Lipidomic Analysis of Fatty Acids and their Derived Lipid Mediators in Disorders of the Endometrium

UoM administered thesis: Phd

  • Authors:
  • Matthew Rosser

Abstract

Introduction Endometriosis and endometrial cancer are conditions thought to originate from abnormalities in endometrial function, yet our understanding of the changes that predispose women to these conditions remains incomplete. One of the pathological characteristics shared by both endometriosis and endometrial cancer is the upregulation of pro-inflammatory lipids. Although there are a large number of lipid mediators of inflammation derived from various fatty acids, only a select few have, to date, been studied in endometriosis or endometrial cancer. Aims The aim of this project is to establish profiles of fatty acids and their derived lipid mediators in the human endometrium across the phases of the menstrual cycle (for localised uterine lipid changes) and the omental adipose (for distal peritoneal lipid changes). These data will then be compared to fatty acid and lipid profiles in endometrial disease states: endometriosis and endometrial cancer, to assess if lipid profiles vary between these tissues and draw conclusions as to the possible contribution of such fatty acids and lipids to disease initiation, progression and treatment. Methods Samples of human endometrium and omental adipose were acquired from St Mary’s Hospital, Manchester; samples of endometrial cancer were acquired from central Manchester university hospital NHS foundation trust (CMFT) biobank. Fatty acids and lipid mediators were extracted for analysis of 38 fatty acids using gas chromatography flame ionisation detection (GC-FID), and 79 lipid mediators using electrospray ionisation tandem mass spectrometry (ESI-MS/MS). Results In the eutopic endometrium, the eicosanoids prostaglandin (PG)E2, PGF2α and 9 hydroxyeicosatetraenoic acid (HETE) were significantly decreased in the endometrium from women with endometriosis compared to those without, only a single difference (5 oxo ETE) was observed in the omental adipose although some preliminary findings indicate omental adipose may secrete factors that alter interleukin (IL)-1β and IL-6 production by endometrial cells. Across all stages of the menstrual cycle, total proportion of lipids derived from cytochrome enzymes were increased (P=0.005) in the endometrium of women with endometriosis. Significant increases in CYP derived 5(6) epoxyeicostrienoic acid (EET), 11(12) EET and 14(15) EET and total CYP lipids were also observed in endometrial cancer samples compared to non-cancerous endometrium. Treatment with the GnRH agonist Prostap appeared to alter the lipid profile in the endometrium of women with endometriosis to more closely resemble that of women without endometriosis. Discussion Results presented in this thesis indicate that there is little difference in the profile of individual lipids in the eutopic endometrium of women with or without endometriosis. These findings show that total cytochrome lipid products were found increased in the endometrium of women with endometriosis and regular menstrual cycles and in endometrial cancer tissue, alterations to lipid metabolising CYP enzymes are therefore a novel future avenue for research into the link between endometriosis and endometrial cancer. The presence of endometriosis did not lead to changes in omental adipose fatty acid or lipid mediator profiles.

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Original languageEnglish
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Award date31 Dec 2018