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Title: The actions and metabolism of glucocorticoids in first trimester trophoblast
Author: Mukherjee, Soma
ISNI:       0000 0004 2723 9185
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2011
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The local actions of glucocorticoids are modulated by 11βhydroxysteroid dehydrogenase (ll~HSD) enzymes which catalyse interconversion of cortisol with its inert metabolite, cortisone. Expression and activity of 11βHSD enzymes has not been well characterised in the first trimester placenta. The aims of this study were to determine the effects of glucocorticoids on trophoblast, and to establish whether glucocorticoid metabolism differs in first trimester placentae from pregnancies at a higher risk of developing pre-eclampsia compared to low risk pregnancies (as determined by uterine artery Doppler ultrasound scanning). Cortisol treatment led to a small increase in extravillous trophoblast (EVT: SGHPL-4 cell line) motility as determined by time-lapse microscopy. Neither cortisol nor cortisone altered trophoblast invasion. ) 11βHSD2 expression was detected in first trimester placental tissue, and was localised to syncytiotrophoblast. Immunocytochemistry confirmed 11βHSD2 expression in EVT explant outgrowths and SGHPL-4 cells. No 11βHSD1 expression was detected. Glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression were both detected in EVT. MR was detected in placental tissue by western blot analysis, but not immunohistochemistry. Enzyme assays confirmed that the 11βHSD2 enzyme inactivates cortisol in first trimester placental tissue. Net cortisol oxidation was significantly greater in placental tissue from pregnancies at higher risk of pre-eclampsia than in lower risk pregnancies; however there was no difference In 11βHSD2 expression. The 11βHSD2 enzyme is thought to protect the fetus from exposure to maternal cortisol. While other studies have suggested that 11βHSD2 is decreased in term pre- eclamptic placentae (relative to normotensive pregnancies), this study suggests that there is increased 11βHSD2 activity in first trimester placentae from pregnancies at higher risk of developing pre-eclampsia. This increase in enzyme activity is not accompanied by an increase in expression of 11βHSD2 consistent with post- translational regulation of enzyme activity. It remains to be determined if this difference is related to the pathophysiology of pre-eclampsia or is a compensatory response to poor trophoblast development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available