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Uterine Fibroids IMPERIAL COLLEGE LONDON Uterine Fibroids Response to novel treatment modalities Stephen Derek Quinn 1st November, 2013 Academic department of Obstetrics and Gynaecology St Mary’s Hospital London Imperial College London Praed Street, London W21NY A thesis submitted in partial fulfilment of the requirements for the degree of MD Res at Imperial College: 2013 I declare that work contained herein is my own and that work of others is appropriately acknowledged. The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 2 Acknowledgements I would like to express my appreciation and thanks to my MD supervisors- Professor Lesley Regan and Professor Wladyslaw Gedroyc. Without their guidance, immense patience and wisdom this thesis would not have been possible. I would also like to thank Mr Raj Rai for his support and advice during the writing of these chapters. Thanks to Dr Bernard North, Imperial College London Statistical Advisory service for his indispensable advice and assistance. I would like to thank Dr John Vedalago, whose enthusiasm, friendship and dedication has been an essential part of this process. Thank you to Dr Mohammad Hamady, Interventional Radiologist, who helped facilitate the cytokine and growth factor portions of this thesis; Miss Casey Murray and Miss Yvonne Bower from the MR-therapy unit at St Mary’s who were very supportive of my work and helped with patient recruitment; Miss Yvonne Clements for her advice and help with multi- plate assays. I also wish to thank Dr Patrick McCabe from the University of Surrey for his assistance with the statistical analysis. This thesis is dedicated to my parents Derek and Sheila, whose steadfast support and encouragement has been truly wonderful. Finally to my wife Annabel, whose understanding and love has made this thesis possible - thank you. 3 Abstract Introduction Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive, thermal ablation treatment for uterine fibroids. There is currently limited data regarding the long-term efficacy of this method and the effect of this treatment on circulating cytokine and growth factors. In this thesis I have: 1. Presented the most accurate method of measuring fibroid volumes, and propose a new classification system for describing fibroid uteri. 2. Reviewed the characteristics of a cohort of uterine fibroid subjects and perform a longitudinal analysis of MRgFUS results. 3. Assessed the fibroid volume treated, pain scores and cytokine levels and growth factor levels following MRgFUS and UAE. Results The Parallel Plannimetric method is an accurate and reliable method of measuring uterine, fibroid and non- perfused volumes. Classifying fibroid uteri by numbers of fibroids and the presence of dominant fibroids is useful for distinguishing between those cases to be treated by MRgFUS or UAE. Since the introduction of MRgFUS to our unit the percentage non-perfused volumes (NPV) achieved have increased from 41.22 to 50.49 (p=0.038), however the re-intervention rate at 5 years remains high at 50%. MRgFUS has an excellent safety record, and the introduction of the new ExAblate 2100 system also appears to be safe and well tolerated, with encouraging initial NPVs achieved. Following both MRgFUS and UAE circulating interleukin-6 (IL-6) is significantly raised, although this is not affected by the degree of pain experienced or the volume of fibroid treated. Following UAE there is rise in circulating vascular endothelial growth factor (VEGF) seen at one week, however no significant change in VEGF levels is seen following MRgFUS. These changes in VEGF are not related to fibroid volume. Discussion MRgFUS is a safe, well tolerated treatment for uterine fibroids, although re-intervention rate is high. Further developments in this treatment modality may continue to improve outcomes, however at present its routine use cannot be recommended. 4 Contents Abstract............................................................................................................................... 4 Abbreviations ....................................................................................................................... 10 List of figures ............................................................................................................................ 12 List of tables ............................................................................................................................. 14 1. Introduction and literature review ................................................................................... 16 Prevalence ............................................................................................................................ 16 Subgroups of uterine fibroids and classification .................................................................. 17 Sub-mucous (SM) fibroids ................................................................................................ 18 Intramural (IM) fibroids .................................................................................................... 20 Sub-serosal (SS) Fibroids ................................................................................................... 21 Cervical fibroids ................................................................................................................ 21 Vaginal fibroids ................................................................................................................. 21 Fibroid symptoms ................................................................................................................. 22 Menstrual symptoms ........................................................................................................ 23 Pressure symptoms .......................................................................................................... 24 Pain ................................................................................................................................... 24 Sub-Fertility ...................................................................................................................... 25 Pregnancy Complications ................................................................................................. 27 Psychological aspects of a diagnosis of uterine fibroids .................................................. 29 Fibroid Aetiology .................................................................................................................. 30 Obesity .............................................................................................................................. 30 Race .................................................................................................................................. 31 Parity ................................................................................................................................. 31 Diet ................................................................................................................................... 31 Smoking and Alcohol ........................................................................................................ 32 5 Hypertension .................................................................................................................... 32 Mechanisms of fibroid growth ......................................................................................... 33 The role of Oestrogen ....................................................................................................... 34 Genetics of uterine fibroids .............................................................................................. 35 Epigenetic factors ............................................................................................................. 37 The Role of the Extracellular Matrix ................................................................................. 37 Vasculature of the fibroid ................................................................................................. 38 Fibroid Histology ............................................................................................................... 39 Fibroid diagnosis .................................................................................................................. 40 History of uterine fibroids and their management .............................................................. 46 Fibroid management ............................................................................................................ 47 Surgical Treatments .......................................................................................................... 50 Hysterectomy ................................................................................................................... 50 Myomectomy.................................................................................................................... 51 Trans-cervical resection of fibroid (TCRF) ........................................................................ 52 Uterine artery embolism (UAE) or uterine fibroid embolization
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