Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.794664
Title: Direct effect of glucocorticoids on the developing cardiovascular system : studies in the chicken embryo
Author: Garrud, Tessa Aimee Catriona
ISNI:       0000 0004 8500 507X
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Abstract:
Glucocorticoid therapy for threatened with preterm labour and in preterm neonates has become common practice in the last 40 years. This treatment is based on the pioneering work of Liggins who discovered that development of fetal tissues was dependent upon the pre-partum surge in fetal cortisol and that exposure to synthetic glucocorticoids in premature offspring could accelerate pulmonary maturation, reducing risk of respiratory complications. Ante- and post-natal glucocorticoid therapy has since been demonstrated to significantly reduce morbidity and mortality in the preterm infant. However, several aspects of this therapy are not optimised including; drug choice (Dexamethasone, Dex, or Betamethasone, Beta), and drug formulation. There is increasing animal and human data that suggest exposure to high doses of synthetic glucocorticoids may have a detrimental effect on the fetal cardiovascular system. The chicken embryo model was used to establish a clinically relevant glucocorticoid treatment at two thirds of development, without compounding influence of maternal or placental physiology, such that the direct effect of glucocorticoid exposure on the fetal cardiovascular system could be characterised. Further to this, the model was used to assess if cardiovascular effects varied between Dex and Beta, and Beta drug formulations - phosphate or acetate. Treatment with any glucocorticoid resulted in a significant asymmetric growth restriction at term, which was more severe following Beta treatment due to the acetate formulation. Ex vivo cardiac systolic and diastolic function was impaired by all treatments, again with Beta having a more severe effect. Divergent effects in the peripheral vasculature were measured with Dex treatment inducing enhanced vasoconstriction, whereas Beta treatments impaired vasodilatation. Dex resulted in cardiomyocyte hypertrophy, whereas Beta treatments resulted in a reduction in total cardiomyocyte number. The molecular pathways activated in the embryonic heart were also divergent. Dex induced oxidative stress, cell stress pathways, caspase-3 mediated apoptosis, and p38 mediated reduced proliferation. Combined Beta treatment resulted in excessive GR activation (due to loss of negative feedback), activation of cell stress pathways, p53 mediated apoptosis and reduced proliferation. Beta acetate shared the loss of GR feedback and enhanced p53 expression, whereas Beta phosphate did not. The data presented in this thesis offer insight into mechanisms of detrimental effects of antenatal glucocorticoid therapy on the cardiovascular system and suggest it may be safer to use Dex for treatment of preterm birth.
Supervisor: Giussani, Dino Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.794664  DOI:
Keywords: cardiovascular ; physiology ; fetal ; development ; antenatal ; glucocorticoids ; cortisol ; steroid ; preterm ; premature ; birth
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