet, all the available evidence suggests that untoward luteolysis is not common in this period and the losses that do occur have other underlying causes. Beyond day 40 the secondary CL receive powerful luteotrophic support from eCG and from day 80-100 until term the supply organ (placenta) and target tissues (endometrium and myometrium) are in direct contact with each other over their entire surface. In the face of this interlocking and failsafe system for progestagen production throughout pregnancy, and despite a paucity of evidence that a deficiency of progesterone production is a cause of pregnancy loss in the mare, it is surprising, and worrying, that annually many thousands of pregnant mares throughout the world are given exogenous progestagen therapy during part or all of their gestation as a form of preventative insurance against the possibility of pregnancy failure. Basic investigative research is required urgently to validate or debunk the practice.

Crosstalk between monocytes and myometrial smooth muscle in culture generates synergistic pro-inflammatory cytokine production and enhances myocyte contraction, with effects opposed by progesterone.

PubMed

Rajagopal, S P; Hutchinson, J L; Dorward, D A; Rossi, A G; Norman, J E

2015-08-01

Both term and preterm parturition are characterized by an influx of macrophages and neutrophils into the myometrium and cervix, with co-incident increased peripheral blood monocyte activation. Infection and inflammation are strongly implicated in the pathology of preterm labour (PTL), with progesterone considered a promising candidate for its prevention or treatment. In this study, we investigated the effect of monocytes on myometrial smooth muscle cell inflammatory cytokine production both alone and in response to LPS, a TLR4 agonist used to trigger PTL in vivo. We also investigated the effect of monocytes on myocyte contraction. Monocytes, isolated from peripheral blood samples from term pregnant women, were cultured alone, or co-cultured with PHM1-41 myometrial smooth muscle cells, for 24 h. In a third set of experiments, PHM1-41 myocytes were cultured for 24 h in isolation. Cytokine secretion was determined by ELISA or multiplex assays. Co-culture of monocytes and myocytes led to synergistic secretion of pro-inflammatory cytokines and chemokines including IL-6, IL-8 and MCP-1, with the secretion being further enhanced by LPS (100 ng/ml). The synergistic secretion of IL-6 and IL-8 from co-cultures was mediated in part by direct cell-cell contact, and by TNF. Conditioned media from co-cultures stimulated contraction of PHM1-41 myocytes, and the effect was inhibited by progesterone. Both progesterone and IL-10 inhibited LPS-stimulated IL-6 and IL-8 secretion from co-cultures, while progesterone also inhibited chemokine secretion. These data suggest that monocytes infiltrating the myometrium at labour participate in crosstalk that potentiates pro-inflammatory cytokine secretion, an effect that is enhanced by LPS, and can augment myocyte contraction. These effects are all partially inhibited by progesterone. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Endocannabinoids modulate apoptosis in endometriosis and adenomyosis.

PubMed

Bilgic, Elif; Guzel, Elif; Kose, Sevil; Aydin, Makbule Cisel; Karaismailoglu, Eda; Akar, Irem; Usubutun, Alp; Korkusuz, Petek

2017-06-01

Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the down regulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct role in the pathogenesis of endometriosis and adenomyosis through apoptosis. Endocannabinoid receptors CB1 and CB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p=0,001 and p=0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p=0,001, p=0,001, p=0,001 and p=0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p=0,001 and p=0,001). CB1 and CB2 receptor agonist mediated dose dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566). Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Adenomyosis with extensive glandular proliferation simulating infiltrating malignancy on magnetic resonance imaging.

PubMed

Funaki, Kaoru; Fukunishi, Hidenobu; Maeda, Tetsuo; Ohbayashi, Chiho; Yamaguchi, Satoshi

2011-05-01

We report a case of multicystic adenomyosis, which is an exceedingly rare benign tumor. The patient complained of an irregular menstrual cycle and abnormal genital bleeding that gradually increased in amount and frequency. The patient finally became severely anemic, and a hysterectomy was therefore performed. T2-weighted magnetic resonance imaging (MRI) indicated hyperplasia of the endometrium, with a myometrial lesion, where a high signal intensity multicystic mass was observed. The preoperative diagnosis was complicated by confusing MRI results. Postoperative macroscopic examination revealed a villous endometrium and a myometrium thickened with multiple small cysts containing serous transparent fluid. The final diagnosis, based on the hysterectomy specimen, was adenomyosis coexisting with simple endometrial hyperplasia. The MRI and positron emission tomography images are presented.

Epithelioid leiomyosarcoma of uterus

PubMed Central

Setia, Aparna; Kanotra, Shalini; Aggarwal, Ritika; Bhavthankar, Dilip Prabhakarrao

2012-01-01

Fibroid most commonly presents in the reproductive age group and presence of fibroid with postmenopausal bleeding is a rare entity and all investigations and measures should be done to rule out leiomyosarcoma. A 45-year-old female had attained menopause 3 year back and developed postmenopausal bleeding since 2 months, with palpable mass, of 24 weeks size. Ultrasonography showed multiple whorled mass lesions, endometrium and myometrium could not be seen separately. Total abdominal hysterectomy with bilateral salpingoophorectomy was performed. Intraoperative findings showed 24 weeks uterine mass with size 17.5×15.5×11.5 cm and weight 1.9 kg with multiple, intramural fibroids. Cut section of removed specimen showed black and yellow necrotic and haemorrhagic areas with degenerative changes suggestive of malignancy. Histopathology reported epithelioid leiomyosarcoma. PMID:22602833

Epithelioid leiomyosarcoma of uterus.

PubMed

Setia, Aparna; Kanotra, Shalini; Aggarwal, Ritika; Bhavthankar, Dilip Prabhakarrao

2012-04-02

Fibroid most commonly presents in the reproductive age group and presence of fibroid with postmenopausal bleeding is a rare entity and all investigations and measures should be done to rule out leiomyosarcoma. A 45-year-old female had attained menopause 3 year back and developed postmenopausal bleeding since 2 months, with palpable mass, of 24 weeks size. Ultrasonography showed multiple whorled mass lesions, endometrium and myometrium could not be seen separately. Total abdominal hysterectomy with bilateral salpingoophorectomy was performed. Intraoperative findings showed 24 weeks uterine mass with size 17.5×15.5×11.5 cm and weight 1.9 kg with multiple, intramural fibroids. Cut section of removed specimen showed black and yellow necrotic and haemorrhagic areas with degenerative changes suggestive of malignancy. Histopathology reported epithelioid leiomyosarcoma.

Escalating placenta invasiveness: repeated placenta accreta at the limit of viability

PubMed Central

Greenbaum, Shirley; Khashper, Alla; Leron, Elad; Ohana, Eric; Meirovitz, Mihai; Hershkovitz, Reli; Erez, Offer

2016-01-01

Placenta percreta is an obstetric condition in which the placenta invades through the myometrium. This is the most severe form of placenta accreta and may result in spontaneous uterine rupture, a rare complication that threatens the life of both mother and fetus. In this case report, we describe a 32-year-old woman in her fourth pregnancy, diagnosed with repeated placenta accreta, which was eventually complicated by spontaneous uterine rupture at 24 weeks’ gestation. This patient had a history of abnormal placentation in prior pregnancies and previous uterine injuries. This case demonstrates a pattern of escalating placental invasiveness, and raises questions regarding the process of abnormal placentation and the manifestation of uterine rupture in scarred uteri. PMID:27143953

Intrapartum uterine rupture with coincidental uterine adenomyosis in an African wild dog (Lycaon pictus).

PubMed

Newell-Fugate, Annie; Lane, Emily

2009-12-01

A 7-yr-old African wild dog (Lycaon pictus) multiparous bitch experienced severe dystocia and death one day after the onset of parturition. Necropsy revealed three placental attachments in the right uterine horn and one in the left. A full-thickness rupture of the right horn at the middle placental attachment and an autolysed fetus free in the abdomen were present. Death was attributed to hypovolemic and endotoxemic shock after uterine rupture. Myometrium adjacent to the rupture and in the left uterine horn was subdivided into irregular pseudolobules by fibrous connective tissue tracts containing small endometrial glandular acini suggestive of adenomyosis, which may have facilitated uterine rupture. This is the first reported case of dystocia-induced uterine rupture and of adenomyosis in a wild dog.

Nitric oxide synthase mRNA expression in human fetal membranes: a possible role in parturition.

PubMed

Dennes, W J; Slater, D M; Bennett, P R

1997-04-07

Nitric oxide (NO) is a potent endogenous smooth-muscle relaxant. It is synthesised from 1-arginine by isoforms of nitric oxide synthase (NOS). Whilst it is clear that the uterus responds to NO by relaxation, NOS expression has not been investigated in fetal membranes or myometrium in human pregnancy. This study has shown, using semi-quantitative RT-PCR, expression of cNOS mRNA in human amnion, chorion-decidua, and placenta. iNOS mRNA expression was demonstrated in human amnion, chorion-decidua, and placenta. It is possible that NO synthesised in fetal membranes may act either directly to inhibit myometrial contractility or indirectly to interact with other labour-associated genes, such as cyclo-oxygenase, to coordinate the onset of labour.

Induction of labor in the obese patient.

PubMed

Ruhstaller, Kelly

2015-10-01

Obese women are at an increased risk of antepartum pregnancy complications and are therefore more likely to require an induction of labor than normal weight women. They also have an increased rate of failing an induction of labor, a rate that rises significantly with increasing body mass index, and subsequent surgical and neonatal complications of an intrapartum cesarean delivery. This increase in induction failure may be due to differences in the myometrium of obese women resulting in decreased contraction strength. There have been only a few studies comparing the efficacy of the various cervical ripening agents in obese women and at this point no recommendation can be made as to what method may result in the greatest chance of a successful induction. Copyright © 2015. Published by Elsevier Inc.

Changes in proliferating and apoptotic markers of leiomyoma following treatment with a selective progesterone receptor modulator or gonadotropin-releasing hormone agonist.

PubMed

Yun, Bo Seong; Seong, Seok Ju; Cha, Dong Hyun; Kim, Ji Yeon; Kim, Mi-La; Shim, Jeong Yun; Park, Ji Eun

2015-08-01

To evaluate changes in proliferating and apoptotic markers of myoma tissue from patients treated with a selective progesterone receptor modulator (SPRM) or GnRH agonist by measuring expression of PDGF-A mRNA, IGF-1 mRNA, bcl-2 mRNA, and PCNA and caspase-3 protein. Between December 2013 and July 2014, women with symptomatic leiomyoma were divided into control (no treatment before surgery), SPRM (treatment with ulipristal acetate [SPRM] for 3 months before surgery), and GnRHa (treatment with leuprolide acetate [GnRH agonist] for 3 months before surgery) groups. Tissue specimens were collected from the myoma core and normal myometrium of all patients. The expression of mRNA and protein was assessed by quantitative real-time reverse transcriptase-polymerase chain reaction and Western blot. A total of 38 patients were enrolled (control group, n=14; SPRM group, n=13; GnRHa group, n=11). PDGF-A mRNA expression was lower in both the myoma core and normal myometrium tissues of the SPRM compared with the control group, but there was no difference between the control and GnRHa group. There were also no group differences in bcl-2 mRNA or IGF-1 mRNA expression. Both PCNA and caspase-3 protein expression were higher in the leiomyoma tissue of the SPRM compared with the control group, but there was no difference between the control and GnRHa groups in the expression of either protein. Both proliferation and apoptosis were increased in the leiomyoma of patients after SPRM treatment, but there was no change following GnRH agonist treatment, in vivo. However, PDGF-A mRNA was decreased after SPRM treatment, indicating a dual effect of progesterone on the regulation of growth factors. Furthermore, there was an increase in caspase-3 protein, but not bcl-2 mRNA, expression in the SPRM group suggesting that SPRM may exert its effects in pathways other than the bcl-2 apoptotic pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A Role for Adrenergic Receptors in the Uterotonic Effects of Ergometrine in Isolated Human Term Nonlaboring Myometrium.

PubMed

Fanning, Rebecca A; Sheehan, Florike; Leyden, Claire; Duffy, Niamh; Iglesias-Martinez, Luis F; Carey, Michael F; Campion, Deirdre P; O'Connor, John J

2017-05-01

Ergometrine is a uterotonic agent that is recommended in the prevention and management of postpartum hemorrhage. Despite its long-standing use, the mechanism by which it acts in humans has never been elucidated fully. The objective of this study was to investigate the role of adrenoreceptors in ergometrine's mechanism of action in human myometrium. The study examined the hypothesis that α-adrenoreceptor antagonism would result in the reversal of the uterotonic effects of ergometrine. Myometrial samples were obtained from women undergoing elective cesarean delivery. The samples were then dissected into strips and mounted in organ bath chambers. After the generation of an ergometrine concentration-response curve (10 to 10 M), strips were treated with increasing concentrations of ergometrine (10 to 10 M) alone and ergometrine (10 to 10 M) in the presence of phentolamine (10 M), prazosin (10 M), propranolol (10 M), or yohimbine (10 M). The effects of adding ergometrine and the effect of drug combinations were analyzed using linear mixed effects models with measures of amplitude (g), frequency (contractions/10 min), and motility index (g×contractions/10 min). A total of 157 experiments were completed on samples obtained from 33 women. There was a significant increase in the motility index (adding 0.342 g × counts/10 min/μM; 95% confidence interval [CI], 0.253-0.431, P < .001), amplitude (0.078 g/μM; 95% CI, 0.0344-0.121, P = 5e-04), and frequency (0.051 counts/10 min/μM; 95% CI, 0.038-0.063, P < .001) in the presence of ergometrine. The α-adrenergic antagonist phentolamine and the more selective α1-adrenergic antagonist prazosin inhibited the ergometrine mediated increase in motility index, amplitude, and frequency (-1.63 g × counts/10 min/μM and -16.70 g × counts/10 min/μM for motility index, respectively). These results provide novel evidence for a role for α-adrenergic signaling mechanisms in the action of ergometrine on human myometrial smooth muscle in the in vitro setting. Information that sheds light on the mechanism of action of ergometrine may have implications for the development of further uterotonic agents.

Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition

PubMed Central

Menon, Ramkumar; Bonney, Elizabeth A.; Condon, Jennifer; Mesiano, Sam; Taylor, Robert N.

2016-01-01

The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments. In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the triggering of parturition. Linkage of these processes allows convergence and integration of the gestational clocks and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive synthesis of the mediators that contribute to the timing of human labor. Integrating these concepts will provide a better understanding of human parturition and ultimately improve pregnancy outcomes. PMID:27363410

Transcription Analysis of the Myometrium of Labouring and Non-Labouring Women

PubMed Central

Hutchinson, James L.; Hibbert, Nanette; Freeman, Tom C.; Saunders, Philippa T. K.; Norman, Jane E.

2016-01-01

An incomplete understanding of the molecular mechanisms that initiate normal human labour at term seriously hampers the development of effective ways to predict, prevent and treat disorders such as preterm labour. Appropriate analysis of large microarray experiments that compare gene expression in non-labouring and labouring gestational tissues is necessary to help bridge these gaps in our knowledge. In this work, gene expression in 48 (22 labouring, 26 non-labouring) lower-segment myometrial samples collected at Caesarean section were analysed using Illumina HT-12 v4.0 BeadChips. Normalised data were compared between labouring and non-labouring groups using traditional statistical methods and a novel network graph approach. We sought technical validation with quantitative real-time PCR, and biological replication through inverse variance-weighted meta-analysis with published microarray data. We have extended the list of genes suggested to be associated with labour: Compared to non-labouring samples, labouring samples showed apparent higher expression at 960 probes (949 genes) and apparent lower expression at 801 probes (789 genes) (absolute fold change ≥1.2, rank product percentage of false positive value (RP-PFP) <0.05). Although half of the women in the labouring group had received pharmaceutical treatment to induce or augment labour, sensitivity analysis suggested that this did not confound our results. In agreement with previous studies, functional analysis suggested that labour was characterised by an increase in the expression of inflammatory genes and network analysis suggested a strong neutrophil signature. Our analysis also suggested that labour is characterised by a decrease in the expression of muscle-specific processes, which has not been explicitly discussed previously. We validated these findings through the first formal meta-analysis of raw data from previous experiments and we hypothesise that this represents a change in the composition of myometrial tissue at labour. Further work will be necessary to reveal whether these results are solely due to leukocyte infiltration into the myometrium as a mechanism initiating labour, or in addition whether they also represent gene changes in the myocytes themselves. We have made all our data available at www.ebi.ac.uk/arrayexpress/ (accession number E-MTAB-3136) to facilitate progression of this work. PMID:27176052

A dynamical systems model of progesterone receptor interactions with inflammation in human parturition.

PubMed

Brubaker, Douglas; Barbaro, Alethea; R Chance, Mark; Mesiano, Sam

2016-08-19

Progesterone promotes uterine relaxation and is essential for the maintenance of pregnancy. Withdrawal of progesterone activity and increased inflammation within the uterine tissues are key triggers for parturition. Progesterone actions in myometrial cells are mediated by two progesterone receptor (PR) isoforms, PR-A and PR-B, that function as ligand-activated transcription factors. PR-B mediates relaxatory actions of progesterone, in part, by decreasing myometrial cell responsiveness to pro-inflammatory stimuli. These same pro-inflammatory stimuli promote the expression of PR-A which inhibits the anti-inflammatory activity of PR-B. Competitive interaction between the progesterone receptors then augments myometrial responsiveness to pro-inflammatory stimuli. The interaction between PR-B transcriptional activity and inflammation in the pregnancy myometrium is examined using a dynamical systems model in which quiescence and labor are represented as phase-space equilibrium points. Our model shows that PR-B transcriptional activity and the inflammatory load determine the stability of the quiescent and laboring phenotypes. The model is tested using published transcriptome datasets describing the mRNA abundances in the myometrium before and after the onset of labor at term. Surrogate transcripts were selected to reflect PR-B transcriptional activity and inflammation status. The model coupling PR-B activity and inflammation predicts contractile status (i.e., laboring or quiescent) with high precision and recall and outperforms uncoupled single and two-gene classifiers. Linear stability analysis shows that phase space bifurcations exist in our model that may reflect the phenotypic states of the pregnancy uterus. The model describes a possible tipping point for the transition of the quiescent to the contractile laboring phenotype. Our model describes the functional interaction between the PR-A:PR-B hypothesis and tissue level inflammation in the pregnancy uterus and is a first step in more sophisticated dynamical systems modeling of human partition. The model explains observed biochemical dynamics and as such will be useful for the development of a range of systems-based models using emerging data to predict preterm birth and identify strategies for its prevention.

Multiple Signals Regulate PLC beta 3 in Human Myometrial Cells

PubMed Central

Zhong, Miao; Murtazina, Dilyara A.; Phillips, Jennifer; Ku, Chun-Ying; Sanborn, Barbara M.

2008-01-01

Summary The regulation of PLCB3-Serine1105 phosphorylation by both negative feedback and negative crosstalk facilitates the integration of multiple signaling pathways in myometrial cells. Phospholipase CB3 (PLCB3) Serine1105, a substrate for multiple protein kinases, represents a potential point of convergence of several signaling pathways in the myometrium. To explore this hypothesis, the regulation of PLCB3-Serine1105 phosphorylation (P-S1105) was studied in immortalized and primary human myometrial cells. CPT-cAMP and calcitonin gene-related peptide (CALCA) transiently increased P-S1105. Relaxin also stimulated P-S1105; this effect was partially blocked by the protein kinase A (PRKA) inhibitor Rp-8-CPT-cAMPS. Oxytocin, which stimulates Gαq-mediated pathways, also rapidly increased P-S1105, as did PGF2α and ATP. Oxytocin-stimulated phosphorylation was blocked by the protein kinase C (PRKC) inhibitor Go6976 and by pretreatment overnight with a phorbol ester. Cypermethrin, a PP2B phosphatase inhibitor, but not okadaic acid, a PP1/PP2A inhibitor, prolonged the effect of CALCA on P-S1105, whereas the reverse was the case for the oxytocin-stimulated increase in P-S1105. PLCB3 was the predominant PLC isoform expressed in the myometrial cells and PLCB3 shRNA constructs significantly attenuated oxytocin-stimulated increases in intracellular calcium. Oxytocin-induced phosphatidylinositol (PI) turnover was inhibited by CPT-cAMP and okadaic acid but enhanced by pretreatment with Go6976. CPT-cAMP inhibited oxytocin-stimulated PI turnover in the presence of overexpressed PLCB3, but not overexpressed PLCB3-S1105A. These data demonstrate that both negative crosstalk from the cAMP/PRKA pathway and a negative feedback loop in the oxytocin/G protein/PLCB pathway involving PRKC operate in myometrial cells and suggest that different protein phosphatases predominate in mediating P-S1105 dephosphorylation in these pathways. The integration of multiple signal components at the level of PLCB3 may be important to its function in the myometrium. PMID:18322273

Effect of reproductive ageing on pregnant mouse uterus and cervix

PubMed Central

Patel, Rima; Moffatt, James D.; Mourmoura, Evangelia; Demaison, Luc; Seed, Paul T.; Poston, Lucilla

2017-01-01

Key points Older pregnant women have a greater risk of operative delivery, still birth and post‐term induction.This suggests that maternal age can influence the timing of birth and processes of parturition.We have found that increasing maternal age in C57BL/6J mice is associated with prolongation of gestation and length of labour.Older pregnant mice also had delayed progesterone withdrawal and impaired myometrial function.Uterine ageing and labour dysfunction should be investigated further in older primigravid women. Abstract Advanced maternal age (≥35 years) is associated with increased rates of operative delivery, stillbirth and post‐term labour induction. The physiological causes remain uncertain, although impaired myometrial function has been implicated. To investigate the hypothesis that maternal age directly influences successful parturition, we assessed the timing of birth and fetal outcome in pregnant C57BL/6J mice at 3 months (young) and 5 months (intermediate) vs. 8 months (older) of age using infrared video recording. Serum progesterone profiles, myometrium and cervix function, and mitochondrial electron transport chain complex enzymatic activities were also examined. Older pregnant mice had a longer mean gestation and labour duration (P < 0.001), as well as reduced litter size (P < 0.01) vs. 3‐month‐old mice. Older mice did not exhibit the same decline in serum progesterone concentrations as younger mice. Cervical tissues from older mice were more distensible than younger mice (P < 0.05). Oxytocin receptor and connexin‐43 mRNA expression were reduced in the myometrium from 8‐month‐old vs. 3‐month‐old mice (P < 0.05 and P < 0.01 respectively) in tandem with more frequent but shorter duration spontaneous myometrial contractions (P < 0.05) and an attenuated contractile response to oxytocin. Myometrial mitochondrial copy number was reduced in older mice, although there were no age‐induced changes to the enzymatic activities of the mitochondrial electron transport chain complexes. In conclusion, 8‐month‐old mice provide a useful model of reproductive ageing. The present study has identified potential causes of labour dysfunction amenable to investigation in older primigravid women. PMID:28083928

Characterization of the myometrial transcriptome in women with an arrest of dilatation during labor

PubMed Central

Chaemsaithong, Piya; Madan, Ichchha; Romero, Roberto; Than, Nandor G; Tarca, Adi L; Draghici, Sorin; Bhatti, Gaurav; Mazor, Moshe; Kim, Chong Jai; Hassan, Sonia S; Chaiworapongsa, Tinnakorn

2014-01-01

Objective The molecular basis of failure to progress in labor is poorly understood. This study was undertaken to characterize the myometrial transcriptome of patients with an arrest of dilatation (AODIL). Study design Human myometrium was prospectively collected from women in the following groups: 1) spontaneous term labor (TL; n=29); and 2) arrest of dilatation (AODIL; n=14). Gene expression was characterized using Illumina® HumanHT-12 microarrays. A moderated student t-test and false discovery rate adjustment were used for analysis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) of selected genes was performed in an independent sample set. Pathway analysis was performed on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database using Pathway Analysis with Down-weighting of Overlapping Genes (PADOG). The Metacore knowledge base was also mined for pathway analysis. Results 1) 42 genes differentially expressed were identified in women with an AODIL; 2) gene ontology analysis indicated enrichment of biological processes, which included: regulation of angiogenesis, response to hypoxia, inflammatory response, and chemokine-mediated signaling pathway. Enriched molecular functions included: transcription repressor activity, Heat shock protein (Hsp) 90 binding, and nitric oxide synthase (NOS) activity; 3) Metacore analysis identified immune response chemokine (C-C motif) ligand 2 (CCL2) signaling, muscle contraction regulation of eNOS activity in endothelial cells, and Triiodothyronine and Thyroxine signaling as significantly over-represented (FDR<0.05); 4) qRT-PCR confirmed overexpression of Nitric oxide synthase 3 NOS3; hypoxic ischemic factor (HIF1A), Chemokine (C-C motif) ligand 2 (CCL2); angiopoietin-like 4 (ANGPTL4), ADAM metallopeptidase with thrombospondin type 1, motif 9 (ADAMTS9), G protein-coupled receptor 4 (GPR4), metallothionein 1A (MT1A), MT2A, selectin E (SELE) in an AODIL. Conclusion The myometrium of women with arrest of dilatation have a stereotypic transcriptome profile. This disorder was associated with a pattern of gene expression involved in muscle contraction, an inflammatory response, and hypoxia. This is the first comprehensive and unbiased examination of the molecular basis of an AODIL. PMID:23893668

Side effects of anastrozole in the experimental pre-menopausal mammary carcinogenesis.

PubMed

Sadlonova, V; Kubatka, P; Kajo, K; Ostatnikova, D; Nosalova, G; Adamicova, K; Sadlonova, J

2009-01-01

The aim of this study was to assess side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats. This model mimicked situation in healthy, but from the point of view of the development of breast cancer, high-risk pre-menopausal women.

Aromatase inhibitor anastrozole was used as a chemopreventive agent taken by the animals in the food during the whole period of time of the experiment. Group 1 - the control group had taken food without anastrozole, the groups 2 and 3 with anastrozole in various concentrations - 0.05 mg/1 kg of food (ANA 0.05) and 0.5 mg/1 kg of food (ANA 0.5).

In anastrozole-treated animals in comparison with untreated animals, macroscopic changes of uterus and vagina were not found. The values of absolute and relative wet weight of uterus and vagina in the groups ANA 0.05 and ANA 0.5 were comparable with the control. Histological examination did not show atrophic changes in endometrium of uterus and in epithelium of vagina in anastrozole-treated animals. In the group ANA 0.5 myometrium was significantly grosser than in the group ANA 0.05 (P<0.05). Anastrozole neither affects parameters of plasma lipid metabolism (triacylglycerols, total cholesterol, low - density lipoprotein cholesterol and high - density lipoprotein cholesterol) nor serum levels of sex hormones (estradiol, testosterone, dehydroepiandrosterone). Compact bone thickness in the groups with anastrozole was significantly increased in comparison with untreated animals (P<0.001). A significant increase in body weight was found in the group ANA 0.5 compared with the control group (P<0.01). The significant increase in body weight gain was not attended by the significant increase in food intake.

The side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats on myometrium, compact bone thickness and body weight gain were observed.

The role of progesterone signaling in the pathogenesis of uterine leiomyoma

PubMed Central

Kim, J. Julie; Sefton, Elizabeth C.

2011-01-01

Uterine leiomyomas are benign tumors that originate from the myometrium. Evidence points to ovarian steroid hormones, in particular, progesterone as major promoters of leiomyoma development and growth. While progesterone action in leiomyomas involves the classical nuclear receptor effects on gene regulation, there is growing evidence that signaling pathways are directly activated by the progesterone receptor (PR) and that PR can interact with growth factor signaling systems to promote proliferation and survival of leiomyomas. Studies investigating the genomic and non-genomic actions of PR and its role in leiomyoma growth are summarized here. Studies testing various selective progesterone receptor modulators for the treatment of leiomyomas are also highlighted. An increased understanding of the mechanisms associated with progesterone-driven growth of leiomyomas is critical in order to develop more efficient and targeted therapies for this prevalent disease. PMID:21672608

Localized neurofibromatosis of the female genital system: a case report and review of the literature.

PubMed

Gómez-Laencina, Ana M; Martínez Díaz, Francisco; Izquierdo Sanjuanes, Blanca; Vicente Sánchez, Elena M; Fernandez Salmerón, Rosario; Meseguer Peña, Francisco

2012-06-01

Neurofibromatosis within the female genital tract is uncommon. The vulva is the most frequent genital location, but it has rarely been reported in the context of the vagina, uterine cervix or ovaries. In spite of its rarity, neurofibroma is a neoplasm that should be considered in the differential diagnosis of pelvic masses, especially in patients with neurofibromatosis. In this paper we describe the case of a 71-year-old patient with pelvic pain and a uterine mass who underwent a hysterectomy after having been diagnosed with an 11-cm neurofibroma occupying the myometrium of the entire uterine corpus. There were no neurofibromas in the endometrium, serosa, fallopian tubes or ovaries. The patient had an unknown von Recklinghausen's disease. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

Use of uterine electromyography to diagnose term and preterm labor

PubMed Central

LUCOVNIK, MIHA; KUON, RUBEN J.; CHAMBLISS, LINDA R.; MANER, WILLIAM L.; SHI, SHAO-QING; SHI, LEILI; BALDUCCI, JAMES; GARFIELD, ROBERT E.

2011-01-01

Current methodologies to assess the process of labor, such as tocodynamometry or intrauterine pressure catheters, fetal fibronectin, cervical length measurement and digital cervical examination, have several major drawbacks. They only measure the onset of labor indirectly and do not detect cellular changes characteristic of true labor. Consequently, their predictive values for term or preterm delivery are poor. Uterine contractions are a result of the electrical activity within the myometrium. Measurement of uterine electromyography (EMG) has been shown to detect contractions as accurately as the currently used methods. In addition, changes in cell excitability and coupling required for effective contractions that lead to delivery are reflected in changes of several EMG parameters. Use of uterine EMG can help to identify patients in true labor better than any other method presently employed in the clinic. PMID:21241260

Magnetic resonance imaging of placenta accreta

PubMed Central

Varghese, Binoj; Singh, Navdeep; George, Regi A.N; Gilvaz, Sareena

2013-01-01

Placenta accreta (PA) is a severe pregnancy complication which occurs when the chorionic villi (CV) invade the myometrium abnormally. Optimal management requires accurate prenatal diagnosis. Ultrasonography (USG) and magnetic resonance imaging (MRI) are the modalities for prenatal diagnosis of PA, although USG remains the primary investigation of choice. MRI is a complementary technique and reserved for further characterization when USG is inconclusive or incomplete. Breath-hold T2-weighted half-Fourier rapid acquisition with relaxation enhancement (RARE) and balanced steady-state free precession imaging in the three orthogonal planes is the key MRI technique. Markedly heterogeneous placenta, thick intraplacental dark bands on half-Fourier acquisition single-shot turbo spin-echo (HASTE), and disorganized abnormal intraplacental vascularity are the cardinal MRI features of PA. MRI is less reliable in differentiating between different degrees of placental invasion, especially between accreta vera and increta. PMID:24604945

Endometrial stromal sarcoma mimicking submucosal myoma protruding to the vagina: MRI findings.

PubMed

Chien, J C W; Hsieh, S C; Lee, R C; Chen, C Y; Cheng, C J; Chan, W P

2005-01-01

A 46-year-old woman complained of persistent abnormal vaginal bleeding over ten days. Her intrauterine device had been removed two years before. Soon after, she suffered from menorrhagia and metrorrhagia. An incidental finding of severe anemia was also noted. In this admission, our initial T2-weighted magnetic resonance imaging (MRI) revealed a well-demarcated mass predominantly in the uterine cavity. The mass was depicted by an isointense signal relative to the myometrium on T1-weighted images, high signal intensity on T2-weighted images, and slightly heterogeneous enhancement on post-contrast images. The patient refused surgery. After two years, follow-up MRI showed a pedunculated mass protruding into the upper third of the vagina with a stalk connecting to the posterior wall of the uterine cavity, simulating submucosal myoma. Histological diagnosis was compatible with low-grade endometrial stromal sarcoma.

Adenomyosis: from the sign to the diagnosis. Imaging, diagnostic pitfalls and differential diagnosis: a pictorial review.

PubMed

Valentini, A L; Speca, S; Gui, B; Soglia, G; Soglia, B G; Miccò, M; Bonomo, L

2011-12-01

Adenomyosis is a pathological gynaecological condition characterised by benign invasion of the endometrium into the myometrium. It is often misdiagnosed, or is not easily recognised, although it is responsible for disabling symptoms such as menorrhagia, abnormal uterine bleeding, dysmenorrhoea and infertility in premenopausal women. The aim of this pictorial review is to analyse the features of adenomyosis by illustrating the most usual and typical imaging patterns, along with the unusual appearances, seen in a vast array of gynaecological imaging modalities. The different findings of focal and diffuse adenomyosis along with the diagnostic limitations of ultrasound, hysterosalpingography and magnetic resonance imaging are described, as are the pitfalls and differential diagnosis with other pathological conditions that are often misdiagnosed as adenomyosis. The role of the different imaging modalities in planning appropriate treatment and their usefulness in monitoring therapy are also discussed.

Effects of space flight on the immunohistochemical demonstration of connexin 26 and connexin 43 in the postpartum uterus of rats

NASA Technical Reports Server (NTRS)

Burden, H. W.; Zary, J.; Alberts, J. R.

1999-01-01

The effect of space flight in a National Aeronautics and Space Administration shuttle was studied in pregnant rats. Rats were launched on day 11 of gestation and recovered on day 20 of gestation. Pregnancy was allowed to proceed to term and rats delivered vaginally on days 22-23, although flight animals required more labour contractions to complete the delivery process. Pups were placed with foster dams and connexin 26 and 43 were examined in the uterus of flight animals approximately 3 h after delivery. Space flight did not affect uterine connexin 26, localized primarily in epithelial cells of the endometrium, but decreased connexin 43, the major gap junction protein in the myometrium. It is suggested that decreased connexin 43 alters synchronization and coordination of labour contractions, resulting in a requirement for more contractions to complete the delivery process.

Placenta accreta: diagnosis, management and the molecular biology of the morbidly adherent placenta.

PubMed

Goh, William A; Zalud, Ivica

2016-01-01

Placenta accreta is now the chief cause of postpartum hemorrhage resulting in maternal and neonatal morbidity. Prenatal diagnosis decreases blood loss at delivery and intra and post-partum complications. Ultrasound is critical for diagnosis and MRI is a complementary tool when the diagnosis is uncertain. Peripartum hysterectomy has been the standard of therapy but conservative management is increasingly being used. The etiology of accreta is due to a deficiency of maternal decidua resulting in placental invasion into the uterine myometrium. The molecular basis for the development of invasive placentation is yet to be elucidated but may involve abnormal paracrine/autocrine signaling between the deficient maternal decidua and the trophoblastic tissue. The interaction of hormones such as Relaxin which is abundant in maternal decidua and insulin-like 4, an insulin-like peptide found in placental trophoblastic tissue may play role in the formation of placenta accreta.

Placenta accreta: Diagnosis, management and the molecular biology of the morbidly adherent placenta

PubMed Central

Goh, William; Zalud, Ivica

2017-01-01

Placenta accreta is now the chief cause of postpartum hemorrhage resulting in maternal and neonatal morbidity. Prenatal diagnosis decreases blood loss at delivery and intra and post-partum complications. Ultrasound is critical for diagnosis and MRI is a complementary tool when the diagnosis is uncertain. Peripartum hysterectomy has been the standard of therapy but conservative management is increasingly being used. The etiology of accreta is due to a deficiency of maternal decidua resulting in placental invasion into the uterine myometrium. The molecular basis for the development of invasive placentation is yet to be elucidated but may involve abnormal paracrine/autocrine signaling between the deficient maternal decidua and the trophoblastic tissue. The interaction of hormones such as Relaxin which is abundant in maternal decidua and INSL4, an insulin like peptide found in placental trophoblastic tissue may play role in the formation of placenta accreta. PMID:26135782

Effects of Progesterone Treatment on Expression of Genes Involved in Uterine Quiescence

PubMed Central

Jeng, Yow-Jiun; Izban, Michael G.; Sinha, Mala; Luxon, Bruce A.; Stamnes, Susan J.; England, Sarah K.

2011-01-01

An important action of progesterone during pregnancy is to maintain the uterus in a quiescent state and thereby prevent preterm labor. The causes of preterm labor are not well understood, so progesterone action on the myometrium can provide clues about the processes that keep the uterus from contracting prematurely. Accordingly, we have carried out Affymetrix GeneChip analysis of progesterone effects on gene expression in immortalized human myometrial cells cultured from a patient near the end of pregnancy. Progesterone appears to inhibit uterine excitability by a number of mechanisms, including increased expression of calcium and voltage-operated K+ channels, which dampens the electrical activity of the myometrial cell, downregulation of agents, and receptors involved in myometrial contraction, reduction in cell signal components that lead to increased intracellular Ca2+ concentrations in response to contractile stimuli, and downregulation of proteins involved in the cross-linking of actin and myosin filaments to produce uterine contractions. PMID:21795739

Androgens in pregnancy: roles in parturition

PubMed Central

Makieva, Sofia; Saunders, Philippa T.K.; Norman, Jane E.

2014-01-01

BACKGROUND Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition. METHODS A review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility. RESULTS Some, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight potential roles for androgens in myometrial relaxation via non-genomic, AR-independent pathways critical for the pregnancy reaching term. Understanding of the molecular events leading to myometrial relaxation is an important step towards development of novel targeted tocolytic drugs. CONCLUSIONS The increase in androgen levels throughout gestation is likely to be important for establishment and maintenance of pregnancy and initiation of parturition. Further investigation of the underlying mechanisms of androgen action on cervical remodelling and myometrial contractility is needed. The insights gained may facilitate the development of new therapeutic approaches to manage pregnancy complications such as preterm birth. PMID:24643344

Diffusion-weighted magnetic resonance imaging in cancer: Reported apparent diffusion coefficients, in-vitro and in-vivo reproducibility

PubMed Central

Jafar, Maysam M; Parsai, Arman; Miquel, Marc E

2016-01-01

There is considerable disparity in the published apparent diffusion coefficient (ADC) values across different anatomies. Institutions are increasingly assessing repeatability and reproducibility of the derived ADC to determine its variation, which could potentially be used as an indicator in determining tumour aggressiveness or assessing tumour response. In this manuscript, a review of selected articles published to date in healthy extra-cranial body diffusion-weighted magnetic resonance imaging is presented, detailing reported ADC values and discussing their variation across different studies. In total 115 studies were selected including 28 for liver parenchyma, 15 for kidney (renal parenchyma), 14 for spleen, 13 for pancreatic body, 6 for gallbladder, 13 for prostate, 13 for uterus (endometrium, myometrium, cervix) and 13 for fibroglandular breast tissue. Median ADC values in selected studies were found to be 1.28 × 10-3 mm2/s in liver, 1.94 × 10-3 mm2/s in kidney, 1.60 × 10-3 mm2/s in pancreatic body, 0.85 × 10-3 mm2/s in spleen, 2.73 × 10-3 mm2/s in gallbladder, 1.64 × 10-3 mm2/s and 1.31 × 10-3 mm2/s in prostate peripheral zone and central gland respectively (combined median value of 1.54×10-3 mm2/s), 1.44 × 10-3 mm2/s in endometrium, 1.53 × 10-3 mm2/s in myometrium, 1.71 × 10-3 mm2/s in cervix and 1.92 × 10-3 mm2/s in breast. In addition, six phantom studies and thirteen in vivo studies were summarized to compare repeatability and reproducibility of the measured ADC. All selected phantom studies demonstrated lower intra-scanner and inter-scanner variation compared to in vivo studies. Based on the findings of this manuscript, it is recommended that protocols need to be optimised for the body part studied and that system-induced variability must be established using a standardized phantom in any clinical study. Reproducibility of the measured ADC must also be assessed in a volunteer population, as variations are far more significant in vivo compared with phantom studies. PMID:26834942

Androgens in pregnancy: roles in parturition.

PubMed

Makieva, Sofia; Saunders, Philippa T K; Norman, Jane E

2014-01-01

Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition. A review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility. Some, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight potential roles for androgens in myometrial relaxation via non-genomic, AR-independent pathways critical for the pregnancy reaching term. Understanding of the molecular events leading to myometrial relaxation is an important step towards development of novel targeted tocolytic drugs. The increase in androgen levels throughout gestation is likely to be important for establishment and maintenance of pregnancy and initiation of parturition. Further investigation of the underlying mechanisms of androgen action on cervical remodelling and myometrial contractility is needed. The insights gained may facilitate the development of new therapeutic approaches to manage pregnancy complications such as preterm birth. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition.

PubMed

Menon, Ramkumar; Bonney, Elizabeth A; Condon, Jennifer; Mesiano, Sam; Taylor, Robert N

2016-09-01

The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments.In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the triggering of parturition. Linkage of these processes allows convergence and integration of the gestational clocks and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive synthesis of the mediators that contribute to the timing of human labor. Integrating these concepts will provide a better understanding of human parturition and ultimately improve pregnancy outcomes. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prostaglandin G/H synthase (PGHS)-2 expression in bovine myometrium: influence of steroid hormones and PGHS inhibitors.

PubMed

Doualla-Bell, F; Guay, J M; Bourgoin, S; Fortier, M A

1998-12-01

Prostaglandins (PGs) are important mediators regulating uterine functions during the reproductive process. The objective of this study was to examine, in myocytes from the circular and longitudinal layers of bovine myometrium, the relative levels of mRNA and proteins corresponding to the gene expression of key enzymes (phospholipase A2; prostaglandin G/H synthase-1 [PGHS-1]; prostaglandin G/H synthase-2 [PGHS-2]; prostaglandin I2 synthase) involved in PG biosynthesis. We examined the influence of estradiol-17beta and progesterone on the expression and activity of these enzymes. Treatment of myocytes with progesterone (P4: 10 nM, 24 h) in the absence or presence of estradiol-17beta (E2: 1 nM, 72 h) suppressed PG biosynthesis by approximately 60% in both myometrial layers. No significant effect was observed after E2 treatment. The combined effect of E2 and P4 on PG accumulation was correlated with the modulation of PGHS-2 protein and mRNA levels in the two myometrial layers without affecting other enzymes of the PG cascade. Selective or nonselective inhibition of PGHS activity with CGP 28238 (PGHS-2-specific; a product from Ciba-Geigy: 6-[2, 4-difluorophenoxy]-5-methyl-sulfonylamino-1-indanone) or indomethacin (PGHS-1 and -2) reduced prostacyclin accumulation (measured as 6-keto-PGF1alpha in the culture medium) in a dose-dependent manner in the two myometrial layers. A significant inhibitory effect was obtained at a low concentration of indomethacin (1 nM, p < 0.05) compared to CGP 28238 (10 nM, p < 0. 05). In both myometrial layers, the maximal effect of indomethacin and/or CGP 28238 on PG accumulation was observed at 100 nM and represented 85% and 65% inhibition, respectively. In the presence of phorbol 12-myristate (100 nM), CGP 28238 (10 nM) significantly suppressed PGHS-2 mRNA level by 44.80 +/- 7.67% (p < 0.01) and 27.83 +/- 7.62% (p < 0.05) in the longitudinal and circular layer, respectively. In contrast, indomethacin did not have any significant effect. These data constitute the first quantitative analysis of key enzymes involved in PG biosynthesis in separated myometrial layers. Furthermore, the results provide interesting information on the CGP 28238 drug modulating both enzymatic activity and mRNA expression of PGHS-2.

The retained placenta.

PubMed

Weeks, Andrew D

2008-12-01

The incidence and importance of retained placenta (RP) varies greatly around the world. In less developed countries, it affects about 0.1% of deliveries but has up to 10% case fatality rate. In more developed countries, it is more common (about 3% of vaginal deliveries) but very rarely associated with mortality. There are three main types of retained placenta following the vagina delivery: placenta adherens (when there is failed contraction of the myometrium behind the placenta), trapped placenta (a detached placenta trapped behind a closed cervix) and partial accreta (when there is a small area of accreta preventing detachment). All can be treated by manual removal of placenta, which should be carried out at 30-60 minutes postpartum. Medical management is also an option for placenta adherens and trapped placenta. The need for manual removal can be reduced by 20% by the use of intraumbilical oxytocin (30 i.u. in 30 mL saline). A trapped placenta may respond to glyceryl trinitrate (500 mcg sublingually) or gentle, persistent, controlled cord traction.

Heparin-like activity in uterine fluid.

PubMed Central

Foley, M E; Griffin, B D; Zuzel, M; Aparicio, S R; Bradbury, K; Bird, C C; Clayton, J K; Jenkins, D M; Scott, J S; Rajah, S M; McNichol, G P

1978-01-01

Uterine fluid was collected from a group of normal patients and a group of patients with menorrhagia. Heparin-like activity was detected in 34 out of 38 samples using an anti-Xa heparin assay. The heparin-like activity in uterine fluid was inhibited by adding the heparin antagonist hexadimethrine bromide to the assay. Concentrations of fibrinogen-fibrin degradation products (FDPs) were measured in five samples of uterine fluid. FDPs in the concentration detected had no effect on the anti-Xa assay. Heparin-like activity was higher in the group with menorrhagia, although the differences were not significant. Heparin-like activity increased throughout the menstrual cycle and decreased during menstruation, suggesting a possible cyclical variation in activity. There was no correlation between mast cell numbers in the endometrium and myometrium and heparin-like activity in uterine fluid and no correlation between the numbers and the stage in the menstrual cycle. In a few patients with intrauterine contraceptive devices (IUCDs) heparin-like activity was increased. PMID:687899

Endocrinology of parturition

PubMed Central

Kota, Sunil K.; Gayatri, Kotni; Jammula, Sruti; Kota, Siva K.; Krishna, S. V. S.; Meher, Lalit K.; Modi, Kirtikumar D.

2013-01-01

The myometrium must remain relatively quiescent during pregnancy to accommodate growth and development of the feto-placental unit, and then must transform into a highly coordinated, strongly contracting organ at the time of labour for successful expulsion of the new born. The control of timing of labour is complex involving interactions between mother, fetus and the placenta. The timely onset of labour and delivery is an important determinant of perinatal outcome. Both preterm birth (delivery before 37 week of gestation) and post term pregnancy (pregnancy continuing beyond 42 weeks) are both associated with a significant increase in perinatal morbidity and mortality. There are multiple paracrine/autocrine events, fetal hormonal changes and overlapping maternal/fetal control mechanisms for the triggering of parturition in women. Our current article reviews the mechanisms for uterine distension and reduced contractions during pregnancy and the parturition cascade responsible for the timely and spontaneous onset of labour at term. It also discusses the mechanisms of preterm labour and post term pregnancy and the clinical implications thereof. PMID:23776853

Sprouting angiogenesis in human midterm uterus and fallopian tube is guided by endothelial tip cells.

PubMed

Rusu, M C; Motoc, A G M; Pop, F; Folescu, R

2013-01-01

Five samples of human midterm fetal uterus and fallopian tube (four donor bodies) were used to assess whether or not processes of angiogenesis are guided by endothelial tip cells (ETCs), and if cytokine-receptors, such as CD117/c-kit and PDGFR-α, are expressed in the microenvironment of the endothelial tubes. CD34 labeled microvessels in the uterine wall (myometrium and endometrium) and in the wall of the uterine (fallopian) tube, and accurately identified ETCs in both organs. We conclude that sprouting angiogenesis in the developing human female tract is guided by ETCs. Moreover, CD117/c-kit antibodies labeled mural networks of pericytes, α-SMA-positive and desmin-negative, related to the endometrial (but not myometrial) microvessels, and similar labeling was identified in the wall of the uterine tube. PDGFR-α positive labeling, stromal and pericytary, was also found. Thus, sprouting angiogenesis in human fetal genital organs appears to be guided by tip cells and is influenced by tyrosine kinase receptor signaling.

Primary Endometrial Squamous Cell Carcinoma In Situ: Report of a rare disease.

PubMed

Jetley, Sujata; Jairajpuri, Zeeba S; Hassan, Mohammad J; Madaan, Garima; Jain, Reena

2015-11-01

Squamous cell carcinoma (SCC) of the endometrium, whether primary or secondary to cervical cancer, is a rare entity. Primary endometrial squamous cell carcinoma in situ is even more uncommon; it usually occurs in postmenopausal women and has a strong association with pyometra. We report a 60-year-old multiparous postmenopausal woman who presented to the Hakeem Abdul Hameed Centenary Hospital, New Delhi, India, in May 2014 with a lower abdominal swelling corresponding in size to a pregnancy of 26 gestational weeks and vaginal discharge of one year's duration. A total abdominal hysterectomy with a bilateral salpingooophorectomy was performed, which revealed an enlarged uterus with pyometra. Histopathology showed that the entire endometrial lining had been replaced with malignant squamous cells without invasion of the myometrium. Immunohistochemistry revealed that the tumour cells were positive for p63 with a high Ki-67 labelling index. No adjuvant therapy was required and the patient was disease-free at a seven-month follow-up.

Histology, immunohistochemistry, and in situ hybridization reveal overlooked Ebola virus target tissues in the Ebola virus disease guinea pig model.

PubMed

Cooper, Timothy K; Huzella, Louis; Johnson, Joshua C; Rojas, Oscar; Yellayi, Sri; Sun, Mei G; Bavari, Sina; Bonilla, Amanda; Hart, Randy; Jahrling, Peter B; Kuhn, Jens H; Zeng, Xiankun

2018-01-19

Survivors of Ebola virus infection may become subclinically infected, but whether animal models recapitulate this complication is unclear. Using histology in combination with immunohistochemistry and in situ hybridization in a retrospective review of a guinea pig confirmation-of-virulence study, we demonstrate for the first time Ebola virus infection in hepatic oval cells, the endocardium and stroma of the atrioventricular valves and chordae tendinae, satellite cells of peripheral ganglia, neurofibroblasts and Schwann cells of peripheral nerves and ganglia, smooth muscle cells of the uterine myometrium and vaginal wall, acini of the parotid salivary glands, thyroid follicular cells, adrenal medullary cells, pancreatic islet cells, endometrial glandular and surface epithelium, and the epithelium of the vagina, penis and, prepuce. These findings indicate that standard animal models for Ebola virus disease are not as well-described as previously thought and may serve as a stepping stone for future identification of potential sites of virus persistence.

Abnormal placentation.

PubMed

Bauer, Samuel T; Bonanno, Clarissa

2009-04-01

Abnormal placentation poses a diagnostic and treatment challenge for all providers caring for pregnant women. As one of the leading causes of postpartum hemorrhage, abnormal placentation involves the attachment of placental villi directly to the myometrium with potentially deeper invasion into the uterine wall or surrounding organs. Surgical procedures that disrupt the integrity of uterus, including cesarean section, dilatation and curettage, and myomectomy, have been implicated as key risk factors for placenta accreta. The diagnosis is typically made by gray-scale ultrasound and confirmed with magnetic resonance imaging, which may better delineate the extent of placental invasion. It is critical to make the diagnosis before delivery because preoperative planning can significantly decrease blood loss and avoid substantial morbidity associated with placenta accreta. Aggressive management of hemorrhage through the use of uterotonics, fluid resuscitation, blood products, planned hysterectomy, and surgical hemostatic agents can be life-saving for these patients. Conservative management, including the use of uterine and placental preservation and subsequent methotrexate therapy or pelvic artery embolization, may be considered when a focal accreta is suspected; however, surgical management remains the current standard of care.

The Contribution of Qualitative CEUS to the Determination of Malignancy in Adnexal Masses, Indeterminate on Conventional US – A Multicenter Study

PubMed Central

Zhang, Xinling; Mao, Yongjiang; Zheng, Rongqin; Zheng, Zhijuan; Huang, Zeping; Huang, Dongmei; Zhang, Jing; Dai, Qing; Zhou, Xiaodong; Wen, Yanling

2014-01-01

The aim of this study is to evaluate the efficacy of qualitative analysis of contrast-enhanced ultrasound (CEUS) in discrimination of adnexal masses which were undetermined by conventional ultrasound (US). A total of 120 patients underwent transabdominal CEUS. The initial enhancement time and intensity compared with the uterine myometrium, contrast agent distribution patterns and dynamic changes of enhancement were assessed. The sensitivity (Sen), specificity (Spe), positive predictive value (PPV), negative predictive value (NPV), accuracy (ACC) and Youden’s index were calculated for contrast variables. The gold standard was the histological diagnosis. There were 48 malignant tumors and 72 benign tumors. The enhancement features of malignant masses were different from benign ones. Earlier or simultaneous enhancement with inhomogeneous enhancement yielded the highest capability in differential diagnosis, and Sen, Spe, PPV, NPV, ACC, Youden’s index was 89.6%, 97.2%, 93.2%, 95.6%, 93.3%, and 0.88, respectively. The qualitative evaluation of CEUS is useful in the differential diagnosis of adnexal masses where conventional US is indeterminate. PMID:24736589

Retrieval of estradiol receptor in paraffin sections of resting porcine uteri by microwave treatment. Immunostaining patterns obtained with different primary antibodies.

PubMed

Sierralta, W D; Thole, H H

1996-05-01

The unmasking of estradiol receptor in paraffin sections of Bouin's-fixed uterine tissue from ovariectomized gilts was attained with microwave treatment. Immunocytochemistry of the receptor was performed using a polyclonal or five monoclonal antibodies, two of which are commercially available, reacting with different domains of the protein and an amplified-peroxidase system for detection. With five of the antibodies, a predominance of nuclear staining was observed in cells of endometrial glands, while one monoclonal antibody (13H2), reacting with the receptor's domain E, showed a preference for the cytoplasmic receptor. In stroma, all antibodies detected more receptor in nuclei than in cytoplasm. In epithelium, the commercially available antibody H222, our monoclonals 13H2 and HT65, and the polyclonal antibody 402 demonstrated more receptor in cytoplasmic than in nuclear areas. In myometrium, the nuclei from longitudinal and ring muscles were definitely stained with the antibodies. We conclude that the accessibilities of the antibody epitopes of the receptor differ according to the functional uterine cell type.

Very early stage adenocarcinoma arising from adenomyosis in the uterus.

PubMed

Hsu, Ming-I; Chou, Szu-Yuan; Lin, Sey-En; Liang, So-Jung; Chiu, Hsiao-Chen; Hsu, Chun-Sen

2006-12-01

Malignant transformations of adenomyosis in premenopausal women with normal endometrium are extremely rare. We report a case of adenocarcinoma arising from an adenomyotic focus in the uterus, which was found unexpectedly in a woman undergoing myomectomy for adenomyosis. A 47-year-old premenopausal woman presented with massive vaginal bleeding and anemia. She was admitted and underwent myomectomy under the initial diagnosis of uterine leiomyoma. Microscopic studies revealed endometrioid adenocarcinoma, which was a malignant transformation of a focus of adenomyosis in the surgical specimen. A total hysterectomy and bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy was then performed. Pathologic studies showed no residual tumors in the entire resected specimen except for the previous lesion. The endometrium had normal thickness with mild proliferative activity throughout the cavity. There was no atrophic or hyperplastic change in the whole endometrium. The adenocarcinoma was present exclusively in the myometrium, and a transition between the carcinoma and the adenomyotic glands was observed. This case report presents evidence that adenocarcinoma may a rise de novo from an adenomyotic lesion in the uterus.

Incidental Finding of Metastatic Cutaneous Malignant Melanoma at Uterine Leiomyoma, A Thai University Hospital Experience: A Case Report.

PubMed

Chanthasenanont, Athita; Nantakomon, Tongta; Kintarak, Jutatip; Vithisuvanakul, Nophadol; Pongrojpaw, Densak; Suwannarurk, Komsun

2015-04-01

Metastatic malignant melanomas to the uterus are extremely rare; to our knowledge, no more than 13 cases have been reported to date. A 44-years-old multigravida woman presented with a black and irregular surface mass at medial aspect of left thigh. There was also an enlarged left groin node. Wide excision with lymph node dissection revealed malignant melanoma. Further examination found a huge pelvic mass with left deep vein thrombosis consequent by pressure effect. Chest and complete abdominal computed tomography revealed an enlarged, fibroid uterus with pressure effect at left common iliac vein. A total abdominal hysterectomy and bilateral adnexectomy were performed. Intra-operative finding was scattered hyperpigment spots at surface of the uterus and its tumor Histopathological report showed metastatic malignant melanoma involving myometrium and uterine serosa. Diagnosis of stage IV malignant melanoma (uterine metastasis) was achieved. The patient was counseled about her diagnosis, stage, prognosis and further treatment. Uterine metastatic malignant melanoma was a rare condition. This report represents the first case of a cutaneous malignant melanoma involving a uterine leiomyoma in Thailand.

Fertility impairment associated with uterine fibroids - a review of literature.

PubMed

Lisiecki, Marek; Paszkowski, Maciej; Woźniak, Sławomir

2017-12-01

Uterine fibroids (also known as leiomyomas or myomas) are the most common benign tumors affecting reproductive organs in women. They are monoclonal tumors of the uterine smooth muscle, which spring from myometrium. It is estimated that they occur in 50-60% of the female population and rise to 70% by the age of 50. While mostly asymptomatic, myomas can be connected with several conditions, including abnormal bleeding with subsequent anemia, pelvic masses, pelvic pain, bulk symptoms, unfavorable impact on fertility and obstetric complications. Factors, which predispose the emergence of fibroids are: hormones, Afro-American ethnicity, age, obesity, adverse pregnancy outcome history, early menarche, genetic factors, alcohol, caffeine or eating too much red meat. On the other hand, there are factors, which can decrease this risk: pregnancy, early menopause and tobacco smoking. There are several mechanisms of fertility impairment in females with fibroids: alternations in uterus function (flawed blood supply, increased contractility), changes in the normal uterus anatomy, local hormonal changes induced by fibroids. In this review the connection between fibroids and infertility is analyzed.

Laser-induced interstitial thermotherapy (LITT) with the KTP 532 laser for the treatment of uterine adenomyosis

NASA Astrophysics Data System (ADS)

Chapman, Roxana; Chapman, Kenneth

1997-05-01

Adenomyosis is a condition in which the myometrium is infiltrated by endometrial glands and stroma. This results in myometrial hyperplasia, uterine enlargement and causes menorrhagia, dysmenorrhoea and dyspareunia for which there is no known cure other than hysterectomy. The success of LITT in the treatment of uterine leiomyomata suggested that this might also be effective for the treatment of adenomyosis. Initially LITT was carried out on patients with adenomyosis prior to hysterectomy, then on patients who had completed child-bearing and finally on those who desired a family. Not only were symptoms relieved but pregnancies occurred spontaneously. The KTP 532 nm component of the KTP/YAG laser, which is absorbed by red pigment, was used with a 600 micrometer fiber with a bare tip via a needle microstat at laparoscopy. Holes were drilled in the abnormal tissue 3 cm apart and the laser fiber then slowly withdrawn, the object being to coagulate the surrounding blood vessels and adenomyotic tissue. The number of joules required depended on the volume of tissue treated.

The contribution of qualitative CEUS to the determination of malignancy in adnexal masses, indeterminate on conventional US - a multicenter study.

PubMed

Zhang, Xinling; Mao, Yongjiang; Zheng, Rongqin; Zheng, Zhijuan; Huang, Zeping; Huang, Dongmei; Zhang, Jing; Dai, Qing; Zhou, Xiaodong; Wen, Yanling

2014-01-01

The aim of this study is to evaluate the efficacy of qualitative analysis of contrast-enhanced ultrasound (CEUS) in discrimination of adnexal masses which were undetermined by conventional ultrasound (US). A total of 120 patients underwent transabdominal CEUS. The initial enhancement time and intensity compared with the uterine myometrium, contrast agent distribution patterns and dynamic changes of enhancement were assessed. The sensitivity (Sen), specificity (Spe), positive predictive value (PPV), negative predictive value (NPV), accuracy (ACC) and Youden's index were calculated for contrast variables. The gold standard was the histological diagnosis. There were 48 malignant tumors and 72 benign tumors. The enhancement features of malignant masses were different from benign ones. Earlier or simultaneous enhancement with inhomogeneous enhancement yielded the highest capability in differential diagnosis, and Sen, Spe, PPV, NPV, ACC, Youden's index was 89.6%, 97.2%, 93.2%, 95.6%, 93.3%, and 0.88, respectively. The qualitative evaluation of CEUS is useful in the differential diagnosis of adnexal masses where conventional US is indeterminate.

Infusion of oxytocin induces successful delivery in prostanoid FP-receptor-deficient mice.

PubMed

Kawamata, Masaki; Yoshida, Masahide; Sugimoto, Yukihiko; Kimura, Tadashi; Tonomura, Yutaka; Takayanagi, Yuki; Yanagisawa, Teruyuki; Nishimori, Katsuhiko

2008-02-13

The dramatic increase of oxytocin (OT) receptor (OTR) in the myometrium as well as circulating progesterone withdrawal has been thought to be the most important factor in the induction and accomplishment of parturition since delivery fails in prostaglandin F2alpha receptor (FP) knockout (FP KO) mice. The expression levels of OTR mRNA/protein were not dramatically increased in the near-term uteri of FP KO mice. However, OT-induced myometrial contractions and the concentration-response curves in FP KO in vitro were almost similar to those in wild-type (WT) mice. OT-infusion (0.3 U/day) enabled FP KO mice to experience successful delivery, and furthermore the duration until the onset was hastened by a higher dose of OT (3 U/day). The plasma progesterone levels of FP KO females were maintained at high levels, but decreased during labor by OT-infusion (3 U/day). These results suggest that OT has potentials to induce strong myometrial contractions in uterus with low expression levels of OTR and luteolysis in ovary, which enabled FP KO females to undergo successful delivery.

Fallopian tube cytology: a histocorrelative study of 150 washings.

PubMed

Mulvany, N J; Arnstein, M; Ostör, A G

1997-06-01

The aim of the study was to assess the relationship between fallopian tube lavage cytology and recognized microscopic prognostic features in cancer of the uterine corpus. Tubal (TW) and peritoneal washing cytology (PW), endometrial tumor grade, and tumor involvement of the cervix, myometrium, myometrial vessels, and peritoneum were assessed in 150 patients. Endometrioid adenocarcinoma grade I was considered a low-grade tumor, while endometrioid carcinoma grades 2/3, serous/clear cell carcinoma, carcinosarcoma, and high-grade stromal sarcoma were considered high grade. The overall concordance rate for paired TWs and PWs was 72% (108/150). Forward stepwise logistic regression analysis of the 150 tumors revealed that only PWs and cervical involvement were independently predictive of TWs. No relationship was evident between TWs and depth of myometrial invasion, myometrial vascular involvement, or peritoneal metastases. It is concluded that retrograde transtubal spread by malignant endometrial cells occurs independently of myometrial histoprognostic features. TWs provide supporting evidence for diagnostically difficult PWs, and malignant TWs may be detected in the presence of minimally invasive serous/clear cell carcinoma and carcinosarcoma of the endometrium.

Ayurvedic intervention in the management of uterine fibroids: A Case series.

PubMed

Dhiman, Kamini

2014-01-01

Uterine enlargement is common in reproductive life of a female. Other than pregnancy, it is seen most frequently in the result of leiomyomas. Leiomyomas, are benign smooth muscle neoplasmas that typically originate from the myometrium, due to fibrous consistency and are also called as fibroid. They may be identified in asymptomatic women during routine pelvic examination or may cause symptoms. Typical complaints include pain, pressure sensations, dysmenorrhea or abnormal uterine bleeding. Management of uterine fibroid through surgery is available to meet urgent need of the patient, but challenges remain to establish a satisfactory conservatory medical treatment till date. Hence, it was critically reviewed in the context of Granthi Roga (disease) and treatment protocol befitting the Samprapti Vighatana of Granthi (encapsulated growth) was subjected in patients of uterine fibroids. Seven cases of uterine fibroid were managed by Ayurvedic intervention. Ultrasonography (USG) of the lower abdomen was the main investigative/diagnostic tool in this study. After 7 weeks, patients presented with USG report as absence of uterine fibroid. Ayurvedic formulations Kanchanara Guggulu, Shigru Guggulu, and Haridra Khand are found to be effective treatment modality in uterine fibroid.

Ayurvedic intervention in the management of uterine fibroids: A Case series

PubMed Central

Dhiman, Kamini

2014-01-01

Uterine enlargement is common in reproductive life of a female. Other than pregnancy, it is seen most frequently in the result of leiomyomas. Leiomyomas, are benign smooth muscle neoplasmas that typically originate from the myometrium, due to fibrous consistency and are also called as fibroid. They may be identified in asymptomatic women during routine pelvic examination or may cause symptoms. Typical complaints include pain, pressure sensations, dysmenorrhea or abnormal uterine bleeding. Management of uterine fibroid through surgery is available to meet urgent need of the patient, but challenges remain to establish a satisfactory conservatory medical treatment till date. Hence, it was critically reviewed in the context of Granthi Roga (disease) and treatment protocol befitting the Samprapti Vighatana of Granthi (encapsulated growth) was subjected in patients of uterine fibroids. Seven cases of uterine fibroid were managed by Ayurvedic intervention. Ultrasonography (USG) of the lower abdomen was the main investigative/diagnostic tool in this study. After 7 weeks, patients presented with USG report as absence of uterine fibroid. Ayurvedic formulations Kanchanara Guggulu, Shigru Guggulu, and Haridra Khand are found to be effective treatment modality in uterine fibroid. PMID:26664240

[Co-adaptation of enzymatic systems of cells and blood supply in smooth muscle tumors of the corpus uteri].

PubMed

Lazaarev, A F; Avbalian, A M; Bobrov, I P; Klimachev, V V; Mischenko, E V

2008-01-01

We investigated co-adaptation of enzymatic systems of cells using data on activity of NAD(Ph)-dependent enzymes and AgNOR proteins of vascular endothelium vis-a-vis angiogenesis in benign and malignant smooth muscle tumors of the corpus uteri. Overall metabolic activity (NAD-H2 diaphorase) was found to directly correlate with angiogenesis and endothelial vessel proliferation (r = 0.76 and 0.84, respectively). SDH-regulated oxidation in the main metabolic succession of a tricarbonic acid cycle depended on blood supply and endothelial vessel proliferation (r = 0.84 and 0.92, respectively; p = 0.04). A similar relationship was shown for anaerobic glycolysis of SDH (LDH content), on the one hand, and blood supply and endothelial vessel proliferation(r = 0.57 and 0.70, respectively; p = 0.02), on the other. Hence, metabolic profile varied in unaltered myometrium and tumor with variable cellular density and peculiar extracellular matrix. The highest levels of metabolic activity with NAD(Ph)-dependent enzyme co-adaptation was observed in sarcomas which were also characterized by the highest vascular density for endothelial proliferation.

MR imaging findings of adenomyosis: correlation with histopathologic features and diagnostic pitfalls.

PubMed

Tamai, Ken; Togashi, Kaori; Ito, Tsuyoshi; Morisawa, Nobuko; Fujiwara, Toshitaka; Koyama, Takashi

2005-01-01

Adenomyosis is a nonneoplastic condition, characterized by benign invasion of ectopic endometrium into the myometrium with hyperplasia of adjacent smooth muscle. The common symptoms include dysmenorrhea, menorrhagia, and abnormal uterine bleeding, but these do not allow diagnosis. Therefore, imaging plays an important role because establishment of the correct preoperative diagnosis is critical to avoid unnecessary intervention. Magnetic resonance (MR) imaging is a highly accurate noninvasive modality for diagnosis of adenomyosis, differentiation of adenomyosis from other gynecologic disorders, and planning of appropriate treatment. Although the typical MR imaging findings are well established, adenomyosis actually varies widely in terms of histopathologic features (adenomyosis with sparse glands), growth patterns (polypoid adenomyoma, adenomyotic cyst, and miniature uterus), responses to hormonal activity (tamoxifen, decidual changes), and responses to treatment (gonadotropin-releasing hormone agonist). The MR imaging findings of adenomyosis occasionally mimic those of uterine malignancy or ovarian cancer. Furthermore, malignancy occasionally develops in otherwise benign adenomyosis. Pitfalls in diagnosis of adenomyosis include myometrial contractions, leiomyoma, adenomatoid tumor, metastases, endometrial carcinoma, and endometrial stromal sarcoma. Knowledge of the various appearances of adenomyosis and the possible pitfalls in differential diagnosis help guide the determination of appropriate treatment options. (c) RSNA, 2005.

The role of invasive trophoblast in implantation and placentation of primates

PubMed Central

Carter, Anthony M.; Enders, Allen C.; Pijnenborg, Robert

2015-01-01

We here review the evolution of invasive placentation in primates towards the deep penetration of the endometrium and its arteries in hominoids. The strepsirrhine primates (lemurs and lorises) have non-invasive, epitheliochorial placentation, although this is thought to be derived from a more invasive type. In haplorhine primates, there is differentiation of trophoblast at the blastocyst stage into syncytial and cellular trophoblast. Implantation involves syncytiotrophoblast that first removes the uterine epithelium then consolidates at the basal lamina before continuing into the stroma. In later stages of pregnancy, especially in Old World monkeys and apes, cytotrophoblast plays a greater role in the invasive process. Columns of trophoblast cells advance to the base of the implantation site where they spread out to form a cytotrophoblastic shell. In addition, cytotrophoblasts advance into the lumen of the spiral arteries. They are responsible for remodelling these vessels to form wide, low-resistance conduits. In human and great apes, there is additional invasion of the endometrium and its vessels by trophoblasts originating from the base of the anchoring villi. Deep trophoblast invasion that extends remodelling of the spiral arteries to segments in the inner myometrium evolved in the common ancestor of gorilla, chimp and human. PMID:25602074

Metastasis of lobular breast carcinoma to the uterus in a patient under anastrozole therapy.

PubMed

Ustaalioglu, Basak B O; Bilici, Ahmet; Seker, Mesut; Salman, Tarik; Gumus, Mahmut; Barisik, Nagehan O; Salepci, Taflan; Yaylaci, Mustafa

2009-07-01

Metastasis of extragenital neoplasms to the uterus are rarely encountered, and usually occur as a manifestation of advanced disease. Lobular carcinoma is the most common type of breast cancer that metastasizes to the uterus. We report on a 56-year-old woman who 3 years previously was diagnosed with invasive lobular carcinoma of the breast and was treated with surgery followed by chemotherapy and radiotherapy. While the patient was on adjuvant anastrozole therapy for 2 years, she complained of vaginal bleeding. Because of endometrial thickening and a uterine leiomyoma detected during abdominal ultrasonographic ex-amination, a total hysterectomy with bilateral salpingo-oophorectomy was performed. Histopathologic examination of the specimens revealed carcinoma infiltration of the myometrium, endometrium, cervix, uterine tube, and left ovary. Immunohistochemical staining of tumoral cells with pancytokeratin and gross cystic disease fluid protein (GCDFP-15) proved the diagnosis of metastatic lobular breast carcinoma to the uterus. To our knowledge, this is the second case of lobular breast carcinoma metastasized to the uterus under anastrozole therapy. In women with lobular breast cancer under adjuvant anastrozole therapy, who present with vaginal bleeding, uterine metastasis of lobular carcinoma should be considered in the differential diagnosis. Copyright 2009 S. Karger AG, Basel.

Assessment of Parturition with Cervical Light-Induced Fluorescence and Uterine Electromyography

PubMed Central

Lucovnik, Miha; Kuon, Ruben J.; Garfield, Robert E.

2013-01-01

Parturition involves increasing compliance (ripening) of the uterine cervix and activation of the myometrium. These processes take place in a different time frame. Softening and shortening of the cervix starts in midpregnancy, while myometrial activation occurs relatively close to delivery. Methods currently available to clinicians to assess cervical and myometrial changes are subjective and inaccurate, which often causes misjudgments with potentially adverse consequences. The inability to reliably diagnose true preterm labor leads to unnecessary treatments, missed opportunities to improve neonatal outcome, and inherently biased research of treatments. At term, the likelihood of cesarean delivery depends on labor management, which in turn depends on accurate assessments of cervical change and myometrial contractility. Studies from our group and others show that noninvasive measurements of light-induced fluorescence (LIF) of cervical collagen and uterine electromyography (EMG) objectively detect changes in the composition of the cervix and myometrial preparedness to labor and are more reliable than clinical observations alone. We present a conceptual model of parturition constructed on cervical LIF and uterine EMG studies. We also explore how these methodologies could be helpful with managing patients experiencing preterm contractions and with optimizing labor management protocols aimed to reduce cesarean section. PMID:24187578

Behaviour of beta 2-adrenoceptors on lymphocytes under continuous and pulsatile tocolysis with Fenoterol.

PubMed

Schmidt-Rhode, Peter; Brunke, Björn; Schröer, Heinrich; Obert, Kirstin; Schlegel, Kerstin; Sturm, Gerhard; Schulz, Klaus-Dieter; von Wichert, Peter

2003-01-01

The present study investigates the population of beta 2-receptors on lymphocytes in pregnant women with premature labor between the 29th and 34th week of pregnancy. The population of receptors on lymphocytes correlates with that on the myometrium, which is not accessible for study during pregnancy. Fourteen patients received a pulsatile tocolysis, while ten women received a continuous tocolysis with Fenoterol. Assuming an equal population of receptors in both groups before commencement of therapy, the numbers of receptors in the patients with continuous tocolysis fell to about 35% of the initial value after 72 hours. Under pulsatile tocolysis, the numbers of receptors remained unchanged for a period of three days and was still only just below 70% of the initial value by the seventh day. Our data demonstrate that continuous administration of the short-acting beta 2-agonist Fenoterol resulted in a substantial loss of beta 2-adrenoceptors on lymphocytes. In contrast, intermittent administration of the same beta 2-adrenergic agonist prevented the onset of receptor down-regulation in pregnant women with preterm labor. Further studies are required to investigate the impact of the decreased loss of beta 2-adrenoceptor density on the good clinical experience with intermittent tocolysis.

Use of progesterone and progestin analogs for inhibition of preterm birth and other uterine contractility disorders

PubMed Central

Garfield, R.E.; Shi, L.; Shi, S-Q.

2012-01-01

In this paper we focus on preterm birth as a uterine contractility disorder caused by hypercontractility of the myometrium. We describe changes in uterine function during term and preterm labor and delivery. We also examine the usefulness of measurement of uterine electromyographic (EMG) activity, noninvasively monitored from the abdominal surface of pregnant patients. The use of progesterone treatment for preterm birth is discussed and we conclude that present therapies with progesterone could be improved by changing the route of administration. Finally we show the results of recent studies that show that progesterone injections completely inhibit uterine EMG activity when given several days to hours before normal delivery. These studies illustrate how progesterone suppresses labor at term or preterm, probably through repression of genes which control excitability and conduction of electrical activity. However, direct profusion of soluble progesterone into the uterine cavity has little immediate inhibitory action and this may demonstrate that progesterone has no direct, nongenomic effects, at least in the rat model used. Further studies are required to determine the effects of progesterone on human uterine EMG activity and whether progesterone treatments will prevent preterm birth. PMID:24753915

Surgical Management of Neurovascular Bundle in Uterine Fibroid Pseudocapsule

PubMed Central

Malvasi, Antonio; Hurst, Brad S.; Tsin, Daniel A.; Davila, Fausto; Dominguez, Guillermo; Dell'edera, Domenico; Cavallotti, Carlo; Negro, Roberto; Gustapane, Sarah; Teigland, Chris M.; Mettler, Liselotte

2012-01-01

The uterine fibroid pseudocapsule is a fibro-neurovascular structure surrounding a leiomyoma, separating it from normal peripheral myometrium. The fibroid pseudocapsule is composed of a neurovascular network rich in neurofibers similar to the neurovascular bundle surrounding a prostate. The nerve-sparing radical prostatectomy has several intriguing parallels to myomectomy. It may serve either as a useful model in modern fibroid surgical removal, or it may accelerate our understanding of the role of the fibrovascular bundle and neurotransmitters in the healing and restoration of reproductive potential after intracapsular myomectomy. Surgical innovations, such as laparoscopic or robotic myomectomy applied to the intracapsular technique with magnification of the fibroid pseudocapsule surrounding a leiomyoma, originated from the radical prostatectomy method that highlighted a careful dissection of the neurovascular bundle to preserve sexual functioning after prostatectomy. Gentle uterine leiomyoma detachment from the pseudocapsule neurovascular bundle has allowed a reduction in uterine bleeding and uterine musculature trauma with sparing of the pseudocapsule neuropeptide fibers. This technique has had a favorable impact on functionality in reproduction and has improved fertility outcomes. Further research should determine the role of the myoma pseudocapsule neurovascular bundle in the formation, growth, and pathophysiological consequences of fibroids, including pain, infertility, and reproductive outcomes. PMID:22906340

Endometrial Metastasis from Ductal Breast Carcinoma: A Case Report with Literature Review.

PubMed

Rahmani, Maryam; Nili, Fatemeh; Tabibian, Elnaz

2018-04-27

BACKGROUND There are few reports of breast cancer cases with uterine metastases; among them, myometrium is more frequently involved than endometrium. The majority of breast cancer metastases to endometrium are lobular type, and there have been only 5 reported cases of ductal type since 1984. Here, we describe a new case of invasive ductal carcinoma with metastases to endometrium and isolated presentation of abnormal uterine bleeding, in addition to reviewing the existing literature on other similar cases. CASE REPORT The patient was a 51-year-old Persian woman with no remarkable past medical or family history of cancer, who presented with a 6-month complaint of menorrhagia to our gynecology clinic. Diagnostic studies including trans-vaginal ultrasonography, pathological examination of endometrial curettage specimen, immunohistochemistry findings, and X-plane and magnetic resonance mammography, and breast core-needle biopsy revealed invasive ductal breast carcinoma as the origin of the endometrial metastasis. CONCLUSIONS Abnormal uterine bleeding in a premenopausal patient should alert clinicians to the possibility of secondary as well as primary neoplasms. It is necessary to differentiate a metastatic tumor from a primary one, since the treatment and prognosis are completely different.

Identification of first-stage labor arrest by electromyography in term nulliparous women after induction of labor.

PubMed

Vasak, Blanka; Graatsma, Elisabeth M; Hekman-Drost, Elske; Eijkemans, Marinus J; Schagen van Leeuwen, Jules H; Visser, Gerard H A; Jacod, Benoit C

2017-07-01

Worldwide induction and cesarean delivery rates have increased rapidly, with consequences for subsequent pregnancies. The majority of intrapartum cesarean deliveries are performed for failure to progress, typically in nulliparous women at term. Current uterine registration techniques fail to identify inefficient contractions leading to first-stage labor arrest. An alternative technique, uterine electromyography has been shown to identify inefficient contractions leading to first-stage arrest of labor in nulliparous women with spontaneous onset of labor at term. The objective of this study was to determine whether this finding can be reproduced in induction of labor. Uterine activity was measured in 141 nulliparous women with singleton term pregnancies and a fetus in cephalic position during induced labor. Electrical activity of the myometrium during contractions was characterized by its power density spectrum. No significant differences were found in contraction characteristics between women with induced labor delivering vaginally with or without oxytocin and women with arrested labor with subsequent cesarean delivery. Uterine electromyography shows no correlation with progression of labor in induced labor, which is in contrast to spontaneous labor. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

Electrical properties of the costo-uterine muscle of the guinea-pig.

PubMed Central

Parkington, H C

1983-01-01

The spontaneous electrical and mechanical activity of the costo-uterine muscle of the guinea-pig are described. The spontaneous electrical activity, recorded intracellularly, is similar to that observed previously in longitudinal myometrium of rat (Marshall, 1959) and ionic substitution suggests that, though calcium may be the predominant ion carrying the current during the upstroke of the action potential, some influence of sodium cannot be ruled out. During dioestrus, when circulating progesterone levels are high, there is an increase in the resting membrane potential and a decrease in the frequency of electrical and mechanical activity. There is a two-fold decrease in the space constant (lambda) during dioestrus. At this time the membrane time constant (tau m) is also decreased. The diameter and length of the smooth muscle cells are smaller during dioestrus. However, the differences in cell diameter do not explain all of the differences observed in lambda at this time and it is suggested that there may be an increase in the resistance to current flow between cells. It is concluded that high circulating progesterone may bring about quiescence of target smooth muscle in two ways: by stabilizing the cell membrane and by restricting the spread of activity. PMID:6683758

Effect of urinary trypsin inhibitor on potassium currents: fetus modulates membrane excitability by production of UTI.

PubMed

Takeuchi, Kinya; Fukuda, Atsuo; Kanayama, Naohiro

2004-01-01

Amniotic fluid contains a significant level of urinary trypsin inhibitor (UTI). Previously, we reported that UTI inhibits calcium influx of myometrium and it is effective in preventing uterine contraction. This study examined the effects of UTI upon potassium channels, which is important for membrane excitability. Whole-cell patch-clamp recordings were performed in fibroblasts derived from human fetal skin. Potassium currents were recorded and the effects of exogenous UTI and/or cadmium determined. Tetraethylammonium sensitive potassium currents were elicited by step or ramp stimulations at depolarized membrane potentials (over +30 mV). Administration of 1 micro M UTI significantly increased these potassium currents by 16.9%. When calcium channels were blocked by the administration of cadmium, UTI increased the rest of the potassium currents by 4.8%. This indicates that UTI increased calcium-dependent potassium currents by 94.8% but only increased voltage-dependent potassium currents by 4.8%. Urinary trypsin inhibitor is a physiological substance of fetal origin that modulates calcium-dependent and voltage-dependent potassium channels. These data suggest that UTI is capable of regulating the membrane properties of the fetal and myometrial cells in contact with amniotic fluid.

Giant Cell Arteritis of the Female Genital Tract With Occult Temporal Arteritis and Marginal Zone Lymphoma Harboring Novel 20q Deletion: A Case Report and Literature Review.

PubMed

Pradhan, Dinesh; Amin, Rajnikant M; Jones, Miroslawa W; Surti, Urvashi; Parwani, Anil V

2016-02-01

Giant cell arteritis (GCA) is an immunologically mediated vasculitis of large and medium-sized vessels, typically affecting the cranial arteries and usually occurring in the elderly. GCA of the female genital tract is extremely rare with only 31 cases reported in the English literature. An 83-year-old white female with postmenopausal vaginal bleeding revealed an endometrial polyp on pelvic ultrasonography following which polypectomy and subsequently hysterectomy with bilateral salpingo-oophorectomy was done. Microscopy revealed a well-differentiated endometrioid adenocarcinoma. Interestingly, classic GCA involving numerous small to medium-sized arteries of the cervix, myometrium, bilateral fallopian tubes, and ovaries was also identified. Hematologic evaluation revealed marginal zone lymphoma with an exceptionally rare 20q deletion. Bilateral temporal artery biopsy was done subsequently, which exhibited GCA on microscopy. Corticosteroid was started that improved her polymyalgia rheumatica symptoms. The patient is on follow-up for 3 years and is doing well. To our knowledge, this is the first case of GCA of the female genital tract associated with a lymphoma and the second case of marginal zone lymphoma with the novel 20q deletion. © The Author(s) 2015.

Surgery in adenomyosis.

PubMed

Oliveira, Marco Aurelio Pinho; Crispi, Claudio Peixoto; Brollo, Leila Cristina; Crispi, Claudio Peixoto; De Wilde, Rudy Leon

2018-03-01

Adenomyosis is defined as the presence of endometrial glands and stroma within the myometrium. The true prevalence is unknown and has been reported to range from 1 to 70%. It has a significantly negative impact on women's quality of life, causing abnormal uterine bleeding, dysmenorrhea, and chronic pelvic pain. The definitive treatment for adenomyosis is hysterectomy, although it does not contemplate patients who wish to preserve their fertility. The aim of this paper is to discuss the latest evidence on the surgical techniques for the treatment of adenomyosis published in medical-scientific databases. A comprehensive literature search for articles published from 1996 to 2017 related to surgery for adenomyosis was made in Pubmed, Medline, the Cochrane Library, and Google Scholar, in English, by the following MeSH terms: adenomyosis, surgery, pathogenesis, dysmenorrhea and infertility. There is extensive evidence on several surgical approaches for the improvement of adenomyosis-related symptoms; however, there is no robust evidence that they are effective for infertility. The management of adenomyosis is quite complex and controversial. Complications after extensive uterine reconstruction, such as uterine rupture, should be considered and discussed with the patient. There are still limited data to support surgery effectiveness, especially for infertility, and further well-designed studies are required.

Magnetic resonance imaging of the female pelvis: initial experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hricak, H.; Alpers, C.; Crooks, L.E.

1983-12-01

The potential of magnetic resonance imaging (MRI) was evaluated in 21 female subjects: seven volunteers, 12 patients scanned for reasons unrelated to the lower genitourinary tract, and two patients referred with gynecologic disease. The uterus at several stages was examined; the premenarcheal uterus (one patient), the uterus of reproductive age (12 patients), the postmenopausal uterus (two patients), and in an 8 week pregnancy (one patient). The myometrium and cyclic endometrium in the reproductive age separated by a low-intensity line (probably stratum basale), which allows recognition of changes in thickness of the cyclic endometrium during the menstrual cycle. The corpus uterimore » can be distinguished from the cervix by the transitional zone of the isthmus. The anatomic relation of the uterus to bladder and rectum is easily outlined. The vagina can be distinguished from the cervix, and the anatomic display of the closely apposed bladder, vagina, and rectum is clear on axial and coronal images. The ovary is identified; the signal intensity from the ovary depends on the acquisition parameter used. Uterine leiomyoma, endometriosis, and dermoid cyst were depicted, but further experience is needed to ascertain the specificity of the findings.« less

Involvement of alpha-adrenoceptors in myometrial responses in the pro-oestral rat.

PubMed Central

Acritopoulou-Fourcroy, S.; Marçais-Collado, H.

1988-01-01

1. Myometrial responses to different agents acting on adrenoceptors were examined in vivo in the pro-oestrous rat. Changes in spontaneous uterine mechanical activity were recorded isometrically and evaluated in terms of amplitude and duration of uterine contractions. 2. Phenylephrine (10 micrograms kg-1) markedly increased the amplitude and duration of contractions and 40 micrograms kg-1 gave rise to tetanic contractions. 3. Administration of either nicergoline (400 micrograms kg-1) or phentolamine (1000 micrograms kg-1) to phenylephrine-primed rat uterus reduced the strength of contractions and phentolamine abolished the phenylephrine-induced uterine contracture. 4. Following blockade of alpha 2-adrenoceptors by yohimbine (1000 micrograms kg-1) and beta-adrenoceptors by propranolol (2400 micrograms kg-1), a single injection of phenylephrine (100 micrograms kg-1) increased the amplitude of uterine contractions by 30%. 5. Noradrenaline reduced the amplitude of contractions and caused elevation of the baseline level. The response of myometrium to the combination of both propranolol and noradrenaline was the establishment of uterine contracture with subsequent increase of the duration of contractions. 6. These results clearly demonstrate the involvement of alpha-adrenoceptors in the myometrial activity of the rat in vivo during pro-oestrus. PMID:2832026

MR imaging of the uterus and cervix in healthy women: determination of normal values.

PubMed

Hauth, Elke A M; Jaeger, Horst J; Libera, Hanna; Lange, Silke; Forsting, Michael

2007-03-01

The purpose of this study was to establish normal values for the volume of the uterus and cervix in MRI based on age and the menstrual cycle phase. We performed MRI of the pelvis in 100 healthy women. For the uterus, they were further divided into two groups: one with myomas and/or adenomyosis and one without either. The volume of the uterus and cervix and thickness of the uterine wall layers were analysed by age and the menstrual cycle phase. The mean volume of the uterus in both groups and the cervix significantly increased with age to reach its peak at 41-50 years, and then dropped. Likewise, the thickness of the endometrium and the junctional zone, but not the myometrium, significantly increased until 41-50 years, and then decreased. When we compared the volume of the uterus and cervix and the thickness of the uterine wall layers between the two phases of the menstrual cycle, we found no significant differences. The volume of the uterus and cervix and the thickness of the endometrium and junctional zone differ significantly with age, but not between the two phases of the menstrual cycle. Knowledge of MRI-related normal values can be expected to aid the early identification of uterine pathologies.

Sentinel lymph node detection in patients with endometrial cancer.

PubMed

Niikura, Hitoshi; Okamura, Chikako; Utsunomiya, Hiroki; Yoshinaga, Kosuke; Akahira, Junichi; Ito, Kiyoshi; Yaegashi, Nobuo

2004-02-01

The purpose of this study was to examine the feasibility of sentinel lymph node (SLN) detection in patients with endometrial cancer using preoperative lymphoscintigraphy and an intraoperative gamma probe. Between June 2001 and January 2003, 28 consecutive patients with endometrial cancer who were scheduled for total abdominal hysterectomy, bilateral salpingo-oophorectomy, total pelvic lymphadenectomy, and paraaortic lymphadenectomy at Tohoku University School of Medicine underwent sentinel lymph node detection. On the day before surgery, preoperative lymphoscintigraphy was performed by injection of 99m-Technetium ((99m)Tc)-labeled phytate into the endometrium during hysteroscopy. At the time of surgery, a gamma-detecting probe was used to locate radioactive lymph nodes. At least one sentinel node was detected in each of 23 of the 28 patients (82%). The mean number of sentinel nodes detected was 3.1 (range, 1-9). Sentinel nodes could be identified in 21 of 22 patients (95%) whose tumor did not invade more than halfway into the myometrium. Eighteen patients had radioactive nodes in the paraaortic area. Most patients had a sentinel node in one of the following three sites: paraaortic, external iliac, and obturator. The sensitivity and specificity for detecting lymph node metastases were both 100%. The combination of preoperative lymphoscintigraphy with intraoperative gamma probe detection may be useful in identifying sentinel nodes in early-stage endometrial cancer.

The linear synchronization measures of uterine EMG signals: Evidence of synchronized action potentials during propagation.

PubMed

Domino, Malgorzata; Pawlinski, Bartosz; Gajewski, Zdzislaw

2016-11-01

Evaluation of synchronization between myoelectric signals can give new insights into the functioning of the complex system of porcine myometrium. We propose a model of uterine contractions according to the hypothesis of action potentials similarity which is possible to detect during propagation in the uterine wall. We introduce similarity measures based on the concept of synchronization as used in matching linear signals such as electromyographic (EMG) time series data. The aim was to present linear measures to assess synchronization between contractions in different topographic regions of the uterus. We use the cross-correlation function (ƒx,y[l], ƒy,z[l]) and the cross-coherence function (Cxy[ƒ], Cyz[ƒ]) to assess synchronization between three data series of a diestral uterine EMG bundles in porcine reproductive tract. Spontaneous uterine activity was recorded using telemetry method directly by three-channel transmitter and three silver bipolar needle electrodes sutured on different topographic regions of the reproductive tract in the sow. The results show the usefulness of the cross-coherence function in that synchronization between uterine horn and corpus uteri for multiple action potentials (bundles) could be observed. The EMG bundles synchronization may be used to investigate the direction and velocity of EMG signals propagation in porcine reproductive tract. Copyright © 2016 Elsevier Inc. All rights reserved.

Distribution of thyroid hormone and thyrotropin receptors in reproductive tissues of adult female rabbits.

PubMed

Rodríguez-Castelán, Julia; Anaya-Hernández, Arely; Méndez-Tepepa, Maribel; Martínez-Gómez, Margarita; Castelán, Francisco; Cuevas-Romero, Estela

2017-02-01

Thyroid dysfunctions are related to anovulation, miscarriages, and infertility in women and laboratory animals. Mechanisms associated with these effects are unknown, although indirect or direct actions of thyroid hormones and thyrotropin could be assumed. The present study aimed to identify the distribution of thyroid hormones (TRs) and thyrotropin (TSHR) receptors in reproductive organs of female rabbits. Ovary of virgin and pregnant rabbits, as well as the oviduct, uterus, and vagina of virgin rabbits were excised, histologically processed, and cut. Slices from these organs were used for immunohistochemical studies for TRα1-2, TRß1, and TSHR. The presence of TRs and TSHR was found in the primordial, primary, secondary, tertiary, and Graafian follicles of virgin rabbits, as well as in the corpora lutea, corpora albicans, and wall of hemorrhagic cysts of pregnant rabbits. Oviductal regions (fimbria-infundibulum, ampulla, isthmus, and utero-tubal junction), uterus (endometrium and myometrium), and vagina (abdominal, pelvic, and perineal portions) of virgin rabbits showed anti-TRs and anti-TSHR immunoreactivity. Additionally, the distal urethra, paravaginal ganglia, levator ani and iliococcygeus muscles, dorsal nerve and body of the clitoris, perigenital skin, and prostate had TRs and TSHR. The wide presence of TRs and TSHR in female reproductive organs suggests varied effects of thyroid hormones and thyrotropin in reproduction.

Uterine Junctional Zone Thickness, Cervical Length and Bioelectrical Impedance Analysis of Body Composition in Women with Endometriosis

PubMed Central

Ayas, Selçuk; Bayraktar, Mesut; Gürbüz, Ayşe; Alkan, Akif; Eren, Sadiye

2012-01-01

Objective: We aimed to evaluate uterine junctional zone thickness, cervical length and bioelectrical impedance analysis of body composition in women with endometriosis. Material and Methods: This is a prospective study conducted in a tertiary teaching hospital. A total of 73 patients were included in the study. Endometriosis was surgically diagnosed in 36 patients (study group). The control group included 37 patients. Main outcome measure(s): Bioelectrical impedance analysis was used to measure body composition. Uterine junctional zone thickness and cervical length were measured by transvaginal ultrasonography. Results: Patients’ characteristics (age, gravida, parity, live baby, age of menarche, lengths of menstrual cycle, percentage of patients with dysmenorrhea, positive family history), body mass index (BMI) (kg/m2), amount of body fat (kg), percentage of body fat were not statistically different between the two groups (p>0.05). The length of menstruation and cervical length were longer in women with endometriosis. Similarly, the inner myometrium was thicker in women with endometriosis than the control group. Conclusion: The relation between endometriosis and demographic features such as age, gravida, parity, gravida, BMI, lengths of the menstrual cycle, age of menarche are controversial. Longer cervical length and thicker inner myometrial layer may be important in the etiopathogenesis of endometriosis. PMID:25207044

ERα inhibited myocardin-induced differentiation in uterine fibroids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liao, Xing-Hua, E-mail: xinghualiao@hotmail.com; Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457; Li, Jun-Yan

Uterine fibroids, also known as uterine leiomyomas, are a benign tumor of the human uterus and the commonest estrogen-dependent benign tumor found in women. Myocardin is an important transcriptional regulator in smooth and cardiac muscle development. The role of myocardin and its relationship with ERα in uterine fibroids have barely been addressed. We noticed that the expression of myocardin was markedly reduced in human uterine fibroid tissue compared with corresponding normal or adjacent myometrium tissue. Here we reported that myocardin induced the transcription and expression of differentiation markers SM22α and alpha smooth muscle actin (α-SMA) in rat primary uterine smoothmore » muscle cells (USMCs) and this effect was inhibited by ERα. Notably, we showed that, ERα induced expression of proliferation markers PCNA and ki-67 in rat primary USMCs. We also found ERα interacted with myocardin and formed complex to bind to CArG box and inhibit the SM22α promoter activity. Furthermore, ERα inhibited the transcription and expression of myocardin, and reduced the levels of transcription and expression of downstream target SM22α, a SMC differentiation marker. Our data thus provided important and novel insights into how ERα and myocardin interact to control the cell differentiation and proliferation of USMCs. Thus, it may provide potential therapeutic target for uterine fibroids.« less

Cesarean scar defects: an underrecognized cause of abnormal uterine bleeding and other gynecologic complications.

PubMed

Tower, Amanda M; Frishman, Gary N

2013-01-01

The gynecologic sequelae due to deficient uterine scar healing after cesarean section are only recently being identified and described. These include conditions such as abnormal bleeding, pelvic pain, infertility, and cesarean scar ectopic pregnancy, as well as a potentially higher risk of complications and difficulties during gynecologic procedures such as uterine evacuation, hysterectomy, endometrial ablation, and insertion of an intrauterine device. The proposed mechanism of abnormal uterine bleeding is a pouch or "isthmocele" in the lower uterine segment that causes delayed menstrual bleeding. The prevalence of symptomatic or clinically relevant cesarean scar defects (CSDs) ranges from 19.4% to 88%. Possible risk factors for CSD include number of cesarean sections, uterine position, labor before cesarean section, and surgical technique used to close the uterine incision. There are no accepted guidelines for the diagnostic criteria of CSD. We propose that a CSD be defined on transvaginal ultrasound or saline infusion sonohysterography as a triangular hypoechoic defect in the myometrium at the site of the previous hysterotomy. We also propose a classification system to aid in standardized classification for future research. Surgical techniques for repair of CSD include laparoscopic excision, resectoscopic treatment, vaginal revision, and endometrial ablation. Copyright © 2013 AAGL. Published by Elsevier Inc. All rights reserved.

The possible impact of advanced glycation end products on pregnancy outcome in women with diabetes mellitus type 1.

PubMed

Pertynska-Marczewska, Magdalena; Cypryk, Katarzyna

2017-09-01

Diabetes mellitus (DM) is a group of metabolic disorders of carbohydrate metabolism in which glucose is underutilized, resulting in hyperglycemia. Reproductive impairment in poorly controlled diabetes mellitus type 1 (T1DM) results from a combined effect of insulin deficiency and hyperglycemia that disrupt the functioning of metabolic signals participating in the regulation of the reproductive system. Good metabolic control as a result of intensive insulin therapy has a great impact on the fertility and childbearing possibilities in the T1DM females. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. The formation and accumulation of AGEs are known to progress at an accelerated rate in diabetes. AGEs either act on the pro-inflammatory cell surface receptors called RAGE or bind to the circulating anti-inflammatory sRAGE that prevents activation of cell-surface RAGE by AGEs and other proinflammatory ligands. Pregnancy has been found to induce a significant increase in RAGE protein levels in both myometrium and omental vasculature. This review will focus on the role of AGEs and RAGE in pregnancy complicated by DM type 1 as well as ways to reduce the rate of congenital malformations in the offspring of diabetic type 1 women.

The role of invasive trophoblast in implantation and placentation of primates.

PubMed

Carter, Anthony M; Enders, Allen C; Pijnenborg, Robert

2015-03-05

We here review the evolution of invasive placentation in primates towards the deep penetration of the endometrium and its arteries in hominoids. The strepsirrhine primates (lemurs and lorises) have non-invasive, epitheliochorial placentation, although this is thought to be derived from a more invasive type. In haplorhine primates, there is differentiation of trophoblast at the blastocyst stage into syncytial and cellular trophoblast. Implantation involves syncytiotrophoblast that first removes the uterine epithelium then consolidates at the basal lamina before continuing into the stroma. In later stages of pregnancy, especially in Old World monkeys and apes, cytotrophoblast plays a greater role in the invasive process. Columns of trophoblast cells advance to the base of the implantation site where they spread out to form a cytotrophoblastic shell. In addition, cytotrophoblasts advance into the lumen of the spiral arteries. They are responsible for remodelling these vessels to form wide, low-resistance conduits. In human and great apes, there is additional invasion of the endometrium and its vessels by trophoblasts originating from the base of the anchoring villi. Deep trophoblast invasion that extends remodelling of the spiral arteries to segments in the inner myometrium evolved in the common ancestor of gorilla, chimp and human. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krall, J.F.; Morin, A.

Cells growing in culture with previously described properties of rat uterine smooth muscle accumulated /sup 45/Ca/sup 2 +/ from the medium. Ca/sup 2 +/ uptake by these cells was stimulated by the addition to the medium of 8-bromo-cGMP but not by 8-bromo-cAMP. Ca/sup 2 +/ uptake was also stimulated by carbachol and by the nitro-vasodilator nitroprusside. Although cholinergic agonists have been shown previously to stimulate contraction but not cGMP synthesis in the rat myometrium, both carbachol and nitroprusside stimulated cGMP production by the cultured cells. These results suggested the cells had cholinergic receptor-medicated functions that reflected some neurotransmitter-sensitive properties ofmore » uterine smooth muscle in situ. When determined by a specific radioligand binding assay, subcellular fractions of the cultured cells bound muscarinic cholinergic agonists and antagonists with affinities expected of the muscarinic receptor. The cells were also sensitive to the ..beta..-adrenergic catecholamine agonist isoproterenol, which stimulated cAMP production but not Ca/sup 2 +/ uptake. Carbachol failed to inhibit isoproterenol-dependent cAMP production, which is an important property of the cholinergic receptor in uterine smooth muscle in situ. These results suggest some but not all acetylcholine-sensitive properties of uterine smooth muscle may be retained in cell culture.« less

Fibroblast growth factor receptor two (FGFR2) regulates uterine epithelial integrity and fertility in mice.

PubMed

Filant, Justyna; DeMayo, Franco J; Pru, James K; Lydon, John P; Spencer, Thomas E

2014-01-01

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate luminal epithelial (LE) cell proliferation in the adult mouse uterus. This study tested the hypothesis that FGFR2 has a biological role in postnatal development and function of the uterus by conditionally deleting Fgfr2 after birth using progesterone receptor (Pgr)-Cre mice. Adult Fgfr2 mutant female mice were initially subfertile and became infertile with increasing parity. No defects in uterine gland development were observed in conditional Fgfr2 mutant mice. In the adult, Fgfr2 mutant mice possessed a histologically normal reproductive tract with the exception of the uterus. The LE of the Fgfr2 mutant uterus was stratified, but no obvious histological differences were observed in the glandular epithelium, stroma, or myometrium. Within the stratified LE, cuboidal basal cells were present and positive for basal cell markers (KRT14 and TRP63). Nulliparous bred Fgfr2 mutants contained normal numbers of blastocysts on Day 3.5 postmating, but the number of embryo implantation sites was substantially reduced on Day 5.5 postmating. These results support the idea that loss of FGFR2 in the uterus after birth alters its development, resulting in LE stratification and peri-implantation pregnancy loss.

Interest of diffusion-weighted echo-planar MR imaging and apparent diffusion coefficient mapping in gynecological malignancies: a review.

PubMed

Levy, Antonin; Medjhoul, Aïcha; Caramella, Caroline; Zareski, Elise; Berges, Oscar; Chargari, Cyrus; Boulet, Bérénice; Bidault, François; Dromain, Clarisse; Balleyguier, Corinne

2011-05-01

Magnetic resonance imaging (MRI) remains the standard modality for the local staging of gynecological malignancies but it has several limitations, particularly for lymph node staging or evaluating peritoneal carcinomatosis. Consequently, there has been a growing interest in functional imaging modalities. Based on molecular diffusion, diffusion-weighted imaging (DWI) is a unique, noninvasive modality that provides excellent tissue contrast and was shown to improve the radiological diagnosis of malignant tumors. Using quantitative apparent diffusion coefficient (ADC) measurement of DWI provides a new tool for better distinguishing malignant tissues from benign tumors. The aim of the present review is to report on the results of DWI for the assessment of patients with gynecological malignancies. An analysis of the literature suggests that DWI studies would improve the diagnosis of cervical and endometrial tumors. It may also improve the assessment of tumor extension in patients with peritoneal carcinomatosis from gynecological malignancies. However, since the signal intensity of some cancers can range from high intensity to low intensity, a degree of uncertainty was demonstrated due to the proximity of the normal uterine myometrium and ovaries. Interestingly, there is also evidence that ADC might improve the follow-up and monitoring of patients who receive anticancer therapies, including chemotherapy or radiation therapy. Copyright © 2011 Wiley-Liss, Inc.

MR Imaging of Uterine Epithelioid Trophoblastic Tumor: A Case Report

PubMed Central

KAGEYAMA, Sakiko; KANOTO, Masafumi; SUGAI, Yukio; SUTO, Takeshi; NAGASE, Satoru; OSAKABE, Mitsumasa; HOSOYA, Takaaki

2016-01-01

Epithelioid trophoblastic tumor (ETT) is a rare gestational trophoblastic neoplasm of chorionic-type intermediate trophoblasts, and it is most frequently located in the lower uterine segment and endocervix. Due to the epithelial-growth pattern with geographic necrosis exhibited by the neoplastic cells, ETT is commonly confused, both clinically and pathologically, with squamous cell carcinoma. Although there have been no previous reports of ETT focusing on computed tomography (CT) or magnetic resonance imaging (MRI) findings, we report a case of uterine ETT with special attention to the MRI findings referring to the pathological findings and MR images of previous reports. A 42-year-old Japanese woman (gravid 1, para 1) presented with uterus enlargement during screening, and complained of recent-onset lower abdominal pain. The MRI showed a solid tumor throughout the entire myometrium of the lower uterine segment, with the hemorrhagic cystic portion extending to the posterior subserosal space. Following hysterectomy, the final pathological diagnosis was ETT. An ETT is essentially a solid tumor composed of intermediate trophoblasts that exhibit an epithelial-like growth pattern and contain geographic necrosis with calcification. In our case, MRI revealed a non-specific-intensity solid tumor in the lower uterine segment with massive necrosis and hemorrhage extending to the subserosa. While it is difficult to distinguish between ETT and uterine carcinomas, recognition of certain tumor shapes and necrosis could enable more accurate diagnosis before treatment. PMID:27001388

Genome-Wide DNA Methylation Indicates Silencing of Tumor Suppressor Genes in Uterine Leiomyoma

PubMed Central

Navarro, Antonia; Yin, Ping; Monsivais, Diana; Lin, Simon M.; Du, Pan; Wei, Jian-Jun; Bulun, Serdar E.

2012-01-01

Background Uterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown. Principal Findings We characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels. Conclusions These results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women. PMID:22428009

Effects of miRNA-197 overexpression on proliferation, apoptosis and migration in levonorgestrel treated uterine leiomyoma cells.

PubMed

Wu, Xiaoli; Ling, Jing; Fu, Ziyi; Ji, Chenbo; Wu, Jiangping; Xu, Qing

2015-04-01

Uterine leiomyoma is the ahead benign tumor of the female genital tract, which resulted in menstrual abnormalities, recurrent pregnancy loss, and other serious gynecological disorders in women. Recently, as the process of exploring the brief molecular mechanisms of tumorgenesis, microRNAs (miRNAs) have attracted much more attention. In this study, we first confirmed that microRNA-197 (miR-197) was down-regulated significantly in human uterus leiomyoma by quantity real-time polymerase chain reaction, compared to normal uterus myometrium. Then we observed the potential effects of miR-197 overexpression on human uterus leiomyoma cells by cell counting kit 8, wound healing assay, and flow cytometric assessment separately. The data showed that miR-197 could inhibit cell proliferation, induce cell apoptosis, and block cell migration in vitro. Coincidently, levonorgestrel (LNG), a well-known uterus leiomyoma therapy, could induce miR-197 expression in human uterus leiomyoma cells, and over-expression of miR-197 showed a synergy effect on human uterus leiomyoma cell proliferation and apoptosis with LNG. In this study, the data showed that miR-197 could play an anti-oncogenic role in human uterus leiomyoma cells, and cooperate with LNG on the cell proliferation and apoptosis, which suggested that miR-197 might be a potential target and provided database for clinical treatment. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Microscopic endometrial perivascular epithelioid cell nodules: a case report with the earliest presentation of a uterine perivascular epithelioid cell tumor

PubMed Central

2012-01-01

Abstract Perivascular epithelioid cell (PEC) tumors (PEComas) are a family of related mesenchymal tumors composed of PECs which co-express melanocytic and smooth muscle markers. Although their distinctive histologic, immunohistochemical, ultrastructural, and genetic features have been clearly demonstrated, their histogenesis and normal counterpart remain largely unknown. Precursor lesions of PEComas have rarely been reported. We herein describe a tuberous sclerosis patient with microscopic PEC nodules in the endometrium of adenomyosis, pelvic endometriosis, an ovarian endometriotic cyst, and the endometrium of the uterine cavity. The nodules showed a mixture of spindle-shaped and epithelioid cells concentrically arranged around small arteries. The cells exhibited uniform nuclei, light eosinophilic cytoplasm, and immunoreactivity with HMB-45 and CD10. Some nodules revealed continuity with a PEComa in the myometrium. These findings support microscopic endometrial PEC nodules possibly being precursor lesions of uterine PEComas. The wide distribution of the nodules in the pelvis may be related to the multicentricity of PEComas in tuberous sclerosis patients. Owing to the immunoreactivity with CD10, microscopic endometrial PEC nodules may be misinterpreted as endothelial stromal cells unless melanocytic markers are stained. To the best of our knowledge, this is a case with the earliest manifestation of PEC lesions occurring in the endometrium. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9658280017862643 PMID:22937790

Microscopic endometrial perivascular epithelioid cell nodules: a case report with the earliest presentation of a uterine perivascular epithelioid cell tumor.

PubMed

Fang, Chia-Lang; Lin, Yun-Ho; Chen, Wei-Yu

2012-09-03

Perivascular epithelioid cell (PEC) tumors (PEComas) are a family of related mesenchymal tumors composed of PECs which co-express melanocytic and smooth muscle markers. Although their distinctive histologic, immunohistochemical, ultrastructural, and genetic features have been clearly demonstrated, their histogenesis and normal counterpart remain largely unknown. Precursor lesions of PEComas have rarely been reported. We herein describe a tuberous sclerosis patient with microscopic PEC nodules in the endometrium of adenomyosis, pelvic endometriosis, an ovarian endometriotic cyst, and the endometrium of the uterine cavity. The nodules showed a mixture of spindle-shaped and epithelioid cells concentrically arranged around small arteries. The cells exhibited uniform nuclei, light eosinophilic cytoplasm, and immunoreactivity with HMB-45 and CD10. Some nodules revealed continuity with a PEComa in the myometrium. These findings support microscopic endometrial PEC nodules possibly being precursor lesions of uterine PEComas. The wide distribution of the nodules in the pelvis may be related to the multicentricity of PEComas in tuberous sclerosis patients. Owing to the immunoreactivity with CD10, microscopic endometrial PEC nodules may be misinterpreted as endothelial stromal cells unless melanocytic markers are stained. To the best of our knowledge, this is a case with the earliest manifestation of PEC lesions occurring in the endometrium. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9658280017862643.

Conditional deletion of Tsc1 in the female reproductive tract impedes normal oviductal and uterine function by enhancing mTORC1 signaling in mice

PubMed Central

Daikoku, Takiko; Yoshie, Mikihiro; Xie, Huirong; Sun, Xiaofei; Cha, Jeeyeon; Ellenson, Lora Hedrick; Dey, Sudhansu K.

2013-01-01

Heightened mammalian target of rapamycin complex 1 (mTORC1) activity by genetic deletion of its direct inhibitor, Tsc1, is associated with aberrant development and dysfunction of the female reproductive tract in mice. Here, we compared the phenotypes of mice with conditional deletion of Tsc1 in the female reproductive tract by either progesterone receptor (PR)-Cre (Tsc1PR(d/d)), which inactivates Tsc1 in all major cell types in the uterus (epithelium, stroma and myometrium), or anti-Mullerian hormone type 2 receptor (Amhr2)-Cre (Tsc1Amhr2(d/d)), which inactivates stromal and myometrial Tsc1. Tsc1PR(d/d) and Tsc1Amhr2(d/d) females are infertile resulting from oviductal hyperplasia, retention of embryos in the oviduct and implantation failure. In contrast to the appropriate embryonic development after fertilization seen in Tsc1Amhr2(d/d) females, embryo development was disrupted in Tsc1PR(d/d) females. In addition, uteri in Tsc1PR(d/d) and Tsc1Amhr2(d/d) females showed epithelial hyperplasia but not endometrial cancer. In conclusion, Tsc1PR(d/d) and Tsc1Amhr2(d/d) have overlapping yet distinct phenotypes in the context of compartment-specific deletion of Tsc1. PMID:23475984

A case of diffuse uterine leiomyomatosis who had two successful pregnancies after medical management.

PubMed

Purohit, Ramkrishna; Sharma, Jay Gopal; Singh, Sarabjeet

2011-06-01

To describe a case report of diffuse uterine leiomyomatosis who had successful pregnancy twice following conservative management. Retrospective report. Private general hospital. A nulliparous woman 25 years of age presented with menorrhagia and infertility. She had innumerable small fibroids of 4-42 mm size throughout the myometrium. Size of the symmetrically enlarged uterus was 131×80×60 mm, clinically corresponding to that of 12 weeks of gestation. She received a GnRH analogue (GnRHa; leuprolide acetate) 3.75 mg per month for 6 months. Reduction of uterus size, menstrual amount, conception, pregnancy outcome. Enlarged uterus reduced to almost normal size after 3 doses of GnRHa. She did not experience heavy bleeding during menstruation. She conceived spontaneously in the first cycle after discontinuation of GnRHa. Antenatal course was uneventful. A healthy male baby of 2.5 kg was delivered by cesarean section at 39 weeks. The placenta weighed 330 g. There was no postpartum hemorrhage. She conceived spontaneously for the second time in the first cycle after resumption of menses. Antenatal, intranatal (cesarean section), and postnatal courses of the second pregnancy were uneventful. The second neonate weighed 3.0 kg and the placenta 400 g. Conservative treatment may help to achieve successful pregnancy in case of diffuse uterine leiomyomatosis. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Dynamic Changes in the Myometrium during the Third Stage of Labor, Evaluated Using Two-Dimensional Ultrasound, in Women with Normal and Abnormal Third Stage of Labor and in Women with Obstetric Complications.

PubMed

Patwardhan, Manasi; Hernandez-Andrade, Edgar; Ahn, Hyunyoung; Korzeniewski, Steven J; Schwartz, Alyse; Hassan, Sonia S; Romero, Roberto

2015-01-01

To investigate dynamic changes in myometrial thickness during the third stage of labor. Myometrial thickness was measured using ultrasound at one-minute time intervals during the third stage of labor in the mid-region of the upper and lower uterine segments in 151 patients including: women with a long third stage of labor (n = 30), postpartum hemorrhage (n = 4), preterm delivery (n = 7) and clinical chorioamnionitis (n = 4). Differences between myometrial thickness of the uterine segments and as a function of time were evaluated. There was a significant linear increase in the mean myometrial thickness of the upper uterine segments, as well as a significant linear decrease in the mean myometrial thickness of the lower uterine segments until the expulsion of the placenta (p < 0.001). The ratio of the measurements of the upper to the lower uterine segments increased significantly as a function of time (p < 0.0001). In women with postpartum hemorrhage, preterm delivery, and clinical chorioamnionitis, an uncoordinated pattern among the uterine segments was observed. A well-coordinated activity between the upper and lower uterine segments is demonstrated in normal placental delivery. In some clinical conditions this pattern is not observed, increasing the time for placental delivery and the risk of postpartum hemorrhage. © 2015 S. Karger AG, Basel.

Dynamic changes in the myometrium during the third stage of labor, evaluated using two-dimensional ultrasound, in women with normal and abnormal third stage of labor and in women with obstetric complications

PubMed Central

Patwardhan, Manasi; Hernandez-Andrade, Edgar; Ahn, Hyunyoung; Korzeniewski, Steven J; Schwartz, Alyse; Hassan, Sonia S; Romero, Roberto

2015-01-01

Objective To investigate dynamic changes in myometrial thickness during the third stage of labor. Methods Myometrial thickness was measured using ultrasound at one-minute time intervals during the third stage of labor in the mid-region of the upper and lower uterine segments in 151 patients including: women with a long third stage of labor (n=30), post-partum hemorrhage (n=4), preterm delivery (n=7) or clinical chorioamnionitis (n=4). Differences between uterine segments and as a function of time were evaluated. Results There was a significant linear increase in the mean myometrial thickness of the upper uterine segments, as well as a significant linear decrease in the mean myometrial thickness of the lower uterine segments until the expulsion of the placenta (p<0.001). The ratio of the measurements of the upper to the lower uterine segments increased significantly as a function of time (p<0.0001). In women with postpartum hemorrhage, preterm delivery and clinical chorioamnionitis, an uncoordinated pattern between the uterine segments was observed. Conclusion A well-coordinated activity between the upper and lower uterine segments is demonstrated in normal placental delivery. In some clinical conditions this pattern is not observed, increasing the time for placental delivery and the risk for post-partum hemorrhage. PMID:25634647

Estrous Cycle and Gestational Age-Dependent Expression of Members of the Interleukin-36 Subfamily in a Semi-Allogeneic Model of Infected and Non-Infected Murine Pregnancy

PubMed Central

Murrieta-Coxca, José Martin; Gómez-Chávez, Fernando; Baeza-Martínez, Damariz Adriana; Cancino-Diaz, Mario Eugenio; Cancino-Diaz, Juan Carlos; Pérez-Tapia, Sonia Mayra; Reyes-Maldonado, Elba; Rodríguez-Martínez, Sandra

2016-01-01

The IL-36 subfamily is a recently described group of cytokines with pro-inflammatory behavior, comprising three agonists (α, β, and γ), its receptor (R), and one antagonist (Ra). The expression and function of IL-36 subfamily members in the estrous cycle in healthy and infected pregnancy has not been described. We evaluated mRNA and protein expression of IL-36 family members during the estrous cycle, implantation, fetal development, and post-labor periods in a model of allogenic pregnancy in mice. We also explored the ability of Listeria monocytogenes to modulate the expression of IL-36 subfamily members during pregnancy. Expression of IL-36 subfamily members showed different expression during the estrous cycle and pregnancy but was induced at estrous, 16.5 days post coitum (dpc), 18.5 dpc, and labor. IL-36 subfamily members showed a characteristic distribution in the glandular epithelium, perimetrium, myometrium, and stratum vasculare. Infection with L. monocytogenes during pregnancy induced strong production of IL-36 subfamily members, an observation that correlated with an increasing prevalence of fetal loss. In conclusion, IL-36 agonists showed specific patterns of mRNA and protein expression that might suggest functional specialization or specific target cells. Infection with L. monocytogenes during pregnancy induced strong production of IL-36 subfamily members. PMID:27713746

A study of monoamine oxidase activity in fetal membranes.

PubMed

Sekizawa, A; Ishikawa, H; Morimoto, T; Hirose, K; Suzuki, A; Saito, H; Yanaihara, T; Arai, Y; Oguchi, K

1996-05-01

To study the role of decidual monoamine oxidase (MAO)-A and -B activities before delivery, the relationship between MAO activity in fetal membranes and catecholamine (CA) concentration in amniotic fluid (AF) was determined. Fetal membranes and AF were obtained at the time of elective Cesarean section (CS group, n = 11) and Cesarean section due to fetal distress without labor pains (FD group, n = 5). MAO-A and -B activities were radiometrically measured using 14C-5-hydroxytriptamine for MAO-A substrate and 14C-benzylamine for MAO-B substrate. CA concentrations in AF were measured by high performance liquid chromatograph with an electro-chemical detector. Both MAO-A and -B activities in decidua obtained from CS were significantly lower than those obtained from FD. Both norepinephrine (NE) and epinephrine (EP) concentrations were significantly lower in the CS group than the FD group. A significant positive correlation between decidual MAO-A activity and NE concentration in AF was observed. No significant correlation was observed between MAO-B activity and the concentration of NE in AF. There was no correlation between EP concentrations and MAO activities. These results suggest that CA concentration in AF may be related to the activity of MAO in fetal membranes, determined by certain physiological processes during pregnancy. It has been suggested that metabolism of monoamines in fetal membranes also plays an important role in reducing monoamine influx into maternal myometrium from the AF.

ERα inhibited myocardin-induced differentiation in uterine fibroids.

PubMed

Liao, Xing-Hua; Li, Jun-Yan; Dong, Xiu-Mei; Wang, Xiuhong; Xiang, Yuan; Li, Hui; Yu, Cheng-Xi; Li, Jia-Peng; Yuan, Bai-Yin; Zhou, Jun; Zhang, Tong-Cun

2017-01-01

Uterine fibroids, also known as uterine leiomyomas, are a benign tumor of the human uterus and the commonest estrogen-dependent benign tumor found in women. Myocardin is an important transcriptional regulator in smooth and cardiac muscle development. The role of myocardin and its relationship with ERα in uterine fibroids have barely been addressed. We noticed that the expression of myocardin was markedly reduced in human uterine fibroid tissue compared with corresponding normal or adjacent myometrium tissue. Here we reported that myocardin induced the transcription and expression of differentiation markers SM22α and alpha smooth muscle actin (α-SMA) in rat primary uterine smooth muscle cells (USMCs) and this effect was inhibited by ERα. Notably, we showed that, ERα induced expression of proliferation markers PCNA and ki-67 in rat primary USMCs. We also found ERα interacted with myocardin and formed complex to bind to CArG box and inhibit the SM22α promoter activity. Furthermore, ERα inhibited the transcription and expression of myocardin, and reduced the levels of transcription and expression of downstream target SM22α, a SMC differentiation marker. Our data thus provided important and novel insights into how ERα and myocardin interact to control the cell differentiation and proliferation of USMCs. Thus, it may provide potential therapeutic target for uterine fibroids. Copyright © 2016 Elsevier Inc. All rights reserved.

Microvascular development and growth of uterine tissue during the estrous cycle in mares.

PubMed

Ferreira-Dias, G M; Serrão, P M; Durão, J F; Silva, J R

2001-04-01

To document uterine growth and microvascular development in the endometrium of uteri with differing degrees of fibrosis as well as uterine growth throughout the estrous cycle of mares. 30 mares. Uterine tissue was obtained during the breeding season from a slaughter facility. Stage of estrous cycle of the mares was assessed on the basis of ovarian structures and plasma progesterone concentrations. Endometrium was characterized by use of light microscopy, and blood vessel walls were marked by histochemical techniques. Microvascular development was evaluated by a computerized image analysis system. Growth of uterine tissue was based on cellular content of DNA and RNA, RNA:DNA, and protein:DNA. Significant differences in vascular density were not observed in the endometrium of uteri obtained from mares euthanatized during the follicular or luteal phase of the estrous cycle, regardless of whether endometrial classification of degree of fibrosis was considered. There was a 3-fold increase in amount of DNA and RNA of endometrial cells in the follicular phase when compared to myometrium. Hypertrophy of endometrial tissue during the luteal phase was reflected by a significant increase in cell protein content and protein:DNA. Endometrial growth of vascular tissues during the estrous cycle may be coordinated with development of nonvascular tissue. Estrogen and progesterone may play a role in regulation of uterine growth and angiogenesis.

Relaxing effects of Valeriana officinalis extracts on isolated human non-pregnant uterine muscle.

PubMed

Occhiuto, Francesco; Pino, Annalisa; Palumbo, Dora Rita; Samperi, Stefania; De Pasquale, Rita; Sturlese, Emanuele; Circosta, Clara

2009-02-01

This study investigated the relaxing effects of Valeriana officinalis L. (Valerianaceae) on human uterine muscle. The major uses of this species in Europe are as a sedative and an anxiolytic; it is also used as a spasmolytic to treat gastrointestinal spasm. We evaluated two valerian extracts (ethanolic and aqueous) in comparison with a natural mixture of valepotriates and nifedipine on spontaneous and agonist-induced contractions in non-pregnant human myometrium in vitro. Qualitative and quantitative chemical analysis was used to correlate the chemical composition of extracts with their spasmolytic effects. Myometrial strips were obtained from hysterectomy specimens of premenopausal women. Longitudinal muscle strips were mounted vertically in tissue baths under physiological conditions to record their isometric contraction. The responses of cumulative concentrations of valerian extracts on spontaneous contractions in the presence and absence of the beta-adrenoceptor blocker atenolol or the cyclooxygenase inhibitor indometacin, and on agonist-induced contractions, were investigated. Valerian extracts and valepotriates inhibited uterine contractility in a concentration-dependent manner. Pretreatment with either atenolol or indometacin did not affect the uterine responses to valerian extracts. Valerian extract reduced the maximal contractile response induced by acetylcholine, phenylephrine and histamine independent of the stimulus. Valerian extracts may have direct inhibitory effects on the contractility of the human uterus and this justifies the traditional use of this plant in the treatment of uterine cramping associated with dysmenorrhoea.

The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in cervical ripening and the induction of labor: a mechanistic approach.

PubMed

Bakker, Ronan; Pierce, Stephanie; Myers, Dean

2017-08-01

Prostaglandins play a critical role in cervical ripening by increasing inflammatory mediators in the cervix and inducing cervical remodeling. Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) exert different effects on these processes and on myometrial contractility. These mechanistic differences may affect outcomes in women treated with dinoprostone, a formulation identical to endogenous PGE2, compared with misoprostol, a PGE1 analog. The objective of this review is to evaluate existing evidence regarding mechanistic differences between PGE1 and PGE2, and consider the clinical implications of these differences in patients requiring cervical ripening for labor induction. We conducted a critical narrative review of peer-reviewed articles identified using PubMed and other online databases. While both dinoprostone and misoprostol are effective in cervical ripening and labor induction, they differ in their clinical and pharmacological profiles. PGE2 has been shown to stimulate interleukin-8, an inflammatory cytokine that promotes the influx of neutrophils and induces remodeling of the cervical extracellular matrix, and to induce functional progesterone withdrawal. Misoprostol has been shown to elicit a dose-dependent effect on myometrial contractility, which may affect rates of uterine tachysystole in clinical practice. Differences in the mechanism of action between misoprostol and PGE2 may contribute to their variable effects in the cervix and myometrium, and should be considered to optimize outcomes.

Relaxant effect of proton pump inhibitors on in vitro myometrium from pregnant women.

PubMed

Terranova, C; Petrella, C; Improta, G; Severini, C; Signore, F; Damiani, P; Plotti, F; Scarpignato, C; Angioli, R

2014-02-14

In this study we investigate in in vitro myometrial tissue samples of pregnant women: (a) the effects of proton pomp inhibitors (PPIs) (omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole) on spontaneous contractions; (b) the muscle-relaxant efficacy of the most active PPI considered (pantoprazole) in comparison with that of other known tocolytics (nifedipine, atosiban, MgSO4, isoxsuprine); (c) the effect of pantoprazole on contractions induced by calcium (Ca(++)), KCl, oxytocin and prostaglandin (PGE2); (d) the possible mediators of pantoprazole relaxant effect. Organ bath studies were performed on myometrial tissue samples (40×10×10 mm) from pregnant women (38-42 weeks of gestational age) undergoing elective caesarian section. All the PPIs studied reduce the spontaneous contraction of the myometrial smooth muscle. Pantoprazole is the most effective and most potent inhibitor among those analyzed. Pantoprazole also reduces the contractions induced by Ca(++), KCl, oxytocin and PGE2. Neither NO, nor PGs, or the activation of Ca(++)-dependent K(+) currents mediate the muscle-relaxant effect of this PPI. These data, together with the fact that PPIs almost do not present side effects, suggest that these drugs can offer new therapeutic strategies for preterm delivery. Undoubtedly, further investigations and clinical studies are necessary before adding PPIs to the list of drugs available for the treatment of preterm delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

CALIX[4]ARENE C-99 INHIBITS MYOSIN ATPase ACTIVITY AND CHANGES THE ORGANIZATION OF CONTRACTILE FILAMENTS OF MYOMETRIUM.

PubMed

Labyntseva, R D; Bevza, A A; Lul'ko, A O; Cherenok, S O; Kalchenko, V I; Kosterin, S O

2015-01-01

Calix[4]arenes are cup-like macrocyclic (polyphenolic) compounds, they are regarded as promising molecular "platforms" for the design of new physiologically active compounds. We have earlier found that calix[4]arene C-99 inhibits the ATPase activity of actomyosin and myosin subfragment-1 of pig uterus in vitro. The aim of this study was to investigate the interaction of calix[4]arene C-99 with myosin from rat uterine myocytes. It was found that the ATPase activity of myosin prepared from pre-incubated with 100 mM of calix[4]arene C-99 myocytes was almost 50% lower than in control. Additionally, we have revealed the effect of calix[4]arene C-99 on the subcellular distribution of actin and myosin in uterus myocytes by the method of confocal microscopy. This effect can be caused by reorganization of the structure of the contractile smooth muscle cell proteins due to their interaction with calix[4]arene. The obtained results demonstrate the ability of calix[4]arene C-99 to penetrate into the uterus muscle cells and affect not only the myosin ATPase activity, but also the structure of the actin and myosin filaments in the myometrial cells. Demonstrated ability of calix[4]arene C-99 can be used for development of new pharmacological agents for efficient normalization of myometrial contractile hyperfunction.

Colon replacement of vagina to restore menstrual function in 11 adolescent girls with vaginal or cervicovaginal agenesis.

PubMed

Kannaiyan, Lavanya; Chacko, Jacob; George, Alice; Sen, Sudipta

2009-08-01

Cervicovaginal or vaginal agenesis with functioning endometrial tissue is rare. We report the construction of a colon conduit which is anastomosed to posterior uterine wall or upper vaginal pouch to allow menstruation. We report seven girls with cervicovaginal agenesis and four with lower vaginal agenesis (aged 12-20 years) who presented with painful cryptomenorrheoa. All the girls wanted to conserve their uterus and menstruate normally. A colon conduit was constructed for the egress of menstrual blood. The colon conduit was anastomosed to the posterior uterine wall in the seven girls with cervicovaginal agenesis and to the distended upper vaginal pouch in the four girls with vaginal agenesis. Utero-colonic neovaginal anastomosis was performed only after excising a circular portion of the posterior myometrium to prevent stenosis. The colon conduit functioned effectively, providing an egress for regular painless menstruation. One patient had stenosis of the perineal neovaginal orifice for which dilations were done. One girl has married and reports satisfactory intercourse. The mean follow up is 2.2 years. This group of patients forms a separate subgroup needing a conduit not only for sexual function but also for menstruation. However, if treated by the method described herein, they should be cautioned against pregnancy if they have cervicovaginal agenesis and against vaginal delivery if they have vaginal agenesis.

Characterization and distribution of natriuretic peptide receptors in the rat uterus.

PubMed

Dos Reis, A M; Fujio, N; Dam, T V; Mukaddam-Daher, S; Jankowski, M; Tremblay, J; Gutkowska, J

1995-10-01

Atrial natriuretic peptide (ANP) receptors were characterized in rat uterus. The binding of [125I]ANP to uterine membranes was completely competed for by increasing concentrations of unlabeled ANP (Kd = 0.39 nM) and brain natriuretic peptide (Kd = 1.24 nM) and partially by C-type natriuretic peptide (CNP; Kd = 80.4 nM), but not by C-ANF. Also, [125I]Tyr-CNP bound to uterine membranes was completely competed by unlabeled CNP (Kd = 1.12 nM). Cross-linking of [125I]ANP to uterine membranes revealed the presence of one band of 130 kilodaltons, corresponding to the guanylyl cyclase (GC-A and/or GC-B) subtypes of natriuretic peptide receptors. The presence of messenger RNA coding for genes of both GC-A and GC-B receptors was shown by quantitative reverse transcriptase polymerase chain reaction. Furthermore, ANP and, to a lesser degree, CNP stimulated the production of cGMP in rat uterus. Autoradiographic studies localized the highest binding of [125I]ANP in the endometrium, whereas [125I]Tyr-CNP binding was distributed in the endometrium as well as in the myometrium. These results demonstrate that rat uterine ANP receptors are of the guanylyl cyclase-coupled subtypes. The uterus is a target of natriuretic peptides where ANP induces its biological effects through the production of cGMP.

Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target.

PubMed

Islam, Md Soriful; Segars, James H; Castellucci, Mario; Ciarmela, Pasquapina

2017-02-01

A growing interest has emerged on dietary phytochemicals to control diverse pathological conditions. Unfortunately, dietary phytochemical research in uterine fibroids is still under construction. Uterine fibroids/leiomyomas are benign tumors developing from the myometrium of the uterus in premenopausal women. They may occur in more than 70% of women, and approximately 25% of women show clinically significant symptoms. These include heavy and prolonged menstrual bleeding, pelvic pressure (urinary frequency, incontinence, and difficulty with urination), pelvic pain, pelvic mass, infertility, and reproductive dysfunction. Due to lack of medical treatments surgery has been definitive choice for fibroid management. Moreover, surgery negatively affects women's quality of life, and its associated cost appears to be expensive. The molecular mechanism of fibroids development and growth is not fully elucidated. However, accumulated evidence shows that several signaling pathways, including Smad 2/3, PI3K/AKT/mTOR, ERK 1/2 and β-catenin are involved in the leiomyoma pathogenesis, indicating that they could serve as targets for prevention and/or treatment of this tumor. Therefore, in this review, we discuss the involvement of signaling pathways in leiomyoma development and growth, and introduce some potential dietary phytochemicals that could modulate those signaling pathways. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Laparoscopic uterine surgery as a risk factor for uterine rupture during pregnancy.

PubMed

Chao, An-Shine; Chang, Yao-Lung; Yang, Lan-Yan; Chao, Angel; Chang, Wei-Yang; Su, Sheng-Yuan; Wang, Chin-Jung

2018-01-01

The incidence of uterine rupture through a previous cesarean scar (CS) is declining as a result of a lower parity and fewer options for vaginal birth after cesarean. However, uterine ruptures attributable to other causes that traumatize the myometrium are on the rise. To determine whether changes in the causes of uterine rupture had occurred in recent years, we retrospective retrieved the clinical records of all singletons with uterine rupture observed in the delivery room of a Taiwanese tertiary obstetric center over a 15-year period. The overall uterine rupture rate was 3.8 per 10,000 deliveries. A total of 22 cases in 20 women (with two of them experiencing two episodes). Seven uterine ruptures occurred through a previous cesarean scar (CS ruptures, 32%), 13 through a non-cesarean scar (non-CS ruptures, 59%), whereas the remaining two (9%) were in women who did not previously undergo any surgery. All of the 13 non-CS ruptures were identified in women with a history of laparoscopic procedures to the uterus. Specifically, 10 (76%) occurred after a previous laparoscopic myomectomy, one (8%) following a hysteroscopic myomectomy, and two (16%) after a laparoscopic wedge resection of cornual ectopic pregnancy. Severe bleeding (blood loss >1500 mL) requiring transfusions was more frequent in women who experienced non-CS compared with CS ruptures (10 versus 1 case, respectively, P = 0.024). Patients with a history of endoscopic uterine surgery should be aware of uterine rupture during pregnancy.

Pirt contributes to uterine contraction-induced pain in mice.

PubMed

Wang, Changming; Wang, Zhongli; Yang, Yan; Zhu, Chan; Wu, Guanyi; Yu, Guang; Jian, Tunyu; Yang, Niuniu; Shi, Hao; Tang, Min; He, Qian; Lan, Lei; Liu, Qin; Guan, Yun; Dong, Xinzhong; Duan, Jinao; Tang, Zongxiang

2015-09-17

Uterine contraction-induced pain (UCP) represents a common and severe form of visceral pain. Nerve fibers that innervate uterine tissue express the transient receptor potential vanilloid channel 1 (TRPV1), which has been shown to be involved in the perception of UCP. The phosphoinositide-interacting regulator of TRP (Pirt) may act as a regulatory subunit of TRPV1. The intraperitoneal injection of oxytocin into female mice after a 6-day priming treatment with estradiol benzoate induces writhing responses, which reflect the presence of UCP. Here, we first compared writhing response between Pirt (+/+) and Pirt (-/-) mice. Second, we examined the innervation of Pirt-expressing nerves in the uterus of Pirt (-/-) mice by immunofluorescence and two-photon microscopy. Third, we identified the soma of dorsal root ganglion (DRG) neurons that innerve the uterus using retrograde tracing and further characterized the neurochemical properties of these DRG neurons. Finally, we compared the calcium response of capsaicin between DRG neurons from Pirt (+/+) and Pirt (-/-) mice. We found that the writhing responses were less intensive in Pirt (-/-) mice than in Pirt (+/+) mice. We also observed Pirt-expressing nerve fibers in the myometrium of the uterus, and that retrograde-labeled cells were small-diameter, unmyelinated, and Pirt-positive DRG neurons. Additionally, we found that the number of capsaicin-responding neurons and the magnitude of evoked calcium response were markedly reduced in DRG neurons from Pirt (-/-) mice. Taken together, we speculate that Pirt plays an important role in mice uterine contraction-induced pain.

Liarozole inhibits transforming growth factor-β3–mediated extracellular matrix formation in human three-dimensional leiomyoma cultures

PubMed Central

Levy, Gary; Malik, Minnie; Britten, Joy; Gilden, Melissa; Segars, James; Catherino, William H.

2014-01-01

Objective To investigate the impact of liarozole on transforming growth factor-β3 (TGF-β3) expression, TGF-β3 controlled profibrotic cytokines, and extracellular matrix formation in a three-dimensional (3D) leiomyoma model system. Design Molecular and immunohistochemical analysis in a cell line evaluated in a three-dimensional culture. Setting Laboratory study. Patient(s) None. Intervention(s) Treatment of leiomyoma and myometrial cells with liarozole and TGF-β3 in a three-dimensional culture system. Main Outcome Measure(s) Quantitative real-time reverse-transcriptase polymerase chain reaction and Western blotting to assess fold gene and protein expression of TGF-β3 and TGF-β3 regulated fibrotic cytokines: collagen 1A1 (COL1A1), fibronectin, and versican before and after treatment with liarozole, and confirmatory immunohistochemical stains of treated three-dimensional cultures. Result(s) Both TGF-β3 gene and protein expression were elevated in leiomyoma cells compared with myometrium in two-dimensional and 3D cultures. Treatment with liarozole decreased TGF-β3 gene and protein expression. Extracellular matrix components versican, COL1A1, and fibronectin were also decreased by liarozole treatment in 3D cultures. Treatment of 3D cultures with TGF-β3 increased gene expression and protein production of COL1A1, fibronectin, and versican. Conclusion(s) Liarozole decreased TGF-β3 and TGF-β3–mediated extracellular matrix expression in a 3D uterine leiomyoma culture system. PMID:24825427

Leiomyoma Cells in 3-Dimensional Cultures Demonstrate an Attenuated Response to Fasudil, a Rho-Kinase Inhibitor, When Compared to 2-Dimensional Cultures

PubMed Central

Malik, Minnie; Britten, Joy; Segars, James

2014-01-01

Uterine leiomyomata are common benign tumors in women of reproductive age and demonstrate an attenuated response to mechanical signaling that involves Rho and integrins. To further characterize the impairment in Rho signaling, we studied the effect of Rho-kinase inhibitor, fasudil, on extracellular matrix production, in 2-dimensional (2D) and 3-dimensional (3D) cultures of leiomyoma and myometrial cells. Leiomyoma 2D cultures demonstrated a rapid decrease in gene transcripts and protein for fibronectin, procollagen 1A, and versican. In 3D cultures, fibronectin and procollagen 1A proteins demonstrated increased levels at lower concentrations of fasudil, followed by a concentration-dependent decrease. Versican protein increased up to 3-fold, whereas fibromodulin demonstrated a significant decrease of 1.92-fold. Myometrial 2D or 3D cultures demonstrated a decrease in all proteins after 72 hours of treatment. The 3D leiomyoma cultures demonstrated a significant increase in active RhoA, followed by a concentration-dependent decrease at higher concentrations. A concentration-dependent increase in phospho-extracellular regulated signal kinase and proapoptotic protein Bax was observed in 3D leiomyoma cultures. Fasudil relaxed the contraction of the 3D collagen gels caused by myometrium and leiomyoma cell growth. These findings indicate that the altered state of Rho signaling in leiomyoma was more clearly observed in 3D cultures. The results also suggest that fasudil may have clinical applicability for treatment of uterine leiomyoma. PMID:25084783

Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 expression and regulation in uterine leiomyoma.

PubMed

Marsh, Erica E; Chibber, Shani; Wu, Ju; Siegersma, Kendra; Kim, Julie; Bulun, Serdar

2016-04-01

To determine the presence, differential expression, and regulation of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) in uterine leiomyomas. Laboratory in vivo and in vitro study with the use of human leiomyoma and myometrial tissue and primary cells. Academic medical center. Leiomyoma and myometrial tissue samples and cultured cells. 5-Aza-2'-deoxycytidine (5-aza-dC) treatment. Fold-change difference between EFEMP1 and fibulin-3 expression in leiomyoma tissue and cells compared with matched myometrial samples, and fold-change difference in EFEMP1 expression with 5-Aza-dC treatment. In vivo, EFEMP1 expression was 3.19-fold higher in myometrial tissue than in leiomyoma tissue. EFEMP1 expression in vitro was 5.03-fold higher in myometrial cells than in leiomyoma cells. Western blot and immunohistochemistry staining of tissue and cells confirmed similar findings in protein expression. Treatment of leiomyoma cells with 5-Aza-dC resulted in increased expression of EFEMP1 in vitro. The EFEMP1 gene and its protein product, fibulin-3, are both significantly down-regulated in leiomyoma compared with myometrium when studied both in vivo and in vitro. The increase in EFEMP1 expression in leiomyoma cells with 5-Aza-dC treatment suggest that differential methylation is responsible, in part, for the differences seen in gene expression. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Expression Profiling of Nuclear Receptors Identifies Key Roles of NR4A Subfamily in Uterine Fibroids

PubMed Central

Yin, Hanwei; Lo, Jay H.; Kim, Ji-Young; Marsh, Erica E.; Kim, J. Julie; Ghosh, Asish K.; Bulun, Serdar

2013-01-01

Uterine fibroids (UFs), also known as uterine leiomyomas, are benign, fibrotic smooth muscle tumors. Although the GnRH analog leuprolide acetate that suppresses gonadal steroid hormones is used as a treatment, it has significant side effects, thereby limiting its use. Availability of more effective therapy is limited because of a lack of understanding of molecular underpinnings of the disease. Although ovarian steroid hormones estrogen and progesterone and their receptors are clearly involved, the role of other nuclear receptors (NRs) in UFs is not well defined. We used quantitative real-time PCR to systematically profile the expression of 48 NRs and identified several NRs that were aberrantly expressed in UFs. Among others, expression of NR4A subfamily members including NGFIB (NR4A1), NURR1 (NR4A2), and NOR1 (NR4A3) were dramatically suppressed in leiomyoma compared with the matched myometrium. Restoration of expression of each of these NR4A members in the primary leiomyoma smooth muscle cells decreased cell proliferation. Importantly, NR4As regulate expressions of the profibrotic factors including TGFβ3 and SMAD3, and several collagens that are key components of the extracellular matrix. Finally, we identify NR4A members as targets of leuprolide acetate treatment. Together, our results implicate several NRs including the NR4A subfamily in leiomyoma etiology and identify NR4As as potential therapeutic targets for treating fibrotic diseases. PMID:23550059

Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma☆

PubMed Central

Norian, John M.; Owen, Carter M.; Taboas, Juan; Korecki, Casey; Tuan, Rocky; Malik, Minnie; Catherino, William H.; Segars, James H.

2012-01-01

Leiomyoma are common tumors arising within the uterus that feature excessive deposition of a stiff, disordered extracellular matrix (ECM). Mechanical stress is a critical determinant of excessive ECM deposition and increased mechanical stress has been shown to be involved in tumorigenesis. Here we tested the viscoelastic properties of leiomyoma and characterized dynamic and static mechanical signaling in leiomyoma cells using three approaches, including measurement of active RhoA. We found that the peak strain and pseudo-dynamic modulus of leiomyoma tissue was significantly increased relative to matched myometrium. In addition, leiomyoma cells demonstrated an attenuated response to applied cyclic uniaxial strain and to variation in substrate stiffness, relative to myometrial cells. However, on a flexible pronectin-coated silicone substrate, basal levels and lysophosphatidic acid-stimulated levels of activated RhoA were similar between leiomyoma and myometrial cells. In contrast, leiomyoma cells plated on a rigid polystyrene substrate had elevated levels of active RhoA, compared to myometrial cells. The results indicate that viscoelastic properties of the ECM of leiomyoma contribute significantly to the tumor’s inherent stiffness and that leiomyoma cells have an attenuated sensitivity to mechanical cues. The findings suggest there may be a fundamental alteration in the communication between the external mechanical environment (extracellular forces) and reorganization of the actin cytoskeleton mediated by RhoA in leiomyoma cells. Additional research will be needed to elucidate the mechanism(s) responsible for the attenuated mechanical signaling in leiomyoma cells. PMID:21983114

Impact of adding a second layer to a single unlocked closure of a Cesarean uterine incision: randomized controlled trial.

PubMed

Bennich, G; Rudnicki, M; Wilken-Jensen, C; Lousen, T; Lassen, P D; Wøjdemann, K

2016-04-01

To investigate short- and long-term effects on residual myometrial thickness (RMT) of adding a second layer to a single unlocked closure of a Cesarean uterine incision. This was a randomized double-blind controlled trial. Healthy nulliparous women scheduled for first-time elective Cesarean delivery were operated on using a modified version of the Misgav Ladach surgical technique. The women were examined by transabdominal ultrasound before discharge from the maternity ward and by transvaginal saline contrast sonohysterography at a minimum of 5 months postpartum. Seventy-six nulliparae met the criteria and agreed to participate in the study. Thirty-five women were assigned to the single-layer technique and 38 to the double-layer unlocked closure technique. Groups were comparable regarding gestational age at delivery, duration of surgery and perioperative blood loss. There was no difference in RMT between the two groups, both at time of discharge (mean ± SD, 20.2 ± 8.0 mm vs 21.0 ± 9.7 mm) and after 5 months postpartum (mean, 5.7 ± 2.9 mm vs 5.7 ± 2.2 mm). RMT was approximately half that of the normal myometrium at both examinations. The results of this study suggest that double-layer closure of a Cesarean uterine incision does not increase RMT compared with single-layer closure when an unlocked technique is used. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Mesenchymal-to-Epithelial Transition Contributes to Endometrial Regeneration Following Natural and Artificial Decidualization

PubMed Central

Patterson, Amanda L.; Zhang, Ling; Arango, Nelson A.; Teixeira, Jose

2013-01-01

Despite being a histologically dynamic organ, mechanisms coordinating uterine regeneration during the menstrual/estrous cycle and following parturition are poorly understood. In the current study, we hypothesized that endometrial epithelial tissue regeneration is accomplished, in part, by mesenchymal-to-epithelial transition (MET). To test this hypothesis, fate mapping studies were completed using a double transgenic (Tg) reporter strain, Amhr2-Cre; Rosa26-Stopfl/fl-EYFP (i.e., flox-stop EYFP reporter). EYFP expression was observed in Müllerian duct mesenchyme-derived stroma and myometrium, but not epithelia in young and peripubertal double Tg female mice. However, mosaic EYFP expression was observed in epithelia of double Tg mice after parturition. To ensure the observed epithelial EYFP expression was not due to leaky Amhr2 promoter activity, resulting in aberrant Cre expression, transgenic mice expressing LacZ under the control of the Amhr2 promoter (Amhr2-LacZ) were used to monitor β-galactosidase (β-Gal) activity within the uterus. β-Gal activity was not detected in luminal or glandular epithelia regardless of age, reproductive status, or degree of damage incurred within the uterus. Lastly, a unique population of transitional cells was identified that expressed the epithelial cell marker, pan-cytokeratin, and the stromal cell marker, vimentin. These cells localized predominantly to the regeneration zone in the mesometrial region of the endometrium. These findings suggest a previously unappreciated role for MET in endometrial regeneration and have important implications for proliferative diseases of the endometrium such as endometriosis. PMID:23216285

The sonographic appearance and obstetric management of placenta accreta

PubMed Central

Cheung, Charleen Sze-yan; Chan, Ben Chong-pun

2012-01-01

Placenta accreta is a condition of abnormal placental implantation in which the placental tissue invades beyond the decidua basalis. It may invade into or even through the myometrium and adjacent organs, such as the urinary bladder. The incidence has been rising in recent years. It is one of the important obstetric complications nowadays, leading to significant maternal morbidity and mortality. In the past, this condition was often diagnosed at the time of delivery when massive and unexpected hemorrhage occurred. Hysterectomy, associated with significant physical and psychological consequences, was usually the only management option. As more obstetricians have become aware of this condition, early identification with antenatal imaging diagnostic technology has become possible. Ultrasound scan plays an important role in the antenatal diagnosis. Various sonographic features with different specificity and sensitivity have been described in the literature. In equivocal cases, magnetic resonance imaging may be helpful. With such information, more accurate counseling can be offered to the mothers and their families before delivery. The delivery can also be arranged at a favorable time and in an institution where multidisciplinary support is available. Input from a hematologist, interventional radiologist, intensive care physician, urology surgeon, and/or other specialist are desirable. Apart from hysterectomy, various forms of conservative management can also be considered when the diagnosis is made prior to delivery. Fertility can therefore be preserved. After delivery, with or without hysterectomy performed, psychological support to the mothers and their families is essential. PMID:23239929

Complication of cesarean section: pregnancy on the cicatrix of a previous cesarean section.

PubMed

Wang, Weimin; Long, Wenqing; Yu, Qunhuan

2002-02-01

To probe into the clinical manifestation, diagnosis, as well as treatment of pregnancy on the cicatrix of a previous cesarean section at the uterine isthmus in the first trimester. Analysis of 14 patients with pregnancy on the cicatrix of a previous cesarean section at the uterine isthmus in the first trimester was made after conservative treatment by drugs from January 1996 to December 1999. The 14 patients with a pregnancy on the cicatrix of a previous cesarean section at the uterine isthmus in the first trimester were painless, had slight vaginal bleeding, and concurrently had increased serum beta-subunit human chorionic gonadotropin (beta-HCG). Doppler ultrasonic examination revealed an obvious enlargement of the previous cesarean section cicatrix in the uterine isthmus, and found a gestational sac or mixed mass attached to the cicatrice, with a very thin myometrium between the gestational sac and bladder walls. Among the 14 patients, 12 patients had crystalline trichosanthes injected into the cervix, mifepristone taken orally, or methotrexate in the form of intramuscular injection. Following this procedure, their serum beta-HCG dropped to normal. The other 2 patients had a total hysterectomy. Pregnancy on the cicatrix of a previous cesarean section at the uterine isthmus in the first trimester is a complication of cesarean section. Early diagnosis and effective conservative treatment by drugs are instrumental in decreasing the potential occurrence of uterine rupture, which is also conducive to preserving the patient's future fertility.

Immune cells in term and preterm labor

PubMed Central

Gomez-Lopez, Nardhy; StLouis, Derek; Lehr, Marcus A; Sanchez-Rodriguez, Elly N; Arenas-Hernandez, Marcia

2014-01-01

Labor resembles an inflammatory response that includes secretion of cytokines/chemokines by resident and infiltrating immune cells into reproductive tissues and the maternal/fetal interface. Untimely activation of these inflammatory pathways leads to preterm labor, which can result in preterm birth. Preterm birth is a major determinant of neonatal mortality and morbidity; therefore, the elucidation of the process of labor at a cellular and molecular level is essential for understanding the pathophysiology of preterm labor. Here, we summarize the role of innate and adaptive immune cells in the physiological or pathological activation of labor. We review published literature regarding the role of innate and adaptive immune cells in the cervix, myometrium, fetal membranes, decidua and the fetus in late pregnancy and labor at term and preterm. Accumulating evidence suggests that innate immune cells (neutrophils, macrophages and mast cells) mediate the process of labor by releasing pro-inflammatory factors such as cytokines, chemokines and matrix metalloproteinases. Adaptive immune cells (T-cell subsets and B cells) participate in the maintenance of fetomaternal tolerance during pregnancy, and an alteration in their function or abundance may lead to labor at term or preterm. Also, immune cells that bridge the innate and adaptive immune systems (natural killer T (NKT) cells and dendritic cells (DCs)) seem to participate in the pathophysiology of preterm labor. In conclusion, a balance between innate and adaptive immune cells is required in order to sustain pregnancy; an alteration of this balance will lead to labor at term or preterm. PMID:24954221

[Dinitrosyl iron complexes with glutathione recover rats with experimental endometriosis].

PubMed

Adamian, L V; Burgova, E N; Tkachev, N A; Mikoian, V D; Stepanian, A A; Sonova, M M; Vanin, A F

2013-01-01

The effect of binuclear dinitrosyl iron complexes (DNIC) with glutathione on endometrioid tumors in rats with experimental endometriosis has been studied. The latter was induced by an autotransplantation model, where two fragments of endometrium with myometrium (2 x 2 mm) from the left uterine horn was grafted to the inner surface of the anterior abdominal wall. The test animals received intraperitoneal injections of 0.5 ml DNIC-glutathione at the dose of 12.5 micromole per kg daily for 12 days 28 days after operation. The injections resulted in more than a 2-fold decrease in the total volume of both large tumors formed from grafts and small additive tumors formed nearby grafts. The disappearance of the additive tumors was also observed in test animals. The EPR signal with g(av) = 2.03 characteristic of protein bound DNIC with thiol-containing ligands was recorded in livers, graft and additive tumors of test and control animals pointing out intensive generation of nitric oxide in rats with experimental endometriosis. Ribonucleotide reductase activation discovered by doublet the EPR signal at g = 2.0 with 2.3 mT hyperfine structure splitting was found in small tumors. The cytotoxic effect of DNIC-glutathione on endometrioid tumors was suggested to be due to DNIC degradation nearby the tumors induced by iron chelating compounds released from the tumors. The degradation resulted in release of a high amount of nitric oxide molecules and nitrosonium ions from DNICs affecting the tumors by way of the cytotoxic effect.

High-temperature thermal treatment of the uterus

NASA Astrophysics Data System (ADS)

Ryan, Thomas P.; Xiao, Jia Hua; Chung, Juh Yun

2003-06-01

More than 200,000 hysterectomies are performed annually in the US due to abnormal uterine bleeding from excessive menstrual flow. A minimally invasive procedure has been developed using thermal treatment combined with pressure to the endometrial lining of the uterus. Results from a 3-D finite element model will be shown, as well as experimental data. Good correlation was seen between simulations and experiments. The study found similar results then temperatures were increased and times for treatment were shortened.More than 200,000 hysterectomies are performed annually in the US due to abnormal uterine bleeding from excessive menstrual flow. A minimally invasive procedure has been developed using a balloon-based thermal treatment combined with pressure to the endometrial lining of the uterus. A 3D finite element model was set up to simulate the balloon ablation device in the human uterus as used in over 150,000 patients to date. Several additional simulations were made at higher temperatures to seek alternative combinations with higher temperature and shorter time intervals for the same depth of penetration, or deeper penetration at longer times and elevated temperatures. A temperature range of 87 to 150°C was explored. The Bioheat Equation was used in the simulations to predict temperature distributions in tissue. The Damage Integral was also used to characterize the location at depth of irreversible damage in the uterus. Treatment safety issues were also analyzed as the simulations showed the depth of penetration into the myometrium, towards the serosa.

Laparoscopic uterine surgery as a risk factor for uterine rupture during pregnancy

PubMed Central

Chao, An-Shine; Chang, Yao-Lung; Yang, Lan-Yan; Chao, Angel; Chang, Wei-Yang; Su, Sheng-Yuan

2018-01-01

The incidence of uterine rupture through a previous cesarean scar (CS) is declining as a result of a lower parity and fewer options for vaginal birth after cesarean. However, uterine ruptures attributable to other causes that traumatize the myometrium are on the rise. To determine whether changes in the causes of uterine rupture had occurred in recent years, we retrospective retrieved the clinical records of all singletons with uterine rupture observed in the delivery room of a Taiwanese tertiary obstetric center over a 15-year period. The overall uterine rupture rate was 3.8 per 10,000 deliveries. A total of 22 cases in 20 women (with two of them experiencing two episodes). Seven uterine ruptures occurred through a previous cesarean scar (CS ruptures, 32%), 13 through a non-cesarean scar (non-CS ruptures, 59%), whereas the remaining two (9%) were in women who did not previously undergo any surgery. All of the 13 non-CS ruptures were identified in women with a history of laparoscopic procedures to the uterus. Specifically, 10 (76%) occurred after a previous laparoscopic myomectomy, one (8%) following a hysteroscopic myomectomy, and two (16%) after a laparoscopic wedge resection of cornual ectopic pregnancy. Severe bleeding (blood loss >1500 mL) requiring transfusions was more frequent in women who experienced non-CS compared with CS ruptures (10 versus 1 case, respectively, P = 0.024). Patients with a history of endoscopic uterine surgery should be aware of uterine rupture during pregnancy. PMID:29787604

Immunohistochemical assessment of collagen types I, III, IV and VI in biopsy samples of the bovine uterine wall collected during the oestrous cycle.

PubMed

Boos, A

2000-01-01

Uterine biopsies were collected at cycle days 1 (oestrous), 8, 15 and 19 in six cows. Unfixed cryostat sections were used to immunolocalise collagen types I, III, IV and VI by an indirect FITC method. Collagen I was sparsely found in the endometrium where it formed a fine meshwork of thin fibres directly below the surface epithelium, clearly visible only at cycle days 8 and 15. Collagen III formed the bulk of connective tissue fibres and was arranged in fine aggregates within the superficial endometrial stroma, while in the deeper areas it consisted of many thick fibre bundles. Collagen IV was found in basement membranes underlying all endometrial epithelia. Furthermore, it surrounded smooth muscle cells of blood vessels. A few single fibrils also stained positively within the endometrial stroma, more numerous at cycle days 1 and 19 as compared to days 8 and 15. Collagen VI formed a mesh of fine and pericellularly situated fibrils within the endometrial stroma. The contribution of the collagen types studied to the connective tissue of caruncles, blood vessels, lymph follicles, and myometrium is also reported. The results of the present study indicate that the connective tissue of the bovine uterine wall is composed of different collagen types, which exhibit a characteristic distribution pattern each. The day of cycle may influence amounts and organisation of collagen types I and IV as demonstrated here at the light-microscopical level. Copyright 2000 S. Karger AG, Basel

Roles of glucocorticoids in human parturition: a controversial fact?

PubMed

Li, X Q; Zhu, P; Myatt, L; Sun, K

2014-05-01

The pivotal role of glucocorticoids in the initiation of parturition has been very well documented in several domestic mammalian animal species. However the role of glucocorticoids in human parturition remains controversial mainly because of the absence of effect of synthetic glucocorticoids, given to promote fetal organ maturation in pregnant women with threatened preterm delivery, on the length of gestation. This article will review studies of glucocorticoids in human parturition and provide evidence for an important role of glucocorticoids in human parturition as well but a simultaneous high concentration of estrogen within the intrauterine tissues may be necessary for GCs to initiate parturition. The synthetic GCs dexamethasone and betamethasone pass through the placenta intact resulting in potent negative feedback on the fetal HPA axis and diminished production of DHEA from fetal adrenal glands for estrogen synthesis by the placenta. This may negate the effect of systemic administration of GCs on the induction of labor, especially in cases where the myometrium is not yet fully primed by estrogen. Endogenous glucocorticoids are inactivated by the placental 11β-HSD2 thus limiting the negative feedback of maternal cortisol on the fetal HPA axis and allowing the simultaneous rise of cortisol and estrogen levels towards the end of gestation. Therefore, endogenous glucocorticoids, particularly glucocorticoids produced locally in the intrauterine tissues may play an important role in parturition in humans by enhancing prostaglandin production in the fetal membranes and stimulating estrogen and CRH production in the placenta. Copyright © 2014 Elsevier Ltd. All rights reserved.

[The conservative treatment of placenta accreta. A clinical case report].

PubMed

Artuso, A; Rocchi, B; Garbo, S; Baudino, G; Repetti, F

1993-09-01

The following description is a clinical case of placenta accreta and its conservative treatment. According to some authors, abnormal adhesion of the placenta depends on the alteration of the equilibrium between the trophoblastic tissue invasion and the reaction of the decidua. Consequently we have various degrees of penetration of the myometrium by chorionic villi into areas of deficit, sparse or absent decidua. Whatever the pathogenetic mechanism, the final clinical picture is slight to deep penetration of the trophoblastic tissue into the uterine wall. That causes absence of the normal plane of cleavage between placenta and maternal decidua, no spontaneous placental detachment during the third stage of labour and no possible manual removal. The patient, primigravida, was admitted at the 36th Week of gestation with PROM and physiologically delivered a neonate weighing 1820 g, after she spontaneously began labour. The newborn was admitted in the neonatal-pathology ward because it was premature although the Apgar score at 1-5 minutes after birth was 5-9. Placental ejection was awaited for 1 hour, then manual exploration of the uterine cavity was undertaken. The normal plane of cleavage between placental tissue and decidua was absent and therefore manual extraction of the placenta was impossible. Surgery was stopped and, after informed consensus was obtained from the patient, a conservative treatment was tried. After cutting the umbilical cord as short as possible and checking for vaginal bleeding, the patient was moved to obstetrics ward.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of epidermal growth factor, interleukin 1 and nitric oxide on prostaglandin production by guinea-pig uterus.

PubMed

Keeble, J E; Poyser, N L

2002-08-01

Initial experiments in the present study investigated the effects of epidermal growth factor (EGF), interleukin 1beta (IL-1beta) and sodium nitroprusside (a nitric oxide donor) on the output of prostaglandins from guinea-pig uterus on day 7 of the oestrous cycle. Superfusion of day 7 guinea-pig uterus in vitro with either EGF or sodium nitroprusside increased the output of PGF(2alpha) and 6-keto-PGF(1alpha), but not of PGE(2). IL-1beta had no effect on the output of these three prostaglandins. EGF still increased the output of PGF(2alpha), but did not increase the output of 6-keto-PGF(1alpha) in a calcium-depleted superfusate. Subsequent experiments investigated the effect of sodium nitroprusside on contractile activity of day 7 guinea-pig uterus. Basal spontaneous activity of both the intact uterus and isolated myometrium superfused in vitro was low. Sodium nitroprusside increased the contractile activity of these tissues two- to fourfold. EGF did not affect the contractile activity of the uterus, indicating that sodium nitroprusside-induced contractions are not due to increased prostaglandin production. Overall, the findings indicate that EGF and nitric oxide may act as mediators in the mechanism by which oestradiol acting on a progesterone-primed uterus stimulates the increase in PGF(2alpha) production by the guinea-pig uterus necessary for luteolysis. Nitric oxide may increase the spontaneous activity of the uterus when this activity is low.

Office hysteroscopy and adenomyosis.

PubMed

Molinas, Carlos Roger; Campo, Rudi

2006-08-01

Adenomyosis, the heterotopic presence of endometrial glands and stroma within the myometrium, has traditionally been diagnosed by the pathologist in hysterectomy specimens. However, the recent development of high-quality non-invasive techniques such as transvaginal sonography (TVS), magnetic resonance imaging (MRI) and hysteroscopy has renewed interest in diagnosing adenomyosis in the office prior to any treatment. Hysteroscopy offers the advantage of direct visualization of the uterine cavity, and since nowadays it is performed in the office, it can be offered as a first-line diagnostic tool for evaluation of uterine abnormalities in patients with abnormal uterine bleeding and/or infertility. The available data clearly indicate that high-quality mini-hysteroscopes, saline as a distension medium, and atraumatic insertion technique are essential for the success of office hysteroscopy. The procedure is indicated in any situation in which an intrauterine anomaly is suspected; it is immediately preceded by a physical exam and a TVS to evaluate uterine characteristics, and it is followed by a second TVS to take advantage of the intracavitary fluid for a contrast image of the uterus. Although diagnostic hysteroscopy does not provide pathognomonic signs for adenomyosis, some evidence suggests that irregular endometrium with endometrial defects, altered vascularization, and cystic haemorrhagic lesion are possibly associated with the entity. In addition to the direct visualization of the uterine cavity, the hysteroscopic approach offers the possibility of obtaining endometrial/myometrial biopsies under visual control. Since they can be performed in the office, the combination of TVS, fluid hysteroscopy and contrast sonography is therefore a powerful screening tool for detecting endometrial and myometrial abnormalities in association with adenomyosis.

Expression of estrogen receptors alpha and beta in the corpus luteum and uterus from non-pregnant and pregnant llamas.

PubMed

Powell, Susan A; Smith, Bradford B; Timm, Karen I; Menino, Alfred R

2007-08-01

Because estrogen may be involved in maternal recognition of pregnancy and embryonic migration in llamas, expression of estrogen receptor subtypes alpha (ERalpha) and beta (ERbeta) was evaluated in corpus luteum (CL), endometrium, and uterus using relative RT-PCR. Tissues were recovered from sterile-mated (SM) and pregnant (PG) females during Days 7-11 and 7-13 (Day 0 = day of mating), respectively, and follicular phase and juvenile females. Luteal expression of ERalpha and beta was similar (P > 0.10) in SM and PG females and within Days 7-11, however, expression of ERalpha in ovarian tissue from follicular phase females was greater (P < 0.05) than Days 7 and 9 CL. Uterus expressed less ERalpha and beta compared to endometrium (P = 0.07 and P < 0.01, respectively). Expression of ERalpha was greater (P < 0.05) in Day 7 and follicular phase uteri than Days 9 and 11, Day 13 PG and juvenile uteri. Uterine ERbeta expression was greater (P = 0.09) in PG versus SM females and in mated compared to follicular phase females (P < 0.05). Endometrial expression of ERalpha and beta did not differ (P > 0.10) between SM and PG females or by day. The presence of luteal ER during this period may mean a role for estradiol in maternal recognition of pregnancy. Observed increases in uterine ER expression with no changes in endometrium suggest expression increased in myometrium and/or perimetrium. Upregulation of myometrial ERbeta in PG females may be involved in supporting uterine migration of the embryo.

Factors affecting the loss of MED12-mutated leiomyoma cells during in vitro growth.

PubMed

Bloch, Jeannine; Holzmann, Carsten; Koczan, Dirk; Helmke, Burkhard Maria; Bullerdiek, Jörn

2017-05-23

Uterine leiomyomas (UL) are the most prevalent symptomatic human tumors at all and somatic mutations of the gene encoding mediator subcomplex 12 (MED12) constitute the most frequent driver mutations in UL. Recently, a rapid loss of mutated cells during in vitro growth of UL-derived cell cultures was reported, resulting in doubts about the benefits of UL-derived cell cultures. To evaluate if the rapid loss of MED12-mutated cells in UL cell cultures depends on in vitro passaging, we set up cell cultures from nine UL from 40-50 year old Caucasian patients with at least one UL. Cultured UL cells were investigated for loss of MED12-mutated cells. Genetic characterization of native tumor samples and adjacent myometrium was done by array analysis. "Aged" primary cultures without passaging were compared to cells of three subsequent passages. Comparative analyses of the mutated/non-mutated ratios between native tissue, primary cells, and cultured tumor cells revealed a clear decrease of MED12-mutated cells. None of the tumors showed gross alterations of the array profiles, excluding the presence of gross genomic imbalances besides the MED12 mutations as a reason for the intertumoral variation in the loss of MED12-mutated cells. Albeit at a lesser rate, loss of MED12-mutated cells from cell cultures of UL occurs even without passaging thus indicating the requirement of soluble factors or matrix components lacking in vitro. Identification of these factors can help to understand the mechanisms of the growth of the most frequent type of uterine leiomyomas and to decipher novel drug targets.

The invasive phenotype of placenta accreta extravillous trophoblasts associates with loss of E-cadherin.

PubMed

Duzyj, C M; Buhimschi, I A; Motawea, H; Laky, C A; Cozzini, G; Zhao, G; Funai, E F; Buhimschi, C S

2015-06-01

Epithelial-to-mesenchymal transition (EMT) is a process of molecular and phenotypic epithelial cell alteration promoting invasiveness. Loss of E-cadherin (E-CAD), a transmembrane protein involved in cell adhesion, is a marker of EMT. Proteolysis into N- and C-terminus fragments by ADAM10 and presenilin-1 (PSEN-1) generates soluble (sE-CAD) and transcriptionally active forms. We studied the protein expression patterns of E-CAD in the serum and placenta of women with histologically-confirmed over-invasive placentation. The patterns of expression and levels of sE-CAD were analyzed by Western blot, immunoassay, and immunoprecipitation. Tissue immunostaining for E-CAD, cytokeratin-7 (epithelial marker), vimentin (mesenchymal marker), ADAM10, PSEN-1 and β-catenin expression were investigated in parallel. N-terminus cleaved 80 kDa sE-CAD fragments were present in serum of pregnant women with gestational age regulation of the circulatory levels. Women with advanced trophoblast invasion did not display circulatory levels of sE-CAD different from those of women with normal placentation. Histologically, extravillous trophoblasts (EVT) closer to the placental-myometrial interface demonstrated less E-CAD staining than those found deeper in the myometrium. These cells expressed both vimentin and cytokeratin, an additional feature of EMT. EVT of placentas with advanced invasion displayed intracellular E-CAD C-terminus immunoreactivity predominating over that of the extracellular N-terminus, a pattern consistent with preferential PSEN-1 processing. Local processing of E-CAD may be an important molecular mechanism controlling the invasive phenotype of accreta EVT. Copyright © 2015 Elsevier Ltd. All rights reserved.

Increased placental trophoblast inclusions in placenta accreta.

PubMed

Adler, E; Madankumar, R; Rosner, M; Reznik, S E

2014-12-01

Trophoblast inclusions (TIs) are often found in placentas of genetically abnormal gestations. Although best documented in placentas from molar pregnancies and chromosomal aneuploidy, TIs are also associated with more subtle genetic abnormalities, and possibly autism. Less than 3% of non-aneuploid, non-accreta placentas have TIs. We hypothesize that placental genetics may play a role in the development of placenta accreta and aim to study TIs as a potential surrogate indicator of abnormal placental genetics. Forty cases of placenta accreta in the third trimester were identified in a search of the medical records at one institution. Forty two third trimester control placentas were identified by a review of consecutively received single gestation placentas with no known genetic abnormalities and no diagnosis of placenta accreta. Forty percent of cases with placenta accreta demonstrated TIs compared to 2.4% of controls. More invasive placenta accretas (increta and percreta) were more likely to demonstrate TIs than accreta (47% versus 20%). Prior cesarean delivery was more likely in accreta patients than controls (67% versus 9.5%). Placenta accreta is thought to be the result of damage to the endometrium predisposing to abnormal decidualization and invasive trophoblast growth into the myometrium. However, the etiology of accreta is incompletely understood with accreta frequently occurring in women without predisposing factors and failing to occur in predisposed patients. This study has shown that TIs are present at increased rates in cases of PA. Further studies are needed to discern what underlying pathogenic mechanisms are in common between abnormal placentation and the formation of TIs. Published by Elsevier Ltd.

Hepatitis A virus cellular receptor 2 (HAVCR2) is decreased with viral infection and regulates pro-labour mediators OA.

PubMed

Liong, Stella; Lim, Ratana; Barker, Gillian; Lappas, Martha

2017-07-01

Intrauterine infection caused by viral infection has been implicated to contribute to preterm birth. Hepatitis A virus cellular receptor 2 (HAVCR2) regulates inflammation in non-gestational tissues in response to viral infection. The aims of this study were to determine the effect of: (i) viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) on HAVCR2 expression; and (ii) HAVCR2 silencing by siRNA (siHAVCR2) in primary amnion and myometrial cells on poly(I:C)-induced inflammation. In human foetal membranes and myometrium, HAVCR2 mRNA and protein expression was decreased when exposed to poly(I:C). Treatment of primary amnion and myometrial cells with poly(I:C) significantly increased the expression and release of pro-inflammatory cytokines TNF, IL1A, IL1B and IL6; the expression of chemokines CXCL8 and CCL2; the expression and secretion of adhesion molecules ICAM1 and VCAM1; and PTGS2 and PTGFR mRNA expression and the release of prostaglandin PGF 2α . This increase was significantly augmented in cells transfected with siHAVCR2. Furthermore, mRNA expression of anti-inflammatory cytokines IL4 and IL10 was significantly decreased. Collectively, our data suggest that HAVCR2 regulates cytokines, chemokines, prostaglandins and cell adhesion molecules in the presence of viral infection. This suggests a potential for HAVCR2 activators as therapeutics for the management of preterm birth associated with viral infections. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Catastrophic antiphospholipid syndrome during pregnancy and puerperium: maternal and fetal characteristics of 15 cases

PubMed Central

Gómez‐Puerta, José A; Cervera, Ricard; Espinosa, Gerard; Asherson, Ronald A; García‐Carrasco, Mario; da Costa, Izaias P; Andrade, Danieli C O; Borba, Eduardo F; Makatsaria, Alexander; Bucciarelli, Silvia; Ramos‐Casals, Manuel; Font, Josep

2007-01-01

Background The catastrophic variant of the antiphospholipid syndrome (APS) is a life‐threatening form of presentation of this syndrome that can be triggered by several factors. Aim To describe the characteristics of patients who developed catastrophic APS triggered during pregnancy and puerperium. Methods A review of the first 255 cases collected in the website‐based “CAPS Registry” was undertaken. Three new and unpublished cases of catastrophic APS developed during pregnancy and puerperium were added. Results Fifteen cases were identified. The mean (range) age was 27 (17–38) years. Most patients had a previous unsuccessful obstetric history. In 7 of 14 (50%) cases with available medical history, the catastrophic APS appeared during pregnancy, in 6 (43%) during the puerperium and in 1 (7%) after curettage for a fetal death. The main clinical and serological characteristics were similar to those patients with catastrophic APS triggered by other factors, except for a history of a higher prevalence of previous abortions (p<0.01). Several specific features were found, including the HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome in 8 (53%) patients, placental infarctions in 4 (27%) patients, and pelvic vein thrombosis and myometrium thrombotic microangiopathy in 1 (7%) patient each. Mortality rate was high for the mothers (46%), and for the babies (54%). Conclusions It is important to consider the possibility of the development of catastrophic APS in those patients with signs of HELLP syndrome and multiorgan failure during pregnancy or puerperium, especially in those patients with previous history of abortions and/or thrombosis. PMID:17223653

Recurrence in Uterine Tumors with Ovarian Sex-Cord Tumor Resemblance: A Case Report and Systematic Review.

PubMed

Cömert, Günsu Kimyon; Kiliç, Çiğdem; Çavuşoğlu, Deniz; Türkmen, Osman; Karalok, Alper; Turan, Taner; Başaran, Derman; Boran, Nurettin

2018-05-10

The aim of this study was to evaluate the prognostic factors of recurrence in uterine tumors resembling ovarian sex-cord tumors (UTROSCT) and to determine clinical-pathological characteristics, treatment options and outcome. An electronic literature search was conducted from 1976 to 2018. After the comprehensive evaluation and conjunction with our case, the study included 79 cases. The median age at initial diagnosis was 49 years (range; 16-86 years). The age was under 40 years in 21 (26.6%) patients. Whereas 68 patients underwent at least hysterectomy, 9 patients had organ sparing surgery. There was necrosis in 4 (5.1%) patients, atypia in 16 (20.3%) patients, and infiltrative tumor border in 34 (43%) patients. At least one mitosis per 10 high power fields was determined in 36 (45.5%) patients. The tumor involved at least part of the myometrium in 54 (68.3%) patients. Median follow-up time was 30 months (range; 3-296 months). Recurrence was determined in 5 (6.3%) patients. The disease free survival (DFS) was significantly related only to surgery type. None of the pathologic features were associated with DFS. The 5-year DFS was 86% and 96% in patients who underwent organ sparing surgery or not, respectively (p=0.038). The accurate pathologic diagnosis of UTROSCT has great value in shaping surgical management and management during the follow-up period. Organ sparing surgery was related to poor DFS. Although recurrence is rare, it should be kept in mind for patients with UTROSCT.

A toxicity cost function approach to optimal CPA equilibration in tissues.

PubMed

Benson, James D; Higgins, Adam Z; Desai, Kunjan; Eroglu, Ali

2018-02-01

There is growing need for cryopreserved tissue samples that can be used in transplantation and regenerative medicine. While a number of specific tissue types have been successfully cryopreserved, this success is not general, and there is not a uniform approach to cryopreservation of arbitrary tissues. Additionally, while there are a number of long-established approaches towards optimizing cryoprotocols in single cell suspensions, and even plated cell monolayers, computational approaches in tissue cryopreservation have classically been limited to explanatory models. Here we develop a numerical approach to adapt cell-based CPA equilibration damage models for use in a classical tissue mass transport model. To implement this with real-world parameters, we measured CPA diffusivity in three human-sourced tissue types, skin, fibroid and myometrium, yielding propylene glycol diffusivities of 0.6 × 10 -6  cm 2 /s, 1.2 × 10 -6  cm 2 /s and 1.3 × 10 -6  cm 2 /s, respectively. Based on these results, we numerically predict and compare optimal multistep equilibration protocols that minimize the cell-based cumulative toxicity cost function and the damage due to excessive osmotic gradients at the tissue boundary. Our numerical results show that there are fundamental differences between protocols designed to minimize total CPA exposure time in tissues and protocols designed to minimize accumulated CPA toxicity, and that "one size fits all" stepwise approaches are predicted to be more toxic and take considerably longer than needed. Copyright © 2017 Elsevier Inc. All rights reserved.

Circulating and myometrial markers of oxidative stress in pregnant women with fetal growth restriction.

PubMed

Biberoglu, Ebru; Biberoglu, Kutay; Kirbas, Ayse; Daglar, Korkut; Genc, Metin; Avci, Aslihan; Danisman, Nuri

2016-01-01

The objective of this study was to identify the relationship between fetal growth restriction (FGR) and oxidative stress. The mechanisms that protect against oxidative stress in the local microenvironment were investigated by comparing the activities of the markers, both in the circulation and myometrium. Myometrial tissue and serum levels of malondialdehyde (MDA), xanthine oxidase (XO), catalase (CAT) and superoxide dismutase (SOD) markers were measured in 20 FGR and 20 healthy pregnancies. The mean duration of gestation at delivery was shorter (P = 0003) and the mean birthweight was lower P < 0001) in the FGR study group compared with the control group, as expected. While MDA and CAT concentrations were higher in the serum (P < 0.02 and P < 0.01, respectively), but lower in the myometrial samples (P < 0.01) in the FGR versus the control group, XO and myometrial SOD values were comparable in both groups. Although our data demonstrated that FGR is associated with oxidative stress, the exact role and mechanism of the oxidant and antioxidant imbalance is obscure. We speculate that despite limited local synthesis of CAT, effective and efficient removal of MDA in the uterine environment explains high MDA and CAT serum concentrations in women with FGR. Alternatively, a well-functioning myometrial system could rescue the fetus from reactive oxygen species, as demonstrated by lowered MDA and depleted CAT resulting from hyperconsumption. Elevated serum MDA and CAT levels in the serum may reflect the 'spillover' of these markers from the uterus to the circulation. © 2015 Japan Society of Obstetrics and Gynecology.

Estradiol, progesterone and genistein differentially regulate levels of aquaporin (AQP)-1, 2, 5 and 7 expression in the uteri of ovariectomized, sex-steroid deficient rats.

PubMed

Chinigarzadeh, Asma; Muniandy, Sekaran; Salleh, Naguib

2016-11-01

In this study, effects of estradiol, progesterone and genistein on uterine aquaporin (AQP)-1, 2, 5 and 7 expression were investigated in sex-steroid deficient state which could help to elucidate the mechanisms underlying uterine fluid volume changes that were reported under these hormone and hormone-like compound influences. Uteri from ovariectomized, female Sprague-Dawley rats receiving seven days estradiol, progesterone or genistein (25, 50 and 100mg/kg/day) were harvested and levels of AQP-1, 2, 5 and 7 proteins and mRNAs were determined by Western blotting and Real-time PCR (qPCR) respectively. Distribution of these proteins in uterus was observed by immunohistochemistry. Genistein caused a dose-dependent increase in uterine AQP-1, 2, 5 and 7 protein and mRNA expression, however at the levels lower than following estradiol or progesterone stimulations. Effects of genistein were antagonized by estradiol receptor blocker, ICI 182780. Estradiol caused the highest AQP-2 protein and mRNA expression while progesterone caused the highest AQP-1, 5 and 7 protein and mRNA expression in uterus. AQP-1, 2, 5 and 7 protein were found to be distributed in the myometrium as well as in uterine luminal and glandular epithelia and endometrial blood vessels. In conclusion, the observed effects of estradiol, progesterone and genistein on uterine AQP-1, 2, 5 and 7 expression could help to explain the differences in the amount of fluid accumulated in the uterus under these different conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of antiprogestin ZK 98. 734 on the ovarian cycle, early pregnancy, and on its binding to progesterone receptors in the myometrium of marmoset Callithrix jacchus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Puri, C.P.; Kholkute, S.D.; Pongubala, J.M.

1988-04-01

The antiprogestin ZK 98.734 (11 beta-(4-dimethylaminophenyl-17 beta-hydroxy-17 alpha-(3-hydroxy-prop-1(Z)-enyl-4,9(10)-estradien-3-one) was administered i.m. (5 mg/day) for three consecutive days to two groups of common marmosets. In one group (nonpregnant, n = 6), it was injected during the luteal phase, and to the second group (pregnant, n = 7), it was injected during early pregnancy, on Days 24-26 of the mid-cycle estradiol peak. Administration of ZK 98.734 during the luteal phase caused a sharp drop in plasma progesterone levels. The luteal phase was shortened whether the drug was administered during the early or the late luteal phase. Similarly, administration of ZK 98.734 duringmore » early pregnancy caused a significant drop in progesterone levels, and pregnancy was terminated in all of the animals. The post-treatment cycles in both groups of animals were ovulatory and of normal duration. /sup 3/H-ZK 98.734 showed specific binding to myometrial cytosol fraction. ZK 98.734 also displaced the binding of /sup 3/H-progesterone to progesterone receptors. However, progesterone had higher binding affinity than did ZK 98.734. The antifertility action of ZK 98.734 could be a result either of its luteolytic action or of its blocking the progesterone receptors in the target tissue. This study, therefore, indicates that in the common marmoset ZK 98.734 is a progesterone antagonist with a potential to terminate early pregnancy.« less

Molecular genetic heterogeneity in undifferentiated endometrial carcinomas.

PubMed

Rosa-Rosa, Juan M; Leskelä, Susanna; Cristóbal-Lana, Eva; Santón, Almudena; López-García, Ma Ángeles; Muñoz, Gloria; Pérez-Mies, Belen; Biscuola, Michele; Prat, Jaime; Esther, Oliva E; Soslow, Robert A; Matias-Guiu, Xavier; Palacios, Jose

2016-11-01

Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumors, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well-differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole-exome sequencing of the endometrioid and undifferentiated components, as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: (a) hypermutated tumors with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); (b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); (c) high copy number alterations (copy-number high) tumors group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%); and (d) low copy number alterations (copy-number low) tumors with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy-number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group, whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumors. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumors, which may have prognostic value.

Molecular genetic heterogeneity in undifferentiated endometrial carcinomas

PubMed Central

Rosa-Rosa, J.M.; Leskelä, S.; Cristóbal-Lana, E.; Santón, A.; López-García, M.A.; Muñoz, G.; Pérez-Mies, B.; Biscuola, M; Prat, J.; Oliva, E.; Soslow, R.A.; Matias-Guiu, X.; Palacios, J.

2017-01-01

Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumours, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole exome sequencing of the endometrioid and undifferentiated components as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: a) hypermutated tumours with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); c) high copy number alterations (copy-number high) tumours group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%) ; and d) low copy number alterations (copy-number low) tumours with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy-number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumours. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumours, which may have prognostic value. PMID:27491810

Distribution and chloramphenicol in the bovine genital tract and pharmacokinetic studies of florfenicol in cattle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bretzlaff, K.N.

1986-01-01

The objectives were to investigate selected aspects of the distribution of chloramphenicol (CAP) in the bovine genital tract and to conduct preliminary pharmacologic studies with florfenicol (FLO), a fluorinated analogue of thiamphenicol, in cattle. After 8 hours' continuous intravenous (IV) infusion of CAP to 7 postpartum cows, steady state plasma-to-genital tissue ratios of CAP were approximately 3. After intrauterine infusion of 20 mg CAP/kg to 3 postpartum cows, approximately 40% of the dose was absorbed into the bloodstream. Tissue concentrations were high at 8 hour postdosing in tissues lining the uterine lumen but were below desired therapeutic concentrations in themore » myometrium of 2 of the cows. Eighty cows with retained fetal membranes (RFM) were assigned to receive on the following treatments: (1) removal of membranes only; (2) removal plus CAP; (3) nonremoval; (4) nonremoval plus CAP. CAP treatment consisted of 5 g administered IU twice daily for 3 days. The majority of cows in all groups acquired endometritis, although CAP reduced the prevalence and severity of the disease. A quantitative assay for FLO in plasma was developed and validated on a high performance liquid chromatographic (HPLC) system. The pharmacokinetics of FLO determined after IV administration of 50 mg FLO/kg to 5 cows were best described by a three-compartment model. FLO was approximately 18% bound to plasma proteins as determined by equilibrium dialysis and ultrafiltration. In an in vitro system, 5, 125, or 1000 ug/ml of CAP had no effect on neutrophils from 6 cows.« less

ADENOCARCINOMA AND TUBERCULOSIS OF THE SIGMOID COLON AND FALLOPIAN TUBE--A RARE ASSOCIATION. A CASE REPORT AND REVIEW OF THE LITERATURE.

PubMed

Ionescu, Lidia; Dănilă, R; Ciobanu, Delia; Ciortescu, Irina; Livadariu, Roxana; Timofte, D

2016-01-01

Association of adenocarcinoma and tuberculosis (TB) of the sigmoid colon is a rare clinical condition even in an endemic country as Romania, with challenging diagnosis and treatment. Case report. We present the case of a 57-year-old female patient who was admitted on emergency basis for a diagnosis of obstructive sigmoid adenocarcinoma. The patient was operated on and it an obstructive sigmoid tumor with serosal invasion, adherent (invading) to the body of uterus and left adnexa and urinary bladder serosa, no liver or peritoneal metastases. A sigmoidectomy was performed "en bloc" with subtotal hysterectomy, left adnexectomy and extramucosal cistectomy. The histopathological exam showed a moderately differentiated, ulcerated adenocarcinoma, widely infiltrating the colon wall invading the myometrium. Ziehl Neelsen (ZN) stain identified the presence of metachromatic bacillary structures in the colonic wall, lymph nodes and adnexal areas. Postoperative course was uneventful and the patient was discharged 10 days postoperatively in good clinical condition. After one year when the patient completed the full course of anti-tubercular drugs, a thorough work-up was performed. Colonoscopy, CT of the thorax, abdomen, pelvis showed no signs of recurrence while tumoral marker CEA (1.62 ng/ml - n<3.4) and QFT (Quantiferon-TB Gold) test were within normal range. Discussion and conclusion. Although digestive tuberculosis is included in differential diagnosis for those patients presenting abdominal pain or obstructive digestive symptoms in endemic regions, in this case the absence of TB infection criteria and positive endoscopic biopsy for colonic adenocarcinoma did not allow a complete pre- or perioperative diagnosis.

Myometrial responses in situ to nicergoline, acebutolol, phentolamine and noradrenaline of the rat in proestrus.

PubMed

Acritopoulou-Fourcroy, S; Clabaut, M; Schrub, J C

1984-12-15

The effects of two adrenoceptor antagonists, nicergoline (alpha 1) and acebutolol (beta 1), on the contraction of myometrium in the proestrous rat were compared to those of noradrenaline and phentolamine. The spontaneous myometrial contractions of Wistar rats on the day of proestrus were recorded isometrically and the data were analysed using Wilcoxon non-parametric statistics. All drugs were administered i.v. and the doses are expressed as microgram/kg body weight. Noradrenaline (1200 micrograms/kg per h) induced a 32.5% reduction (P less than 0.001) of the uterine contraction amplitude. Nicergoline did not alter uterine motility significantly when administered alone at doses ranging from 400 to 1600 micrograms/kg. However, successive injections of nicergoline in the same range given during noradrenaline infusion at 600 micrograms/kg per h potentiated the relaxing action of the latter (38%, P less than 0.01). Phentolamine (120 micrograms/kg) reduced myometrial activity by 25% (P less than 0.05). This inhibitory response rose to 65% (P less than 0.001) when the dose of phentolamine was increased to 960 micrograms/kg. When a single injection of nicergoline (400 micrograms/kg) was followed by the administration of increasing doses of acebutolol (120, 1200, 2400 micrograms/kg) the slight inhibitory effect on uterine motility observed after administration of each of the two agents separately became more pronounced (P less than 0.05). It appears from these results that combining noradrenaline with nicergoline and nicergoline with acebutolol leads to potentiation of their relaxing effects. Furthermore the results confirm that nicergoline is a partial alpha-blocker.

A Preliminary Study: Human Fibroid Stro-1+/CD44+ Stem Cells Isolated From Uterine Fibroids Demonstrate Decreased DNA Repair and Genomic Integrity Compared to Adjacent Myometrial Stro-1+/CD44+ Cells.

PubMed

Prusinski Fernung, Lauren E; Al-Hendy, Ayman; Yang, Qiwei

2018-01-01

Although uterine fibroids (UFs) continue to place a major burden on female reproductive health, the mechanisms behind their origin remain undetermined. Normal myometrial stem cells may be transformed into tumor-initiating stem cells, causing UFs, due to unknown causes of somatic mutations in MED12, found in up to 85% of sporadically formed UFs. It is well established in other tumor types that defective DNA repair increases the risk of such tumorigenic somatic mutations, mechanisms not yet studied in UFs. To examine the putative cause(s) of this stem cell transformation, we analyzed DNA repair within stem cells from human UFs compared to those from adjacent myometrium to determine whether DNA repair in fibroid stem cells is compromised. Human fibroid (F) and adjacent myometrial (Myo) stem cells were isolated from fresh tissues, and gene expression relating to DNA repair was analyzed. Fibroid stem cells differentially expressed DNA repair genes related to DNA double- (DSBs) and single-strand breaks. DNA damage was measured using alkaline comet assay. Additionally, DNA DSBs were induced in these stem cells and DNA DSB repair evaluated (1) by determining changes in phosphorylation of DNA DSB-related proteins and (2) by determining differences in γ-H2AX foci formation and relative DNA repair protein RAD50 expression. Overall, F stem cells demonstrated increased DNA damage and altered DNA repair gene expression and signaling, suggesting that human F stem cells demonstrate impaired DNA repair. Compromised F stem cell DNA repair may contribute to further mutagenesis and, consequently, further growth and propagation of UF tumors.

In vitro activity of Spirulina platensis water extract against different Candida species isolated from vulvo-vaginal candidiasis cases.

PubMed

Marangoni, Antonella; Foschi, Claudio; Micucci, Matteo; Nahui Palomino, Rogers Alberto; Gallina Toschi, Tullia; Vitali, Beatrice; Camarda, Luca; Mandrioli, Mara; De Giorgio, Marta; Aldini, Rita; Corazza, Ivan; Chiarini, Alberto; Cevenini, Roberto; Budriesi, Roberta

2017-01-01

The high incidence of vulvo-vaginal candidiasis, combined with the growing problems about azole resistance and toxicity of antifungal drugs, highlights the need for the development of new effective strategies for the treatment of this condition. In this context, natural compounds represent promising alternatives. The cyanobacterium Spirulina platensis, a blue-green alga, exhibits antimicrobial activities against several microorganisms. Nevertheless, only few data about the antifungal properties of Spirulina platensis are available and its potential toxic effects have not been largely investigated. The aim of this study was to evaluate the in vitro activity of a fully-characterized water extract of Spirulina platensis against 22 strains of Candida spp. Prior to considering its potential topical use, we both investigated whether the extract exerted target activities on guinea pig uterine smooth muscle, and the impact of Spirulina platensis on the dominant microorganisms of the vaginal microbiota (i.e., lactobacilli), in order to exclude possible adverse events. By means of a broth microdilution assay, we found that the microalga extract possesses good antifungal properties (MIC: 0.125-0.5 mg/ml), against all the Candida species with a fungicidal activity. At the concentrations active against candida, Spirulina platensis did not modify the spontaneous basic waves pattern of uterine myometrium as underlined by the absence of aberrant contractions, and did not affect the main health-promoting bacteria of the vaginal ecosystem. Finally, we evaluated the selectivity index of our extract by testing its cytotoxicity on three different cell lines and it showed values ranging between 2 and 16. Further in vivo studies are needed, in particular to evaluate the use of control-release formulations in order to maintain Spirulina platensis concentrations at anti-Candida active doses but below the toxic levels found in the present work.

Spontaneous myometrial contractility in cows suffering from endometritis-Influence of localisation, smooth muscle layer and cycle phase. An in vitro study.

PubMed

Hirsbrunner, Gaby; Kaufmann, Ch; Keller, Ch; Hüsler, J; Steiner, A

2010-04-01

Contractility of the healthy bovine myometrium depends on the reproductive state. Furthermore, contractility is influenced by localisation and the direction of smooth muscle strips. However, little is known about the contractile behaviour of the uterus when affected by endometritis. In our study, myometrial specimens from the larger horn (near the corpus and near the tip) in cows suffering from endometritis in estrus (n=8) or diestrus (n=8) were collected after slaughter. Two strips were prepared from each region corresponding to the circular and the longitudinal muscle layers, respectively. The spontaneous contractility of these strips was recorded in an organ bath. To analyse the results, the 2.5h recordings were divided into five periods of 30 min each. The variables area under curve (AUC) and maximal (A(max)) and minimal amplitude (A(min)) were calculated separately for each period, and the results were analysed using a non-parametric model regarding the influence of cycle phase (estrus vs. diestrus), region (corpus vs. tip) and muscle layer (circular vs. longitudinal). The values of both AUC and A(max) increased significantly over time. Muscle layer had a significant effect on AUC (corpus, tip) and A(max) (tip): the values of circular layers were increased compared to longitudinal layers. Dividing the data into subgroups allowed us to analyse them additionally according to muscle layer: In longitudinal layers, A(max) was increased at the corpus as compared with the tip. In this model, the factor cycle phase did not produce any significant difference in spontaneous myometrial activity. However, data of all variables showed non-significant higher values in estrus than in diestrus samples. Copyright 2009 Elsevier B.V. All rights reserved.

[Tissue penetration and clinical effects of ceftazidime in the field of obstetrics and gynecology].

PubMed

Ogawa, E; Ota, H; Maki, M

1983-12-01

To study concentrations in the gynecological organs, ceftazidime (CAZ) was given intravenously by one shot of 0.5 g to 1 patient and of 1.0 g to 10 patients who underwent simple hysterectomy because of uterine myoma. Also, clinical effect of the drug was studied in 3 cases. The levels of CAZ in sera in uterine artery and elbow vein, and tissue concentrations in various sites of the gynecological organs obtained during 50 to 425 minutes after administration were determined by the paper-disc method with P. mirabilis ATCC 21100 strain. Concentrations of CAZ at 92 minutes after administration of 1.0 g i.v. were 39.8 mcg/ml in serum of uterine artery, 47.6 mcg/ml in serum of elbow vein, 20.5 mcg/g (tissue/serum ratio 0.43) in the ovary, 18.0 mcg/g (0.38) in the fallopian tube, 16.1 mcg/g (0.34) in the endometrium, 34.5 mcg/g (0.72) in the myometrium, 30.8 mcg/g (0.65) in the uterine cervix, 36.4 mcg/g (0.76) in the portio vaginalis and then gradually decreased time-dependently. Tissue concentrations were higher than those in serum in the endometrium, uterine cervix and portio vaginalis at 147 minutes after administration. CAZ concentrations of adipose tissue between 353 and 365 minutes after injection of 1.0 g were lower than 0.8 mcg/g. The clinical responses to CAZ in intrapelvic infections were good in all cases. Slight elevation of total bilirubin, to 1.5 mg/dl, was observed in a case. In the light of these clinical findings, CAZ appears to be a potent antibiotic effective in the clinical application.

The Challenging Intrauterine Contraceptive: In-office Hysteroscopic Approach.

PubMed

Di Spiezio Sardo, Attilio; da Cunha Vieira, Mariana; Scognamiglio, Marianna; Zizolfi, Brunella; Nappi, Carmine; de Angelis, Carlo

2016-01-01

To describe 3 cases of misplaced or retained Intrauterine Contraceptive (IUC) that were successfully resolved by hysteroscopy performed in an ambulatory setting using miniaturized electrosurgical and mechanical operative instruments. Step-by-step description of the technique using slides, pictures, and video (educative video) (Canadian Task Force classification III). Misplaced or retained IUC may be related to several causes; incorrect insertion is the leading cause. In these cases, patients may complain of abnormal bleeding, pelvic pain, or pregnancy or they may remain asymptomatic. When a displaced IUC is suspected, transvaginal ultrasonography is the primary investigation followed by radiography in cases in which the IUC is not seen within the uterus. Additional imaging such as computed tomographic scanning or magnetic resonance imaging may be needed. Hysteroscopy represents the gold standard for diagnostic clarification and management of a dislocated or embedded IUC. The hysteroscopic approach of the 3 cases was the following: removal of a partially perforating IUD in the cesarean scar pouch, repositioning of a dislocated IUS in the isthmocele, and removal of an embedded IUS in the cornual area. The procedures were performed in an ambulatory setting using a 5-mm continuous flow hysteroscope and vaginoscopic approach without any analgesia and/or anesthesia. The alternate use of mechanical and electrosurgical 5F instruments allowed us to separate the IUC from the myometrial uterine wall, respecting the healthy myometrium and without causing significant patient discomfort or complications. The possibility of using miniaturized electrosurgical and mechanical instruments with small-diameter hysteroscopes offers the possibility of an effective, safe, cost-efficient, and well-tolerated removal or repositioning of a misplaced or retained IUC. This minimally invasive approach can be performed in an office setting to avoid more invasive and traumatic approaches. Copyright © 2016 AAGL. Published by Elsevier Inc. All rights reserved.

The effect of metritis and subclinical hypocalcemia on uterine involution in dairy cows evaluated by sonomicrometry

PubMed Central

HEPPELMANN, Maike; KRACH, Karoline; KRUEGER, Lars; BENZ, Philipp; HERZOG, Kathrin; PIECHOTTA, Marion; HOEDEMAKER, Martina; BOLLWEIN, Heinrich

2015-01-01

The objective of this study was to examine the effects of metritis and subclinical hypocalcemia on reduction of uterine size in dairy cows using ultrasonography and sonomicrometry. Four piezoelectric crystals were implanted via laparotomy into the myometrium of the pregnant uterine horn of 12 pluriparous Holstein Friesian cows 3 weeks before the calculated calving date. Sonometric measurements were conducted daily from 2 days before parturition (= Day 0) until Day 14 after calving and then every other day until Day 28. Distances between adjacent crystals were expressed in relation to reference values obtained before calving. The diameter of the formerly pregnant uterine horn was measured using transrectal B-Mode sonography starting on Day 10. Cows were retrospectively divided into the following groups: cows without metritis (M–; n = 7), cows with metritis (M+; n = 5), cows with normocalcemia (SH–; Ca > 2.0 mmol/l on Days 1 to 3; n = 5) and cows with subclinical hypocalcemia (SH+; Ca < 2.0 mmol/l in at least one sample between Days 1 and 3; n = 7). Metritis did not affect (P > 0.05) sonometric measurements, but the diameter of the formerly pregnant horn was larger (P ≤ 0.05) between Days 15 and 21 in M+ cows than in M‒ cows. Reduction in uterine length in hypocalcemic cows was delayed (P ≤ 0.05) between Days 8 and 21 compared with normocalcemic cows, but the uterine horn diameter was not related to calcium status. In conclusion, both diseases affected reduction of uterine size until Day 28. Cows with metritis had a larger uterine diameter, possibly attributable to accumulation of lochia, and cows with subclinical hypocalcemia had delayed reduction of uterine length, presumably related to reduction of myometrial contractility. PMID:26400127

Primary Human Uterine Leiomyoma Cell Culture Quality Control: Some Properties of Myometrial Cells Cultured under Serum Deprivation Conditions in the Presence of Ovarian Steroids.

PubMed

Bonazza, Camila; Andrade, Sheila Siqueira; Sumikawa, Joana Tomomi; Batista, Fabrício Pereira; Paredes-Gamero, Edgar J; Girão, Manoel J B C; Oliva, Maria Luiza V; Castro, Rodrigo Aquino

2016-01-01

Cell culture is considered the standard media used in research to emulate the in vivo cell environment. Crucial in vivo experiments cannot be conducted in humans and depend on in vitro methodologies such as cell culture systems. However, some procedures involving the quality control of cells in culture have been gradually neglected by failing to acknowledge that primary cells and cell lines change over time in culture. Thus, we report methods based on our experience for monitoring primary cell culture of human myometrial cells derived from uterine leiomyoma. We standardized the best procedure of tissue dissociation required for the study of multiple genetic marker systems that include species-specific antigens, expression of myofibroblast or myoblast markers, growth curve, serum deprivation, starvation by cell cycle synchronization, culture on collagen coated plates, and 17 β-estradiol (E2) and progesterone (P4) effects. The results showed that primary myometrial cells from patients with uterine leiomyoma displayed myoblast phenotypes before and after in vitro cultivation, and leiomyoma cells differentiated into mature myocyte cells under the appropriate differentiation-inducing conditions (serum deprivation). These cells grew well on collagen coated plates and responded to E2 and P4, which may drive myometrial and leiomyoma cells to proliferate and adhere into a focal adhesion complex involvement in a paracrine manner. The establishment of these techniques as routine procedures will improve the understanding of the myometrial physiology and pathogenesis of myometrium-derived diseases such as leiomyoma. Mimicking the in vivo environment of fibrotic conditions can prevent false results and enhance results that are based on cell culture integrity.

Oxidative stress: a key regulator of leiomyoma cell survival.

PubMed

Fletcher, Nicole M; Abusamaan, Mohammed S; Memaj, Ira; Saed, Mohammed G; Al-Hendy, Ayman; Diamond, Michael P; Saed, Ghassan M

2017-06-01

To determine the effects of attenuating oxidative stress with the use of dichloroacetate (DCA) on the expression of key redox enzymes myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) as well as on apoptosis. Prospective experimental study. University medical center. Cells established from myometrium and uterine fibroid from the same patients. Cells were exposed to normal (20% O 2 ) or hypoxic (2% O 2 ) conditions for 24 hours with or without DCA (20 μg/mL), a metabolic modulator that shifts anaerobic to aerobic metabolism. Nitrate/nitrite (iNOS activity indicator), iNOS, Bcl-2/Bax ratio, MPO, and caspase-3 activities and levels were determined by means of Greiss assay, real-time reverse-transcription polymerase chain reaction, and ELISA. Data were analyzed with the use of SPSS by means of one-way analysis of variance with Tukey post hoc analysis and independent t tests. MPO, iNOS, and nitrate/nitrite expression were higher in leiomyoma than in myometrial cells, and they were further enhanced by hypoxia in myometrial cells. Treatment with the use of DCA decreased MPO, iNOS, and nitrate/nitrite levels and negated the effect of hypoxia in both types of cells. Leiomyoma cells showed less apoptosis, as indicated by both caspase-3 activity and the Bcl-2/Bax ratio, than myometrial cells. Hypoxia further decreased apoptosis in myometrial cells with no further effect on leiomyoma cells. Treatment with DCA resulted in increased apoptosis in both types of cells, even in the presence of hypoxia. Shifting anaerobic to aerobic metabolism with the use of DCA resulted in an increase in apoptosis in leiomyoma cells and protected myometrial cells from the acquisition of the leiomyoma-like phenotype. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Primary Human Uterine Leiomyoma Cell Culture Quality Control: Some Properties of Myometrial Cells Cultured under Serum Deprivation Conditions in the Presence of Ovarian Steroids

PubMed Central

Sumikawa, Joana Tomomi; Batista, Fabrício Pereira; Paredes-Gamero, Edgar J.; Girão, Manoel J. B. C.; Oliva, Maria Luiza V.

2016-01-01

Cell culture is considered the standard media used in research to emulate the in vivo cell environment. Crucial in vivo experiments cannot be conducted in humans and depend on in vitro methodologies such as cell culture systems. However, some procedures involving the quality control of cells in culture have been gradually neglected by failing to acknowledge that primary cells and cell lines change over time in culture. Thus, we report methods based on our experience for monitoring primary cell culture of human myometrial cells derived from uterine leiomyoma. We standardized the best procedure of tissue dissociation required for the study of multiple genetic marker systems that include species-specific antigens, expression of myofibroblast or myoblast markers, growth curve, serum deprivation, starvation by cell cycle synchronization, culture on collagen coated plates, and 17 β-estradiol (E2) and progesterone (P4) effects. The results showed that primary myometrial cells from patients with uterine leiomyoma displayed myoblast phenotypes before and after in vitro cultivation, and leiomyoma cells differentiated into mature myocyte cells under the appropriate differentiation-inducing conditions (serum deprivation). These cells grew well on collagen coated plates and responded to E2 and P4, which may drive myometrial and leiomyoma cells to proliferate and adhere into a focal adhesion complex involvement in a paracrine manner. The establishment of these techniques as routine procedures will improve the understanding of the myometrial physiology and pathogenesis of myometrium-derived diseases such as leiomyoma. Mimicking the in vivo environment of fibrotic conditions can prevent false results and enhance results that are based on cell culture integrity. PMID:27391384

The post-menopausal ovary displays a unique pattern of steroidogenic enzyme expression.

PubMed

Havelock, Jon C; Rainey, William E; Bradshaw, Karen D; Carr, Bruce R

2006-01-01

While menopause results in the loss of cyclic steroid production, evidence exists for persistent, albeit reduced, ovarian androgen production. In order to continue to synthesize ovarian androgens, the steroidogenic enzymes necessary for androgen biosynthesis must be present. Few studies have selectively analysed some of the steroidogenic enzymes present in the post-menopausal ovary (PMO), and a comprehensive study of this matter has never been undertaken. RNA and protein were obtained from PMO, pre-menopausal ovarian stroma, corpora lutea (CL), ovarian follicles, placenta, and myometrium. Oligonucleotide microarray analysis was performed to compare the gene expression profiles of PMO with pre-menopausal ovarian stroma. Real-time RT-PCR was performed for LH/HCG receptor (LHCGR), steroidogenic acute regulatory (StAR), cholesterol side-chain cleavage (CYP11A), 3beta-hydroxysteroid dehydrogenase type I (HSD3B1) and type II (HSD3B2, 3betaHSD), 17a-hydroxylase (CYP17), cytochrome b5 (CytB5), and aromatase (CYP19). Western blot analysis was performed for StAR, CYP11A, CYP17,and 3betaHSD. The PMO and pre-menopausal ovarian stroma had a similar pattern of steroidogenic enzyme expression. The PMO had persistent, but reduced, levels of LHCGR and most steroidogenic enzymes. CYP19 and HSD3B2 mRNA were greatly reduced in PMO in comparison with CL (50-fold and 2000-fold less respectively). HSD3B2 was not detectable in PMO by western analysis. This study supports the idea that the PMO retains some steroidogenic capacity. However, based on steroidogenic enzyme expression, the PMO has a unique pattern of steroidogenic enzyme expression that favors Delta5 steroid formation over Delta4 steroid formation.

Insulin-like growth factors and their binding proteins define specific phases of myometrial differentiation during pregnancy in the rat.

PubMed

Shynlova, Oksana; Tsui, Prudence; Dorogin, Anna; Langille, B Lowell; Lye, Stephen J

2007-04-01

While the insulin-like growth factor (IGF) system is known to regulate uterine function during the estrous cycle, there are limited data on its role in myometrial growth and development during pregnancy. To address this issue, we defined the expression of the Igf hormones (1 and 2), their binding proteins (Igfbp 1-6), and Igf1r receptor genes in pregnant, laboring, and postpartum rat myometrium by real-time PCR. IGF family genes were differentially expressed throughout gestation. Igf1 and Igfbp1 mRNA levels were upregulated during proliferative phase (Days 6-12) of rat gestation. Igfbp3 gene expression also was elevated in proliferating smooth muscle cells (SMCs) and was highest at the time of transition between proliferative and synthetic phases (Days 12-15). Igfbp6 gene expression profile paralleled plasma progesterone (P4) concentrations, peaking during the synthetic phase (Days 17-19) and decreasing thereafter. Administration of P4 at late pregnancy (starting from Day 20) to maintain elevated plasma P4 concentrations blocked the onset of labor and prevented the fall in Igfbp6 mRNA levels. In contrast, the treatment of pregnant rats with the P4 receptor antagonist RU486 on Day 19 induced preterm labor and the premature decrease of Igfbp6 gene expression. Igfbp2 gene expression was transiently upregulated during the contractile phase of gestation (Days 21-23) solely in the gravid horn of unilaterally pregnant rats, but it was not affected in P4- or RU486-treated animals, supporting a role for mechanical stretch imposed by the growing fetuses. Igfbp5 gene was induced during postpartum involution. Our results suggest the importance of the IGF system in phenotypic and functional changes of myometrial SMCs throughout gestation in preparation for labor.

Biochemical and pharmacological properties of SR 49059, a new, potent, nonpeptide antagonist of rat and human vasopressin V1a receptors.

PubMed

Serradeil-Le Gal, C; Wagnon, J; Garcia, C; Lacour, C; Guiraudou, P; Christophe, B; Villanova, G; Nisato, D; Maffrand, J P; Le Fur, G

1993-07-01

SR 49059, a new potent and selective orally active, nonpeptide vasopressin (AVP) antagonist has been characterized in several in vitro and in vivo models. SR 49059 showed high affinity for V1a receptors from rat liver (Ki = 1.6 +/- 0.2) and human platelets, adrenals, and myometrium (Ki ranging from 1.1 to 6.3 nM). The previously described nonpeptide V1 antagonist, OPC-21268, was almost inactive in human tissues at concentrations up to 100 microM. SR 49059 exhibited much lower affinity (two orders of magnitude or more) for AVP V2 (bovine and human), V1b (human), and oxytocin (rat and human) receptors and had no measurable affinity for a great number of other receptors. In vitro, AVP-induced contraction of rat caudal artery was competitively antagonized by SR 49059 (pA2 = 9.42). Furthermore, SR 49059 inhibited AVP-induced human platelet aggregation with an IC50 value of 3.7 +/- 0.4 nM, while OPC-21268 was inactive up to 20 microM. In vivo, SR 49059 inhibited the pressor response to exogenous AVP in pithed rats (intravenous) and in conscious normotensive rats (intravenous and per os) with a long duration of action (> 8 h at 10 mg/kg p.o). In all the biological assays used, SR 49059 was devoid of any intrinsic agonistic activity. Thus, SR 49059 is the most potent and selective nonpeptide AVP V1a antagonist described so far, with marked affinity, selectivity, and efficacy toward both animal and human receptors. With this original profile, SR 49059 constitutes a powerful tool for exploring the therapeutical usefulness of a selective V1a antagonist.

Effects of d- and l-limonene on the pregnant rat myometrium in vitro.

PubMed

Hajagos-Tóth, Judit; Hódi, Ágnes; Seres, Adrienn B; Gáspár, Róbert

2015-10-01

To study the effects of d- and l-limonene on pregnant rat myometrial contractility in vitro, and investigate how these effects are modified by other agents. D- and l-limonene (10(-13)-10(-8) M) caused myometrial contraction in a dose-dependent manner. Contractions of uterine rings from 22-day-pregnant rats were measured in an organ bath in the presence of d- or l-limonene (10(-13)-10(-8) M) and nifedipine (10(-8) M), tetraethyl-ammonium (10(-3) M), theophylline (10(-5) M), or paxilline (10(-5) M). Uterine cyclic adenosine monophosphate (cAMP) level was detected by enzyme immunoassay. Oxidative damage was induced by methylglyoxal (3×10(-2) M) and the alteration was measured via noradrenaline (1×10(-9) to 3×10(-5) M) -induced contractions. Pre-treatment with nifedipine (10(-8) M), tetraethylammonium (10(-3) M), and theophylline (10(-5) M) attenuated the contracting effect of d- and l-limonene, while in the presence of paxilline (10(-5) M) d- and l-limonene were ineffective. The two enantiomers decreased the myometrial cAMP level, but after paxilline pretreatment the cAMP level was not altered compared with the control value. Additionally, l-limonene (10(-6) M) diminished consequences of oxidative damage caused by methylglyoxal (3×10(-2) M) on contractility, whereas d-limonene was ineffective. Our findings suggest that l-limonene has an antioxidant effect and that both d-and l-limonene cause myometrial contraction through activation of the A2A receptor and opening of the voltage-gated Ca(2+) channel. It is possible that limonene-containing products increase the pregnant uterus contractility and their use should be avoided during pregnancy.

Electromagnetic image guidance in gynecology: prospective study of a new laparoscopic imaging and targeting technique for the treatment of symptomatic uterine fibroids.

PubMed

Galen, Donald I

2015-10-15

Uterine fibroids occur singly or as multiple benign tumors originating in the myometrium. Because they vary in size and location, the approach and technique for their identification and surgical management vary. Reference images, such as ultrasound images, magnetic resonance images, and sonohystograms, do not provide real-time intraoperative findings. Electromagnetic image guidance, as incorporated in the Acessa Guidance System, has been cleared by the FDA to facilitate targeting and ablation of uterine fibroids during laparoscopic surgery. This is the first feasibility study to verify the features and usefulness of the guidance system in targeting symptomatic uterine fibroids-particularly hard-to-reach intramural fibroids and those abutting the endometrium. One gynecologic surgeon, who had extensive prior experience in laparoscopic ultrasound-guided identification of fibroids, treated five women with symptomatic uterine fibroids using the Acessa Guidance System. The surgeon evaluated the system and its features in terms of responses to prescribed statements; the responses were analyzed prospectively. The surgeon strongly agreed (96 %) or agreed (4 %) with statements describing the helpfulness of the transducer and handpiece's dynamic animation in targeting each fibroid, reaching the fibroid quickly, visualizing the positions of the transducer and handpiece within the pelvic cavity, and providing the surgeon with confidence when targeting the fibroid even during "out-of-plane" positioning of the handpiece. The surgeon's positive user experience was evident in the guidance system's facilitation of accurate handpiece tip placement during targeting and ablation of uterine fibroids. Continued study of electromagnetic image guidance in the laparoscopic identification and treatment of fibroids is warranted. ClinicalTrials.gov Identifier: NCT01842789.

Identification of a myometrial molecular profile for dystocic labor

PubMed Central

2011-01-01

Background The most common indication for cesarean section (CS) in nulliparous women is dystocia secondary to ineffective myometrial contractility. The aim of this study was to identify a molecular profile in myometrium associated with dystocic labor. Methods Myometrial biopsies were obtained from the upper incisional margins of nulliparous women undergoing lower segment CS for dystocia (n = 4) and control women undergoing CS in the second stage who had demonstrated efficient uterine action during the first stage of labor (n = 4). All patients were in spontaneous (non-induced) labor and had received intrapartum oxytocin to accelerate labor. RNA was extracted from biopsies and hybridized to Affymetrix HuGene U133A Plus 2 microarrays. Internal validation was performed using quantitative SYBR Green Real-Time PCR. Results Seventy genes were differentially expressed between the two groups. 58 genes were down-regulated in the dystocia group. Gene ontology analysis revealed 12 of the 58 down-regulated genes were involved in the immune response. These included (ERAP2, (8.67 fold change (FC)) HLA-DQB1 (7.88 FC) CD28 (2.60 FC), LILRA3 (2.87 FC) and TGFBR3 (2.1 FC)) Hierarchical clustering demonstrated a difference in global gene expression patterns between the samples from dystocic and non-dystocic labours. RT-PCR validation was performed on 4 genes ERAP2, CD28, LILRA3 and TGFBR3 Conclusion These findings suggest an underlying molecular basis for dystocia in nulliparous women in spontaneous labor. Differentially expressed genes suggest an important role for the immune response in dystocic labor and may provide important indicators for new diagnostic assays and potential intrapartum therapeutic targets. PMID:21999197

Ultrasonographic evaluation of myometrial thickness and prediction of a successful external cephalic version.

PubMed

Buhimschi, Catalin S; Buhimschi, Irina A; Wehrum, Mark J; Molaskey-Jones, Sherry; Sfakianaki, Anna K; Pettker, Christian M; Thung, Stephen; Campbell, Katherine H; Dulay, Antonette T; Funai, Edmund F; Bahtiyar, Mert O

2011-10-01

To test the hypothesis that myometrial thickness predicts the success of external cephalic version. Abdominal ultrasonographic scans were performed in 114 consecutive pregnant women with breech singletons before an external cephalic version maneuver. Myometrial thickness was measured by a standardized protocol at three sites: the lower segment, midanterior wall, and the fundal uterine wall. Independent variables analyzed in conjunction with myometrial thickness were: maternal age, parity, body mass index, abdominal wall thickness, estimated fetal weight, amniotic fluid index, placental thickness and location, fetal spine position, breech type, and delivery outcomes such as final mode of delivery and birth weight. Successful version was associated with a thicker ultrasonographic fundal myometrium (unsuccessful: 6.7 [5.5-8.4] compared with successful: 7.4 [6.6-9.7] mm, P=.037). Multivariate regression analysis showed that increased fundal myometrial thickness, high amniotic fluid index, and nonfrank breech presentation were the strongest independent predictors of external cephalic version success (P<.001). A fundal myometrial thickness greater than 6.75 mm and an amniotic fluid index greater than 12 cm were each associated with successful external cephalic versions (fundal myometrial thickness: odds ratio [OR] 2.4, 95% confidence interval [CI] 1.1-5.2, P=.029; amniotic fluid index: OR 2.8, 95% CI 1.3-6.0, P=.008). Combining the two variables resulted in an absolute risk reduction for a failed version of 27.6% (95% CI 7.1-48.1) and a number needed to treat of four (95% CI 2.1-14.2). Fundal myometrial thickness and amniotic fluid index contribute to success of external cephalic version and their evaluation can be easily incorporated in algorithms before the procedure. III.

Postpartum Hemorrhage Treated with Gelfoam Slurry Embolization Using the Superselective Technique: Immediate Results and 1-Month MRI Follow-up

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pellerin, Olivier, E-mail: olivier.pellerin@egp.aphp.fr; Bats, Anne-Sophie; Primio, Massimiliano Di

To evaluate the efficacy and safety of superselective embolization of the uterine arteries in a postpartum hemorrhage. Between November 2004 and January 2011, a total of 44 consecutive women (median {+-} standard deviation age 34 {+-} 3 years, range 23-41 years) were referred to our institution for postpartum intractable hemorrhage management. All patients were embolized with a microcatheter that was placed deep into the uterine arteries upstream of the cervical arteries. The embolic agent was a mixture of contrast medium and 5 Multiplication-Sign 5 Multiplication-Sign 5 cm pieces of gelfoam (Gelita-Spon) modified into a gelatin emulsion as follows: rapid mixingmore » through a three-way stopcock with two 2.5-ml syringes. A 1-ml syringe was used for injection. One month after embolization, all patients underwent magnetic resonance imaging and clinical examination. Technical and clinical success was obtained in all cases. Thirty-five patients experienced bleeding related to poor retraction of the uterus, 7 patients because of a tear of the cervix and 2 because of a vaginal hematoma. Pre- and postembolization red blood cell transfusions were (mean {+-} standard deviation [SD]) 6 {+-} 1.2 (range 3-8) U and 2 {+-} 0.7 (range 2-4) U, respectively. One-month magnetic resonance imaging follow-up revealed no sign of ischemic myometrium or necrosis, and no instances of uterine rupture and no pelvic vein thrombosis. Incidental findings included two small intramyometrial hematic collections. All uterine arteries were patent via magnetic resonance angiography. Seventeen patients had concomitant fibroids, all of which appeared hypovascular. This technique permits good, safe clinical results with no marked damage to the uterine arteries or the uterus itself.« less

Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract

PubMed Central

Prunskaite-Hyyryläinen, Renata; Skovorodkin, Ilya; Xu, Qi; Miinalainen, Ilkka; Shan, Jingdong; Vainio, Seppo J.

2016-01-01

The Müllerian duct (MD) is the anlage of the oviduct, uterus and upper part of the vagina, the main parts of the female reproductive tract. Several wingless-type mouse mammary tumor virus (MMTV) integration site family member (Wnt) genes, including Wnt4, Wnt5a and Wnt7a, are involved in the development of MD and its derivatives, with Wnt4 particularly critical, since the MD fails to develop in its absence. We use, here, Wnt4EGFPCre-based fate mapping to demonstrate that the MD tip cells and the subsequent MD cells are derived from Wnt4+ lineage cells. Moreover, Wnt4 is required for the initiation of MD-forming cell migration. Application of anti-Wnt4 function-blocking antibodies after the initiation of MD elongation indicated that Wnt4 is necessary for the elongation as well, and consistent with this, cell culture wound-healing assays with NIH3T3 cells overexpressing Wnt4 promoted cell migration by comparison with controls. In contrast to the Wnt4 null embryos, some Wnt4monomeric cherry/monomeric cherry (Wnt4mCh/mCh) hypomorphic mice survived to adulthood and formed MD in ∼45% of cases. Nevertheless, the MD of the Wnt4mCh/mCh females had altered cell polarization and basement membrane deposition relative to the controls. Examination of the reproductive tract of the Wnt4mCh/mCh females indicated a poorly coiled oviduct, absence of the endometrial glands and an undifferentiated myometrium, and these mice were prone to develop a hydro-uterus. In conclusion, the results suggest that the Wnt4 gene encodes signals that are important for various aspects of female reproductive tract development. PMID:26721931

Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality

PubMed Central

Pirianov, Grisha; MacIntyre, David A; Lee, Yun; Waddington, Simon N; Terzidou, Vasso; Mehmet, Huseyin; Bennett, Phillip R

2015-01-01

Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-κB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-κB, showed that selective inhibition of NF-κB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-κB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain. PMID:26183892

Retosiban Prevents Stretch-Induced Human Myometrial Contractility and Delays Labor in Cynomolgus Monkeys.

PubMed

Aye, Irving L M H; Moraitis, Alexandros A; Stanislaus, Dinesh; Charnock-Jones, D Stephen; Smith, Gordon C S

2018-03-01

Stretch of the myometrium promotes its contractility and is believed to contribute to the control of parturition at term and to the increased risk of preterm birth in multiple pregnancies. To determine the effects of the putative oxytocin receptor (OTR) inverse agonist retosiban on (1) the contractility of human myometrial explants and (2) labor in nonhuman primates. Human myometrial biopsies were obtained at planned term cesarean, and explants were exposed to stretch in the presence and absence of a range of drugs, including retosiban. The in vivo effects of retosiban were determined in cynomolgus monkeys. Prolonged mechanical stretch promoted myometrial extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Moreover, stretch-induced stimulation of myometrial contractility was prevented by ERK1/2 inhibitors. Retosiban (10 nM) prevented stretch-induced stimulation of myometrial contractility and phosphorylation of ERK1/2. Moreover, the inhibitory effect of retosiban on stretch-induced ERK1/2 phosphorylation was prevented by coincubation with a 100-fold excess of a peptide OTR antagonist, atosiban. Compared with vehicle-treated cynomolgus monkeys, treatment with oral retosiban (100 to 150 days of gestational age) reduced the risk of spontaneous delivery (hazard ratio = 0.07, 95% confidence interval 0.01 to 0.60, P = 0.015). The OTR acts as a uterine mechanosensor, whereby stretch increases myometrial contractility through agonist-free activation of the OTR. Retosiban prevents this through inverse agonism of the OTR and, in vivo, reduced the likelihood of spontaneous labor in nonhuman primates. We hypothesize that retosiban may be an effective preventative treatment of preterm birth in high-risk multiple pregnancies, an area of unmet clinical need.

Tamoxifen-DNA adduct formation in monkey and human reproductive organs.

PubMed

Hernandez-Ramon, Elena E; Sandoval, Nicole A; John, Kaarthik; Cline, J Mark; Wood, Charles E; Woodward, Ruth A; Poirier, Miriam C

2014-05-01

The estrogen analog tamoxifen (TAM), used for adjuvant therapy of breast cancer, induces endometrial and uterine tumors in breast cancer patients. Proliferation stimulus of the uterine endometrium is likely involved in tumor induction, but genotoxicity may also play a role. Formation of TAM-DNA adducts in human tissues has been reported but remains controversial. To address this issue, we examined TAM-DNA adducts in uteri from two species of monkeys, Erythrocebus patas (patas) and Macaca fascicularis (macaque), and in human endometrium and myometrium. Monkeys were given 3-4 months of chronic TAM dosing scaled to be equivalent to the daily human dose. In the uteri, livers and brains from the patas (n = 3), and endometrium from the macaques (n = 4), TAM-DNA adducts were measurable by TAM-DNA chemiluminescence immunoassay. Average TAM-DNA adduct values for the patas uteri (23 adducts/10(8) nucleotides) were similar to those found in endometrium of the macaques (19 adducts/10(8) nucleotides). Endometrium of macaques exposed to both TAM and low-dose estradiol (n = 5) averaged 34 adducts/10(8) nucleotides. To examine TAM-DNA persistence in the patas, females (n = 3) were exposed to TAM for 3 months and to no drug for an additional month, resulting in low or non-detectable TAM-DNA in livers and uteri. Human endometrial and myometrial samples from women receiving (n = 8) and not receiving (n = 8) TAM therapy were also evaluated. Women receiving TAM therapy averaged 10.3 TAM-DNA adducts/10(8) nucleotides, whereas unexposed women showed no detectable TAM-DNA. The data indicate that genotoxicity, in addition to estrogen agonist effects, may contribute to TAM-induced human endometrial cancer.

Clinical aspects and antenatal diagnosis of invasive placenta: a review of ten-years’ experience of a multi-profile hospital in Lithuania

PubMed Central

Volochovič, Jelena; Ramašauskaitė, Diana; Šimkevičiūtė, Ramunė

2017-01-01

Background. Invasive placenta is a rare obstetrical pathology that is life-threatening to mother and child. It is important to diagnose this pathology as early as possible and to plan further optimal care of patients in order to minimize life-threatening complications. The aim of this study was to analyze the frequency of cases of invasive placenta, the peculiarities of their clinical manifestation in women who gave birth from 2006 to 2015, to evaluate diagnostic and treatment options of this pathology, and to review their changes when the level of services provided by the institution changes. Materials and methods. A retrospective study was performed of the ten-year period of 2006 to 2015. The study consisted of examining the data of medical records of a group of 14 women. Results. The incidence of invasive placenta at the secondary level hospital was 1/2170 births, 1:934 births at the tertiary level. There were only three patients (21.4%) diagnosed with invasive placenta during pregnancy at Vilnius University Hospital Santaros Klinikos Obstetrics and Gynaecology Centre. Before the surgery, pre-occlusive balloons were ushered into the internal iliac artery and inflated to reduce bleeding after the newborn delivery. The amount of blood loss in the whole group ranged from 1000 to 6500 ml (avg. 3130.7 ml). Radical treatment was given to eleven patients. Conclusion. Invasive placenta is a life-threatening condition. Tertiary-level hospitals have a greater capacity for antenatal diagnostics. Timely diagnosis of placental invasion and evaluation of the level of the myometrium damage before delivery is instrumental in planning patient care and preparing for delivery and operation. PMID:29217972

Placenta accreta is associated with decreased decidual natural killer (dNK) cells population: a comparative pilot study.

PubMed

Laban, Mohamed; Ibrahim, Eman Abdel-Salam; Elsafty, Mohammed Saeed Eldin; Hassanin, Alaa Sayed

2014-10-01

Placenta accreta is a general term describes abnormal adherent placenta to the uterine wall. When the chorionic villi invade the myometrium, the term placenta increta is appropriate. Nowadays, it is one of the increasing causes of materno-fetal morbidities and mortality. The aim of this research was to evaluate density of decidual natural killer cells (dNK, CD56+(bright)) in decidua basalis in patients with placenta accreta. We recruited 76 patients from Ain Shams Maternity Hospital between June 2012 to August 2013, they were divided into study subgroup (A) which included 10 patients who underwent cesarean hysterectomy due to unseparated placenta accreta, study subgroup (B) included 16 patients with separated placenta accreta, a comparison group included 25 patients with placenta previa and a control group included 25 patients with normally situated placenta. All patients underwent elective cesarean delivery. Decidual biopsies were taken during the operation. An immunohistochemical staining for (dNK, CD56+(bright)) and a semi quantitative scoring were done. One-way ANOVA and Fisher Exact tests were used for statistical correlation. The mean dNK cells scores were (0.4±0.5, 1.9±1, 3.3±0.5 and 3.5±0.5) for study subgroups (A), (B) comparison and control groups respectively) with a highly significant statistical difference (P<0.001). There was a significant statistical difference between study subgroups (A) and (B) P=0.002 .There was an insignificant statistical correlation between dNK scores and number of previous uterine scars (P=0.46). These findings suggest that low dNK score was associated with cases of morbidly adherent placenta accreta. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Secretory function of ovarian cells and myometrial contractions in cow are affected by chlorinated insecticides (chlordane, heptachlor, mirex) in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wrobel, Michael Hubert, E-mail: m.wrobel@pan.olszt

The aim of the study was to investigate the effect of chlordane, heptachlor and mirex, on hormonal regulation of the force of myometrial contractions. Myometrial, endometrial, granulosa and luteal cells as well as strips of myometrium from non-pregnant cows were incubated with three insecticides at environmentally relevant doses (0.1, 1 or 10 ng/ml). None of the insecticides affected the viability of studied cells. Chlordane stimulated, while heptachlor and mirex inhibited, secretion of testosterone and estradiol from granulosa cells as well as secretion of progesterone from luteal cells, respectively. Secretion of oxytocin (OT) from granulosa cells was increased after incubation withmore » all studied insecticides. Only mirex stimulated OT secretion from luteal cells, while heptachlor inhibited this effect. None of them affected synthesis of OT in luteal cells and prostaglandins (PGF2 and PGE2) secretion from uterine cells, except PGE2 secretion from endometrial cells was decreased when the cells were incubated with 0.1 ng/ml of chlordane. Basal and OT-stimulated myometrial contractions were increased by mirex and decreased by heptachlor. The data show that the insecticides altered secretory function of ovarian cells. Heptachlor and mirex affected also myometrial contractions in vitro, but uterine secretion of prostaglandins were not involved in the mechanism of that adverse effect of insecticides. The data indicate on potential of these insecticides to disturb fertilisation, blastocyst implantation or even the length of gestation. - Highlights: • The studied insecticides affected steroids and oxytocin secretion from ovaries. • Mirex stimulated bovine myometrial contractions. • Heptachlor inhibited bovine myometrial contractions. • Prostaglandins are not involved in adverse effect of the insecticides on uterine contractions.« less

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.

PubMed

Migale, Roberta; MacIntyre, David A; Cacciatore, Stefano; Lee, Yun S; Hagberg, Henrik; Herbert, Bronwen R; Johnson, Mark R; Peebles, Donald; Waddington, Simon N; Bennett, Phillip R

2016-06-13

Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies.

Co-expression of cytokeratins and vimentin by highly invasive trophoblast in the white-winged vampire bat, Diaemus youngi, and the black mastiff bat, Molossus ater, with observations on intermediate filament proteins in the decidua and intraplacental trophoblast.

PubMed

Badwaik, N K; Rasweiler, J J; Muradali, F

1998-11-01

Histological and immunocytochemical studies of gravid reproductive tracts obtained from the white-winged vampire bat (Diaemus youngi) and the black mastiff bat (Molossus ater) have established that both species develop unusually invasive trophoblast. This is released by the developing discoidal haemochorial placenta, expresses both cytokeratins and vimentin, and invades the myometrium and adjacent tissues (including the ovaries) via interstitial migration within the walls of maternal blood vessels. Hence, this trophoblast is noteworthy for the extent to which it undergoes an epithelial-mesenchymal transformation. In Molossus, it originates from the cytotrophoblastic shell running along the base of the placenta, is mononuclear, and preferentially invades maternal arterial vessels serving the discoidal placenta. This trophoblast may have a role in dilatation of these vessels when the discoidal placenta becomes functional. In Diaemus, the highly invasive trophoblast appears to originate instead from a layer of syncytiotrophoblast on the periphery of the placenta is multinucleated, and vigorously invades both arterial and venous vessels. During late pregnancy, it becomes extensively branched and sends attenuated processes around many of the myometrial smooth muscle fibres. In view of its distribution, this trophoblast could have important influences upon myometrial contractility and the function of blood vessels serving the gravid tract. Other aspects of intermediate filament expression in the uteri and placentae of these bats are also noteworthy. Many of the decidual giant cells in Molossus co-express cytokeratins and vimentin, while the syncytiotrophoblast lining the placental labyrinth in Diaemus late in pregnancy expresses little cytokeratin.

Early ovarian cancer surgery with indocyanine-green-guided targeted compartmental lymphadenectomy (TCL, pelvic part).

PubMed

Kimmig, Rainer; Buderath, Paul; Rusch, Peter; Mach, Pawel; Aktas, Bahriye

2017-09-01

Para-aortic indocyanine-green (ICG)-guided targeted compartmental lymphadenectomy is feasible in early ovarian cancer; systematic pelvic and para-aortic lymphadenectomy could potentially be avoided if thoroughly investigated sentinel nodes could predict whether residual nodes will be involved or free of disease. In contrast to advanced ovarian cancer, where the therapeutic potential of lymphadenectomy will soon be clarified by the results of the Arbeitsgemeinschaft Gynäkologische Onkologie lymphadenectomy in ovarian neoplasms (AGO LION) trial, systematic lymphadenectomy seems to be mandatory for diagnostic and also therapeutic purposes in early ovarian cancer. Sentinel node biopsy or resection of the regional lymphatic network may reduce morbidity compared to systematic lymphadenectomy as shown already for other entities. Apart from the ovarian mesonephric pathway, a second Müllerian uterine pathway exists for lymphatic drainage of the ovary. Lymphatic valves apparently do not exist at this level of the utero-ovarian network since injection of radioactivity into the ovarian ligaments also labelled pelvic nodes. We applied ICG using 4×0.5 mL of a 1.66 mg/mL ICG solution for transcervical injection into the fundal and midcorporal myometrium at each side [10] instead of injection into the infundibulopelvic ligament, since the utero-ovarian drainage was intact. In this case a 1.8 cm cancer of the right ovary was removed in continuity with its draining lymphatic vessels and at least the first 2 sentinel nodes in each channel "en bloc" as shown in this video for the pelvic part, consistent with the loco-regional ontogenetic approach. This could potentially avoid most of systematic lymphadenectomies in early ovarian cancer. Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology

[The uterotropismus of halothane, chloroform or methoxyflurane in clinical use (author's transl)].

PubMed

Fassolt, A; Schubiger, V; Hauser, G A

1976-11-01

To perform episiotomy, 89 women after childbirth were anaesthetized with either halothane (50 patients), methoxyflurane (24 patients) or chloroform (15 patients). The activity of the uterus was registered tocodynamographically. To examine the alternate influence of narcotics and uterotonica, 57 patients were pre-medicated with sintocinon and methergin i.m. as a prophylaxis. The second group (32 patients) received no premedication to stimulate labor activity, however in 18 cases towards the end of narcosis oxytocin and methergin were given i.v. In addition to these examinations 5 vaginal deliveries were anaesthetised with halothane only. Concerning our own experimental study it can be observed: 1. The relaxative properties of halothane wich suppresses completly the activity of myometrium during the deep stages of anaesthesia are superior to chloroform and methoxyflurane. 2. More rapid relaxation of the uterus with halothane compared with chloroform and methoxyflurane. 3. After the use of halothane a quicker return of the activity of the uterus compared with chloroform and methoxyflurane. 4. The value of a prophylaxis with uterotonica can be demonstrated by a comparatively reduced slowing-down of labour-activity during anaesthesia. 5. In every one of the cases, an interuption of the labour-suppressing, caused by the anaesthesia, can be obtained by injecting intravenously oxytocin or methergin. 6. During vaginal delivery, compared to the post placentar phase, there is no need for higher concentrations of halothane to be used to suppress labour contractions. The discussion deals with the intensity of reduction of the uterus contraction caused by the above mentioned narcotics, the dangers of the atony of the uterus, and the indications and contra-indications of obstetrical anaesthesia with halothane or methoxyflurane.

Regulation of the stimulant actions of neurokinin a and human hemokinin-1 on the human uterus: a comparison with histamine.

PubMed

Pennefather, Jocelyn N; Patak, Eva; Ziccone, Sebastian; Lilley, Alison; Pinto, Francisco M; Page, Nigel M; Story, Margot E; Grover, Sonia; Candenas, M Luz

2006-09-01

Regulation of the contractile effects of tachykinins and histamine on the human uterus was investigated with biopsy sections of the outer myometrial layer. The effects of neurokinin A (NKA) and human hemokinin-1 (hHK-1) in tissues from pregnant but not from nonpregnant women were enhanced by the inhibition of neprilysin. The effects of NKA and eledoisin were blocked by the NK2 receptor antagonist SR 48968 but not by the NK1 receptor antagonist SR 140333 in tissues from both groups of women. Human HK-1 acted as a partial agonist blocked by SR 48968 and, to a lesser extent, by SR 140333; endokinin D was inactive. In tissues from pregnant women, responses to high potassium-containing Krebs solution were 2-3-fold higher than those from nonpregnant women. Mepyramine-sensitive maximal responses to histamine were similarly enhanced. The absolute maximum responses to NKA and its stable NK2 receptor-selective analogue, [Lys5MeLeu9Nle10]NKA(4-10), were increased in pregnancy, but their efficacies relative to potassium responses were decreased. Tachykinin potencies were lower in tissues from pregnant women than in those from nonpregnant women. These data 1) show for the first time that hHK-1 is a uterine stimulant in the human, 2) confirm that the NK2 receptor is predominant in mediating tachykinin actions on the human myometrium, and 3) indicate that mammalian tachykinin effects are tightly regulated during pregnancy in a manner that would negate an inappropriate uterotonic effect. The potencies of these peptides in tissues from nonpregnant women undergoing hysterectomy are consistent with their possible role in menstrual and menopausal disorders.

Refractoriness of the gravid rat uterus to tocolytic and biochemical effects of atrial natriuretic peptide.

PubMed Central

Potvin, W.; Varma, D. R.

1990-01-01

1. Effects of atrial natriuretic peptide (ANP) on tension development, particulate guanylate cyclase activity and guanosine 3':5'-cyclic monophosphate (cyclic GMP) concentrations of uteri from oestrogen-treated, progesterone-treated, ovariectomized and pregnant rats were determined in vitro. 2. ANP inhibited the tension development by myometrial tissues from oestrogen-treated virgin rats and the sterile horn of 10 to 14 day pregnant rats but not of the uterus from pregnant and progesterone-treated rats. 3. Inhibition of cyclo-oxygenase and lipoxygenase activities did not restore the tocolytic activity of ANP on gravid uterus. ANP exerted a tocolytic effect on nongravid uterus submaximally stimulated by prostaglandin F2 alpha (PGF2 alpha), oxytocin, vasopressin, angiotensin II or 5-hydroxytryptamine (5-HT). 4. Ovariectomy decreased the tocolytic effects of ANP, which could be restored by oestrogen treatment. 5. The refractoriness to the tocolytic effect of ANP in pregnant rats was not accompanied by a decrease in its relaxant effects on isolated aortic strips. 6. Tocolytic effects of isoprenaline, isobutylmethyl xanthine and hydroxylamine were not influenced by pregnancy or progesterone treatment. Up to a concentration of 3 mM, sodium nitroprusside did not affect myometrial tension development. 7. Pregnancy and progesterone treatment markedly inhibited ANP-induced increases in myometrial particulate guanylate cyclase activity and cyclic GMP concentrations but did not influence the effects of ANP on aortic cyclic GMP concentrations. 8. It is concluded that exposure of the myometrium to circulating and placentally-produced progesterone is responsible for the pregnancy-induced decrease in the effects of ANP on myometrial particulate guanylate cyclase activity and cyclic GMP concentrations and in turn on myometrial tension development. PMID:1974161

Value of ultrasound shear wave elastography in the diagnosis of adenomyosis.

PubMed

Acar, S; Millar, E; Mitkova, M; Mitkov, V

2016-11-01

The aim of the study was to assess the accuracy of ultrasound shear wave elastography in the diagnosis of adenomyosis. One hundred and fifty three patients were examined. Ninety-seven patients were with suspected adenomyosis and 56 patients were with unremarkable myometrium. Adenomyosis was confirmed in 39 cases (A subgroup) and excluded in 14 cases (B subgroup) in the main group based on morphological examination. All patients underwent ultrasound examination using an Aixplorer (Supersonic Imagine, France) scanner with application of shear wave elastography during transvaginal scanning. Retrospective analysis of the elastography criteria against the findings from morphological/histological examination was performed. The following values of Young's modulus were found in subgroup A (adenomyosis): Emean - 72.7 (22.6-274.2) kPa (median, 5-95th percentiles), Emax - 94.8 (29.3-300.0) kPa, SD - 9.9 (2.6-26.3) kPa; in subgroup B (non adenomyosis) - 28.3 (12.7-59.5) kPa, 33.6 (16.0-80.8) kPa, 3.0 (1.4-15.6) kPa; in the control group - 24.4 (17.9-32.4) kPa, 29.8 (21.6-40.8) kPa, 2.3 (1.3-6.1) kPa, respectively (P < 0.05 for all comparison with subgroup В and the control group). The Emean cut-off value for adenomyosis diagnosis was 34.6 kPa. The sensitivity, specificity, positive predictive value, negative predictive value and area under curve (AUC) were 89.7%, 92.9%, 97.2%, 76.5% and 0.908. The Emax cut-off value was 45.4 kPa (89.7%, 92.9%, 97.2%, 76.5% and 0.907, respectively). This study showed a significant increase of the myometrial stiffness estimated with shear wave elastography use in patients with adenomyosis.

Pregnancy and labor increase the capacity of human myometrial cells to secrete parathyroid hormone-related protein.

PubMed

Shenberger, J S; Dixon, P S; Choate, J; Helal, K; Shew, R L; Barth, W

2001-02-16

Parathyroid hormone-related protein (PTHrP), a oncofetal gene product possessing smooth muscle relaxant properties, has been found in rat and human uterine smooth muscle cells (USMC) where it is postulated to regulate myometrial tone and/or blood flow. Studies investigating the gestational regulation of PTHrP in human USMC have not been performed. This study was conducted to determine if pregnancy alters the capacity of USMC to secrete or respond to PTHrP. USMC cultures were established from 8 hysterectomy specimens (H) and 7 non-laboring (NP) and 5 laboring term pregnant uterine biopsies (LP). PTHrP secretion was measured at baseline and in response to TGF-beta1 using a immunoradiometric assay. The USMC response to PTHrP was assessed by incubating cultures with human (1-34)PTHrP and measuring cellular cAMP by radioimmunoassay. We found that cultures from the groups did not differ with respect to basal PTHrP secretion. TGF-beta1, on the other hand, produced dose-dependent increases in secreted PTHrP in each group such that LP>NP>H at 12 hrs and LP>NP and H 24 hrs. Maximal responses were found at 24 hrs in cells treated with 10 ng/ml TGF-beta1 (LP: 2034+/-366 vs NP: 1485+/-427; H: 1250+/-202 fmol/mg). Incubation of cultures with PTHrP produced dose-dependent increases in cAMP production, with 10(-7) M increasing levels by 64%. Neither pregnancy nor labor significantly affected the cAMP response. These findings indicate that the human myometrium has the capacity to increase PTHrP secretion during pregnancy and labor through a TGF-beta-dependent pathway. Such findings are consistent with a role of PTHrP in enhancing uterine blood flow.

Toll-Like Receptor 4 Is an Essential Upstream Regulator of On-Time Parturition and Perinatal Viability in Mice.

PubMed

Wahid, Hanan H; Dorian, Camilla L; Chin, Peck Yin; Hutchinson, Mark R; Rice, Kenner C; Olson, David M; Moldenhauer, Lachlan M; Robertson, Sarah A

2015-10-01

An inflammatory response is instrumental in the physiological process of parturition but the upstream signals initiating inflammation are undefined. Because endogenous ligands for Toll-like receptor 4 (TLR4) are released in late gestation, we hypothesized that on-time labor requires TLR4 signaling, to trigger a cytokine and leukocyte response and accelerate the parturition cascade. In pregnant TLR4-deficient (Tlr4-/-) mice, average gestation length was extended by 13 hours and increased perinatal mortality was seen compared with wild-type controls. Quantification of cytokine and uterine activation gene expression showed that late gestation induction of Il1b, Il6, Il12b, and Tnf expression seen in control placenta and fetal membranes was disrupted in Tlr4-/- mice, and accompanied by a transient delay in expression of uterine activation genes, including prostaglandin F receptor, oxytocin receptor, and connexin-43. Leukocyte populations were altered before birth in TLR4-deficient females, with fewer neutrophils and macrophages in the placenta, and fewer dendritic cells and more regulatory T cells in the myometrium. Administration of TLR4 ligand lipopolysaccharide to pregnant wild-type mice induced cytokine expression and fetal loss, whereas Tlr4-/- pregnancies were protected. The small molecule TLR4 antagonist (+)-naloxone increased mean duration of gestation by 16 hours in wild-type mice. Collectively, these data demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Because causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in postterm pregnancy.

Toll-Like Receptor 4 Is an Essential Upstream Regulator of On-Time Parturition and Perinatal Viability in Mice

PubMed Central

Wahid, Hanan H.; Dorian, Camilla L.; Chin, Peck Yin; Hutchinson, Mark R.; Rice, Kenner C.; Olson, David M.; Moldenhauer, Lachlan M.

2015-01-01

An inflammatory response is instrumental in the physiological process of parturition but the upstream signals initiating inflammation are undefined. Because endogenous ligands for Toll-like receptor 4 (TLR4) are released in late gestation, we hypothesized that on-time labor requires TLR4 signaling, to trigger a cytokine and leukocyte response and accelerate the parturition cascade. In pregnant TLR4-deficient (Tlr4−/−) mice, average gestation length was extended by 13 hours and increased perinatal mortality was seen compared with wild-type controls. Quantification of cytokine and uterine activation gene expression showed that late gestation induction of Il1b, Il6, Il12b, and Tnf expression seen in control placenta and fetal membranes was disrupted in Tlr4−/− mice, and accompanied by a transient delay in expression of uterine activation genes, including prostaglandin F receptor, oxytocin receptor, and connexin-43. Leukocyte populations were altered before birth in TLR4-deficient females, with fewer neutrophils and macrophages in the placenta, and fewer dendritic cells and more regulatory T cells in the myometrium. Administration of TLR4 ligand lipopolysaccharide to pregnant wild-type mice induced cytokine expression and fetal loss, whereas Tlr4−/− pregnancies were protected. The small molecule TLR4 antagonist (+)-naloxone increased mean duration of gestation by 16 hours in wild-type mice. Collectively, these data demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Because causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in postterm pregnancy. PMID:26151355

Robotic surgery in complicated gynecologic diseases: experience of Tri-Service General Hospital in Taiwan.

PubMed

Tan, Shun-Jen; Lin, Chi-Kung; Fu, Pei-Te; Liu, Yung-Liang; Sun, Cheng-Chian; Chang, Cheng-Chang; Yu, Mu-Hsien; Lai, Hung-Cheng

2012-03-01

Minimally invasive surgery has been the trend in various specialties and continues to evolve as new technology develops. The development of robotic surgery in gynecology remains in its infancy. The present study reports the first descriptive series of robotic surgery in complicated gynecologic diseases in Taiwan. From March 2009 to February 2011, the records of patients undergoing robotic surgery using the da Vinci Surgical System were reviewed for patient demographics, indications, operative time, hospital stay, conversion to laparotomy, and complications. Sixty cases were reviewed in the present study. Forty-nine patients had benign gynecologic diseases, and 11 patients had malignancies. These robot-assisted laparoscopic procedures include nine hysterectomy, 15 subtotal hysterectomy, 13 myomectomy, eight staging operation, two radical hysterectomy, five ovarian cystectomy, one bilateral salpingo-oophorectomy and myomectomy, two resections of deep pelvic endometriosis, one pelvic adhesiolysis, three sacrocolpopexy and one tuboplasty. Thirty-three patients had prior pelvic surgery, and one had a history of pelvic radiotherapy. Adhesiolysis was necessary in 38 patients to complete the whole operation. Robotic myomectomy was easily accomplished in patients with huge uterus or multiple myomas. The suturing of myometrium or cervical stump after ligation of the uterine arteries minimized the blood loss. In addition, it was much easier to dissect severe pelvic adhesions. The dissection of para-aortic lymph nodes can be easily accomplished. All these surgeries were performed smoothly without ureteral, bladder or bowel injury. The present analyses include various complicated gynecologic conditions, which make the estimation of the effectiveness of robotic surgery in each situation individually not appropriate. However, our experiences do show that robotic surgery is feasible and safe for patients with complicated gynecologic diseases. Copyright © 2012. Published by Elsevier B.V.

Umbilical cord mesenchyme stem cell local intramuscular injection for treatment of uterine niche: Protocol for a prospective, randomized, double-blinded, placebo-controlled clinical trial.

PubMed

Fan, Dazhi; Wu, Shuzhen; Ye, Shaoxin; Wang, Wen; Guo, Xiaoling; Liu, Zhengping

2017-11-01

Uterine niche is defined as a triangular anechoic structure at the site of the scar or a gap in the myometrium at the site of a previous caesarean section. The main clinical manifestations are postmenstrual spotting and intrauterine infection, which may seriously affect the daily life of nonpregnant women. Trials have shown an excellent safety and efficacy for the potential of mesenchymal stem cells (MSCs) as a therapeutic option for scar reconstruction. Therefore, this study is designed to investigate the safety and efficacy of using MSCs in the treatment for the uterine niche. This phase II clinical trial is a single-center, prospective, randomized, double-blind, placebo-controlled with 2 arms. One hundred twenty primiparous participants will be randomly (1:1 ratio) assigned to receive direct intramuscular injection of MSCs (a dose of 1*10 cells in 1 mL of 0.9% saline) (MSCs group) or an identical-appearing 1 mL of 0.9% saline (placebo-controlled group) near the uterine incision. The primary outcome of this trial is to evaluate the proportion of participants at 6 months who is found uterine niche in the uterus by transvaginal utrasonography. Adverse events will be documented in a case report form. The study will be conducted at the Department of Obstetric of Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan. This trial is the first investigation of the potential for therapeutic use of MSCs for the management of uterine niche after cesarean delivery. This protocol will help to determine the efficacy and safety of MSCs treatment in uterine niche and bridge the gap with regards to the current preclinical and clinical evidence. NCT02968459 (Clinical Trials.gov: http://clinicaltrials.gov/).

Umbilical cord mesenchyme stem cell local intramuscular injection for treatment of uterine niche

PubMed Central

Fan, Dazhi; Wu, Shuzhen; Ye, Shaoxin; Wang, Wen; Guo, Xiaoling; Liu, Zhengping

2017-01-01

Abstract Background: Uterine niche is defined as a triangular anechoic structure at the site of the scar or a gap in the myometrium at the site of a previous caesarean section. The main clinical manifestations are postmenstrual spotting and intrauterine infection, which may seriously affect the daily life of nonpregnant women. Trials have shown an excellent safety and efficacy for the potential of mesenchymal stem cells (MSCs) as a therapeutic option for scar reconstruction. Therefore, this study is designed to investigate the safety and efficacy of using MSCs in the treatment for the uterine niche. Methods/design: This phase II clinical trial is a single-center, prospective, randomized, double-blind, placebo-controlled with 2 arms. One hundred twenty primiparous participants will be randomly (1:1 ratio) assigned to receive direct intramuscular injection of MSCs (a dose of 1∗107 cells in 1 mL of 0.9% saline) (MSCs group) or an identical-appearing 1 mL of 0.9% saline (placebo-controlled group) near the uterine incision. The primary outcome of this trial is to evaluate the proportion of participants at 6 months who is found uterine niche in the uterus by transvaginal utrasonography. Adverse events will be documented in a case report form. The study will be conducted at the Department of Obstetric of Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan. Discussion: This trial is the first investigation of the potential for therapeutic use of MSCs for the management of uterine niche after cesarean delivery. Conclusion: This protocol will help to determine the efficacy and safety of MSCs treatment in uterine niche and bridge the gap with regards to the current preclinical and clinical evidence. Trial registration number: NCT02968459 (Clinical Trials.gov: http://clinicaltrials.gov/). PMID:29095305

Prevalence, potential risk factors for development and symptoms related to the presence of uterine niches following Cesarean section: systematic review.

PubMed

Bij de Vaate, A J M; van der Voet, L F; Naji, O; Witmer, M; Veersema, S; Brölmann, H A M; Bourne, T; Huirne, J A F

2014-04-01

To review systematically the medical literature reporting on the prevalence of a niche at the site of a Cesarean section (CS) scar using various diagnostic methods, on potential risk factors for the development of a niche and on niche-related gynecological symptoms in non-pregnant women. The PubMed and EMBASE databases were searched. All types of clinical study reporting on the prevalence, risk factors and/or symptoms of a niche in non-pregnant women with a history of CS were included, apart from case reports and case series. Twenty-one papers were selected for inclusion in the review. A wide range in the prevalence of a niche was found. Using contrast-enhanced sonohysterography in a random population of women with a history of CS, the prevalence was found to vary between 56% and 84%. Nine studies reported on risk factors and each study evaluated different factors, which made it difficult to compare studies. Risk factors could be classified into four categories: those related to closure technique, to development of the lower uterine segment or location of the incision or to wound healing, and miscellaneous factors. Probable risk factors are single-layer myometrium closure, multiple CSs and uterine retroflexion. Six out of eight studies that evaluated niche-related symptoms described an association between the presence of a niche and postmenstrual spotting. The reported prevalence of a niche in non-pregnant women varies depending on the method of detection, the criteria used to define a niche and the study population. Potential risk factors can be categorized into four main categories, which may be useful for future research and meta-analyses. The predominant symptom associated with a niche is postmenstrual spotting. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Investigation of uterotonic properties of Ananas comosus extracts.

PubMed

Monji, Faezeh; Adaikan, P Ganesan; Lau, Lang Chu; Bin Said, Baharudin; Gong, Yinhan; Tan, Huey Min; Choolani, Mahesh

2016-12-04

In folklore medicine Ananas comosus (pineapple) is reputed to act as an abortifacient and in expectant women as a means of inducing labor. Several reports have claimed abortifacient property of A. comosus fruit (ripe or unripe). Ripe fruit has been used orally as traditional medicine in inducing abortion in Kerala state of India while the juice of unripe fruit was used for abortion in Bangladesh. However, scientific evidence supporting the efficacy of pineapple extracts in inducing uterine contractions is clearly lacking. This study investigated the pharmacological effects of different fractions of pineapple extract with a range of maturities to identify the most potent uterotonic fraction. The ethanolic crude extracts of pineapple (edible part) were prepared and fractionated through a series of liquid-liquid partitions. Fractions were separately tested on isolated uterine muscle from pregnant SD rats and human pregnant myometrium, which were cut into strips along the longitudinal axis of uterus. The strips were mounted vertically in organ baths (37°C) and exposed to cumulative addition of fractions (0.1-10mgml -1 ), serotonin (0.05-5µM) and different inhibitors to delineate the mechanism of action of the active ingredients of the extract. Aqueous fraction (F4) possesses uterine stimulant property which was blocked by verapamil but unaffected by indomethacin, prazosin and atosiban. Notably, ketanserin (10µM) diminished the maximal contractile response induced by both F4 and 5HT by 74.3% and 92.1% respectively. These results may indicate the presence of 5HT or 5HT-like compound(s) and serotonergic pathways may contribute to the uterotonic activity of pineapple extract. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Endometrial Stromal Sarcoma of the Uterus: Magnetic Resonance Imaging Findings Including Apparent Diffusion Coefficient Value and Its Correlation With Ki-67 Expression.

PubMed

Li, Hai Ming; Liu, Jia; Qiang, Jin Wei; Gu, Wei Yong; Zhang, Guo Fu; Ma, Feng Hua

2017-11-01

This study aimed to investigate the conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) features of endometrial stromal sarcoma (ESS) including a preliminary investigation of the correlation between the apparent diffusion coefficient (ADC) value and Ki-67 expression. The clinical and MRI data of 15 patients with ESS confirmed by surgery and pathology were analyzed retrospectively. The conventional MR morphological features, signal intensity on DWI, ADC value (n = 14), and clinicopathological marker Ki-67 (n = 13) were evaluated. Of 15 patients with ESS, 13 tumors were low-grade ESS (LGESS), and the remaining 2 were high-grade ESS (HGESS); 9 tumors were located in the myometrium, 5 were located in the endometrium and/or cervical canal, and 1 was located in extrauterine. Thirteen (87%) of 15 tumors showed a homo- or heterogeneous isointensity on T1-weighted imaging and a heterogeneous hyperintensity on T2-weighted imaging. The hypointense bands were observed in 11 tumors (73%) on T2-weighted imaging. The degenerations (cystic/necrosis/hemorrhage) were observed in 7 LGESS tumors and 2 HGESS tumors. The DWI hyperintensity was observed in 13 tumors (93%) and isointensity in remaining 1. The mean ADC value of the solid components in 14 ESSs was (1.05 ± 0.20) × 10mm/s. The contrast-enhanced MRI showed an obvious enhancement in 14 tumors (93%) (heterogeneous in 7 LGESSs and 2 HGESSs; homogeneous in 5 LGESSs). The ADC value was inversely correlated with the Ki-67 expression (r = -0.613, P = 0.026). Patients with ESS showed some characteristics on conventional MRI and DWI, and there was an inverse correlation between the ADC value and Ki-67 expression.

Novel orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium

PubMed Central

Catherino, William H.; Malik, Minnie; Driggers, Paul; Chappel, Scott; Segars, James; Davis, Joseph

2012-01-01

Context Uterine leiomyomas are highly prevalent and often symptomatic. Current medical therapies are limited. A novel, potent, selective, orally active therapy is needed. Objective and Methods To determine the progesterone receptor (PR) specificity and activation, endometrial response, and impact on proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947 in human immortalized leiomyoma and patient-matched myometrial cells. Receptor binding in vitro was assessed using LNCaP, Ishikawa, T-47D, and HeLa cell extracts for AR, ER-α, PR, and GR, respectively. Progestational activity assessed by alkaline phosphatase assay in T47D cells and ER-α expression in human leiomyoma and myometrial cells. In vivo progestational activity assayed by the McPhail assay. Proliferation and gene expression studies (q RT-PCR and western blot) were performed in immortalized leiomyoma and myometrial cells. Results Both CP8863 and CP8947 is highly selective for PR but not for ER-α, AR, and GR. Both induced alkaline phosphatase comparably to progesterone, while CP8947 induced ER-α in leiomyoma cells but not myometrial cells. CP8947 was progestational in rabbit endometrium. Nanomolar CP8947 treatment inhibited human leiomyoma but not myometrial cell proliferation. The decreased proliferation correlated with increased TRAIL and caspase -7, suggesting induction of apoptosis in leiomyoma cells. ECM components were decreased in leiomyoma cells, including COL1A1 and COL7A1 at nanomolar concentrations. Conclusions CP8947 was a potent novel non-steroidal SPRM that was selective for PR, showed progestational activity in endometrium, inhibited leiomyoma cell proliferation (potentially via induction of apoptosis), and decreased ECM component production, without disrupting myometrial cell proliferation. PMID:20493256

Levothyroxine treatment generates an abnormal uterine contractility patterns in an in vitro animal model.

PubMed

Corriveau, Stéphanie; Blouin, Simon; Raiche, Évelyne; Nolin, Marc-Antoine; Rousseau, Éric; Pasquier, Jean-Charles

2015-12-01

Abnormal uterine contraction patterns were recently demonstrated in uterine strips from pregnant women treated with Levothyroxine (T4). These abnormalities were correlated with an increased risk of C-section delivery and associated surgical complications. To date, no study has investigated whether uterine contractility is modified by hypothyroidism or T4 treatment. Herein, we analyze the physiological role of T4 on uterine contractions. Female non-pregnant Sprague-Dawley rats ( N  = 22) were used and divided into four groups: 1) control, 2) hypothyroidism, 3) hypothyroidism treated with low T4 doses (20 μg/kg/day) and 4) with high T4 doses (100 μg/kg/day). Hypothyroidism was induced by an iodine-deficient diet. Isometric tension measurements were performed in vitro on myometrium tissues in isolated organ baths. Contractile activity parameters were quantified (amplitude, duration, frequency and area under the curve) using pharmacological tools to assess their effect. Screening of thyroid function confirmed a hypothyroid state for all rats under iodine-free diet to which T4 was subsequently administered to counterbalance hypothyroidism. Results demonstrate that hypothyroidism significantly decreased contractile duration (-17%) and increased contractile frequency (+26%), while high doses of T4 increased duration (+200%) and decreased frequency (-51%). These results thus mimic the pattern of abnormal contractions previously observed in uterine tissue from T4-treated hypothyroid pregnant women. Our data suggest that changes in myometrial reactivity are induced by T4 treatment. Thus, in conjunction with our previous observations on human myometrial strips, management of hypothyroidism should be improved to reduce the rate of C-sections in this group of patients.

The Local and Systemic Immune Response to Intrauterine LPS in the Prepartum Mouse1

PubMed Central

Edey, Lydia F.; O'Dea, Kieran P.; Herbert, Bronwen R.; Hua, Renyi; Waddington, Simon N.; MacIntyre, David A.; Bennett, Philip R.; Takata, Masao; Johnson, Mark R.

2016-01-01

Inflammation plays a key role in human term and preterm labor (PTL). Intrauterine LPS has been widely used to model inflammation-induced complications of pregnancy, including PTL. It has been shown to induce an intense myometrial inflammatory cell infiltration, but the role of LPS-induced inflammatory cell activation in labor onset and fetal demise is unclear. We investigated this using a mouse model of PTL, where an intrauterine injection of 10 μg of LPS (serotype 0111:B4) was given at E16 of CD1 mouse pregnancy. This dose induced PTL at an average of 12.7 h postinjection in association with 85% fetal demise. Flow cytometry showed that LPS induced a dramatic systemic inflammatory response provoking a rapid and marked leucocyte infiltration into the maternal lung and liver in association with increased cytokine levels. Although there was acute placental inflammatory gene expression, there was no corresponding increase in fetal brain inflammatory gene expression until after fetal demise. There was marked myometrial activation of NFκB and MAPK/AP-1 systems in association with increased chemokine and cytokine levels, both of which peaked with the onset of parturition. Myometrial macrophage and neutrophil numbers were greater in the LPS-injected mice with labor onset only; prior to labor, myometrial neutrophils and monocytes numbers were greater in PBS-injected mice, but this was not associated with an earlier onset of labor. These data suggest that intrauterine LPS induces parturition directly, independent of myometrial inflammatory cell infiltration, and that fetal demise occurs without fetal inflammation. Intrauterine LPS provokes a marked local and systemic inflammatory response but with limited inflammatory cell infiltration into the myometrium or placenta. PMID:27760748

High-Throughput Screening of Myometrial Calcium-Mobilization to Identify Modulators of Uterine Contractility

PubMed Central

Herington, Jennifer L.; Swale, Daniel R.; Brown, Naoko; Shelton, Elaine L.; Choi, Hyehun; Williams, Charles H.; Hong, Charles C.; Paria, Bibhash C.; Denton, Jerod S.; Reese, Jeff

2015-01-01

The uterine myometrium (UT-myo) is a therapeutic target for preterm labor, labor induction, and postpartum hemorrhage. Stimulation of intracellular Ca2+-release in UT-myo cells by oxytocin is a final pathway controlling myometrial contractions. The goal of this study was to develop a dual-addition assay for high-throughput screening of small molecular compounds, which could regulate Ca2+-mobilization in UT-myo cells, and hence, myometrial contractions. Primary murine UT-myo cells in 384-well plates were loaded with a Ca2+-sensitive fluorescent probe, and then screened for inducers of Ca2+-mobilization and inhibitors of oxytocin-induced Ca2+-mobilization. The assay exhibited robust screening statistics (Z´ = 0.73), DMSO-tolerance, and was validated for high-throughput screening against 2,727 small molecules from the Spectrum, NIH Clinical I and II collections of well-annotated compounds. The screen revealed a hit-rate of 1.80% for agonist and 1.39% for antagonist compounds. Concentration-dependent responses of hit-compounds demonstrated an EC50 less than 10μM for 21 hit-antagonist compounds, compared to only 7 hit-agonist compounds. Subsequent studies focused on hit-antagonist compounds. Based on the percent inhibition and functional annotation analyses, we selected 4 confirmed hit-antagonist compounds (benzbromarone, dipyridamole, fenoterol hydrobromide and nisoldipine) for further analysis. Using an ex vivo isometric contractility assay, each compound significantly inhibited uterine contractility, at different potencies (IC50). Overall, these results demonstrate for the first time that high-throughput small-molecules screening of myometrial Ca2+-mobilization is an ideal primary approach for discovering modulators of uterine contractility. PMID:26600013

Progesterone and gravidity differentially regulate expression of extracellular matrix components in the pregnant rat myometrium.

PubMed

Shynlova, Oksana; Mitchell, Jennifer A; Tsampalieros, Anne; Langille, B Lowell; Lye, Stephen J

2004-04-01

Myometrial growth and remodeling during pregnancy depends on increased synthesis of interstitial matrix proteins. We hypothesize that the presence of mechanical tension in a specific hormonal environment regulates the expression of extracellular matrix (ECM) components in the uterus. Myometrial tissue was collected from pregnant rats on Gestational Days 0, 12, 15, 17, 19, 21, 22, 23 (labor), and 1 day postpartum and ECM expression was analyzed by Northern blotting. Expression of fibronectin, laminin beta2, and collagen IV mRNA was low during early gestation but increased dramatically on Day 23 during labor. Expression of fibrillar collagens (type I and III) peaked Day 19 and decreased near term. In contrast, elastin mRNA remained elevated from midgestation onward. Injection of progesterone (P4) on Days 20-23 (to maintain elevated plasma P4 levels) delayed the onset of labor, caused dramatic reductions in the levels of fibronectin and laminin mRNA, and prevented the fall of collagen III mRNA levels on Day 23. Treatment of pregnant rats with the progesterone receptor antagonist RU486 on Day 19 induced preterm labor on Day 20 and a premature increase in mRNA levels of collagen IV, fibronectin, and laminin. Analysis of the uterine tissue from unilaterally pregnant rats revealed that most of the changes in ECM gene expression occurred specifically in the gravid horn. Our results show a decrease in expression of fibrillar collagens and a coordinated temporal increase in expression of components of the basement membrane near term associated with decreased P4 and increased mechanical tension. These ECM changes contribute to myometrial growth and remodeling during late pregnancy and the preparation for the synchronized contractions of labor.

Genistein promotes DNA demethylation of the steroidogenic factor 1 (SF-1) promoter in endometrial stromal cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsukura, Hiroshi, E-mail: hmatsukura.epi@mri.tmd.ac.jp; Aisaki, Ken-ichi; Igarashi, Katsuhide

2011-08-26

Highlights: {yields} Genistein (GEN) is a phytoestrogen found in soy products. {yields} GEN demethylated/unsilenced the steroidogenic factor 1 gene in endometrial tissue. {yields} GEN thus altered mRNA expression in uteri of ovariectomized (OVX) mice. {yields} A high-resolution melting assay was used to screen for epigenetic change. {yields} We isolated an endometrial cell clone that was epigenetically modulated by GEN. -- Abstract: It has recently been demonstrated that genistein (GEN), a phytoestrogen in soy products, is an epigenetic modulator in various types of cells; but its effect on endometrium has not yet been determined. We investigated the effects of GEN onmore » mouse uterine cells, in vivo and in vitro. Oral administration of GEN for 1 week induced mild proliferation of the endometrium in ovariectomized (OVX) mice, which was accompanied by the induction of steroidogenic factor 1 (SF-1) gene expression. GEN administration induced demethylation of multiple CpG sites in the SF-1 promoter; these sites are extensively methylated and thus silenced in normal endometrium. The GEN-mediated promoter demethylation occurred predominantly on the luminal side, as opposed to myometrium side, indicating that the epigenetic change was mainly shown in regenerated cells. Primary cultures of endometrial stromal cell colonies were screened for GEN-mediated alterations of DNA methylation by a high-resolution melting (HRM) method. One out of 20 colony-forming cell clones showed GEN-induced demethylation of SF-1. This clone exhibited a high proliferation capacity with continuous colony formation activity through multiple serial clonings. We propose that only a portion of endometrial cells are capable of receiving epigenetic modulation by GEN.« less

Pathologic features of uteri and leiomyomas following uterine artery embolization for leiomyomas.

PubMed

Colgan, Terence J; Pron, Gaylene; Mocarski, Eva J M; Bennett, John D; Asch, Murray R; Common, Andrew

2003-02-01

The objectives of this study were to identify the presence/absence and location of any embolic material and to describe the morphologic appearance of the leiomyoma and adjacent tissues of cases undergoing surgical intervention following uterine artery embolization (UAE) for leiomyomas. A total of 555 women underwent UAE using polyvinyl alcohol particles (PVA) in a multicenter clinical trial. The histopathologic slides from 17 of 18 women who subsequently underwent myomectomy or hysterectomy in the follow-up period (median 8.2 months) were reviewed without knowledge of the indication for surgery or time elapsed since UAE. The presence/absence and distribution of PVA emboli, associated inflammatory response, and necrosis were noted. Necrosis of leiomyoma(s) was classified as hyaline-type, coagulative tumor cell necrosis, and/or acute suppurative necrosis. In all cases PVA emboli were identified within smooth muscle tumors of the uterine body, its periphery, cervix, uterine body, myometrium, and/or the adnexa. A florid foreign body giant cell type of chronic inflammatory reaction was seen within 1 week of UAE and persisted with visible PVA for up to 14 months post-UAE. Typically, post-UAE leiomyomas showed hyaline-type, but rarely coagulative tumor cell necrosis and acute suppurative necrosis could be seen as well. Five of eight cases coming to surgery for complications showed necrotizing endomyometritis with tissue infarction. PVA particles are recognizable in post-UAE specimens. Leiomyoma necrosis is typically of the hyaline type; coagulative tumor cell necrosis was rarely seen. In some cases with complications, uterine and/or cervical necrosis occurred. The applicability of these findings for UAE patients who have been successfully treated and not resected is uncertain.

Dose-dependent effects and reversibility of the injuries caused by nandrolone decanoate in uterine tissue and fertility of rats.

PubMed

Belardin, Larissa Berloffa; Simão, Vinícius Augusto; Leite, Gabriel Adan Araújo; Chuffa, Luiz Gustavo de Almeida; Camargo, Isabel Cristina Cherici

2014-04-01

This study is the first to investigate the effects of different doses of nandrolone decanoate (ND) upon uterine tissue and fertility, and if the reproductive alterations can be restored after cessation of the treatment. Wistar female rats were treated with ND at doses of 1.87, 3.75, 7.5, and 15 mg/kg body weight, diluted in vehicle (n = 30/group), or received only mineral oil (control group, n = 45). The animals were divided into three periods of study: ND-treated receiving a daily subcutaneous injection for 15 consecutive days (1), and treatment with ND followed by 30-day recovery (2), and 60-day recovery (3). At the end of each period, five females per group were induced to death to histopathological analysis and the others were allowed to fertility evaluation (at 19th gestational day). Animals that received ND followed by 30-day recovery exhibited persistent diestrous and marked suppression of reproductive capacity. Conversely, after 60-day recovery, only lowest doses females (1.87 and 3.75 mg/kg) exhibited restoration of normal estrous cyclicity. Uterine weights were increased after ND treatment similarly to that of the controls after 60-day recovery. The ND-treated groups showed histopathological changes in the endometrium, myometrium, and perimetrium, and an increase in the thickness of both muscular and serous layers. Notably, the recovery of uterine tissue after ND treatment was dose- and period-dependent. We reported that administration of ND promoted damage in uterine tissue and fertility of rats, and the recovery periods were insufficient to restore all of the side effects caused by ND under a dose-dependent response. © 2014 Wiley Periodicals, Inc.

Maternal obesogenic diet induces endometrial hyperplasia, an early hallmark of endometrial cancer, in a diethylstilbestrol mouse model.

PubMed

Owuor, Theresa O; Reid, Michaela; Reschke, Lauren; Hagemann, Ian; Greco, Suellen; Modi, Zeel; Moley, Kelle H

2018-01-01

Thirty-eight percent of US adult women are obese, meaning that more children are now born of overweight and obese mothers, leading to an increase in predisposition to several adult onset diseases. To explore this phenomenon, we developed a maternal obesity animal model by feeding mice a diet composed of high fat/ high sugar (HF/HS) and assessed both maternal diet and offspring diet on the development of endometrial cancer (ECa). We show that maternal diet by itself did not lead to ECa initiation in wildtype offspring of the C57Bl/6J mouse strain. While offspring fed a HF/HS post-weaning diet resulted in poor metabolic health and decreased uterine weight (regardless of maternal diet), it did not lead to ECa. We also investigated the effects of the maternal obesogenic diet on ECa development in a Diethylstilbestrol (DES) carcinogenesis mouse model. All mice injected with DES had reproductive tract lesions including decreased number of glands, condensed and hyalinized endometrial stroma, and fibrosis and increased collagen deposition that in some mice extended into the myometrium resulting in extensive disruption and loss of the inner and outer muscular layers. Fifty percent of DES mice that were exposed to maternal HF/HS diet developed several features indicative of the initial stages of carcinogenesis including focal glandular and atypical endometrial hyperplasia versus 0% of their Chow counterparts. There was an increase in phospho-Akt expression in DES mice exposed to maternal HF/HS diet, a regulator of persistent proliferation in the endometrium, and no difference in total Akt, phospho-PTEN and total PTEN expression. In summary, maternal HF/HS diet exposure induces endometrial hyperplasia and other precancerous phenotypes in mice treated with DES. This study suggests that maternal obesity alone is not sufficient for the development of ECa, but has an additive effect in the presence of a secondary insult such as DES.

Periparturient stress and immune suppression as a potential cause of retained placenta in highly productive dairy cows: examples of prevention.

PubMed

Mordak, Ryszard; Stewart, Peter Anthony; Anthony, Stewart Peter

2015-12-02

The immune system during the periparturient period is impaired. At this time the most important factor causing immune-suppression in highly productive cows is metabolic stress resulting from hormonal and metabolic fluctuations, a negative energy balance, shortage of proteins, minerals and vitamins which are required to meet the demands of the fetus as well as the onset of lactation. This stress can activate the hypothalamic-pituitary-adrenocortical axis (HPA), which results in increase plasma corticosteroids. As a result, the cortisol concentration during the periparturient period increases by several folds particularly on the day of calving. Cortisol is a powerful immune-suppressive agent. During stress, this hormone causes depression of the leukocyte proliferation and their functions. Decreased phagocytosis of neutrophils, decreased cytotoxic ability of lymphocytes, as well as depressed activity of their cytokines, make it impossible for the normal, efficient maternal immune recognition and rejection of fetal membranes (as a foreign, allogeneic tissue expressed fetal antigens-MHC class I proteins by trophoblast cells) and finally results in their retention in cows. The metabolic periparturient stress also activates production of catecholamines, especially adrenalin. Adrenalin activates adrenoreceptors of the myometrium and then causes hypotony or atony of the uterus. Thus, cortisol and adrenalin inhibit rejection and expulsion of fetal membranes and cause their retention. These mechanisms of retained placenta (RP) often have a metabolic etiology and occur in herds, where important infectious diseases causing placentitis are absent or prevented. The aim of this article is to show the fundamental mechanisms occurring during periparturient stress and the accompanied immune-suppression in cows, as well as their consequences in relation to RP. The paper also gives examples of the symptomatic prevention of RP in cows caused by metabolic and immune suppressive factors. The prevention of RP was carried out using drugs which inhibit the activity of cortisol or adrenalin in dairy cows during calving.

The value of specific MRI features in the evaluation of suspected placental invasion.

PubMed

Lax, Allison; Prince, Martin R; Mennitt, Kevin W; Schwebach, J Reid; Budorick, Nancy E

2007-01-01

The objective of this study was to determine imaging features that may help predict the presence of placenta accreta, placenta increta or placenta percreta on prenatal MRI scanning. A retrospective review of the prenatal MR scans of 10 patients with a diagnosis of placenta accreta, placenta increta or placenta percreta made by pathologic and clinical reports and of 10 patients without placental invasion was performed. Two expert MRI readers were blinded to the patients' true diagnosis and were asked to score a total of 17 MRI features of the placenta and adjacent structures. The interrater reliability was assessed using kappa statistics. The features with a moderate kappa statistic or better (kappa > .40) were then compared with the true diagnosis for each observer. Seven of the scored features had an interobserver reliability of kappa > .40: placenta previa (kappa = .83); abnormal uterine bulging (kappa = .48); intraplacental hemorrhage (kappa = .51); heterogeneity of signal intensity on T2-weighted (T2W) imaging (kappa = .61); the presence of dark intraplacental bands on T2W imaging (kappa = .53); increased placental thickness (kappa = .69); and visualization of the myometrium beneath the placenta on T2W imaging (kappa = .44). Using Fisher's two-sided exact test, there was a statistically significant difference between the proportion of patients with placental invasion and those without placental invasion for three of the features: abnormal uterine bulging (Rater 1, P = .005; Rater 2, P = .011); heterogeneity of T2W imaging signal intensity (Rater 1, P = .006; Rater 2, P = .010); and presence of dark intraplacental bands on T2W imaging (Rater 1, P = .003; Rater 2, P = .033). MRI can be a useful adjunct to ultrasound in diagnosing placenta accreta prenatally. Three features that are seen on MRI in patients with placental invasion appear to be useful for diagnosis: uterine bulging; heterogeneous signal intensity within the placenta; and the presence of dark intraplacental bands on T2W imaging.

Mechanisms underlying aberrant expression of miR-29c in uterine leiomyoma.

PubMed

Chuang, Tsai-Der; Khorram, Omid

2016-01-01

To determine the expression of miR-29c and its target genes in leiomyoma and the role of NF-κB, specific protein 1 (SP1), and DNA methylation in its regulation. Experimental study. Academic research laboratory. Women undergoing hysterectomy for leiomyoma. Over- and underexpression of miR-29c; blockade of transcription factors. MiR-29c and its target gene levels in leiomyoma and the effects of blockade of transcription factors on miR-29c expression. Leiomyoma as compared with myometrium expressed significantly lower levels of miR-29c, with an inverse relationship with expression of its targets, COL3A1 and DNMT3A. Gain of function of miR-29c inhibited the expression of COL3A1 and DNMT3A at protein and mRNA levels, secreted COL3A1, and rate of cell proliferation. Loss of function of miR-29c had the opposite effect. E2, P, and their combination inhibited miR-29c in leiomyoma smooth muscle cells (LSMC). Phosphorylated NF-κB (p65) and SP1 protein expression were significantly increased in leiomyoma. SiRNA knockdown of SP1 and DNMT3A or their specific inhibitors significantly increased the expression of miR-29c, accompanied by the inhibition of cellular and secreted COL3A1 in siRNA-treated cells. Knockdown of p65 also induced miR-29c expression but had no effect on COL3A1 expression. MiR-29c expression is suppressed in leiomyoma, resulting in an increase in expression of its targets COL3A1 and DNMT3A. The suppression of miR-29c in LSMC is primarily mediated by SP1, NF-κB signaling, and epigenetic modification. Collectively, these results indicate a significant role for miR-29c in leiomyoma pathogenesis. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Strategy for laparoscopic cervical myomectomy.

PubMed

Matsuoka, Shozo; Kikuchi, Iwaho; Kitade, Mari; Kumakiri, Jun; Kuroda, Keiji; Tokita, Sachiko; Kuroda, Masako; Takeda, Satoru

2010-01-01

Myoma of the uterine cervix is rare, accounting for about 5% of all myomas. Compared with myomas that occur in the uterine corpus, cervical myomas are closer to other organs such as the bladder, ureter, and rectum, and the approach needs to be modified because the organs that have to be considered differ depending on the location of the myoma. We divided cervical myomas into 2 types according to location, comprising an intracervical type and extracervical types. A clear outline of surgical treatment for cervical myoma has not described in previous papers. We then investigated the surgical strategy for these types. Subjects comprised 16 patients who were diagnosed with cervical myoma in our hospital between January 2005 and April 2009, and who underwent laparoscopic myomectomy. Mean operative time was 105.8 + or - 43.2 (82.8-128.8) min, mean blood loss was 105 + or - 117 (42.6-167.4) ml, and mean specimen weight was 208.3 + or - 195.4 (99.3-306.2) g. Histopathological examination showed atypical myoma in 1 case and leiomyoma in others. 16 cases of cervical myomectomy were performed safely by developing a uniform strategy that uses a fixed operative procedure, even with laparotomy, if sufficient attention is paid to the following 6 points: 1) attempting to reduce the size of the myoma with the use of preoperative GnRH; 2) determining the positional relationship between the myoma and surrounding organs; 3) temporarily blocking uterine artery blood flow with the use of vessel clips; 4) suppressing bleeding during myomectomy with the use of vasopressin; 5) minimizing the risk of damaging surrounding organs by positioning the incision in the myometrium somewhat lateral to the uterine corpus; and 6) the bottom of the wound after enculation should be pulled up by the forceps for suturing to avoid making dead space. Copyright 2010 AAGL. Published by Elsevier Inc. All rights reserved.

Cytologic, hormonal, and ultrasonographic correlates of the menstrual cycle of the New World monkey Cebus apella.

PubMed

Ortiz, R E; Ortiz, A C; Gajardo, G; Zepeda, A J; Parraguez, V H; Ortiz, M E; Croxatto, H B

2005-07-01

Few reports on the reproductive physiology of Cebus apella have been published. In this study we characterized menstrual cycle events by means of vaginal cytology, ultrasonography (US), and hormonal measurements in serum during three consecutive cycles in 10 females, and assessed the probability that ovulation would occur in the same ovary in consecutive cycles in 18 females. The lengths and phases of the cycles were determined according to vaginal cytology. Taking the first day of endometrial bleeding as the first day of the cycle, the mean cycle length +/- SEM was 19.5+/-0.4 days, with follicular and luteal phases lasting 8.2+/-0.2 and 11.3+/-0.4 days, respectively. The follicular phase included menstruation and the periovulatory period, which was characterized by the presence of a large number of superficial eosinophilic cells in the vaginal smear. The myometrium, endometrium, and ovaries were clearly distinguished on US examination. During each menstrual cycle a single follicle was recruited at random from either ovary. The follicle grew from 3 mm to a maximum diameter of 8-9 mm over the course of 8 days, in association with increasing estradiol (E(2)) serum levels (from 489+/-41 to 1600+/-92 pmol/L). At ovulation, the mean diameter of the dominant follicle usually decreased by >20%, 1 day after the maximum E(2) level was reached. Ovulation was associated with an abrupt fall in E(2), a decreased number of eosinophilic cells, the presence of leukocytes and intermediate cells in the vaginal smear, and a progressive increase in progesterone (P) levels that reached a maximum of 892+/-65 nmol/L on days 3-6 of the luteal phase. The menstrual cycle of Cebus apella differs in several temporal and quantitative aspects from that in humans and Old World primates, but it exhibits the same correlations between ovarian endocrine and morphologic parameters. (c) 2005 Wiley-Liss, Inc.

Diffusion-weighted magnetic resonance imaging using different b-value combinations for the evaluation of treatment results after volumetric MR-guided high-intensity focused ultrasound ablation of uterine fibroids.

PubMed

Ikink, Marlijne E; Voogt, Marianne J; van den Bosch, Maurice A A J; Nijenhuis, Robbert J; Keserci, Bilgin; Kim, Young-sun; Vincken, Koen L; Bartels, Lambertus W

2014-09-01

To assess the value of diffusion-weighted magnetic resonance imaging (DWI) and apparent diffusion coefficient (ADC) mapping using different b-value combinations for treatment evaluation after magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) of uterine fibroids. Fifty-six patients with 67 uterine fibroids were treated with volumetric MR-HIFU. Pre-treatment and post-treatment images were obtained using contrast-enhanced T1-weighted MRI (CE-T1WI) and DWI using b = 0, 200, 400, 600, 800 s/mm(2). ADC maps were generated using subsets of b-values to investigate the effects of tissue ablation on water diffusion and perfusion in fibroids treated with MR-HIFU. Four combinations of b-values were used: (1) all b-values; (2) b = 0, 200 s/mm(2); (3) b = 400, 600, 800 s/mm(2); and (4) b = 0, 800 s/mm(2). Using the lowest b-values (0 and 200 s/mm(2)), the mean ADC value in the ablated tissue reduced significantly (p < 0.001) compared with baseline. Calculating the ADC value with the highest b-values (400, 600, 800 s/mm(2)), the ADC increased significantly (p < 0.001) post-treatment. ADC maps calculated with the lowest b-values resulted in the best visual agreement of non-perfused fibroid tissue detected on CE images. Other b-value combinations and normal myometrium showed no difference in ADC after MR-HIFU treatment. A decrease in contrast agent uptake within the ablated region on CE-T1WI was correlated to a significantly decreased ADC when b = 0 and 200 s/mm(2) were used. DWI could be useful for treatment evaluation after MR-HIFU of uterine fibroids. The ADC in fibroid tissue is influenced by the choice of b- values. Low b-values seem the best choice to emphasise perfusion effects after MR-HIFU.

Detection of lymphovascular invasion by D2-40 (podoplanin) immunoexpression in endometrial cancer.

PubMed

Weber, Sarah K; Sauerwald, Axel; Pölcher, Martin; Braun, Michael; Debald, Manuel; Serce, Nuran Bektas; Kuhn, Walther; Brunagel-Walgenbach, Giesela; Rudlowski, Christian

2012-10-01

Lymph node involvement is a major feature in tumor spread of endometrial cancer and predicts prognosis. Therefore, evaluation of lymph vessel invasion (LVI) in tumor tissue as a predictor for lymph node metastasis is of great importance. Immunostaining of D2-40 (podoplanin), a specific marker for lymphatic endothelial cells, might be able to increase the detection rate of LVI compared with conventional hematoxylin-eosin (H-E) staining. The aim of this retrospective study was to analyze the eligibility of D2-40-based LVI evaluation for the prediction of lymph node metastases and patients' outcome. Immunohistochemical staining with D2-40 monoclonal antibodies was performed on paraffin-embedded tissue sections of 182 patients with primary endometrioid adenocarcinoma treated in 1 gynecologic cancer center. Tumors were screened for the presence of LVI. Correlations with clinicopathological features and clinical outcome were assessed. Immunostaining of D2-40 significantly increased the frequency LVI detection compared with conventional H-E staining. Lymph vessel invasion was identified by D2-40 in 53 (29.1%) of 182 tumors compared with 34 (18.3%) of 182 carcinomas by routine H-E staining (P = 0.001). D2-40 LVI was detectable in 81.0% (17/21) of nodal-positive tumors and significantly predicted lymph node metastasis (P = 0.001). Furthermore, D2-40 LVI was an independent prognostic factor for patients overall survival considering tumor stage, lymph node involvement, and tumor differentiation (P < 0.01). D2-40-negative tumors confined to the inner half of the myometrium showed an excellent outcome (5-year overall survival, 97.8%). D2-40-based LVI assessment improves the histopathological detection of lymphovascular invasion in endometrial cancer. Furthermore, LVI is of prognostic value and predicts lymph node metastasis. D2-40 LVI detection might help to select endometrial cancer patients who will benefit from a lymphadenectomy.

Does the presence of placental basal plate myometrial fibres increase the risk of subsequent morbidly adherent placenta: a case-control study.

PubMed

Miller, E S; Linn, R L; Ernst, L M

2016-12-01

Antenatal diagnosis of morbidly adherent placenta has been shown to improve outcomes, but existing predictors lack sensitivity. Our objective was to determine whether the presence of myometrial fibres attached to the placental basal plate (BPMYO) in an antecedent pregnancy is associated with subsequent morbidly adherent placenta. A case-control study. Departments of Obstetrics and Gynecology and Pathology, Northwestern University, Chicago, IL, USA. Women who had at least two pregnancies with placental pathological evaluation. Cases were defined as women with evidence of morbidly adherent placenta (both clinically and pathologically) in their most recent pregnancy whereas women without evidence of morbidly adherent placenta served as controls. Pathological specimens of placentas from previous pregnancies were evaluated for BPMYO. The presence of BPMYO on a previous placenta was evaluated to determine whether it could be used to improve the antenatal diagnosis of morbidly adherent placenta. Of the 25 cases of morbidly adherent placenta, 19 (76%) had BPMYO present on their previous placenta compared with 41 (41%) of controls (odds ratio 4.8, 95% CI 1.8-13.0). Adding BPMYO to a regression including other risk factors for morbidly adherent placenta (i.e. maternal age, number of previous caesarean sections, placenta praevia, previous multiple gestation, any previous curettage, and ultrasonographic suspicion of placenta accreta) significantly improved the sensitivity of antenatal diagnosis of morbidly adherent placenta (61% versus 39%, P < 0.001) without a change in specificity (97% versus 97%, P = 1.00). BPMYO on previous placental pathology is associated with an increased risk of morbidly adherent placenta in a subsequent pregnancy. These findings may shed light on the pathophysiology of accreta and inform future research on predictors of accreta. Previous basal plate myometrium improves the ability to detect subsequent morbidly adherent placenta. © 2015 Royal College of Obstetricians and Gynaecologists.

Roles of microRNA-34a in the pathogenesis of placenta accreta.

PubMed

Umemura, Kota; Ishioka, Shin-Ichi; Endo, Toshiaki; Ezaka, Yoshiaki; Takahashi, Madoka; Saito, Tsuyoshi

2013-01-01

MicroRNA-34a (miR-34a) is associated with invasion and metastasis of various cancers. The trophoblastic cells of placenta accreta invade into the myometrium in a similar way to the invasion of cancers. We studied the roles of miR-34a in the pathogenesis of placenta accreta. The human choriocarcinoma cell line JAR was used for in vitro experiments as a model of trophoblasts, and placental tissues from the operative specimen of patients with or without placenta accreta were used for experiments in vivo. Morpholino antisense oligomer against miR-34a (miR-34a Morpho/AS) was added to JAR, and the expression of miR-34a and plasminogen activator inhibitor-1 (PAI-1) was determined by real time PCR. The effects of antisense, interleukin (IL)-6 and IL-8 in the process of invasion were studied with an invasion assay. Expression of miR-34a in vivo was studied with the use of fluorescent in situ hybridization (FISH). Expression of miR-34a was inhibited by 65% with the administration of antisense, and a slight increase in miR-34a expression was observed with the addition of IL-6 and IL-8. PAI-1 expression decreased with the addition of IL-6 and IL-8, and increased with the administration of antisense. There was an increase in invasive capacity through the inhibition of miR-34a expression. Strong FISH expression of miR-34a was observed in trophoblast cells of non-placenta accreta, and a clear decrease in miR-34a expression was observed in those of placenta accreta. Expression of miR-34a was downregulated in placenta accreta. In vitro experiments also showed that the invasive potential of JAR increased by suppressing miR-34a, probably through the expression of PAI-1. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

Imaging for Polyps and Leiomyomas in Women With Abnormal Uterine Bleeding: A Systematic Review.

PubMed

Maheux-Lacroix, Sarah; Li, Fiona; Laberge, Philippe Y; Abbott, Jason

2016-12-01

To evaluate the accuracy of saline infusion sonohysterography in comparison with transvaginal ultrasonography for diagnosing polyps and submucosal leiomyomas in women with abnormal uterine bleeding. We searched the databases MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov as well as citations and reference lists to the end of November 2015. Two authors screened 5,347 citations for eligibility. We included randomized controlled trials or prospective cohort studies published in English, assessing the accuracy of saline infusion sonohysterography and transvaginal ultrasonography for diagnosing polyps and submucosal leiomyomas in women with abnormal uterine bleeding. We considered studies using histopathologic specimens obtained at either hysteroscopy or hysterectomy as criterion standard. Twenty-five studies were eligible. Two authors extracted data and assessed the quality of included studies. Bivariate random-effects models were used to compare the different tests and evaluate sources of heterogeneity. Saline infusion sonohysterography was superior to transvaginal ultrasonography with pooled sensitivity and specificity of 0.92 and 0.89 compared with 0.64 and 0.90, respectively (P<.001). Transvaginal ultrasound sensitivity for diagnosing polyps was particularly low (0.51). Saline infusion sonohysterography was also compared with hysteroscopy in seven studies and had similar sensitivity but inferior specificity (0.93 and 0.83 compared with 0.95 and 0.90, respectively, P=.007). All three procedures were well-tolerated by women. Saline infusion sonohysterography was successfully completed in 95% of women. Technical variations such as the use of balloon catheters were not found to affect diagnostic accuracy. Transvaginal ultrasonography lacks sensitivity to be used alone to exclude the presence of polyps and leiomyomas in women with abnormal uterine bleeding. Although less specific than hysteroscopy, saline infusion sonohysterography offers a similar detection rate and permits concomitant visualization of the ovaries and myometrium. Cost, convenience, and tolerability of different imaging techniques require further evaluation. PROSPERO International prospective register of systematic reviews, http://www.crd.york.ac.uk/PROSPERO, CRD42016034005.

Longitudinal transvaginal ultrasound evaluation of cesarean scar niche incidence and depth in the first two years after single- or double-layer uterotomy closure: a randomized controlled trial.

PubMed

Bamberg, Christian; Hinkson, Larry; Dudenhausen, Joachim W; Bujak, Verena; Kalache, Karim D; Henrich, Wolfgang

2017-12-01

Cesarean deliveries are the most common abdominal surgery procedure globally, and the optimal way to suture the hysterotomy remains a matter of debate. The aim of this study was to assess the incidence of cesarean scar niches and the depth after single- or double-layer uterine closure. We performed a randomized controlled trial in which women were allocated to three uterotomy suture techniques: continuous single-layer unlocked, continuous locked single-layer, or double-layer sutures. Transvaginal ultrasound was performed six weeks and 6-24 months after cesarean delivery [Clinicaltrials.gov (NCT02338388)]. The study included 435 women. Six weeks after delivery, the incidence of niche was not significantly different between the groups (p = 0.52): 40% for single-layer unlocked, 32% for single-layer locked and 43% for double-layer sutures. The mean ± SD niche depths were 3.0 ± 1.4 mm for single-layer unlocked, 3.6 ± 1.7 mm for single-layer locked and 3.3 ± 1.3 mm for double-layer sutures (p = 1.0). There were no significant differences (p = 0.58) in niche incidence between the three groups at the second ultrasound follow up: 30% for single-layer unlocked, 23% for single-layer locked and 29% for double-layer sutures. The mean ± SD niche depth was 3.1 ± 1.5 mm after single-layer unlocked, 2.8 ± 1.5 mm after single-layer locked and 2.5 ± 1.2 mm after double-layer sutures (p = 0.61). There was a trend (p = 0.06) for the residual myometrium thickness to be thicker after double-layer repair at the long-term follow up. The incidence of cesarean scar niche formation and the niche depth was independent of the hysterotomy closure technique. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

A Prospective Randomized Clinical Trial of Single vs. Double Layer Closure of Hysterotomy at the Time of Cesarean Delivery: The Effect on Uterine Scar Thickness.

PubMed

Bamberg, Christian; Dudenhausen, Joachim W; Bujak, Verena; Rodekamp, Elke; Brauer, Martin; Hinkson, Larry; Kalache, Karim; Henrich, Wolfgang

2018-06-01

 We undertook a randomized clinical trial to examine the outcome of a single vs. a double layer uterine closure using ultrasound to assess uterine scar thickness.  Participating women were allocated to one of three uterotomy suture techniques: continuous single layer unlocked suturing, continuous locked single layer suturing, or double layer suturing. Transvaginal ultrasound of uterine scar thickness was performed 6 weeks and 6 - 24 months after Cesarean delivery. Sonographers were blinded to the closure technique.  An "intent-to-treat" and "as treated" ANOVA analysis included 435 patients (n = 149 single layer unlocked suturing, n = 157 single layer locked suturing, and n = 129 double layer suturing). 6 weeks postpartum, the median scar thickness did not differ among the three groups: 10.0 (8.5 - 12.3 mm) single layer unlocked vs. 10.1 (8.2 - 12.7 mm) single layer locked vs. 10.8 (8.1 - 12.8 mm) double layer; (p = 0.84). At the time of the second follow-up, the uterine scar was not significantly (p = 0.06) thicker if the uterus had been closed with a double layer closure 7.3 (5.7 - 9.1 mm), compared to single layer unlocked 6.4 (5.0 - 8.8 mm) or locked suturing techniques 6.8 (5.2 - 8.7 mm). Women who underwent primary or elective Cesarean delivery showed a significantly (p = 0.03, p = 0.02, "as treated") increased median scar thickness after double layer closure vs. single layer unlocked suture.  A double layer closure of the hysterotomy is associated with a thicker myometrium scar only in primary or elective Cesarean delivery patients. © Georg Thieme Verlag KG Stuttgart · New York.

Effects of tachykinins on uterine smooth muscle.

PubMed

Patak, E N; Pennefather, J N; Story, M E

2000-11-01

1. Sensory nerves supplying the mammalian uterus have been shown to contain substance P (SP) and neurokinin (NK)A. This review presents some of the advances that have led to a greater understanding of the effects of tachykinins on uterine smooth muscle. 2. The cell-surface peptidase neprilysin (EC.3 24.11, endopeptidase 24.11, enkephalinase, CALLA, CD10) has been shown to play a major role in regulating the actions of tachykinins on both rat and human myometrium. Because this peptidase is known to be regulated by steroids and pregnancy, its effects may be of physiological relevance. 3. Tachykinins produce contractions of isolated myometrial preparations from non-pregnant rats and mice. The NK2 receptor mediates these effects in rat uterus, while the NK1 receptor may mediate these effects in the mouse uterus. 4. The effects of tachykinins have been examined on myometrial preparations obtained at Caesarean section from near-term pregnant women. In the presence of the peptidase inhibitors (thiorphan, captopril and bestatin), the mammalian tachykinins SP, NKA and NKB produced concentration-dependent uterine contractions. 5. The order of agonist potency NKA > SP = NKB suggested that NK2 receptors mediate uterine contractions in the human. This was confirmed using the stable analogues [Sar9,Met(O2)11]SP, [Lys5MeLeu9Nle10]NKA(4-10) and [N-MePhe7]NKB, which are NK1, NK2 and NK3 receptor selective, respectively. Only [Lys5MeLeu9Nle10]NKA(4-10) produced concentration-related contractions of human uterine smooth muscle. 6. The experimental findings described in the present review, taken together with results published previously in the literature, indicate that tachykinin peptides may play a physiological or pathophysiological role in regulating uterine smooth muscle activity. However, more extensive research will be required to confirm such a role for these peptides.

Mice Deficient in Surfactant Protein A (SP-A) and SP-D or in TLR2 Manifest Delayed Parturition and Decreased Expression of Inflammatory and Contractile Genes

PubMed Central

Montalbano, Alina P.; Hawgood, Samuel

2013-01-01

Previously we obtained compelling evidence that the fetus provides a critical signal for the initiation of term labor through developmental induction of surfactant protein (SP)-A expression by the fetal lung and secretion into amniotic fluid (AF). We proposed that interactions of AF macrophage (Mφ) Toll-like receptors (TLRs) with SP-A, at term, or bacterial components, at preterm, result in their activation and migration to the pregnant uterus. Herein the timing of labor in wild-type (WT) C57BL/6 mice was compared with mice homozygous null for TLR2, SP-A, SP-D, or doubly deficient in SP-A and SP-D. Interestingly, TLR2−/− females manifested a significant (P < 0.001) delay in timing of labor compared with WT as well as reduced expression of the myometrial contraction-associated protein (CAP) gene, connexin-43, and Mφ marker, F4/80, at 18.5 d postcoitum (dpc). Whereas in first pregnancies, SP-A−/−, SP-D−/−, and SP-A/D−/− females delivered at term (∼19.5 dpc), in second pregnancies, parturition was delayed by approximately 12 h in SP-A−/− (P = 0.07) and in SP-A/D−/− (P <0.001) females. Myometrium of SP-A/D−/− females expressed significantly lower levels of IL-1β, IL-6, and CAP genes, connexin-43, and oxytocin receptor at 18.5 dpc compared with WT. F4/80+ AF Mφs from TLR2−/− and SP-A/D−/− mice expressed significantly lower levels of both proinflammatory and antiinflammatory activation markers (e.g. IL-1β, IL-6, ARG1, YM1) compared with gestation-matched WT AF Mφs. These novel findings suggest that the pulmonary collectins acting via TLR2 serve a modulatory role in the timing of labor; their relative impact may be dependent on parity. PMID:23183169

Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19.

PubMed

Park, Min Ju; Shen, Hailian; Spaeth, Jason M; Tolvanen, Jaana H; Failor, Courtney; Knudtson, Jennifer F; McLaughlin, Jessica; Halder, Sunil K; Yang, Qiwei; Bulun, Serdar E; Al-Hendy, Ayman; Schenken, Robert S; Aaltonen, Lauri A; Boyer, Thomas G

2018-03-30

Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit MED12 occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate cyclin C (CycC)-dependent kinase 8 (CDK8) in Mediator, implicating impaired Mediator-associated CDK8 activity in the molecular pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of MED12 mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, we find that within the Mediator kinase module, MED13 directly binds to the MED12 C terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC-CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation and reveal an additional step in the MED12-dependent activation process, one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that UF-linked mutations in MED12 disrupt composite Mediator-associated kinase activity and identify CDK8/19 as prospective therapeutic targets in UFs. © 2018 Park et al.

Changes in the mRNA expression of structural proteins, hormone synthesis and secretion from bovine placentome sections after DDT and DDE treatment.

PubMed

Wojciechowska, A; Mlynarczuk, J; Kotwica, J

2017-01-15

Disorders in the barrier function and secretory activity of the placenta can be caused by xenobiotics (XB) present in the environment and their accumulation in tissues of living organisms. Thus, the aim of this study was to investigate the effect of 1,1,1-trichloro-2,2,-bis-4-chlorophenyl-ethane (DDT) and its metabolite 1,1-dichloro-2,2-bis-4-chlorophenyl-ethene (DDE) (for 24 or 48h) at doses of 1, 10 or 100ng/ml on the function of cow placentome sections in the second trimester of pregnancy. DDT and DDE affected neither (P>0.05) the viability nor hypoxia inducible factor 1 (HIF1α) mRNA expression of the sections. XB decreased (P<0.05) connexin (Cx) 26, 32, 43 and placenta-specific 1 (PLAC-1) mRNA expression but did not affect (P>0.05) keratin 8 (KRT8) mRNA expression. DDT and DDE also reduced (P<0.05) prostaglandin F2α (PGF2α) synthase (PGFS) mRNA expression, while DDT increased (P<0.05) prostaglandin E2 (PGE2) synthase (PGES) mRNA expression. Neither cyclooxygenase 2 (COX-2) mRNA expression nor PGF2α and PGE2 secretion were affected. Both DDT and DDE increased (P<0.05) neurophysin I/oxytocin (NP1/OT) mRNA expression and oxytocin (OT), oestradiol (E2) and progesterone (P4) secretion while DDT stimulated only 3β-hydroxysteroid dehydrogenase (3βHSD) and cholesterol side-chain cleavage enzyme (CYP11A1) mRNA expression (P<0.05). In summary, DDT and DDE impaired the barrier function and secretory activity of the placenta. Thus, these compounds can disrupt trophoblast invasion, myometrium contractility and gas/nutrient exchange throughout pregnancy in cows. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of d- and l-limonene on the pregnant rat myometrium in vitro

PubMed Central

Hajagos-Tóth, Judit; Hódi, Ágnes; Seres, Adrienn B.; Gáspár, Róbert

2015-01-01

Aim To study the effects of d- and l-limonene on pregnant rat myometrial contractility in vitro, and investigate how these effects are modified by other agents. D- and l-limonene (10−13-10−8 M) caused myometrial contraction in a dose-dependent manner. Methods Contractions of uterine rings from 22-day-pregnant rats were measured in an organ bath in the presence of d- or l-limonene (10−13-10−8 M) and nifedipine (10−8 M), tetraethyl-ammonium (10−3 M), theophylline (10−5 M), or paxilline (10−5 M). Uterine cyclic adenosine monophosphate (cAMP) level was detected by enzyme immunoassay. Oxidative damage was induced by methylglyoxal (3 × 10−2 M) and the alteration was measured via noradrenaline (1 × 10−9 to 3 × 10−5 M) -induced contractions. Results Pre-treatment with nifedipine (10−8 M), tetraethylammonium (10−3 M), and theophylline (10−5 M) attenuated the contracting effect of d- and l-limonene, while in the presence of paxilline (10−5 M) d- and l-limonene were ineffective. The two enantiomers decreased the myometrial cAMP level, but after paxilline pretreatment the cAMP level was not altered compared with the control value. Additionally, l-limonene (10−6 M) diminished consequences of oxidative damage caused by methylglyoxal (3 × 10−2 M) on contractility, whereas d-limonene was ineffective. Conclusion Our findings suggest that l-limonene has an antioxidant effect and that both d-and l-limonene cause myometrial contraction through activation of the A2A receptor and opening of the voltage-gated Ca2+ channel. It is possible that limonene-containing products increase the pregnant uterus contractility and their use should be avoided during pregnancy. PMID:26526880

Value of ultrasound shear wave elastography in the diagnosis of adenomyosis

PubMed Central

Millar, E; Mitkova, M; Mitkov, V

2016-01-01

Background The aim of the study was to assess the accuracy of ultrasound shear wave elastography in the diagnosis of adenomyosis. Methods One hundred and fifty three patients were examined. Ninety-seven patients were with suspected adenomyosis and 56 patients were with unremarkable myometrium. Adenomyosis was confirmed in 39 cases (A subgroup) and excluded in 14 cases (B subgroup) in the main group based on morphological examination. All patients underwent ultrasound examination using an Aixplorer (Supersonic Imagine, France) scanner with application of shear wave elastography during transvaginal scanning. Retrospective analysis of the elastography criteria against the findings from morphological/histological examination was performed. Results The following values of Young’s modulus were found in subgroup A (adenomyosis): Emean – 72.7 (22.6–274.2) kPa (median, 5–95th percentiles), Emax – 94.8 (29.3–300.0) kPa, SD – 9.9 (2.6–26.3) kPa; in subgroup B (non adenomyosis) – 28.3 (12.7–59.5) kPa, 33.6 (16.0–80.8) kPa, 3.0 (1.4–15.6) kPa; in the control group – 24.4 (17.9–32.4) kPa, 29.8 (21.6–40.8) kPa, 2.3 (1.3–6.1) kPa, respectively (P < 0.05 for all comparison with subgroup В and the control group). The Emean cut-off value for adenomyosis diagnosis was 34.6 kPa. The sensitivity, specificity, positive predictive value, negative predictive value and area under curve (AUC) were 89.7%, 92.9%, 97.2%, 76.5% and 0.908. The Emax cut-off value was 45.4 kPa (89.7%, 92.9%, 97.2%, 76.5% and 0.907, respectively). Conclusion This study showed a significant increase of the myometrial stiffness estimated with shear wave elastography use in patients with adenomyosis. PMID:27847535

In vitro activity of Spirulina platensis water extract against different Candida species isolated from vulvo-vaginal candidiasis cases

PubMed Central

Nahui Palomino, Rogers Alberto; Gallina Toschi, Tullia; Vitali, Beatrice; Camarda, Luca; Mandrioli, Mara; De Giorgio, Marta; Aldini, Rita; Corazza, Ivan; Chiarini, Alberto; Cevenini, Roberto; Budriesi, Roberta

2017-01-01

The high incidence of vulvo-vaginal candidiasis, combined with the growing problems about azole resistance and toxicity of antifungal drugs, highlights the need for the development of new effective strategies for the treatment of this condition. In this context, natural compounds represent promising alternatives. The cyanobacterium Spirulina platensis, a blue-green alga, exhibits antimicrobial activities against several microorganisms. Nevertheless, only few data about the antifungal properties of Spirulina platensis are available and its potential toxic effects have not been largely investigated. The aim of this study was to evaluate the in vitro activity of a fully-characterized water extract of Spirulina platensis against 22 strains of Candida spp. Prior to considering its potential topical use, we both investigated whether the extract exerted target activities on guinea pig uterine smooth muscle, and the impact of Spirulina platensis on the dominant microorganisms of the vaginal microbiota (i.e., lactobacilli), in order to exclude possible adverse events. By means of a broth microdilution assay, we found that the microalga extract possesses good antifungal properties (MIC: 0.125–0.5 mg/ml), against all the Candida species with a fungicidal activity. At the concentrations active against candida, Spirulina platensis did not modify the spontaneous basic waves pattern of uterine myometrium as underlined by the absence of aberrant contractions, and did not affect the main health-promoting bacteria of the vaginal ecosystem. Finally, we evaluated the selectivity index of our extract by testing its cytotoxicity on three different cell lines and it showed values ranging between 2 and 16. Further in vivo studies are needed, in particular to evaluate the use of control-release formulations in order to maintain Spirulina platensis concentrations at anti-Candida active doses but below the toxic levels found in the present work. PMID:29190763

Partial agonist clonidine mediates alpha(2)-AR subtypes specific regulation of cAMP accumulation in adenylyl cyclase II transfected DDT1-MF2 cells.

PubMed

Limon-Boulez, I; Bouet-Alard, R; Gettys, T W; Lanier, S M; Maltier, J P; Legrand, C

2001-02-01

alpha2-Adrenergic receptor (alpha(2)-AR) activation in the pregnant rat myometrium at midterm potentiates beta(2)-AR stimulation of adenylyl cyclase (AC) via Gbetagamma regulation of the type II isoform of adenylyl cyclase. However, at term, alpha(2)-AR activation inhibits beta(2)-AR stimulation of AC. This phenomenon is associated with changes in alpha(2)-AR subtype expression (midterm alpha(2A/D)-AR > alpha(2B)-AR; term alpha(2B) >or =alpha(2A/D)-AR), without any change in ACII mRNA, suggesting that alpha(2A/D)- and alpha(2B)-AR differentially regulate beta(2)-cAMP production. To address this issue, we have stably expressed the same density of alpha(2A/D)- or alpha(2B)-AR with AC II in DDT1-MF2 cells. Clonidine (partial agonist) increased beta(2)-AR-stimulated cAMP production in alpha(2A/D)-AR-ACII transfectants but inhibited it in alpha(2B)-AR-ACII transfectants. In contrast, epinephrine (full agonist) enhanced beta(2)-stimulated ACII in both alpha(2A)- and alpha(2B)-ACII clonal cell lines. 4-Azidoanilido-[alpha-(32)P]GTP-labeling of activated G proteins indicated that, in alpha(2B)-AR transfectants, clonidine activated only Gi(2), whereas epinephrine, the full agonist, effectively coupled to Gi(2) and Gi(3). Thus, partial and full agonists selectively activate G proteins that lead to drug specific effects on effectors. Moreover, these data indicate that Gi(3) activation is required for potentiation of beta(2)-AR stimulation of AC by alpha(2A/D) and alpha(2B)-AR in DDT1-MF2 cells. This may reflect an issue of the amount of Gbetagamma released upon receptor activation and/or betagamma composition of Gi(3) versus Gi(2).

Clinical and imaging predictors of management in retained products of conception.

PubMed

Kamaya, Aya; Krishnarao, Priya Menon; Nayak, Nita; Jeffrey, R Brooke; Maturen, Katherine E

2016-12-01

To determine if clinical and ultrasound (US) imaging features help predict management in clinically suspected retained products of conception (RPOC). 334 patients sonographically evaluated for RPOC were included in this IRB-approved retrospective study. Of the 334 patients, 176 had sonographic diagnosis of RPOC and comprised the final study group. Patients were managed expectantly, medically, or surgically in accordance with clinical judgment of treating physicians. Pelvic sonograms were retrospectively reviewed for endometrial stripe thickness and vascularity was graded on a 0-3 scale based on appearance relative to myometrium (Grade 0: no vascularity, Grade 1: minimal vascularity, Grade 2: moderate vascularity, Grade 3: marked vascularity). Clinical and imaging predictors of management were evaluated in univariate and multivariate analysis. Mean patient age was 29.6 years and mean gestational age was 17.4 weeks. Most (74.4%) women presented with vaginal bleeding. 83 patients (47.2%) were treated conservatively with expectant management, 42 (23.8%) were treated medically, and 51 (29.0%) required surgical intervention. Mean endometrial stripe thickness was 21.3 mm. 47 women (26.7%) had vascularity score of 0; 50 (28.4%) had score 1; 52 (29.6%) had score 2; and 27 (15.3%) had score 3. In univariate analysis, serum hemoglobin (Hb) (p < 0.0001), endometrial stripe thickness on US (p < 0.005), presenting symptoms (p = 0.03), and US vascularity score (p < 0.005) were statistically significant predictors of final management. In multivariate logistic regression, serum Hb (OR 0.69, 95% CI 0.55-0.86, p < 0.0009), endometrial stripe thickness (OR 1.08, 95% CI 1.04-1.12, p < 0.0001), and US vascularity score (OR 1.77, 95% CI 1.16-2.70, p < 0.01) were statistically significant predictors of need for surgery. Serum Hb, endometrial stripe thickness, and US vascularity score were significant predictors of clinical management, particularly the need for surgical intervention, in women with clinically suspected RPOC.

MicroRNA-15b regulates reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression in human uterine leiomyoma.

PubMed

Guan, Yichun; Guo, Lankai; Zukerberg, Lawrence; Rueda, Bo R; Styer, Aaron K

2016-08-17

Human uterine leiomyoma (fibroids; LYO) are the most common benign neoplasms in reproductive-aged women. Dysregulated extracellular matrix and irregular LYO reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression are thought to be mediated by aberrant microRNA (miR) expression. The relationship of miR-15b and RECK expression in LYO has not been studied. The expression levels of miR-15b and RECK were determined by quantitative RT-PCR, Western blot, and immunohistochemistry in cultures derived from commercial primary leiomyoma (cpLYO) and myometrial (cpMYO) cell lines and leiomyoma (pLYO) and myometrium (pMYO) tissue from surgical samples respectively. The relationship between miR-15b and RECK expression in cpLYO and pLYO (compared to their respective myometrial controls) was evaluated following transfection of cell cultures with either miR-15b mimic or inhibitor. Elevated levels of miR-15b were observed in cpLYO (2.82-fold; p = 0.04) and pLYO cell (1.30-fold; p = 0.0001) cultures respectively compared to corresponding MYO cell controls. Following transfection with miR-15b mimic, cpLYO cells (0.62-fold; p < 0.0001) and pLYO cells (0.68-fold; p < 0.0001) demonstrated reduced RECK protein expression. Following transfection with miR-15b inhibitor, cpLYO cells (1.20-fold; p < 0.0001) and pLYO cells (1.31-fold; p = 0.0007) demonstrated elevated RECK protein expression. RECK protein expression was reduced in pLYO tissues (0.73-fold; p < 0.0001) and pLYO (0.47-fold; p = 0.047) cells when compared to the corresponding MYO tissue controls. Our findings suggest that miR-15b negatively regulates RECK expression in LYO, and increased miR-15b and decreased RECK expression may contribute to the pathobiology of LYO. The functional significance of miR-15b and RECK expression warrants further investigation as potential therapeutic targets for the treatment of human LYO.

Proteomics Identification of Annexin A2 as a Key Mediator in the Metastasis and Proangiogenesis of Endometrial Cells in Human Adenomyosis*

PubMed Central

Zhou, Shengtao; Yi, Tao; Liu, Rui; Bian, Ce; Qi, Xiaorong; He, Xiang; Wang, Kui; Li, Jingyi; Zhao, Xia; Huang, Canhua; Wei, Yuquan

2012-01-01

Adenomyosis is a common estrogen-dependent disorder of females characterized by a downward extension of the endometrium into the uterine myometrium and neovascularization in ectopic lesions. It accounts for chronic pelvic pain, dysmenorrhea, menorrhagia, and infertility in 8.8–61.5% women worldwide. However, the molecular mechanisms for adenomyosis development remain poorly elucidated. Here, we utilized a two-dimensional polyacrylamide gel electrophoresis/MS-based proteomics analysis to compare and identify differentially expressed proteins in matched ectopic and eutopic endometrium of adenomyosis patients. A total of 93 significantly altered proteins were identified by tandem MS analysis. Further cluster analysis revealed a group of estrogen-responsive proteins as dysregulated in adenomyosis, among which annexin A2, a member of annexin family proteins, was found up-regulated most significantly in the ectopic endometrium of adenomyosis compared with its eutopic counterpart. Overexpression of ANXA2 was validated in ectopic lesions of human adenomyosis and was found to be tightly correlated with markers of epithelial to mesenchymal transition and dysmenorrhea severity of adenomyosis patients. Functional analysis demonstrated that estrogen could remarkably up-regulate ANXA2 and induce epithelial to mesenchymal transition in an in vitro adenomyosis model. Enforced expression of ANXA2 could mediate phenotypic mesenchymal-like cellular changes, with structural and functional alterations in a β-catenin/T-cell factor (Tcf) signaling-associated manner, which could be reversed by inhibition of ANXA2 expression. We also proved that enforced expression of ANXA2 enhanced the proangiogenic capacity of adenomyotic endometrial cells through HIF-1α/VEGF-A pathway. In vivo, we demonstrated that ANXA2 inhibition abrogated endometrial tissue growth, metastasis, and angiogenesis in an adenomyosis nude mice model and significantly alleviated hyperalgesia. Taken together, our data unraveled a dual role for ANXA2 in the pathogenesis of human adenomyosis through conferring endometrial cells both metastatic potential and proangiogenic capacity, which could serve as a potential therapeutic target for the treatment of adenomyosis patients. PMID:22493182

[MR Imaging of the pelvis in the diagnosis of the endometrium in breast cancer patients in tamoxifen therapy].

PubMed

Hauth, E; Libera, H; Kimmig, R; Forsting, M

2006-03-01

The purpose of the study was to determine the value of MR imaging of the pelvis in the diagnostic work-up of the endometrium in breast cancer patients in tamoxifen therapy. MR imaging of the pelvis was performed on 24 patients (mean: 62 years, range: 51 - 74 years) and 30 healthy women (mean: 65 years, range: 51 - 73 years). The volume of the uterus and cervix and the maximal thickness of the endometrium, junctional zone and myometrium of the uterus were determined and compared to the confidence interval of the parameters in healthy women. The Mann-Whitney U-test was used to identify differences in the volume of the uterus and cervix and in the thickness of the uterine wall layers in both groups. A comparison of the volume of the uterus and cervix and the thickness of the uterine wall layers in the two groups yielded no significant differences. The volume of the uterus and cervix showed no statistical differences between the two groups. The maximal height of the endometrium in the patient group showed a mean of 0.6 cm (range: 0.1 - 2.2 cm), and a mean of 0.4 cm (range: 0.1 - 1.2 cm) in the group of healthy women. The differences were not statistically significant. In all healthy women the endometrium showed homogeneous signal intensity in the sagittal T2-weighted images. In 12 of the 24 breast cancer patients, the endometrium showed inhomogeneous signal intensity. In 9 of 12 patients with an inhomogeneous endometrium with a thickness equal to or greater than 0.6 cm, histopathology confirmed polyps. In 3 patients endometrium hyperplasia was found. In one patient histopathology revealed a polyp and an endometrium carcinoma in stage T1 a N0. The endometrium carcinoma was not able to be seen via MR imaging. MR imaging might be helpful in the diagnosis of endometrium pathologies during tamoxifen therapy. Therefore, MR imaging of the pelvis could be used as a diagnostic tool in the follow-up diagnosis of the endometrium in breast cancer patients in tamoxifen therapy.

Development and external validation of new ultrasound-based mathematical models for preoperative prediction of high-risk endometrial cancer.

PubMed

Van Holsbeke, C; Ameye, L; Testa, A C; Mascilini, F; Lindqvist, P; Fischerova, D; Frühauf, F; Fransis, S; de Jonge, E; Timmerman, D; Epstein, E

2014-05-01

To develop and validate strategies, using new ultrasound-based mathematical models, for the prediction of high-risk endometrial cancer and compare them with strategies using previously developed models or the use of preoperative grading only. Women with endometrial cancer were prospectively examined using two-dimensional (2D) and three-dimensional (3D) gray-scale and color Doppler ultrasound imaging. More than 25 ultrasound, demographic and histological variables were analyzed. Two logistic regression models were developed: one 'objective' model using mainly objective variables; and one 'subjective' model including subjective variables (i.e. subjective impression of myometrial and cervical invasion, preoperative grade and demographic variables). The following strategies were validated: a one-step strategy using only preoperative grading and two-step strategies using preoperative grading as the first step and one of the new models, subjective assessment or previously developed models as a second step. One-hundred and twenty-five patients were included in the development set and 211 were included in the validation set. The 'objective' model retained preoperative grade and minimal tumor-free myometrium as variables. The 'subjective' model retained preoperative grade and subjective assessment of myometrial invasion. On external validation, the performance of the new models was similar to that on the development set. Sensitivity for the two-step strategy with the 'objective' model was 78% (95% CI, 69-84%) at a cut-off of 0.50, 82% (95% CI, 74-88%) for the strategy with the 'subjective' model and 83% (95% CI, 75-88%) for that with subjective assessment. Specificity was 68% (95% CI, 58-77%), 72% (95% CI, 62-80%) and 71% (95% CI, 61-79%) respectively. The two-step strategies detected up to twice as many high-risk cases as preoperative grading only. The new models had a significantly higher sensitivity than did previously developed models, at the same specificity. Two-step strategies with 'new' ultrasound-based models predict high-risk endometrial cancers with good accuracy and do this better than do previously developed models. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Increased Speed and Image Quality for Pelvic Single-Shot Fast Spin-Echo Imaging with Variable Refocusing Flip Angles and Full-Fourier Acquisition

PubMed Central

Litwiller, Daniel V.; Saranathan, Manojkumar; Vasanawala, Shreyas S.

2017-01-01

Purpose To assess image quality and speed improvements for single-shot fast spin-echo (SSFSE) with variable refocusing flip angles and full-Fourier acquisition (vrfSSFSE) pelvic imaging via a prospective trial performed in the context of uterine leiomyoma evaluation. Materials and Methods Institutional review board approval and informed consent were obtained. vrfSSFSE and conventional SSFSE sagittal and coronal oblique acquisitions were performed in 54 consecutive female patients referred for 3-T magnetic resonance (MR) evaluation of known or suspected uterine leiomyomas. Two radiologists who were blinded to the image acquisition technique semiquantitatively scored images on a scale from −2 to 2 for noise, image contrast, sharpness, artifacts, and perceived ability to evaluate uterine, ovarian, and musculoskeletal structures. The null hypothesis of no significant difference between pulse sequences was assessed with a Wilcoxon signed rank test by using a Holm-Bonferroni correction for multiple comparisons. Results Because of reductions in specific absorption rate, vrfSSFSE imaging demonstrated significantly increased speed (more than twofold, P < .0001), with mean repetition times compared with conventional SSFSE imaging decreasing from 1358 to 613 msec for sagittal acquisitions and from 1494 to 621 msec for coronal oblique acquisitions. Almost all assessed image quality and perceived diagnostic capability parameters were significantly improved with vrfSSFSE imaging. These improvements included noise, sharpness, and ability to evaluate the junctional zone, myometrium, and musculoskeletal structures for both sagittal acquisitions (mean values of 0.56, 0.63, 0.42, 0.56, and 0.80, respectively; all P values < .0001) and coronal oblique acquisitions (mean values of 0.81, 1.09, 0.65, 0.93, and 1.12, respectively; all P values < .0001). For evaluation of artifacts, there was an insufficient number of cases with differences to allow statistical testing. Conclusion Compared with conventional SSFSE acquisition, vrfSSFSE acquisition increases 3-T imaging speed via reduced specific absorption rate and leads to significant improvements in perceived image quality and perceived diagnostic capability when evaluating pelvic structures. © RSNA, 2016 Online supplemental material is available for this article. PMID:27564132

[Clinical analysis on hysteroscopic surgery for the treatment of type Ⅱ cesarean scar pregnancy in the first trimester].

PubMed

Chen, Z Y; Li, X Y; Zhao, D; Zhou, M; Xu, P; Huang, X F; Zhang, X M

2017-10-25

Objective: To investigate the safety and efficacy of hysterosopic management of type Ⅱ cesarean scar pregnancy (CSP) and the value of prophylactic uterine artery embolization (UAE). Methods: Totally 104 patients with type Ⅱ CSP treated with hysteroscopic surgery at the Women ' s Hospital, School of Medicine, Zhejiang University, during Jan. 2009 to Jun. 2016 were analyzed retrospectively, 67 patients combined with UAE (UAE group) and 37 patients without combined with UAE (non-UAE group). Laparoscopy or sonography guidance was conducted simultaneously. The following clinical parameters were compared, including: primary cure rate, uterine packing rate, uterine perforation rate, hemoglobin level change, the time for the mass absorption and the return of β-hCG to normal, complications, hospital days and hospital stay cost. Results: Median gestational age, size of mass, thickness of the anterior myometrium and β-hCG level in UAE group versus non-UAE group were 47 versus 47 days, 30 versus 30 mm,2 versus 2 mm, 36 524 versus 32 226 U/L (all P> 0.05). Out of 104, 100 patients were managed successfully with hysteroscopic surgery, and 4 patients transformed to laparoscopic or laparotomy surgery. Hysteroscopic surgery was effective in 63 out of 67 patients (94%) in UAE group and 34 out of 37 patients (92%) in non-UAE group ( P> 0.05). There was no significant differences regarding uterine perforation rate, uterine packing rate, hemoglobin change and recovery time between UAE group and non-UAE group (all P> 0.05). The median hospital day was 7 days in UAE group versus 5 days in non-UAE group ( P< 0.01). The median hospital stay cost was 13 654 yuan in UAE group versus 9 108 yuan in non-UAE group ( P< 0.01). Serious complication occurred in 4 patients (6%, 4/67) in UAE group and 2 patients (5%, 2/67) in non-UAE group ( P= 0.906). Conclusions: Hysteroscopic surgery is effective and safe for patients with type Ⅱ CSP in the first trimester with size ≤30 mm in diameter and gestation age<7 weeks. The value of prophylactic UAE is uncertain.

Functional characterization of tachykinin NK1 receptors in the mouse uterus.

PubMed

Patak, Eva; Pennefather, Jocelyn N; Fleming, Anna; Story, Margot E

2002-12-01

1. Contractility studies were undertaken to determine the nature of the receptors mediating responses to tachykinins in uteri of oestrogen-treated mice. 2. In the presence of thiorphan (3 microM), captopril (10 microM), and bestatin (10 microM), substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) produced concentration-related contractions of uterine preparations. The order of potency was SP > or =NKA>NKB. 3. Neither atropine (0.1 microM) nor l-NOLA (100 microM), nor indomethacin (10 microM) alone or in combination with either ranitidine (10 microM) or mepyramine (10 microM), affected responses to SP. These findings indicate that SP actions are not mediated or modulated through the release of acetylcholine, nitric oxide, prostanoids or histamine. 4. In the presence of peptidase inhibitors, the tachykinin NK(1) receptor-selective agonist [Sar(9)Met(O(2))(11)]SP, produced a concentration-dependent contractile effect. The tachykinin NK(2) and NK(3) receptor-selective agonists [Lys(5)MeLeu(9)Nle(10)]NKA(4-10) and [MePhe(7)]NKB were relatively inactive. The potencies of SP analogues in which Glu replaced Gln(5) and/or Gln(6) were similar to that of SP. 5. The tachykinin NK(1) receptor-selective antagonist, SR140333 (10 nM), alone or combined with the tachykinin NK(2) receptor-selective antagonist, SR48968 (10 nM), shifted log concentration curves to SP, NKA and NKB to the right. SR140333 (10 nM) reduced the effect of [Sar(9)Met(O(2))(11)]SP. SR48968 did not affect responses to SP or [Sar(9)Met(O(2))(11)]SP, but reduced the effect of higher concentrations of NKA and shifted the log concentration-response curve to NKB to the right. The tachykinin NK(3) receptor-selective antagonist, SR 142801 (0.3 microM), had little effect on responses to SP and NKB. 6. We conclude that the tachykinin NK(1) receptor mediates contractile effects of SP, NKA and NKB and [Sar(9)Met(O(2))(11)]SP in myometrium from the oestrogen-primed mouse. The tachykinin NK(2) receptor may also participate in the responses to NKA and NKB.

VE-cadherin Y685F knock-in mouse is sensitive to vascular permeability in recurrent angiogenic organs.

PubMed

Sidibé, Adama; Polena, Helena; Pernet-Gallay, Karin; Razanajatovo, Jeremy; Mannic, Tiphaine; Chaumontel, Nicolas; Bama, Soumalamaya; Maréchal, Irène; Huber, Philippe; Gulino-Debrac, Danielle; Bouillet, Laurence; Vilgrain, Isabelle

2014-08-01

Covalent modifications such as tyrosine phosphorylation are associated with the breakdown of endothelial cell junctions and increased vascular permeability. We previously showed that vascular endothelial (VE)-cadherin was tyrosine phosphorylated in vivo in the mouse reproductive tract and that Y685 was a target site for Src in response to vascular endothelial growth factor in vitro. In the present study, we aimed to understand the implication of VE-cadherin phosphorylation at site Y685 in cyclic angiogenic organs. To achieve this aim, we generated a knock-in mouse carrying a tyrosine-to-phenylalanine point mutation of VE-cadherin Y685 (VE-Y685F). Although homozygous VE-Y685F mice were viable and fertile, the nulliparous knock-in female mice exhibited enlarged uteri with edema. This phenotype was observed in 30% of females between 4 to 14 mo old. Histological examination of longitudinal sections of the VE-Y685F uterus showed an extensive disorganization of myometrium and endometrium with highly edematous uterine glands, numerous areas with sparse cells, and increased accumulation of collagen fibers around blood vessels, indicating a fibrotic state. Analysis of cross section of ovaries showed the appearance of spontaneous cysts, which suggested increased vascular hyperpermeability. Electron microscopy analysis of capillaries in the ovary showed a slight but significant increase in the gap size between two adjacent endothelial cell membranes in the junctions of VE-Y685F mice (wild-type, 11.5 ± 0.3, n = 78; and VE-Y685F, 12.48 ± 0.3, n = 65; P = 0.045), as well as collagen fiber accumulation around capillaries. Miles assay revealed that either basal or vascular endothelial growth factor-stimulated permeability in the skin was increased in VE-Y685F mice. Since edema and fibrotic appearance have been identified as hallmarks of initial increased vascular permeability, we conclude that the site Y685 in VE-cadherin is involved in the physiological regulation of capillary permeability. Furthermore, this knock-in mouse model is of potential interest for further studies of diseases that are associated with abnormal vascular permeability. Copyright © 2014 the American Physiological Society.

Management of long-term and reversible hysteroscopic sterilization: a novel device with nickel-titanium shape memory alloy

PubMed Central

2014-01-01

Background Female sterilization is the second most commonly used method of contraception in the United States. Female sterilization can now be performed through laparoscopic, abdominal, or hysteroscopic approaches. The hysteroscopic sterilization may be a safer option than sterilization through laparoscopy or laparotomy because it avoids invading the abdominal cavity and undergoing general anaesthesia. Hysteroscopic sterilization mainly includes chemical agents and mechanical devices. Common issues related to the toxicity of the chemical agents used have raised concerns regarding this kind of contraception. The difficulty of the transcervical insertion of such mechanical devices into the fallopian tubes has increased the high incidence of device displacement or dislodgment. At present, Essure® is the only commercially available hysteroscopic sterilization device being used clinically. The system is irreversible and is not effective immediately. Presentation of the hypothesis Our new hysteroscopic sterility system consists of nickel-titanium (NiTi) shape memory alloy and a waterproof membrane. The NiTi alloy is covered with two coatings to avoid toxic Ni release and to prevent stimulation of epithelial tissue growth around the oviducts. Because of the shape memory effect of the NiTi alloy, the device works like an umbrella: it stays collapsed at low temperature before placement and opens by the force of shape memory activated by the body temperature after it is inserted hysteroscopically into the interstitial tubal lumen. The rim of the open device will incise into interstitial myometrium during the process of unfolding. Once the device is fixed, it blocks the tube completely. When the patient no longer wishes for sterilization, the device can be closed by perfusing liquid with low temperature into the uterine cavity, followed by prospective hysteroscopic removal. After the device removal, the fallopian tube will revert to its physiological functions. Testing the hypothesis Currently, experimental and clinical studies are needed to attest the safety, efficiency and reversibility of the novel sterilization device. Implications of the hypothesis If our hypothesis is confirmed, appropriate and reversible contraceptive can be achieved with the device we have designed, which may have significant repercussions for numerous women worldwide. PMID:24999021

In vivo 3 T MR diffusion tensor imaging for detection of the fibre architecture of the human uterus: a feasibility and quantitative study

PubMed Central

Fiocchi, F; Nocetti, L; Siopis, E; Currà, S; Costi, T; Ligabue, G; Torricelli, P

2012-01-01

Objective The aim of this study was to investigate the feasibility of depicting fibre architecture of human uteri in vivo using 3 T MR diffusion tensor imaging (MR-DTI) with a three-dimensional (3D) tractography approach. Quantitative results were provided. Methods In vivo 3 T MR-DTI was performed on 30 volunteers (9 Caesarean delivery). Main diffusion directions reflecting the fibre orientation were determined using sensitivity-encoding single-shot echo planar imaging with diffusion-sensitised gradients (b=600 mm2 s−1) along 32 directions. A deterministic fibre-tracking algorithm was used to show in vivo fibre architecture, compared with ex vivo histological slides of cadaveric uteri. The number of fibres, the fibre density, the fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) were measured in 13 volunteers. Results Anisotropy was found in most regions of normal uteri and the preferential order of uterine fibres depicted, consisting of two representative fibre directions: circular and longitudinal, as in ex vivo studies. Two-thirds of uteri with a Caesarean scar did not have the same orientation of fibres in the anterior isthmus when compared with non-scarred myometrium. Quantitative data were obtained from 13 volunteers: Caesarean-scarred uteri (n=5) showed lower fibre number and density in the scarred anterior isthmus than the nulliparous uteri (n=8). No significant differences were found in FA (0.42±0.02, 0.41±0.02; p=0.25) and ADC (1.82±0.18×10−3 mm2 s−1, 1.93±0.25×10−3 mm2 s−1; p=0.20). Conclusion Fibre architecture of the human uterus can be depicted in vivo using 3 T MR-DTI. Advances in knowledge 3 T MR-DTI can help to provide an in vivo insight of uterine anatomy non-invasively, especially in females with previous Caesarean surgery, in order to provide better management of subsequent deliveries. PMID:22744322

Hysteroscopic enlargement metroplasty for T-shaped uterus: 24 years' experience at the Strasbourg Medico-Surgical and Obstetrical Centre (CMCO).

PubMed

Ducellier-Azzola, G; Lecointre, L; Hummel, M; Pontvianne, M; Garbin, O

2018-05-12

What is the impact of hysteroscopic enlargement metroplasty for T-shaped uterus on the live birth rate? Performing enlargement metroplasty appears to improve the obstetrical prognosis and fertility in patients with a T-shaped uterus. T-shaped uterus is linked to an excess of myometrium in the uterine walls giving rise to a subcornual constriction ring which causes dysmorphism and hypoplasia of the uterine cavity. It is commonly associated with infertility or a sequence of repeated miscarriages. Single-centre observational cohort study in 112 patients who underwent enlargement metroplasty for T-shaped uterus between 1992 and 2016 in a Strasbourg university hospital centre. The mean age of patients was 33.2; they had been attempting to conceive on average for 56 months for subfertile patients and 42.2 months for infertile patients. Prior to surgery, patients had succeeded in becoming pregnant 161 times, i.e. a mean gravidity of 1.4 pregnancies. For subfertile patients the mean gravidity was 2.67. Mean parity was 0.04. In the overall population, one hundred pregnancies occurred following enlargement metroplasty. The live birth rate increased in a statistically significant manner following enlargement metroplasty: 4 (2.5%) vs. 60 (60%), p < 0.05. In parallel, the miscarriage rate was statistically reduced: 126 (78.3%) vs. 22 (22%), pnull< .05. Intraoperative complications were 1 case of cervical laceration (0.9%) and 1 case of false passage (0.9%). Subsequent pregnancies remained at risk of miscarriage (22%) and premature delivery (20%) but not extra uterine gestation. Delivery took place by Caesarean section in 61% of cases. In the subgroup of infertile patients, the live birth rate was also markedly increased and 49% of pregnancies which occurred were spontaneous. This study was descriptive and retrospective. These results are consistent with those in the literature. Hysteroscopic enlargement metroplasty is now a well-established technique with few complications but which should nevertheless be reserved for symptomatic patients. Copyright © 2018 Elsevier B.V. All rights reserved.

[Perioperative management of abdominal aortic balloon occlusion in patients complicated with placenta percteta: a case report].

PubMed

Zeng, Hong; Wang, Yan; Wang, Yang; Guo, Xiang-yang

2015-12-18

When placenta previa complicated with placenta percreta, the exposure of operative field is difficult and the routine methods are difficult to effectively control the bleeding, even causing life-threatening results. A 31-year-old woman, who had been diagnosed with a complete type of placenta previa and placenta percreta with bladder invasion at 34 weeks gestation. Her ultrasound results showed a complete type of placenta previa and there was a loss of the decidual interface between the placenta and the myometrium on the lower part of the uterus, suggestive of placenta increta. For further evaluation of the placenta, pelvis magnetic resonance imaging was performed, which revealed findings suspicious of a placenta percreta. She underwent elective cecarean section at 36 weeks of gestation. Firstly, two ureteral stents were placed into the bilateral ureter through the cystoscope. After the infrarenal abdominal aorta catheter was inserted via the femoral artery (9 F sheath ), subarachnoid anesthesia had been established. A healthy 2 510 g infant was delivered, with Apgar scores of 10 at 1 min and 10 at 5 min. Immediately after the baby was delivered, following which there was massive haemorrhage and general anaesthesia was induced. The balloon catheter was immediately inflated until the wave of dorsal artery disappeared. With the placenta retained within the uterus, a total hysterectomy was performed. The occluding time was 30 min. The intraoperative blood loss was 2 500 mL. The occluding balloon was deflated at the end of the operation. The patient had stable vital signs and normal laboratory findings during the recovery period and the hemoglobin was 116 g/L. She was discharged six days after delivery without intervention-related complications. This case illustrates that temporary occlusion of the infrarenal abdominal aorta using balloon might be a safe and effective treatment option for patients with placenta previa complicated with placenta percreta, who were at high risk for peripartum hemorrhage. Early removal of the endovascular catheter and close postoperative surveillance of the vascular system are required with this procedure to minimize the risk of vascular complications. However, further studies are needed to determine whether the potential benefits of temporary occlusion of the infrarenal abdominal aorta using balloon outweigh the potential risks.

History of uterine leiomyomata and incidence of breast cancer

PubMed Central

Wise, Lauren A.; Radin, Rose G.; Rosenberg, Lynn; Adams-Campbell, Lucile; Palmer, Julie R.

2015-01-01

Purpose Uterine leiomyomata (UL), benign tumors of the myometrium, are influenced by sex steroid hormones. A history of UL diagnosis has been associated with a higher risk of uterine malignancies. The relation between UL and breast cancer, another hormonally-responsive cancer, has not been studied. Methods We investigated the association between self-reported physician-diagnosed UL and incidence of breast cancer in the Black Women's Health Study, a prospective cohort study. We followed 57,747 participants without a history of breast cancer from 1995 to 2013. UL diagnoses were reported at baseline and biennially. Breast cancer was reported on biennial questionnaires and confirmed by pathology data from medical records or cancer registries. Cox regression was used to derive incidence rate ratios (IRRs) and 95% confidence intervals (CI) and adjust for potential confounders. Results There were 2,276 incident cases of breast cancer (1,699 invasive, 394 in situ, and 183 unknown) during 879,672 person-years of follow-up. The multivariable IRR for the overall association between history of UL and breast cancer incidence was 0.99 (95% CI: 0.90-1.08), with similar results for ER+ (IRR=1.03) and ER− breast cancer (IRR=1.05). IRRs for early diagnosis of UL (before age 30) were slightly above 1.0, with IRRs of 1.14 (95% CI: 0.99-1.31) for overall breast cancer, 1.14 (95% CI: 0.93-1.40) for ER+ breast cancer, and 1.20 (95% CI: 0.89-1.61) for ER− breast cancer. IRRs for early diagnosis of UL were elevated for breast cancer diagnosed before age 40 years (IRR=1.39, 95% CI: 0.97-1.99) and premenopausal breast cancer (IRR=1.26, 95% CI: 1.01-1.58). No consistent patterns in risk were observed across estrogen receptor subtypes, and IRRs did not differ appreciably within strata of BMI, female hormone use, mammography recency, or family history of breast cancer. Conclusions The present study of U.S. black women suggests that a history of UL diagnosis is unrelated to the incidence of breast cancer overall. The positive associations observed for early-diagnosed UL with breast cancer before age 40 and with premenopausal breast cancer require confirmation in future studies. PMID:26250515

The effect of delaying childbirth on primary cesarean section rates.

PubMed

Smith, Gordon C S; Cordeaux, Yolande; White, Ian R; Pasupathy, Dharmintra; Missfelder-Lobos, Hannah; Pell, Jill P; Charnock-Jones, D Stephen; Fleming, Michael

2008-07-01

The relationship between population trends in delaying childbirth and rising rates of primary cesarean delivery is unclear. The aims of the present study were (1) to characterize the association between maternal age and the outcome of labor, (2) to determine the proportion of the increase in primary cesarean rates that could be attributed to changes in maternal age distribution, and (3) to determine whether the contractility of uterine smooth muscle (myometrium) varied with maternal age. We utilized nationally collected data from Scotland, from 1980 to 2005, and modeled the risk of emergency cesarean section among women delivering a liveborn infant in a cephalic presentation at term. We also studied isolated myometrial strips obtained from 62 women attending for planned cesarean delivery in Cambridge, England, from 2005 to 2007. Among 583,843 eligible nulliparous women, there was a linear increase in the log odds of cesarean delivery with advancing maternal age from 16 y upwards, and this increase was unaffected by adjustment for a range of maternal characteristics (adjusted odds ratio for a 5-y increase 1.49, 95% confidence interval [CI] 1.48-1.51). Increasing maternal age was also associated with a longer duration of labor (0.49 h longer for a 5-y increase in age, 95% CI 0.46-0.51) and an increased risk of operative vaginal birth (adjusted odds ratio for a 5-y increase 1.49, 95% CI 1.48-1.50). Over the period from 1980 to 2005, the cesarean delivery rate among nulliparous women more than doubled and the proportion of women aged 30-34 y increased 3-fold, the proportion aged 35-39 y increased 7-fold, and the proportion aged > or =40 y increased 10-fold. Modeling indicated that if the age distribution had stayed the same over the period of study, 38% of the additional cesarean deliveries would have been avoided. Similar associations were observed in multiparous women. When studied in vitro, increasing maternal age was associated with reduced spontaneous activity and increased likelihood of multiphasic spontaneous myometrial contractions. Delaying childbirth has significantly contributed to rising rates of intrapartum primary cesarean delivery. The association between increasing maternal age and the risk of intrapartum cesarean delivery is likely to have a biological basis.

SSR126768A (4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, hydrochloride): a new selective and orally active oxytocin receptor antagonist for the prevention of preterm labor.

PubMed

Serradeil-Le Gal, Claudine; Valette, Gérard; Foulon, Loïc; Germain, Guy; Advenier, Charles; Naline, Emmanuel; Bardou, Marc; Martinolle, Jean-Pierre; Pouzet, Brigitte; Raufaste, Danielle; Garcia, Corinne; Double-Cazanave, Eléonore; Pauly, Maxime; Pascal, Marc; Barbier, Alain; Scatton, Bernard; Maffrand, Jean-Pierre; Le Fur, Gérard

2004-04-01

4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide, hydrochloride (SSR126768A), a new potent and selective, orally active oxytocin (OT) receptor antagonist was characterized in several biochemical and pharmacological models. In binding studies, SSR126768A showed nanomolar affinity for rat and human recombinant and native OT receptors (K(i) = 0.44 nM) and exhibited much lower affinity for V(1a), V(1b), and V(2) receptors. In addition, it did not interact with a large number of other receptors, enzymes, and ion channels (1 microM). In autoradiographic experiments performed on at-term human pregnant uterus sections, SSR126768A dose dependently displaced [I(125)]d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8) (125)I-Tyr-NH(2)(9)]VT in situ labeling to OT receptors highly expressed in these tissues. In functional studies, SSR126768A behaved as a full antagonist and potently antagonized OT-induced intracellular Ca(2+) increase (K(i) = 0.50 nM) and prostaglandin release (K(i) = 0.45 nM) in human uterine smooth muscle cells. In rat isolated myometrium, OT-induced uterine contractions were competitively antagonized by SSR126768A (pA(2) = 8.47). Similarly, in human pregnant myometrial strips, SSR126768A inhibited the contractile uterine response to OT. In conscious telemetrated rats, oral administration of SSR126768A (1-10 mg/kg) produced a competitive inhibition of the dose response to OT on uterine contractions up to 24 h at 3 mg/kg p.o.; no tachyphylaxis was observed after 4-day repeated treatment. Finally, SSR126768A (30 mg/kg p.o.) significantly delayed parturition in pregnant rats in labor similar to ritodrine (10 mg/kg p.o.). Thus, SSR126768A is a potent, highly selective, orally active OT receptor antagonist with a long duration of action. This molecule could find therapeutic application as a tocolytic agent for acute and chronic oral management of preterm labor.

Modelling maternal obesity: the effects of a chronic high-fat, high-cholesterol diet on uterine expression of contractile-associated proteins and ex vivo contractile activity during labour in the rat.

PubMed

Muir, Ronan; Ballan, Jean; Clifford, Bethan; McMullen, Sarah; Khan, Raheela; Shmygol, Anatoly; Quenby, Siobhan; Elmes, Matthew

2016-02-01

Maternal obesity is associated with prolonged and dysfunctional labour and emergency caesarean section, but the mechanisms are unknown. The present study investigated the effects of an adiposity-inducing high-fat, high-cholesterol (HFHC) diet on uterine contractile-associated protein (CAP) expression and ex vivo uterine contractility in term non-labouring (TNL) and term labouring (TL) rats. Female rats were fed either control chow (CON n=20) or HFHC (n=20) diet 6 weeks before conception and during pregnancy. On gestational day 21 (TNL) or day 22 (TL) CON and HFHC (n=10) rats were killed to determine plasma cholesterol, triacylglycerol and progesterone concentrations and collection of myometrium for contractility studies and expression of CAPs caveolin-1 (Cav-1), connexin-43 (CX-43) and it's phosphorylated form (pCX-43), oxytocin receptor (OXTR) and cyclooxygenase-2 (COX-2). HFHC feeding increased visceral fat (P≤0.001), plasma cholesterol (P≤0.001) and triacylglycerol (P=0.039) concentrations. Stage of labour effected uterine expression of CAV-1 (P<0.02), pCX43 and COX-2 (both P<0.03). CAV-1 and pCX43 decreased but COX-2 increased with parturition. Significant diet- and labour-stage interactions were evident for CX-43 and pCX43 (P<0.03 and P<0.004 respectively). CX-43 decreased with TL in HFHC animals but was unaltered in CON. pCX-43 fell with labour in CON but remained high in HFHC. OXTR expression was significantly higher in HFHC compared with CON animals (P<0.03). Progesterone was higher in HFHC rats at term (P<0.014) but fell significantly with labour to similar concentrations as CON. Contractility studies identified synchronous contractions of stable amplitude in lean animals, but unstable asynchronous contractions with obesity. Uterine dose response to oxytocin was blunted during labour in HFHC rats with a log EC50 of -8.84 compared with -10.25 M in CON for integral activity (P<0.05). In conclusion, our adiposity model exhibits adverse effects on contractile activity during labour that can be investigated further to unravel the mechanisms causing uterine dystocia in obese women. © 2016 The Author(s).

History of uterine leiomyomata and incidence of breast cancer.

PubMed

Wise, Lauren A; Radin, Rose G; Rosenberg, Lynn; Adams-Campbell, Lucile; Palmer, Julie R

2015-10-01

Uterine leiomyomata (UL), benign tumors of the myometrium, are influenced by sex steroid hormones. A history of UL diagnosis has been associated with a higher risk of uterine malignancies. The relation between UL and breast cancer, another hormonally responsive cancer, has not been studied. We investigated the association between self-reported physician-diagnosed UL and incidence of breast cancer in the Black Women's Health Study, a prospective cohort study. We followed 57,747 participants without a history of breast cancer from 1995 to 2013. UL diagnoses were reported at baseline and biennially. Breast cancer was reported on biennial questionnaires and confirmed by pathology data from medical records or cancer registries. Cox regression was used to derive incidence rate ratios (IRRs) and 95 % confidence intervals (CI) and adjust for potential confounders. There were 2,276 incident cases of breast cancer (1,699 invasive, 394 in situ, and 183 unknown) during 879,672 person-years of follow-up. The multivariable IRR for the overall association between history of UL and breast cancer incidence was 0.99 (95 % CI 0.90-1.08), with similar results for ER + (IRR = 1.03) and ER - breast cancer (IRR = 1.05). IRRs for early diagnosis of UL (before age 30) were slightly above 1.0, with IRRs of 1.14 (95 % CI 0.99-1.31) for overall breast cancer, 1.14 (95 % CI 0.93-1.40) for ER + breast cancer, and 1.20 (95 % CI 0.89-1.61) for ER - breast cancer. IRRs for early diagnosis of UL were elevated for breast cancer diagnosed before 40 years of age (IRR = 1.39, 95 % CI 0.97-1.99) and premenopausal breast cancer (IRR = 1.26, 95 % CI 1.01-1.58). No consistent patterns in risk were observed across estrogen receptor subtypes, and IRRs did not differ appreciably within strata of BMI, female hormone use, mammography recency, or family history of breast cancer. The present study of US black women suggests that a history of UL diagnosis is unrelated to the incidence of breast cancer overall. The positive associations observed for early diagnosed UL with breast cancer before age 40 and with premenopausal breast cancer require confirmation in future studies.

Study of pharmacological properties of the methanolic extract of Dichrostachys cinerea bark (L.) Wight et Arn (Leguminosae) in isolated myometrium from pregnant rats.

PubMed

Aworet Samseny, Reine Rr; Angone, Sophie Aboughe; Madingou, Noreen Koumba; Mounanga, Marlaine Boukandou; Datté, Jacques Y

2015-07-01

The use of medicinal plants in Gabon contributes widely to the primary health care of the people of this area of Central Africa. This paper investigates the pharmacological properties of Dichrostachys cinerea, the plant barks are traditionally used by Gabonese and Ivorian populations to treat bronchial asthma, rheumatism, and other various diseases. Although D. cinerea barks have been reported to be used by population to facilitate childbirth, to the best of our knowledge no scientific evidence has been published. In the present study, we investigated the pharmacological properties of D. cinerea methanolic extract, on isolated uterine smooth muscle and compared its effects to those of oxytocin, which is used by obstetricians to facilitate childbirth. We also explored the possible mechanism pathways of the in vitro uterine contraction induced by D. cinerea. The effects of different concentrations (3.2µg/ml, 16µg/ml, 80µg/ml, 400µg/ml, and 2mg/ml) of the methanolic extract of D. cinerea on isolated strips of the uteri of pregnant rats were studied. These effects were compared to those of oxytocin (8.4×10(-5)µg/ml, 8.4×10(-4)µg/ml, 8.4×10(-3)µg/ml, 8.4×10(-2)µg/ml). The EC (50) and E (max) was determined graphically and statistically analysed using one-way ANOVA and Dunnett post hoc test. Cumulative concentrations of D. cinerea have caused rise in the contractile force of the uterine fragments that were isolated from the pregnant rats, as seen with oxytocin concentrations. We observed contractions amplitude of 30.41mN (12%) at 80µg/ml and amplitude of 39.68mN (14.17%) at 400µg/ml for D. cinerea. In parallel, oxytocin concentration of 8.4×10(-3)µg/ml induced contractions of 45.82mN with the highest concentration (8.4×10(-2)µg/ml) that induced contractions of 55.82mN. Our results revealed that D. cinerea increased the contractile force and the frequency of muscle contractions. These findings support the use of D. cinerea to facilitate childbirth, as it has been used in traditional medicine. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dynamic contrast enhanced MRI of the placenta: A tool for prenatal diagnosis of placenta accreta?

PubMed

Millischer, A E; Deloison, B; Silvera, S; Ville, Y; Boddaert, N; Balvay, D; Siauve, N; Cuenod, C A; Tsatsaris, V; Sentilhes, L; Salomon, L J

2017-05-01

Ultrasound (US) is the primary imaging modality for the diagnosis of placenta accreta, but it is not sufficiently accurate. MRI morphologic criteria have recently emerged as a useful tool in this setting, but their analysis is too subjective. Recent studies suggest that gadolinium enhancement may help to distinguish between the stretched myometrium and placenta within a scar area. However, objective MRI criteria are still required for prenatal diagnosis of placenta accreta. The purpose of this study was to assess the diagnostic value of dynamic contrast gadolinium enhancement (DCE) MRI patterns for placenta accreta. MR images were acquired with a 1.5-T unit at 30-35 weeks of gestation in women with a history of Caesarian section, a low-lying anterior placenta, and US features compatible with placenta accreta. Sagittal, axial and coronal SSFP (Steady State Free Precession) sequences were acquired before injection. Then, contrast-enhanced dynamic T1-weighted images were acquired through the entire cross-sectional area of the placenta. Images were obtained sequentially at 10- to 14-s intervals for 2 min, beginning simultaneously with the bolus injection. Functional analysis was performed retrospectively, and tissular relative enhancement parameters were extracted from the recorded images. The suspected area of accreta (SAA) was placed in the region of the previous scar, and a control area (CA) of similar size was placed on the same image plane, as far as possible from the SAA. Semi-quantitative analysis of DCE-MR images was based on the kinetic enhancement curves in these two regions of interest (ROI). Three tissular relative enhancement parameters were compared according to the pregnancy outcomes, namely time to peak, maximal signal intensity, and area under the enhancement curve. We studied 9 women (43%) with accreta and 12 women (57%) with a normal placenta. All three tissular relative enhancement parameters differed significantly between the two groups (p < 10 -3 ). The use of dynamic contrast-enhanced MRI at 30-35 weeks of gestation in women with a high risk of placenta accreta allows the extraction of tissular enhancement parameters that differ significantly between placenta accreta and normal placenta. It therefore provides objective parameters on which to base the diagnosis and patient management. Copyright © 2017. Published by Elsevier Ltd.

Downregulation of miR-29a/b/c in placenta accreta inhibits apoptosis of implantation site intermediate trophoblast cells by targeting MCL1.

PubMed

Gu, Yongzhong; Bian, Yuehong; Xu, Xiaofei; Wang, Xietong; Zuo, Changting; Meng, Jinlai; Li, Hongyan; Zhao, Shigang; Ning, Yunnan; Cao, Yongzhi; Huang, Tao; Yan, Junhao; Chen, Zi-Jiang

2016-12-01

Placenta accreta is defined as abnormal adhesion of placental villi to the uterine myometrium. Although this condition has become more common as a result of the increasing rate of cesarean sections, the underlying causative mechanism(s) remain elusive. Because microRNA-29a/b/c (miR-29a/b/c) have been shown to play important roles in placental development, this study evaluated the roles of these microRNAs in placenta accreta. Expression of miR-29a/b/c and myeloid cell leukemia-1 (MCL1) were quantified in patient tissues and HTR8/SVneo trophoblast cells using the real-time quantitative polymerase chain reaction. Western blotting was used to analyze expression of the MCL1 protein in HTR8/SVneo trophoblast cells with altered expression of miR-29a/b/c. To determine their role in apoptosis, miR-29a/b/c were overexpressed in HTR-8/SVneo cells, and levels of apoptosis were analyzed by flow cytometry. Luciferase activity assays were used to determine whether MCL1 is a target gene of miR-29a/b/c. Expression of miR-29a/b/c was significantly lower in creta sites compared to noncreta sites (p = 0.018, 0.041, and 0.022, respectively), but expression of MCL1 was upregulated in creta sites (p = 0.039). MCL1 expression was significantly downregulated in HTR-8/SVneo cells overexpressing miR-29a/b/c (p = 0.002, 0.008, and 0.013, respectively). Luciferase activity assays revealed that miR-29a/b/c directly target the 3' untranslated region of MCL1 in 293T cells. Over-expression of miR-29a/b/c induced apoptosis in the HTR-8/SVneo trophoblast cell line. Moreover, histopathological evaluation revealed that the number of implantation site intermediate trophoblast (ISIT) cells was increased in creta sites and that these cells were positive for MCL1. Our results demonstrate that in placenta accreta, miR-29a/b/c inhibits apoptosis of ISIT cells by targeting MCL1. These findings provide new insights into the pathogenesis of placenta accreta. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Effect of Delaying Childbirth on Primary Cesarean Section Rates

PubMed Central

Smith, Gordon C. S; Cordeaux, Yolande; White, Ian R; Pasupathy, Dharmintra; Missfelder-Lobos, Hannah; Pell, Jill P; Charnock-Jones, D. Stephen; Fleming, Michael

2008-01-01

Background The relationship between population trends in delaying childbirth and rising rates of primary cesarean delivery is unclear. The aims of the present study were (1) to characterize the association between maternal age and the outcome of labor, (2) to determine the proportion of the increase in primary cesarean rates that could be attributed to changes in maternal age distribution, and (3) to determine whether the contractility of uterine smooth muscle (myometrium) varied with maternal age. Methods and Findings We utilized nationally collected data from Scotland, from 1980 to 2005, and modeled the risk of emergency cesarean section among women delivering a liveborn infant in a cephalic presentation at term. We also studied isolated myometrial strips obtained from 62 women attending for planned cesarean delivery in Cambridge, England, from 2005 to 2007. Among 583,843 eligible nulliparous women, there was a linear increase in the log odds of cesarean delivery with advancing maternal age from 16 y upwards, and this increase was unaffected by adjustment for a range of maternal characteristics (adjusted odds ratio for a 5-y increase 1.49, 95% confidence interval [CI] 1.48–1.51). Increasing maternal age was also associated with a longer duration of labor (0.49 h longer for a 5-y increase in age, 95% CI 0.46–0.51) and an increased risk of operative vaginal birth (adjusted odds ratio for a 5-y increase 1.49, 95% CI 1.48–1.50). Over the period from 1980 to 2005, the cesarean delivery rate among nulliparous women more than doubled and the proportion of women aged 30–34 y increased 3-fold, the proportion aged 35–39 y increased 7-fold, and the proportion aged ≥40 y increased 10-fold. Modeling indicated that if the age distribution had stayed the same over the period of study, 38% of the additional cesarean deliveries would have been avoided. Similar associations were observed in multiparous women. When studied in vitro, increasing maternal age was associated with reduced spontaneous activity and increased likelihood of multiphasic spontaneous myometrial contractions. Conclusions Delaying childbirth has significantly contributed to rising rates of intrapartum primary cesarean delivery. The association between increasing maternal age and the risk of intrapartum cesarean delivery is likely to have a biological basis. PMID:18597550

Distinct Spatiotemporal Expression of Serine Proteases Prss23 and Prss35 in Periimplantation Mouse Uterus and Dispensable Function of Prss35 in Fertility

PubMed Central

Diao, Honglu; Xiao, Shuo; Li, Rong; Zhao, Fei; Ye, Xiaoqin

2013-01-01

PRSS23 and PRSS35 are homologous proteases originally identified in mouse ovaries. In the periimplantation mouse uterus, Prss23 was highly expressed in the preimplantation gestation day 3.5 (D3.5) uterine luminal epithelium (LE). It disappeared from the postimplantation LE and reappeared in the stromal compartment next to the myometrium on D6.5. It was undetectable in the embryo from D4.5 to D6.5 but highly expressed in the embryo on D7.5. Prss35 became detectable in the uterine stromal compartment surrounding the embryo on D4.5 and shifted towards the mesometrial side of the stromal compartment next to the embryo from D5.5 to D7.5. In the ovariectomized uterus, Prss23 was moderately and Prss35 was dramatically downregulated by progesterone and 17β-estradiol. Based on the expression of Prss35 in granulosa cells and corpus luteum of the ovary and the early pregnant uterus, we hypothesized that PRSS35 might play a role in female reproduction, especially in oocyte development, ovulation, implantation, and decidualization. This hypothesis was tested in Prss35(−/−) mice, which proved otherwise. Between wild type (WT) and Prss35(−/−) mice, superovulation of immature females produced comparable numbers of cumulus-oocyte complexes; there were comparable numbers of implantation sites detected on D4.5 and D7.5; there were no obvious differences in the expression of implantation and decidualization marker genes in D4.5 or D7.5 uteri. Comparable mRNA expression levels of a few known protease-related genes in the WT and Prss35(−/−) D4.5 uteri indicated no compensatory upregulation. Comparable litter sizes from WT × WT and Prss35 (−/−)× Prss35 (−/−) crosses suggested that Prss35 gene was unessential for fertility and embryo development. Prss35 gene has been linked to cleft lip/palate in humans. However, no obvious such defects were observed in Prss35(−/−) mice. This study demonstrates the distinct expression of Prss23 and Prss35 in the periimplantation uterus and the dispensable role of Prss35 in fertility and embryo development. PMID:23451081

A portrait of tissue phosphoprotein stability in the clinical tissue procurement process.

PubMed

Espina, Virginia; Edmiston, Kirsten H; Heiby, Michael; Pierobon, Mariaelena; Sciro, Manuela; Merritt, Barbara; Banks, Stacey; Deng, Jianghong; VanMeter, Amy J; Geho, David H; Pastore, Lucia; Sennesh, Joel; Petricoin, Emanuel F; Liotta, Lance A

2008-10-01

Little is known about the preanalytical fluctuations of phosphoproteins during tissue procurement for molecular profiling. This information is crucial to establish guidelines for the reliable measurement of these analytes. To develop phosphoprotein profiles of tissue subjected to the trauma of excision, we measured the fidelity of 53 signal pathway phosphoproteins over time in tissue specimens procured in a community clinical practice. This information provides strategies for potential surrogate markers of stability and the design of phosphoprotein preservative/fixation solutions. Eleven different specimen collection time course experiments revealed augmentation (+/-20% from the time 0 sample) of signal pathway phosphoprotein levels as well as decreases over time independent of tissue type, post-translational modification, and protein subcellular location (tissues included breast, colon, lung, ovary, and uterus (endometrium/myometrium) and metastatic melanoma). Comparison across tissue specimens showed an >20% decrease of protein kinase B (AKT) Ser-473 (p < 0.002) and myristoylated alanine-rich C-kinase substrate protein Ser-152/156 (p < 0.0001) within the first 90-min postexcision. Proteins in apoptotic (cleaved caspase-3 Asp-175 (p < 0.001)), proliferation/survival/hypoxia (IRS-1 Ser-612 (p < 0.0003), AMP-activated protein kinase beta Ser-108 (p < 0.005), ERK Thr-202/Tyr-204 (p < 0.003), and GSK3alphabeta Ser-21/9 (p < 0.01)), and transcription factor pathways (STAT1 Tyr-701 (p < 0.005) and cAMP response element-binding protein Ser-133 (p < 0.01)) showed >20% increases within 90-min postprocurement. Endothelial nitric-oxide synthase Ser-1177 did not change over the time period evaluated with breast or leiomyoma tissue. Treatment with phosphatase or kinase inhibitors alone revealed that tissue kinase pathways are active ex vivo. Combinations of kinase and phosphatase inhibitors appeared to stabilize proteins that exhibited increases in the presence of phosphatase inhibitors alone (ATF-2 Thr-71, SAPK/JNK Thr-183/Tyr-185, STAT1 Tyr-701, JAK1 Tyr-1022/1023, and PAK1/PAK2 Ser-199/204/192/197). This time course study 1) establishes the dynamic nature of specific phosphoproteins in excised tissue, 2) demonstrates augmented phosphorylation in the presence of phosphatase inhibitors, 3) shows that kinase inhibitors block the upsurge in phosphorylation of phosphoproteins, 4) provides a rational strategy for room temperature preservation of proteins, and 5) constitutes a foundation for developing evidence-based tissue procurement guidelines.

[Studies on antimicrobial concentrations of flomoxef in serum, pelvic dead space exudate, and pelvic organs/tissues].

PubMed

Obata, T; Koishi, K; Sasaki, J; Eguchi, M; Yamamoto, Y

1987-10-01

To women undergoing radical and total hysterectomy, flomoxef (FMOX, 6315-S) in a dose of 2 g was administered by intravenous drip infusion over 1 hour and drug concentrations in serum and pelvic dead space exudate as well as pelvic organs/tissues were determined over time. The following results were obtained: 1. Serum concentrations of FMOX after intravenous infusion showed the peak value of 92.86 +/- 17.05 micrograms/ml at the end of infusion and then gradually decreased to 29.00 +/- 10.49 micrograms/ml in 1 hour and 1.16 +/- 1.08 micrograms/ml in 6 hours. 2. Concentrations in pelvic dead space exudate, which were 6.54 +/- 3.21 micrograms/ml at the end of intravenous infusion, gradually increased to 31.28 +/- 12.69 micrograms/ml in 30 minutes, and the peak of 35.21 +/- 13.29 micrograms/ml in 1 hour. Exudate concentrations gradually decreased to 11.10 +/- 6.64 micrograms/ml at 6 hours after infusion. 3. The serum concentration at the ligature of uterine artery was 103.21 +/- 51.69 micrograms/ml. Among concentrations in pelvic organ/tissues 37.17 +/- 18.20 micrograms/ml in uterine cervix was the highest, followed by 35.77 +/- 7.68 micrograms/g in portio vaginalis, 26.35 +/- 14.15 micrograms/g in tube, 21.62 +/- 12.15 micrograms/g in ovary, 20.56 +/- 9.82 micrograms/g in myometrium, and 16.45 +/- 8.10 micrograms/g in endometrium, in this order. 4. From an analysis of the two-compartment model, the maximum serum concentration was 92.81 micrograms/ml, which was very high. The time of 50% reduction of concentration in beta phase was 1.21 hours. In the pelvic dead space exudate, the maximum concentration was 32.38 micrograms/ml and the time of 50% reduction was 2.44 hours. The AUC was 147 micrograms.hr/ml in serum and 201 micrograms.hr/ml in the pelvic dead space. The shift to the pelvic dead space was 137% when AUC's were used as the basis of the comparison. 5. Clinically, FMOX was excellently effective against adnexitis caused by Peptostreptococcus asaccharolyticus, intrauterine infection caused by Staphylococcus aureus, cystitis caused by Klebsiella and Escherichia coli, vaginal stump infection caused by Streptococcus and E. coli and many other infections.

Systematic analysis of gene expression pattern in has-miR-197 over-expressed human uterine leiomyoma cells.

PubMed

Ling, Jing; Wu, Xiaoli; Fu, Ziyi; Tan, Jie; Xu, Qing

2015-10-01

Our previous study showed that the expression of miR-197 in leiomyoma was down-regulated compared with myometrium. Further, miR-197 has been identified to affect uterine leiomyoma cell proliferation, apoptosis, and metastasis ability, though the responsible molecular mechanism has not been well elucidated. In this study, we sought to determine the expression patterns of miR-197 targeted genes and to explore their potential functions, participating Pathways and the networks that are involved in the biological behavior of human uterine leiomyoma. After transfection of human uterine leiomyoma cells with miR-197, we confirmed the expression level of miR-197 using quantitative real-time PCR (qRT-PCR), and we detected the gene expression profiles after miR-197 over-expression through DNA microarray analysis. Further, we performed GO and Pathway analysis. The dominantly dys-regulated genes, which were up- or down-regulated by more than 10-fold, compared with parental cells, were confirmed using qRT-PCR technology. Compared with the control group, miR-197 was up-regulated by 30-fold after miR-197 lentiviral transfection. The microarray data showed that 872 genes were dys-regulated by more than 2-fold in human uterine leiomyoma cells after miR-197 overexpression, including 537 up-regulated and 335 down-regulated genes. The GO analysis indicated that the dys-regulated genes were primarily involved in response to stimuli, multicellular organ processes, and the signaling of biological progression. Further, Pathway analysis data showed that these genes participated in regulating several signaling Pathways, including the JAK/STAT signaling Pathway, the Toll-like receptor signaling Pathway, and cytokine-cytokine receptor interaction. The qRT-PCR results confirmed that 17 of the 66 selected genes, which were up- or down-regulated more than 10-fold by miR-197, were consistent with the microarray results, including tumorigenesis-related genes, such as DRT7, SLC549, SFMBT2, FLJ37956, FBLN2, C10orf35, HOXD12, CACNG7, and LOC100134279. Our study explored gene expression patterns after miR-197 overexpression and confirmed 17 dominantly dys-regulated genes, which could expand the insights into the function of miR-197 and the molecular mechanisms during the development and progression of uterine leiomyomas. This study might afford new clues for understanding the pathogenesis of uterine leiomyomas, and it could likely provide a unique method for diagnosing or predicting prognosis in the clinical treatment of leiomyoma. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

The effect of DDT and its metabolite (DDE) on prostaglandin secretion from epithelial cells and on contractions of the smooth muscle of the bovine oviduct in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wrobel, Michal H.; Mlynarczuk, Jaroslaw; Kotwica, Jan, E-mail: janko@pan.olsztyn.pl

2012-03-01

The insecticide DDT and its metabolite (DDE), due to their lipolytic nature and resistance to biodegradation, are accumulated in the living tissues. In cows, DDT and DDE were found to affect prostaglandin (PG) secretion from the endometrium and contractions of the myometrium. In this study, the impact of both xenobiotics (0.1, 1, 10 or 100 ng/ml) on the function of epithelial cells and muscle strips of bovine oviducts from 1 to 5 day of the oestrous cycle was examined. Therefore the concentration of PGE2 and PGFM (a metabolite of PGF2α) in culture media, mRNA expression of genes involved in PGsmore » synthesis in epithelial cells and the force and amplitude of strips contractions were measured after 2 and 24 or 48 h of incubation. Neither DDT nor DDE affected the viability of cells after 48 h (P > 0.05). Both DDT and DDE increased the concentrations of PGFM in culture medium and secretion of PGE2 after only 2 h of cell culture (P < 0.05). Similar effects were seen for the influence of DDE on amount of PGFM after 48 h, while DDT decreased secretion of PGE2 (P < 0.05). DDT after 2 h increased (P < 0.05) mRNA expression of PGF2α synthase (PGFS), while both xenobiotics decreased (P < 0.05) mRNA expression of cyclooxygenase-2 (COX-2) after 24 h. DTT also increased the force of isthmus contractions after 2 h, as did both xenobiotics after 48 h (P < 0.05). Moreover, after 2 and 48 h, DDE stimulated the amplitude of contractions of the isthmus as well as the ampulla, (P < 0.05). The effect of both compounds on oviduct contractions was diminished by indomethacin, which blocks PG synthesis. We conclude that oviductal secretion of prostaglandins is affected, by DDT and DDE. The influence of these xenobiotics on PGF2α and PGE2 secretion and ratio may be part of the mechanism by which both DDT and its metabolite disturb the contractions of oviductal muscle. -- Highlights: ► DDT and its metabolite – DDE are accumulated in the living tissues. ► The insecticides affected PGF2α and PGE2 release from epithelial cells of oviduct. ► They also stimulated markedly the contractions of oviductal strips. ► Prostaglandins were involved in the effect of insecticides on oviduct function.« less

An ATP-gated cation channel with some P2Z-like characteristics in gastric smooth muscle cells of toad.

PubMed Central

Ugur, M; Drummond, R M; Zou, H; Sheng, P; Singer, J J; Walsh, J V

1997-01-01

1. Whole-cell and single-channel currents elicited by extracellular ATP were studied in freshly dissociated smooth muscle cells from the stomach of the toad Bufo marinus using standard patch clamp and microfluorimetric techniques. 2. This ATP-gated cation channel shares a number of pharmacological and functional properties with native rat myometrium receptors, certain native P2Z purinoceptors and the recently cloned P2X7 purinoceptor. But, unlike the last two, the ATP-gated channel does not mediate the formation of large non-specific pores. Thus, it may represent a novel member of the P2X or P2Z class. 3. Extracellular application of ATP (> or = 150 microM) elicited an inward whole-cell current at negative holding potentials that was inwardly rectifying and showed no sign of desensitization. Na+, Cs+ and, to a lesser degree, the organic cation choline served as charge carriers, but Cl- did not. Ratiometric fura-2 measurements indicated that the current is carried in part by Ca2+. The EC50 for ATP was 700 microM in solutions with a low divalent cation concentration. 4. ATP (> or = 100 microM) at the extracellular surface of cell-attached or excised patches elicited inwardly rectifying single-channel currents with a 22 pS conductance. Cl- did not serve as a charge carrier but both Na+ and Cs+ did, as did choline to a lesser extent. The mean open time of the channel was quite long, with a range in hundreds of milliseconds at a holding potential of -70 mV. 5. Mg2+ and Ca2+ decreased the magnitude of the ATP-induced whole-cell currents. Mg2+ decreased both the amplitude and the activity of ATP-activated single-channel currents. 6. ADP, UTP, P1, P5-di-adenosine pentaphosphate (AP5A), adenosine and alpha, beta-methylene ATP (alpha, beta-Me-ATP) did not induce significant whole-cell current. ATP-gamma-S and 2-methylthio ATP (2-Me-S-ATP) were significantly less effective than ATP in inducing whole-cell currents, whereas benzoylbenzoyl ATP (BzATP) was more effective. BzATP, alpha, beta-Me-ATP, ATP-gamma-S and 2-Me-S-ATP induced single-channel currents, but a higher concentration of alpha, beta-Me-ATP was required. 7. BzATP did not induce the formation of large non-specific pores, as assayed using mag-fura-2 as a high molecular mass probe. PMID:9032690

Effects of changing the ionic environment on passive and active membrane properties of pregnant rat uterus

PubMed Central

Abe, Y.

1971-01-01

1. In pregnant rat myometrium electrotonic potentials, produced by externally applied current, were recorded intracellularly. 2. The space constant, λ, was 1·8 mm, the time constant, τm, 120 msec. The values obtained on the 7th day and on the 20th day of pregnancy were the same. 3. The magnitude of the electrotonic potential and the time constant of the membrane were increased in the absence of potassium from the external solution and decreased by excess potassium. 4. The magnitude of the electrotonic potential and the time constant of the membrane were increased by the replacement of chloride with C6H5SO3- or SO42-, and decreased with NO3- or I- replacement. 5. When the sodium chloride was replaced with sucrose (16·7 mM sodium remaining in the buffers) the spontaneous spikes deteriorated and activity stopped within 30 min. However, for periods up to 4 hr, a spike of larger amplitude and faster rate of rise than in normal solution could be evoked when a depolarizing current was applied. 6. When the external calcium concentration was raised (5 and 10 mM) the amplitude and the rate of rise of the evoked spike were increased. They were decreased by reducing calcium. In zero calcium spontaneous activity stopped within 15 min. 7. The effects of calcium deficiency were much less marked and slower in onset when, simultaneously, the sodium concentration was reduced to 16·7 mM. 8. When calcium was replaced with strontium (2·5 mM), the membrane was depolarized and the duration of the spontaneous and evoked action potential was prolonged, mainly due to a slowed rate of repolarization. When the concentration of strontium was raised to 7·5 or 12·5 mM the membrane was hyperpolarized, the duration of the action potential became short and the amplitude of the spike was increased. 9. Addition of barium or the replacement of calcium with barium caused depolarization and oscillatory membrane activity. However, a spike could be evoked by applying conditioning hyperpolarization. 10. Manganese abolished the spontaneous and evoked spike. Tetrodotoxin had no effect. 11. The results show that rat uterus has cable-like properties. The action potential may be due to calcium entry, while sodium, by influencing the membrane potential in competition with calcium, may be involved in the spontaneous spike generation and the spread of excitation. PMID:5103422

Pre- and post-partum mild underfeeding influences gene expression in the reproductive tract of cyclic dairy cows.

PubMed

Valour, D; Hue, I; Degrelle, S A; Déjean, S; Marot, G; Dubois, O; Germain, G; Humblot, P; Ponter, A A; Charpigny, G; Grimard, B

2013-06-01

Undernutrition before and after calving has a detrimental effect on the fertility of dairy cows. The effect of nutritional stress was previously reported to influence gene expression in key tissues for metabolic health and reproduction such as the liver and the genital tract early after calving, but not at breeding, that is, between 70 and 90 days post-partum. This study investigated the effects of pre- and post-partum mild underfeeding on global gene expression in the oviduct, endometrium and corpus luteum of eight multiparous Holstein cows during the early and middle phases of an induced cycle 80 days post-partum. Four control cows received 100% of energy and protein requirements during the dry period and after calving, while four underfed received 80% of control diet. Oestrous synchronization treatment was used to induce ovulation on D80 post-partum. Oviducts, ovaries and the anterior part of each uterine horn were recovered surgically 4, 8, 12 and 15 days after ovulation. Corpora lutea were dissected from the ovaries, and the endometrium was separated from the stroma and myometrium in each uterine horn. The oviduct segments were comprised of ampulla and isthmus. RNAs from ipsi- and contralateral samples were pooled on an equal weight basis. In each tissue, gene expression was assessed on a custom bovine 10K array. No differentially expressed gene (DEG) in the corpus luteum was identified between underfed and control, conversely to 293 DEGs in the oviduct vs 1 in the endometrium under a false discovery rate (FDR) < 0.10 and 1370 DEGs vs 3, respectively, under FDR < 0.15. Additionally, we used dedicated statistics (regularized canonical correlation analysis) to correlate the post-partum patterns of six plasma metabolites and hormones related to energy metabolism measured weekly between calving and D80 with gene expression. High correlations were observed between post-partum patterns of IGF-1, insulin, β-hydroxybutyrate and the expression in the oviduct of genes related to reproductive system disease, connective tissue disorders and metabolic disease. Moreover, we found special interest in the literature to retinoic acid-related genes (e.g. FABP5/CRABP2) that might indicate abnormalities in post-partum tissue repair mechanisms. In conclusion, this experiment highlights relationships between underfeeding and gene expression in the oviduct and endometrium after ovulation in cyclic Holstein cows. This might help to explain the effect of mild undernutrition on fertilization failure and early embryonic mortality in post-partum dairy cows. © 2012 Blackwell Verlag GmbH.

Laparoscopic Myomectomy for a Plethora of Submucous Myomas.

PubMed

Paul, P G; Paul, George; Radhika, K T; Bulusu, Saumya; Shintre, Hemant

To demonstrate a laparoscopic myomectomy technique for the removal of multiple submucous myomas. A step-by-step demonstration of the surgical procedure (Canadian Task Force classification III-C). In cases of multiple submucous myomas, hysteroscopic resection of myomas might not be a viable option, especially in cases requiring fertility preservation. It may cause significant damage to the endometrial surface, leading to the formation of endometrial synechiae [1]. The procedure is technically challenging and requires prolonged operating time owing to impaired visibility and the need for repeated specimen removal. This can lead to complications, such as fluid overload and, rarely, air embolism [2]. Thus, laparoscopic myomectomy may be a better option in such cases [1]. A 30-year-old nulligravida presented with a 3-year history of heavy menstrual bleeding and dysmenorrhea. She had received no symptom relief with hormonal medications and magnetic resonance-guided focused ultrasound. On examination, she was anemic, and her uterus was enlarged to 16-weeks gravid size. Ultrasonography revealed an intramural fundal myoma of 6 × 4.2 cm and numerous submucous myomas of 1 to 3.2 cm. During hysteroscopy, multiple submucous myomas of varying sizes ranging from type 0 to type 1 were seen. On laparoscopy, an incision was made on the uterine fundus with an ultrasonic device after injecting vasopressin (20 U in 200 mL dilution), and the fundal myoma was enucleated. The incision was then extended to open the endometrial cavity for the removal of the submucous myomas. Most of the myomas were removed with mechanical force, along with the minimal use of ultrasonic energy. A total of 46 myomas were removed, and the myometrium was closed in 2 layers. The duration of the surgery was 210 minutes, and estimated blood loss was 850 mL. The patient did not require blood transfusion, but was advised to take hematinics. At a 6-month follow-up, the patient reported significant improvement in her symptoms. A repeat hysteroscopy revealed moderate synechiae in the midline and 2 small submucous myomas near the internal os. The synechiae were incised with hysteroscopic scissors, and the submucous myomas were resected with a bipolar resectoscope. The patient was advised to attempt conception after 2 months. Laparoscopic myomectomy is an alternative to hysteroscopic resection for multiple submucous myomas. A repeat hysteroscopy is useful for identifying any residual myomas and synechiae. Copyright © 2017 AAGL. Published by Elsevier Inc. All rights reserved.

Carcinoma of the endometrium.

PubMed

Southcott, B M

2001-01-01

The incidence of endometrial cancer is highest among relatively affluent Caucasians. Although it has a comparatively low mortality rate compared with other gynaecological cancers, it is capable of aggressive behaviour. Endometrial cancer is uncommon in premenopausal women. The incidence rises with age and is significantly increased when there is exposure to unopposed estrogen, including hormone replacement therapy (HRT). Even when HRT is given in the form of estrogen and cyclical progesterone there is probably some increased risk. The long term use of tamoxifen for breast cancer is also associated with an increased incidence of endometrial cancer. Transvaginal ultrasound and pipelle or hysteroscopy endometrial biopsies are tending to replace the traditional dilation and curettage in establishing a diagnosis. 90% of endometrial tumours are surgically resectable on presentation. This remains the first line management--minimally, a total abdominal hysterectomy and bi-lateral salpingo oophorectomy. Prognostic factors include the histological grade, the depth of invasion of the myometrium, the presence or absence of lymph-vascular space invasion and involved regional nodes, tumour volume, and the presence or absence of involvement of the cervix. The pelvis is a major anatomical site at risk of recurrence, and since cytotoxic chemotherapy and hormone therapies have limited effectiveness, radiotherapy is the adjuvant therapy of choice where adverse prognostic factors are present. A move towards more radical surgery--the addition of lymphadenectomy with a total abdominal hysterectomy and bi-lateral salpingo oophorectomy, may modify the value of adjuvant therapy and has highlighted the need to demonstrate the exact place of post operative radiotherapy in the management of endometrial cancer. The ASTEC trial in the UK, run by the Medical Research Council, has the dual aims of determining the benefit of lymphadenectomy and of post operative adjuvant radiotherapy in patients with endometrial cancer confined to the corpus. Patients who are not medically fit for surgery or who have inoperable disease are managed with radical radiotherapy but the results in both these groups are inferior to those obtained with radical surgery. Spread outside the pelvis to para-aortic nodes may still be salvaged with local irradiation, but systemic disease is incurable and treatment is largely palliative including consideration of local irradiation, hormone therapy or chemotherapy for symptomatic relief. As reliable techniques for diagnosis are refined an even larger proportion of patients will be diagnosed with early disease. This, together with the development of new cytotoxic agents and sophisticated radiotherapy techniques to reduce normal tissue morbidity, will require the establishment of further clinical trials to refine optimal management.

Lactate produced during labor modulates uterine inflammation via GPR81 (HCA1).

PubMed

Madaan, Ankush; Nadeau-Vallée, Mathieu; Rivera, Jose Carlos; Obari, Dima; Hou, Xin; Sierra, Estefania Marin; Girard, Sylvie; Olson, David M; Chemtob, Sylvain

2017-01-01

Uterine inflammatory processes trigger prolabor pathways and orchestrate on-time labor onset. Although essential for successful labor, inflammation needs to be regulated to avoid uncontrolled amplification and resolve postpartum. During labor, myometrial smooth muscle cells generate ATP mainly via anaerobic glycolysis, resulting in accumulation of lactate. Aside from its metabolic function, lactate has been shown to activate a G protein-coupled receptor, GPR81, reported to regulate inflammation. We therefore hypothesize that lactate produced during labor may act via GPR81 in the uterus to exert in a feedback manner antiinflammatory effects, to resolve or mitigate inflammation. We sought to investigate the role of lactate produced during labor and its receptor, GPR81, in regulating inflammation in the uterus. We investigated the expression of GPR81 in the uterus and the pharmacological role of lactate acting via GPR81 during labor, using shRNA-GPR81 and GPR81 -/- mice. (1) Uterine lactate levels increased substantially from 2 to 9 mmol/L during labor. (2) Immunohistological analysis revealed expression of GPR81 in the uterus with high expression in myometrium. (3) GPR81 expression increased during gestation, and peaked near labor. (4) In primary myometrial smooth muscle cell and ex vivo uteri from wild-type mice, lactate decreased interleukin-1β-induced transcription of key proinflammatory Il1b, Il6, Ccl2, and Pghs2; suppressive effects of lactate were not observed in cells and tissues from GPR81 -/- mice. (5) Conversely, proinflammatory gene expression was augmented in the uterus at term in GPR81 -/- mice and wild-type mice treated intrauterine with lentiviral-encoded shRNA-GPR81; GPR81 silencing also induced proinflammatory gene transcription in the uterus when labor was induced by endotoxin (lipopolysaccharide). (6) Importantly, administration to pregnant mice of a metabolically stable specific GPR81 agonist, 3,5-dihydroxybenzoic acid, decreased endotoxin-induced uterine inflammation, preterm birth, and associated neonatal mortality. Collectively, our data uncover a novel link between the anaerobic glycolysis and the control of uterine inflammation wherein the high levels of lactate produced during labor act on uterine GPR81 to down-regulate key proinflammatory genes. This discovery may represent a novel feedback mechanism to regulate inflammation during labor, and conveys a potential rationale for the use of GPR81 agonists to attenuate inflammation and resulting preterm birth. Copyright © 2016 Elsevier Inc. All rights reserved.

Continuous prostaglandin-F 2 infusion for middle-trimester abortion.

PubMed

Lauersen, N H; Wilson, K H

1973-05-26

Induction of midtrimester abortion with a continuous intravenous infusion of prostaglandin (PG) was described by Karim and Filshie and Roth-Brandel et al. in 1970, but the effective dose of PGF2alpha was associated with side effects severely limiting clinical usefulness. Karim and Sharma induced abortion by intravaginal PG, but again this route also seemed complicated by severe side effects. Independent reports followed of successful induction of midtrimester abortion by intraamniotic PGF2alpha and PGE2 with few side effects. Although we also successfully induced abortion in 20 patients with a single intraamniotic instillation of 40 mg PGF2alpha, there is a potential hazard in this method; i.e., PG may leak from the amniotic cavity around the catheter and pass in large quantity into the systemic circulation, resulting in undesirable, severe side effects. A more reasonable and effective method would be to inject the PGF2alpha directly at the target organ, the myometrium, by extraovular administration. Side effects could thus be minimized and effective doses of PG reduced. Such intrauterine extraovular administration of PG has been reported. The incidence of side effects was greatly reduced, although the instillation of PG was required every 1-3 hours and there were some incomplete abortions. The investigation of extraovular PGF2alpha administration for induction of abortion in gestations between 12 and 16 weeks has been especially interesting. The procedure outlined by Wiqvist and Bygdeman and Embrey and Hillier was the 1 that the authors followed initially. 250 mcg PGF2alpha was instilled initially and was followed by 750 mcg in 5 minutes and 1 mg in 30 minutes. 1 mg was then instilled at 6 hour intervals. However, the failure rate with this dosage schedule was quite high. There was a good initial uterine response, but during the administrationsat 12, 18, and 24 hours, the response diminished considerably . The frequency of administration was then increased to every 2-3 hours and the amount instilled was increased to 2-3 mg. Although somewhat more successful than the original dose schedule, this method was also unsatisfactory. It appeared from our results that the closer the injections, the higher the success rate. Thus, a brief case report is presented using continuous extraovular administration of PGF2alpha with a Harvard pump, and the results indicate it is quite satisfactory. The patients complained of very little pain and side effects have been slight. The mean abortion time for 15 patients was 14 hours. The mean time for multiparas, 11.7 hours, was faster than the 15.8 hours for primiparas.

Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.

PubMed

Paul, Jonathan W; Hua, Susan; Ilicic, Marina; Tolosa, Jorge M; Butler, Trent; Robertson, Sarah; Smith, Roger

2017-03-01

The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs. Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor. We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice. Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor-targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect. Our results demonstrate that oxytocin receptor-targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus. Copyright © 2016. Published by Elsevier Inc.

Role of nuclear progesterone receptor isoforms in uterine pathophysiology

PubMed Central

Patel, Bansari; Elguero, Sonia; Thakore, Suruchi; Dahoud, Wissam; Bedaiwy, Mohamed; Mesiano, Sam

2015-01-01

BACKGROUND Progesterone is a key hormonal regulator of the female reproductive system. It plays a major role to prepare the uterus for implantation and in the establishment and maintenance of pregnancy. Actions of progesterone on the uterine tissues (endometrium, myometrium and cervix) are mediated by the combined effects of two progesterone receptor (PR) isoforms, designated PR-A and PR-B. Both receptors function primarily as ligand-activated transcription factors. Progesterone action on the uterine tissues is qualitatively and quantitatively determined by the relative levels and transcriptional activities of PR-A and PR-B. The transcriptional activity of the PR isoforms is affected by specific transcriptional coregulators and by PR post-translational modifications that affect gene promoter targeting. In this context, appropriate temporal and cell-specific expression and function of PR-A and PR-B are critical for normal uterine function. METHODS Relevant studies describing the role of PRs in uterine physiology and pathology (endometriosis, uterine leiomyoma, endometrial cancer, cervical cancer and recurrent pregnancy loss) were comprehensively searched using PubMed, Cochrane Library, Web of Science, and Google Scholar and critically reviewed. RESULTS Progesterone, acting through PR-A and PR-B, regulates the development and function of the endometrium and induces changes in cells essential for implantation and the establishment and maintenance of pregnancy. During pregnancy, progesterone via the PRs promotes myometrial relaxation and cervical closure. Withdrawal of PR-mediated progesterone signaling triggers menstruation and parturition. PR-mediated progesterone signaling is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen on eutopic normal endometrium, and on ectopic implants in endometriosis. Similarly, ligand-activated PRs function as tumor suppressors in endometrial cancer cells through inhibition of key cellular signaling pathways required for growth. In contrast, progesterone via PR activation appears to increase leiomyoma growth. The exact role of PRs in cervical cancer is unclear. PRs regulate implantation and therefore aberrant PR function may be implicated in recurrent pregnancy loss (RPL). PRs likely regulate key immunogenic factors involved in RPL. However, the exact role of PRs in the pathophysiology of RPL and the use of progesterone for therapeutic benefit remains uncertain. CONCLUSIONS PRs are key mediators of progesterone action in uterine tissues and are essential for normal uterine function. Aberrant PR function (due to abnormal expression and/or function) is a major cause of uterine pathophysiology. Further investigation of the underlying mechanisms of PR isoform action in the uterus is required, as this knowledge will afford the opportunity to create progestin/PR-based therapeutics to treat various uterine pathologies. PMID:25406186

Expression of progesterone receptor protein in the ovine uterus during the estrous cycle: Effects of nutrition, arginine and FSH.

PubMed

Grazul-Bilska, Anna T; Thammasiri, Jiratti; Kraisoon, Aree; Reyaz, Arshi; Bass, Casie S; Kaminski, Samantha L; Navanukraw, Chainarong; Redmer, Dale A

2018-03-01

To evaluate expression of progesterone receptor (PGR) AB in follicle stimulating hormone (FSH)-treated or non-treated sheep administered with arginine (Arg) or saline (Sal) fed a control (C), excess (O) or restricted (U) diet, uterine tissues were collected at the early, mid and/or late luteal phases. In exp. 1, ewes from each diet were randomly assigned to one of two treatments, Arg or Sal administration three times daily from day 0 of the first estrous cycle until uterine tissue collection. In exp. 2, ewes were injected twice daily with FSH on days 13-15 of the first estrous cycle. Uterine tissues were immunostained to detect PGR followed by image analysis. PGR were detected in luminal epithelium (LE), endometrial glands (EG), endometrial stroma (ES), myometrium (Myo), and endometrial and myometrial blood vessels. The percentage of PR-positive cells and/or intensity of staining were affected by phase of the estrous cycle, plane of nutrition, and/or FSH but not by Arg. In exp. 1, percentage of PGR-positive cells in LE and EG but not in ES and Myo was greater at the early and mid than late luteal phase, was not affected by plane of nutrition, and was similar in LE and EG. Intensity of staining was affected by phase of the estrous cycle and plane of nutrition in LE, EG and Myo, and was the greatest in LE, less in EG, and least in ES and Myo. In exp. 2, percentage of PGR-positive cells in LE, EG, ES and Myo was affected by phase of the estrous cycle, but not by plane of nutrition; was greater at the early than mid luteal phase; and was greatest in LE and EG, less in luminal (superficial) ES and Myo and least in deep ES. Intensity of staining was affected by phase of the estrous cycle and plane of nutrition in all compartments but ES, and was the greatest in LE and luminal EG, less in deep EG, and least in ES and Myo. Comparison of data for FSH (superovulated) and Sal-treated (non-superovulated) ewes demonstrated that FSH affected PR expression in all evaluated uterine compartments depending on plane of nutrition and phase of the estrous cycle. Thus, PGR are differentially distributed in uterine compartments, and PGR expression is affected by nutritional plane and FSH, but not Arg depending on phase of the estrous cycle. Such changes in dynamics of PGR expression indicate that diet plays a regulatory role and that FSH-treatment may alter uterine functions. Copyright © 2017 Elsevier Inc. All rights reserved.

Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface.

PubMed

Bukowski, Radek; Sadovsky, Yoel; Goodarzi, Hani; Zhang, Heping; Biggio, Joseph R; Varner, Michael; Parry, Samuel; Xiao, Feifei; Esplin, Sean M; Andrews, William; Saade, George R; Ilekis, John V; Reddy, Uma M; Baldwin, Donald A

2017-01-01

Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, research of the preterm birth is hindered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. Here we comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor in tissues comprising the pregnancy using precisely phenotyped samples. The four complementary phenotypes together provide comprehensive insight into preterm and term parturition. Samples of maternal blood, chorion, amnion, placenta, decidua, fetal blood, and myometrium from the uterine fundus and lower segment ( n  = 183) were obtained during cesarean delivery from women with four complementary phenotypes: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). Enrolled were 35 pregnant women with four precisely and prospectively defined phenotypes: PL ( n  = 8), PNL ( n  = 10), TL ( n  = 7) and TNL ( n  = 10). Gene expression data were analyzed using shrunken centroid analysis to identify a minimal set of genes that uniquely characterizes each of the four phenotypes. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified each of the four phenotypes. The shrunken centroid analysis and 10 times 10-fold cross-validation was also used to minimize false positive finings and overfitting. Identified were the pathways and molecular processes associated with and the cis-regulatory elements in gene's 5' promoter or 3'-UTR regions of the set of genes which expression uniquely characterized the four phenotypes. The largest differences in gene expression among the four groups occurred at maternal fetal interface in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5'and 3' UTR regions. The results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection.

Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface

PubMed Central

Sadovsky, Yoel; Goodarzi, Hani; Zhang, Heping; Biggio, Joseph R.; Varner, Michael; Parry, Samuel; Xiao, Feifei; Esplin, Sean M.; Andrews, William; Saade, George R.; Ilekis, John V.; Reddy, Uma M.; Baldwin, Donald A.

2017-01-01

Background Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, research of the preterm birth is hindered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. Here we comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor in tissues comprising the pregnancy using precisely phenotyped samples. The four complementary phenotypes together provide comprehensive insight into preterm and term parturition. Methods Samples of maternal blood, chorion, amnion, placenta, decidua, fetal blood, and myometrium from the uterine fundus and lower segment (n = 183) were obtained during cesarean delivery from women with four complementary phenotypes: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). Enrolled were 35 pregnant women with four precisely and prospectively defined phenotypes: PL (n = 8), PNL (n = 10), TL (n = 7) and TNL (n = 10). Gene expression data were analyzed using shrunken centroid analysis to identify a minimal set of genes that uniquely characterizes each of the four phenotypes. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified each of the four phenotypes. The shrunken centroid analysis and 10 times 10-fold cross-validation was also used to minimize false positive finings and overfitting. Identified were the pathways and molecular processes associated with and the cis-regulatory elements in gene’s 5′ promoter or 3′-UTR regions of the set of genes which expression uniquely characterized the four phenotypes. Results The largest differences in gene expression among the four groups occurred at maternal fetal interface in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5′and 3′ UTR regions. Conclusions The results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection. PMID:28879060

Serum lactate dehydrogenase profile as a retrospective indicator of uterine preparedness for labor: a prospective, observational study

PubMed Central

2013-01-01

Background Lactate dehydrogenase (LDH) isoenzymes are required for adenosine triphosphate production, with each of five different isoenzymes having varying proficiencies in anaerobic versus aerobic environments. With advancing pregnancy, the isoenzyme profile in uterine muscle shifts toward a more anaerobic profile, speculatively to facilitate uterine efficiency during periods of low oxygen that accompany labor contractions. Profile shifting may even occur throughout labor. Maternal serum LDH levels between 24–48 hours following delivery predominantly originate from uterine muscle, reflecting the enzymatic state of the myometrium during labor. Our purpose was to describe serum LDH isoenzymes 24–30 hours post-delivery to determine if cervical dilation rates following labor admission were associated with a particular LDH profile. We also compared differences in post-delivery LDH isoenzyme profiles between women admitted in pre-active versus established active labor. Methods Low-risk, nulliparous women with spontaneous labor onset were sampled (n = 91). Maternal serum LDH was measured at labor admission and 24–30 hours post-vaginal delivery. Rates of cervical dilation during the first four hours after admission were also measured. Spearman’s rho coefficients were used for association testing and t tests evaluated for group and paired-sample differences. Results More efficient dilation following admission was associated with decreased LDH1 (p = 0.029) and increased LDH3 and LDH4 (p = 0.017 and p = 0.017, respectively) in the post-delivery period. Women admitted in established active labor had higher relative serum levels of LDH3 (t = 2.373; p = 0.023) and LDH4 (t = 2.268; p = 0.029) and lower levels of LDH1 (t = 2.073; p = 0.045) and LDH5 (t = 2.041; p = 0.048) when compared to women admitted in pre-active labor. Despite having similar dilatations at admission (3.4 ± 0.5 and 3.7 ± 0.6 cm, respectively), women admitted in pre-active labor had longer in-hospital labor durations (12.1 ± 4.3 vs. 5.3 ± 1.4 hours; p < 0.001) and were more likely to receive oxytocin augmentation (95.5% vs. 34.8%; p < 0.001). Conclusions More efficient cervical dilation following labor admission is associated with a more anaerobic maternal serum LDH profile in the post-delivery period. Since LDH profile shifting may occur throughout labor, watchful patience rather than intervention in earlier labor may allow LDH shifting within the uterus to more fully manifest. This may improve uterine efficiency during labor and decrease rates of oxytocin augmentation, thereby improving birth safety. PMID:23759027

[The first Mexican consensus of endometrial cancer. Grupo de Investigación en Cáncer de Ovario y Tumores Ginecológicos de México].

PubMed

Ruvalcaba-Limón, Eva; Cantú-de-León, David; León-Rodríguez, Eucario; Cortés-Esteban, Patricia; Serrano-Olvera, Alberto; Morales-Vásquez, Flavia; Sosa-Sánchez, Ricardo; Poveda-Velasco, Andrés; Crismatt-Zapata, Alejandro; Santillán-Gómez, Antonio; Aguilar-Jiménez, Carmen; Alanís-López, Patricia; Alfaro-Ramírez, Paulino; Alvarez-Avitia, Miguel Angel; Aranda-Flores, Carlos Eduardo; Arias-Ceballos, José Héctor Reynaldo; Arrieta-Rodríguez, Oscar; Barragán-Curiel, Eduardo; Botello-Hernández, Daniel; Brom-Valladares, Rocío; Cabrera-Galeana, Paula Anel; Cantón-Romero, Juan Carlos; Capdeville-García, Daniel; Cárdenas-Sánchez, Jesús; Castorena-Roji, Gerardo; Cepeda-López, Friedman Rafael; Cervantes-Sánchez, Guadalupe; Cetina-Pérez, Lucely de Carmen; Coronel-Martínez, Jaime Alberto; Cortés-Cárdenas, Seir Alfonso; Cruz-López, Juan Carlos; de la Garza-Salazar, Jaime G; Díaz-Romero, Consuelo; Dueñas-González, Alfonso; Valle-Solís, Aura Erazo; Escudero-de los Ríos, Pedro; Flores-Alvarez, Efrén; García-Matus, Rolando; Gerson-Cwilich, Raquel; González-Enciso, Aarón; González-de-León, César; Guevara-Torres, Alfonso Genaro; Herbert-Núñez, Guillermo Sidney; Hernández-Hernández, Carlos; Hernández-Hernández, Dulce María; Isla-Ortiz, David; Jesús-Sandoval, Ramiro; Jiménez-Cervantes, Carlos; Kuri-Exsome, Roberto; López-Obispo, José Luis; Maffuz-Aziz, Antonio; Martínez-Barrera, Luis Manuel; Medina-Castro, Juan Manuel; Montalvo-Esquivel, Gonzalo; Mora-Aguilar, Víctor Hugo; Morales-Palomares, Miguel Angel; Morán-Mendoza, Andrés; Morgan-Villela, Gilberto; Mota-García, Aída; Muñoz-González, David Eduardo; Murillo-Cruz, Dino Alberto; Novoa-Vargas, Arturo; Ochoa-Carrillo, Francisco J; Oñate-Ocaña, Luis Fernando; Ortega-Rojo, Andrea; Palacios-Martínez, Alma Georgina; Palomeque-López, Antonio; Pérez-Montiel, María Delia; Quijano-Castro, Félix; Rivera-Rivera, Samuel; Rivera-Rubí, Lesbia María; Robles-Flores, Juan Ubaldo; Rodríguez-Trejo, Amelia; Salas-Gonzáles, Efraín; Silva, Juan Alejandro; Solorza-Luna, Gilberto; Souto-del-Bosque, Rosalía; Tirado-Gómez, Laura Leticia; Torrescano-González, Salvador; Torres-Lobatón, Alfonso; Trejo-Durán, Elizabeth; Villavicencio-Valencia, Verónica; Gallardo-Rincón, Dolores

2010-01-01

Endometrial cancer (EC) is the second most common gynecologic malignancy worldwide in the peri and postmenopausal period. Most often for the endometrioid variety. In early clinical stages long-term survival is greater than 80%, while in advanced stages it is less than 50%. In our country there is not a standard management between institutions. GICOM collaborative group under the auspice of different institutions have made the following consensus in order to make recommendations for the management of patients with this type of neoplasm. The following recommendations were made by independent professionals in the field of Gynecologic Oncology, questions and statements were based on a comprehensive and systematic review of literature. It took place in the context of a meeting of four days in which a debate was held. These statements are the conclusions reached by agreement of the participant members. Screening should be performed women at high risk (diabetics, family history of inherited colon cancer, Lynch S. type II). Endometrial thickness in postmenopausal patients is best evaluated by transvaginal US, a thickness greater than or equal to 5 mm must be evaluated. Women taking tamoxifen should be monitored using this method. Abnormal bleeding in the usual main symptom, all post menopausal women with vaginal bleeding should be evaluated. Diagnosis is made by histerescopy-guided biopsy. Magnetic resonance is the best image method as preoperative evaluation. Frozen section evaluates histologic grade, myometrial invasion, cervical and adnexal involvement. Total abdominal hysterectomy, bilateral salpingo oophorectomy, pelvic and para-aortic lymphadenectomy should be performed except in endometrial histology grades 1 and 2, less than 50% invasion of the myometrium without evidence of disease out of the uterus. Omentectomy should be done in histologies other than endometriod. Surgery should be always performed by a Gynecologic Oncologist or Surgical Oncologist, laparoscopy is an alternative, especially in patients with hypertension and diabetes for being less morbid. Adjuvant treatment after surgery includes radiation therapy to the pelvis, brachytherapy, and chemotherapy. Patients with Stages III and IV should have surgery with intention to achieve optimal cytoreduction because of the impact on survival (51 m vs. 14 m), the treatment of recurrence can be with surgery depending on the pattern of relapse, systemic chemotherapy or hormonal therapy. Follow-up of patients is basically clinical in a regular basis. Screening programme is only for high risk patients. Multidisciplinary treatment impacts on survival and local control of the disease, including surgery, radiation therapy and chemotherapy, hormonal treatment is reserved to selected cases of recurrence. This is the first attempt of a Mexican Collaborative Group in Gynecology to give recommendations is a special type of neoplasm.

The study of progesterone action in human myometrial explants

PubMed Central

Georgiou, E.X.; Lei, K.; Lai, P.F.; Yulia, A.; Herbert, B.R.; Castellanos, M.; May, S.T.; Sooranna, S.R.; Johnson, M.R.

2016-01-01

STUDY HYPOTHESIS Myometrial explants represent a superior model compared with cell culture models for the study of human myometrial progesterone (P4) signalling in parturition. STUDY FINDING Gene expression analysis showed myometrial explants closely resemble the in vivo condition and the anti-inflammatory action of P4 is not lost with labour onset. WHAT IS KNOWN ALREADY Circulating P4 levels decline before the onset of parturition in most animals, but not in humans. This has led to the suggestion that there is a functional withdrawal of P4 action at the myometrial level prior to labour onset. However, to date, no evidence of a loss of P4 function has been provided, with studies hampered by a lack of a physiologically relevant model. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Myometrial biopsies obtained at Caesarean section were dissected into explants after a portion was immediately snap frozen (t = 0). Microarray analysis was used to compare gene expression of t = 0 with paired (i) explants, (ii) passage 4 myometrial cell cultures or (iii) the hTERT myometrial cell line. Western blotting and chemokine/cytokine assays were used to study P4 signalling in myometrial explants. MAIN RESULTS AND THE ROLE OF CHANCE Gene expression comparison of t = 0 to the three models demonstrated that explants more closely resemble the in vivo status. At the protein level, explants maintain both P4 receptor (PR) and glucocorticoid receptor (GR) levels versus t = 0 whereas cells only maintain GR levels. Additionally, treatment with 1 µM P4 led to a reduction in interleukin-1 (IL-1) β-driven cyclooxygenase-2 in explants but not in cells. P4 signalling in explants was PR-mediated and associated with a repression of p65 and c-Jun phosphorylation. Furthermore, the anti-inflammatory action of P4 was maintained after labour onset. LIMITATIONS/REASONS FOR CAUTION There is evidence of basal inflammation in the myometrial explant model. WIDER IMPLICATIONS OF THE FINDINGS Myometrial explants constitute a novel model to study P4 signalling in the myometrium and can be used to further elucidate the mechanisms of P4 action in human labour. LARGE SCALE DATA Data deposited at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=gvmpggkurbgxfqf&acc=GSE77830. STUDY FUNDING AND COMPETING INTEREST This work was supported by grants from the Joint Research Committee of the Westminster Medical School Research Trust, Borne (No. 1067412-7; a sub-charity of the Chelsea and Westminster Health Charity) and the Imperial NIHR Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS or the Department of Health. The authors have no conflict of interest. PMID:27235325

[Application of uterine lower part breakwater-like suture operation in placenta previa].

PubMed

Zhao, Y; Zhu, J W; Wu, D; Wang, Q H; Lu, S S; Liu, X X; Zou, L

2018-04-25

Objective: To explore the efficacy and safety of uterine lower posterior wall breakwater-like suture technique in controlling the intraoperative bleeding of placenta previa. Methods: From June 2016 to June 2017, 47 patients were diagnosed placenta previa in Union Hospital, Tongji Medical College of Huazhong University of Science and Technology. Posterior wall breakwater-like suture technique was used preferentially, as for cases with poor myometrium layer, lower anterior wall stitch suture was used at the same time. Bilateral descending branches of uterine artery ligation and Cook balloon compression of uterine lower segment was conducted when necessary. The clinic data of the 47 cases were analyzed. Results: Thirty cases (63.8, 30/47) were diagnosed placenta inccreta or percreta by ultrasound or MRI preoperatively. Senventeen cases were diagnosed as placenta accreta (36.2%, 17/47) . Thirty-four cases had the previous history of cesarean section. The average cervical canal length of 47 patients was (2.8±0.9) cm. There were 19 cases (40.4%,19/47) with 1 time posterior wall breakwater-like sutured and 16 cases (34.0%,16/47) with 2 or 3 times posterior wall breakwater-like sutured; 12 cases (25.5%,12/47) were treated with anterior wall stitch suture simultaneously.Ten cases (21.3%, 10/47) underwent uterine artery ligation, 17 cases (36.2%, 17/47) underwent COOK balloon compression on the staxis surface of lower segment. None of them had postpartum hemorrhage or performed internal iliac artery embolization. The median blood loss in the operation was 700 ml, the percentiles 25 was 500 ml, and the percentiles 75 was 1 200 ml. The blood loss ≥1 000 ml in 18 (38.3%, 18/47) patients,and the most serious one was 2 500 ml. The median blood transfusion volume (including allogenetic transfusion and autotransfusion) was 450 ml, the percentiles 25 was 228 ml, and the percentiles 75 was 675 ml. The average vaginal bleeding volume was (150±63) ml first day after operation. The mean hospitalization time was (4.7±1.0) days. The mean gestational weeks of pregnancy termination was (36.1±1.5) weeks, and the mean birth weight of newborns was (2 817±492) g. Apgar score:1-minute 7.8±1.1, 5-minute 8.9±0.8. No neonatal death, 16 cases were transferred to neonatal ICU (34.0%, 16/47) mainly for premature delivery and low birth weight. No complication was found in 6 months post-operation. Conclusions: Uterine posterior wall breakwater-like suture technique is a simple, safe and effective way in controlling intraoperative bleeding of placental previa.Lower anterior wall stitch suture could effectively stop bleeding and restore the normal uterine shape. Combined application of various methods could significantly reduce the incidence of postpartum hemorrhage and hysterectomy, and improve maternal and fetal prognosis.

Pre-clinical evaluation of a nanoparticle-based blood-pool contrast agent for MR imaging of the placenta.

PubMed

Ghaghada, Ketan B; Starosolski, Zbigniew A; Bhayana, Saakshi; Stupin, Igor; Patel, Chandreshkumar V; Bhavane, Rohan C; Gao, Haijun; Bednov, Andrey; Yallampalli, Chandrasekhar; Belfort, Michael; George, Verghese; Annapragada, Ananth V

2017-09-01

Non-invasive 3D imaging that enables clear visualization of placental margins is of interest in the accurate diagnosis of placental pathologies. This study investigated if contrast-enhanced MRI performed using a liposomal gadolinium blood-pool contrast agent (liposomal-Gd) enables clear visualization of the placental margins and the placental-myometrial interface (retroplacental space). Non-contrast MRI and contrast-enhanced MRI using a clinically approved conventional contrast agent were used as comparators. Studies were performed in pregnant rats under an approved protocol. MRI was performed at 1T using a permanent magnet small animal scanner. Pre-contrast and post-liposomal-Gd contrast images were acquired using T1-weighted and T2-weighted sequences. Dynamic Contrast enhanced MRI (DCE-MRI) was performed using gadoterate meglumine (Gd-DOTA, Dotarem ® ). Visualization of the retroplacental clear space, a marker of normal placentation, was judged by a trained radiologist. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated for both single and averaged acquisitions. Images were reviewed by a radiologist and scored for the visualization of placental features. Contrast-enhanced CT (CE-CT) imaging using a liposomal CT agent was performed for confirmation of the MR findings. Transplacental transport of liposomal-Gd was evaluated by post-mortem elemental analysis of tissues. Ex-vivo studies in perfused human placentae from normal, GDM, and IUGR pregnancies evaluated the transport of liposomal agent across the human placental barrier. Post-contrast T1w images acquired with liposomal-Gd demonstrated significantly higher SNR (p = 0.0002) in the placenta compared to pre-contrast images (28.0 ± 4.7 vs. 6.9 ± 1.8). No significant differences (p = 0.39) were noted between SNR in pre-contrast and post-contrast liposomal-Gd images of the amniotic fluid, indicating absence of transplacental passage of the agent. The placental margins were significantly (p < 0.001) better visualized on post-contrast liposomal-Gd images. DCE-MRI with the conventional Gd agent demonstrated retrograde opacification of the placenta from fetal edge to the myometrium, consistent with the anatomy of the rat placenta. However, no consistent and reproducible visualization of the retroplacental space was demonstrated on the conventional Gd-enhanced images. The retroplacental space was only visualized on post-contrast T1w images acquired using the liposomal agent (SNR = 15.5 ± 3.4) as a sharply defined, hypo-enhanced interface. The retroplacental space was also visible as a similar hypo-enhancing interface on CE-CT images acquired using a liposomal CT contrast agent. Tissue analysis demonstrated undetectably low transplacental permeation of liposomal-Gd, and was confirmed by lack of permeation through a perfused human placental model. Contrast-enhanced T1w-MRI performed using liposomal-Gd enabled clear visualization of placental margins and delineation of the retroplacental space from the rest of the placenta; the space is undetectable on non-contrast imaging and on post-contrast T1w images acquired using a conventional, clinically approved Gd chelate contrast agent. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibition of PIM1 kinase attenuates inflammation-induced pro-labour mediators in human foetal membranes in vitro.

PubMed

Lim, Ratana; Barker, Gillian; Lappas, Martha

2017-06-01

Does proviral integration site for Moloney murine leukaemic virus (PIM)1 kinase play a role in regulating the inflammatory processes of human labour and delivery? PIM1 kinase plays a critical role in foetal membranes in regulating pro-inflammatory and pro-labour mediators. Infection and inflammation have strong causal links to preterm delivery by stimulating pro-inflammatory cytokines and collagen degrading enzymes, which can lead to rupture of membranes. PIM1 has been shown to have a role in immune regulation and inflammation in non-gestational tissues; however, its role has not been explored in the field of human labour. PIM1 expression was analysed in myometrium and/or foetal membranes obtained at term and preterm (n = 8-9 patients per group). Foetal membranes, freshly isolated amnion cells and primary myometrial cells were used to investigate the effect of PIM1 inhibition on pro-labour mediators (n = 5 patients per treatment group). Foetal membranes, from term and preterm, were obtained from non-labouring and labouring women, and from preterm pre-labour rupture of membranes (PPROM) (n = 9 per group). Amnion was collected from women with and without preterm chorioamnionitis (n = 8 per group). Expression of PIM1 kinase was determined by qRT-PCR and western blotting. To determine the effect of PIM1 kinase inhibition on the expression of pro-inflammatory and pro-labour mediators induced by bacterial products lipopolysaccharide (LPS) (10 μg/ml) and flagellin (1 μg/ml) and pro-inflammatory cytokine tumour necrosis factor (TNF) (10 ng/ml), chemical inhibitors SMI-4a (20 μM) and AZD1208 (50 μM) were used in foetal membrane explants and siRNA against PIM1 was used in primary amnion cells. Statistical significance was set at P < 0.05. PIM1 expression was significantly increased in foetal membranes after spontaneous term labour compared to no labour at term and in amnion with preterm chorioamnionitis compared to preterm with no chorioamnionitis. There was no change in PIM1 expression with preterm labour or PPROM compared to preterm with no labour or PPROM. In human foetal membranes, PIM1 inhibitors SMI-4a and AZD1208 significantly decreased the expression of pro-inflammatory cytokine interleukin-6 (IL6) and chemokines CXCL8 and CCL2 mRNA and release, prostaglandin prostaglandin F2α (PGF2α) release, adhesion molecule intercellular adhesion molecule 1 mRNA expression and release, and oxidative stress marker 8-isoprostane release after stimulation with either LPS or flagellin. Primary amnion cells transfected with PIM1 siRNA also showed decreased expression of IL6, CXCL8 and CCL2, PTGS2 mRNA and PGF2α release, and matrix metalloproteinase-9 (MMP9) expression, when stimulated with TNF. None. The conclusions were drawn from in vitro experiments using foetal membrane explants and primary cells isolated from amnion. Animal models are necessary to determine whether PIM1 kinase inhibitors can prevent spontaneous preterm birth in vivo. PIM1 kinase inhibitors may provide a novel therapeutic approach for preventing spontaneous preterm birth. Associate Professor Martha Lappas is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; grant no. 1047025). Funding for this study was provided by the NHMRC (grant no. 1058786), Norman Beischer Medical Research Foundation and the Mercy Research Foundation. The authors have no conflict of interest. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ultrasound diagnosis and management of acquired uterine enhanced myometrial vascularity/arteriovenous malformations.

PubMed

Timor-Tritsch, Ilan E; Haynes, Meagan Campol; Monteagudo, Ana; Khatib, Nizar; Kovács, Sándor

2016-06-01

Arteriovenous malformation is a short circuit between an organ's arterial and venous circulation. Arteriovenous malformations are classified as congenital and acquired. In the uterus, they may appear after curettage, cesarean delivery, and myomectomy among others. Their clinical feature is usually vaginal bleeding, which may be severe, if curettage is performed in unrecognized cases. Sonographically on 2-dimensional grayscale ultrasound scanning, the pathologic evidence appears as irregular, anechoic, tortuous, tubular structures that show evidence of increased vascularity when color Doppler is applied. Most of the time they resolve spontaneously; however, if left untreated, they may require involved treatments such as uterine artery embolization or hysterectomy. In the past, uterine artery angiography was the gold standard for the diagnosis; however, ultrasound scanning has diagnosed successfully and helped in the clinical management. Recently, arteriovenous malformations have been referred to as enhanced myometrial vascularities. The purpose of this study was to evaluate the role of transvaginal ultrasound scanning in the diagnosis and treatment of acquired enhanced myometrial vascularity/arteriovenous malformations to outline the natural history of conservatively followed vs treated lesions. This was a retrospective study to assess the presentation, treatment, and clinical pictures of patients with uterine Enhanced myometrial vascularity/arteriovenous malformations that were diagnosed with transvaginal ultrasound scanning. We reviewed both (1) ultrasound data (images, measured dimensions, and Doppler blood flow that were defined by its peak systolic velocity and (2) clinical data (age, reproductive status, clinical presentation, inciting event or procedure, surgical history, clinical course, time intervals that included detection to resolution or detection to treatment, and treatment rendered). The diagnostic criteria were "subjective" with a rich vascular network in the myometrium with the use of color Doppler images and "objective" with a high peak systolic velocity of ≥20 cm/sec in the vascular web. Statistical analysis was performed and coded with statistical software where necessary. Twenty-seven patients met the diagnostic criteria of uterine enhanced myometrial vascularity/arteriovenous malformation. Mean age was 31.8 years (range, 18-42 years). Clinical diagnoses of the patients included 10 incomplete abortions, 6 missed abortions, 5 spontaneous complete abortions, 5 cesarean scar pregnancies, and 1 molar pregnancy. Eighty-nine percent of patients had bleeding (n = 24/27), although 1 patient was febrile, and 2 patients were asymptomatic. Recent surgical procedures were performed in 55.5% patients (15/27) that included curettage (n = 10), cesarean deliveries (n = 5), or both (n = 1); 4 patients had a remote history of uterine surgery that included myomectomy. Treatment was varied and included expectant treatment alone in 48% of the patients with serial ultrasound scans and serum human chorionic gonadotropin until resolution (n = 13/27 patients), uterine artery embolization (29.6%; 8/27 patients), methotrexate administration (22.2%; 6/27 patients), hysterectomy (7.4%; 2/27 patients), and curettage (3.7%; 1/27 patients). Three patients required a blood transfusion. Of the 9 patients whose condition required embolization, the conditions of 7 patients resolved after the procedure although 1 patient's condition required operative hysteroscopy and 1 patient's condition required hysterectomy for intractable bleeding. Average peak systolic velocity after embolization in the 9 patients was 85.2 cm/sec (range, 35-170 cm/sec); the average peak systolic velocity of the 16 patients with spontaneous resolution was 58.5 cm/sec (range, 23-90 cm/sec). Acquired enhanced myometrial vascularity/arteriovenous malformations occurred after unsuccessful pregnancies or treatment procedures that included uterine curettage, cesarean delivery, or cesarean scar pregnancy. Triage of patients for expectant treatment vs intervention with uterine artery embolization based on their clinical status, which was supplemented by objective measurements of blood velocity measurement in the arteriovenous malformation, appears to be a good predictor of outcome. Ultrasound evaluation of patients with early pregnancy failure and persistent bleeding should be considered for evaluation of a possible enhanced myometrial vascularity/arteriovenous malformation. Copyright © 2016 Elsevier Inc. All rights reserved.

The management of uterine fibroids in women with otherwise unexplained infertility.

PubMed

Carranza-Mamane, Belina; Havelock, Jon; Hemmings, Robert

2015-03-01

To provide recommendations regarding the best management of fibroids in couples who present with infertility. Usual and novel treatment options for fibroids will be reviewed with emphasis on their applicability in women who wish to conceive. Management of fibroids in women wishing to conceive first involves documentation of the presence of the fibroid and determination of likelihood of the fibroid impacting on the ability to conceive. Treatment of fibroids in this instance is primarily surgical, but must be weighed against the evidence of surgical management improving clinical outcomes, and risks specific to surgical management and approach. The outcomes of primary concern are the improvement in pregnancy rates and outcomes with management of fibroids in women with infertility. Published literature was retrieved through searches of PubMed, MEDLINE, the Cochrane Library in November 2013 using appropriate controlled vocabulary (e.g., leiomyoma, infertility, uterine artery embolization, fertilization in vitro) and key words (e.g., fibroid, myomectomy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English and French. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2013. Grey (unpublished literature) was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence in this document was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). These recommendations are expected to allow adequate management of women with fibroids and infertility, maximizing their chances of pregnancy by minimizing risks introduced by unnecessary myomectomies. Reducing complications and eliminating unnecessary interventions are also expected to decrease costs to the health care system. Summary Statements 1. Subserosal fibroids do not appear to have an impact on fertility; the effect of intramural fibroids remains unclear. If intramural fibroids do have an impact on fertility, it appears to be small and to be even less significant when the endometrium is not involved. (II-3) 2. Because current medical therapy for fibroids is associated with suppression of ovulation, reduction of estrogen production, or disruption of the target action of estrogen or progesterone at the receptor level, and it has the potential to interfere in endometrial development and implantation, there is no role for medical therapy as a stand-alone treatment for fibroids in the infertile population. (III) 3. Preoperative assessment of submucosal fibroids is essential to the decision on the best approach for treatment. (III) 4. There is little evidence on the use of Foley catheters, estrogen, or intrauterine devices for the prevention of intrauterine adhesions following hysteroscopic myomectomy. (II-3) 5. In the infertile population, cumulative pregnancy rates by the laparoscopic and the minilaparotomy approaches are similar, but the laparoscopic approach is associated with a quicker recovery, less postoperative pain, and less febrile morbidity. (II-2) 6. There are lower pregnancy rates, higher miscarriage rates, and more adverse pregnancy outcomes following uterine artery embolization than after myomectomy. (II-3) Studies also suggest that uterine artery embolization is associated with loss of ovarian reserve, especially in older patients. (III) Recommendations 1. In women with infertility, an effort should be made to adequately evaluate and classify fibroids, particularly those impinging on the endometrial cavity, using transvaginal ultrasound, hysteroscopy, hysterosonography, or magnetic resonance imaging. (III-A) 2. Preoperative assessment of submucosal fibroids should include, in addition to an assessment of fibroid size and location within the uterine cavity, evaluation of the degree of invasion of the cavity and thickness of residual myometrium to the serosa. A combination of hysteroscopy and transvaginal ultrasound or hysterosonography are the modalities of choice. (III-B) 3. Submucosal fibroids are managed hysteroscopically. The fibroid size should be < 5 cm, although larger fibroids have been managed hysteroscopically, but repeat procedures are often necessary. (III-B) 4. A hysterosalpingogram is not an appropriate exam to evaluate and classify fibroids. (III-D)  5. In women with otherwise unexplained infertility, submucosal fibroids should be removed in order to improve conception and pregnancy rates. (II-2A) 6. Removal of subserosal fibroids is not recommended. (III-D) 7. There is fair evidence to recommend against myomectomy in women with intramural fibroids (hysteroscopically confirmed intact endometrium) and otherwise unexplained infertility, regardless of their size. (II-2D) If the patient has no other options, the benefits of myomectomy should be weighed against the risks, and management of intramural fibroids should be individualized. (III-C) 8. If fibroids are removed abdominally, efforts should be made to use an anterior uterine incision to minimize the formation of postoperative adhesions. (II-2A) 9. Widespread use of the laparoscopic approach to myomectomy may be limited by the technical difficulty of this procedure. Patient selection should be individualized based on the number, size, and location of uterine fibroids and the skill of the surgeon. (III-A) 10. Women, fertile or infertile, seeking future pregnancy should not generally be offered uterine artery embolization as a treatment option for uterine fibroids. (II-3E).