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Cartwright R.,Institute of Reproductive and Developmental Biology | Afshan I.,Northwick Park Hospital | Derpapas A.,Imperial College London | Vijaya G.,Imperial College London | Khullar V.,Imperial College London
Nature Reviews Urology | Year: 2011

Biomarkers constitute any objectively measurable indicator of a biological process. The classic biomarker used in the diagnosis of overactive bladder (OAB) has been detrusor overactivity, which is assessed urodynamically. In the search for a reliable, noninvasive alternative to urodynamics, interest has focused on genetic, imaging, and urinary factors. Along with other cytokines detectable in urine, prostaglandin E2 and nerve growth factor are indicators of low-grade inflammation. Although they correlate with OAB symptom severity, they have not been shown to have independent prognostic benefit. Imaging biomarkers have been investigated since the earliest days of video urodynamics. Despite extensive research on the ultrasonographic estimation of bladder wall thickness, further standardization of the technique is required before conclusions can be reached regarding diagnostic accuracy. Genetic factors contribute approximately half of the total risk for urgency incontinence. Functional polymorphisms of the cytochrome P450 IID6 gene significantly alter the metabolism of some commonly used anticholinergic drugs, but no genetic loci that influence risk of OAB have been definitively identified. The first genome-wide association studies for OAB are in progress, and should identify new susceptibility genes. Although current putative biomarkers correlate with OAB severity, much future work is required to assess their prognostic value, and establish their role in clinical practice. © 2011 Macmillan Publishers Limited. All rights reserved. Source

Wathes D.C.,Reproduction Group | Cheng Z.,Reproduction Group | Fenwick M.A.,Reproduction Group | Fenwick M.A.,Institute of Reproductive and Developmental Biology | And 3 more authors.
Reproduction | Year: 2011

Postpartum dairy cows enter a period of negative energy balance (NEB) associated with low circulating IGF1, during which the uterus must undergo extensive repair following calving. This study investigated the effects of NEB on expression of IGF family members and related genes in the involuting uterus. Cows were allocated to two treatments using differential feeding and milking regimes to produce mild NEB or severe NEB (SNEB). Uterine endometrial samples collected 2 weeks post partum were analysed by quantitative PCR. The expression of IGF-binding protein 4 (IGFBP4) mRNA increased in the endometrium of SNEB cows, with trends towards increased IGFBP1 and reduced IGFBP6 expression. There were no significant differences between treatments in mRNA expression of IGF1, IGF2 or of any hormone receptor studied, but significant correlations across all cows in the expression levels of groups of receptors suggested common regulatory mechanisms: type 1 IGF receptor (IGF1R), IGF2R and insulin receptor (INSR); GHR with ESR1; and ESR2 with NR3C1. The expression of IGF1R and INSR also positively correlated with the circulating urea concentration. Matrix metalloproteinases (MMPs) are important in tissue remodelling and can affect IGF signalling via interaction with IGFBPs. The expression levels of MMP1, MMP3, MMP9 and MMP13 mRNAs all showed major upregulation in the endometrium of cows in SNEB and all except MMP9 were highly correlated with expression of IGFBP4. Alpha(2)-HS-glycoprotein (AHSG) and PDK4, two genes implicated in insulin resistance, were also highly expressed in SNEB. These results suggest that cows in SNEB experience alterations to the IGF and insulin signalling pathways in the postpartum endometrium. This may affect the rate of tissue repair with a possible negative impact on subsequent fertility. © 2011 Society for Reproduction and Fertility. Source

Kandola M.K.,Imperial College London | Sykes L.,Imperial College London | Lee Y.S.,Imperial College London | Johnson M.R.,Imperial College London | And 2 more authors.
Endocrinology | Year: 2014

Prostaglandin (PG) E2 (PGE2) plays a central role in the regulation of smooth muscle contractions. Classically, PGE2 stimulates contractions via EP1 and EP3 receptors, whereas EP2 and EP4 maintain quiescence. Labor involves a change from myometrial quiescence to contractions with a shift from anti- to proinflammatory pathways. EP2, a Gαs-coupled receptor, is known to mediate its actions via cAMP signaling. However, we have recently shown that EP2 also activates the proinflammatory PG G/H synthase-2 (PGHS-2). Here, we identify the mechanism underlying the ability of EP2 to maintain uterine quiescence and activate a proinflammatory/prolabor response in term-pregnant human myometrium. Human myometrial biopsies for in vivo and in vitro studies were taken at cesarean section at term, before or after the onset of labor. Activation of EP2 increased intracellular levels ofcAMPand reduced contractility. Contrastingly, EP2 stimulation increased levels of PGHS-2, membrane-associated PGE synthase-1, and PGE2. This was entirely dependent on EP2-mediated activation of calcium signaling. Both calcium signaling and up-regulation of PGHS-2 were insensitive to the Gαi inhibitor pertussis toxin but inhibited by small interfering RNA knockdown of Gαq/11. There were no differences in EP2mRNAor protein levels between upper or lower segment myometrium or between pre- and postlabor myometrium. However, in myocytes taken after the onset of labor, cAMP signaling was markedly attenuated, whereas activation of calcium and PGHS-2 was preserved. Overall, the dual coupling of EP2 to Gαs-cAMP and Gαq/11-calcium pathways underlies its ability to mediate contrasting functions in term pregnancy and the "switching" to a prolabor receptor. Copyright © 2014 by the Endocrine Society. Source

Bansal A.S.,St. Helier Hospital | Bora S.A.,The London Clinic | Saso S.,Institute of Reproductive and Developmental Biology | Smith J.R.,Imperial College London | And 2 more authors.
Expert Review of Clinical Immunology | Year: 2012

Human chorionic gonadotrophin (hCG) is released within hours of fertilization and has a profound ability to downregulate maternal cellular immunity against trophoblastic paternal antigens. It also promotes angiogenic activity of the extravillous trophoblast, and impairment of this function may lead to inadequate placentation and an increased risk of preeclampsia. There is increasing evidence that hCG alters the activity of dendritic cells via an upregulation of indoleamine 2,3-dioxygenase activity. This reduces T-cell activation and cytokine production, as well as encouraging Treg cell recruitment to the fetal-maternal interface. These changes are critical in promoting maternal tolerance. hCG is also able to increase the proliferation of uterine natural killer cells, while reducing the activity of cytotoxic peripheral blood natural killer cells. There are rare reports of autoantibodies directed against hCG or the luteinizing hormone/hCG receptor in women with recurrent miscarriage. These autoantibodies are more frequent in women with thyroid autoimmunity. This may explain the association between thyroid autoimmunity and impaired fertility. Downregulating these anti-hCG and anti-luteinizing hormone/hCG receptor autoantibodies may be helpful in some women with early miscarriage or recurrent failed in vitro fertilization. © 2012 2012 Expert Reviews Ltd. Source

Milona A.,Institute of Reproductive and Developmental Biology
Hepatology (Baltimore, Md.) | Year: 2010

Pregnancy alters bile acid homeostasis and can unmask cholestatic disease in genetically predisposed but otherwise asymptomatic individuals. In this report, we show that normal pregnant mice have raised hepatic bile acid levels in the presence of procholestatic gene expression. The nuclear receptor farnesoid X receptor (FXR) regulates the transcription of the majority of these genes, and we show that both ablation and activation of Fxr prevent the accumulation of hepatic bile acids during pregnancy. These observations suggest that the function of Fxr may be perturbed during gestation. In subsequent in vitro experiments, serum from pregnant mice and humans was found to repress expression of the Fxr target gene, small heterodimer partner (Shp), in liver-derived Fao cells. Estradiol or estradiol metabolites may contribute to this effect because coincubation with the estrogen receptor (ER) antagonist fulvestrant (ICI 182780) abolished the repressive effects on Shp expression. Finally, we report that ERα interacts with FXR in an estradiol-dependent manner and represses its function in vitro. CONCLUSION: Ligand-activated ERα may inhibit FXR function during pregnancy and result in procholestatic gene expression and raised hepatic bile acid levels. We propose that this could cause intrahepatic cholestasis of pregnancy in genetically predisposed individuals. Source

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