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The Role of Oral Contraceptives in Optic Neuritis: the Story Behind the Study, Initial Experiences, and Lessons Learned

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The Role of Oral Contraceptives in Optic Neuritis: the Story Behind the Study, Initial Experiences, and Lessons Learned University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2013-07-15 The role of oral contraceptives in optic neuritis: the story behind the study, initial experiences, and lessons learned Trufyn, Jessie J. Trufyn, J. J. (2013). The role of oral contraceptives in optic neuritis: the story behind the study, initial experiences, and lessons learned (Unpublished master's thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/28340 http://hdl.handle.net/11023/817 master thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY The role of oral contraceptives in optic neuritis: the story behind the study, initial experiences, and lessons learned by Jessie J. Trufyn A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF NEUROSCIENCE CALGARY, ALBERTA JULY, 2013 © Jessie J. Trufyn 2013 Abstract There is accumulating evidence of sex differences in multiple sclerosis, making hormones a possible research avenue for therapeutic agents. Oral contraceptives are a source of synthetic hormones, however, it is unclear whether hormone-based therapies help, hinder, or have no effect on the disease in women. In an attempt to elucidate the role of sex hormones, we are currently conducting an observational study of oral contraceptives in optic neuritis, a condition that often occurs in parallel with multiple sclerosis. The thesis describes the study rational and supporting evidence for the hypothesis that oral contraceptive use in our study population will be associated with beneficial outcomes. I also share experiences with study implementation and preliminary data. The final section of the thesis offers insight for researchers on the areas of optical coherence tomography, hormones, and human research. ii Preface My journey began in Fall 2008 when I started my position at the Calgary Multiple Sclerosis Clinic as a health research coordinator under the supervision of Ms. Winona Wall and Dr. Luanne Metz. My experiences there, and interaction with Dr. Fiona Costello and Dr. Jodie Burton led me on the pursuit of my Masters degree and this thesis. iii Acknowledgements There are many people I owe thanks to. First, my boyfriend. I met Michael Keough at the beginning of my graduate school adventure. His hard work has been an inspiration, his strength a pillar, and his friendship a source of happiness. My parents for their unconditional support, positive thinking, and for making every trip home a mini vacation. The staff at the MS Clinic and Eye Clinic for their smiling faces and smorgasbord of treats. Dr. Michael Hill for recommending and lending me the book Epidemiology in Medicine. My supervisory committee, Dr. Gordon Fick, Dr. Bernard Corenblum, and especially Dr. V Wee Yong, for shaping my project and success. Also, Dr. Bill Fletcher for being my external examiner. Above all, Dr. Fiona Costello and Dr. Jodie Burton, my supervisors. Dr. Costello, with her gumption and fortitude, has kept me moving forward, and instilled in me life lessons and good energy that I hope to always carry. Dr. Burton, with her commitment, brilliance, and instrumental feedback, has made this project and my experience something I am proud of. Merged together, their support has enabled me to grow and and achieve. Jodie and Fiona, I will forever feel privileged to have worked with you. iv Dedication This thesis is dedicated to study patients, who selflessly contribute to science during stressful times of their lives. v Table of Contents Abstract ............................................................................................................................... ii Preface ............................................................................................................................... iii Acknowledgements ............................................................................................................ iv Dedication ............................................................................................................................ v Table of Contents ............................................................................................................... vi List of Tables ....................................................................................................................... x List of Figures and Illustrations ......................................................................................... xi List of Symbols, Abbreviations and Nomenclature .......................................................... xii CHAPTER ONE: INTRODUCTION .................................................................................. 1 Chapter overview ............................................................................................................. 1 Background ...................................................................................................................... 1 Multiple sclerosis ....................................................................................................... 1 Clinical course ..................................................................................................... 2 Etiology and pathogenesis ................................................................................... 3 Treatment ............................................................................................................. 4 Overview of sex differences ....................................................................................... 5 Sex differences in multiple sclerosis .......................................................................... 7 Epidemiology and clinical course ........................................................................ 7 Pathological features ............................................................................................ 8 Response to therapy ............................................................................................. 9 Neuroendocrine axis .......................................................................................... 10 Optic neuritis recovery ...................................................................................... 12 Chapter summary and thesis objectives ......................................................................... 12 CHAPTER TWO: LITERATURE REVIEW .................................................................... 14 Chapter overview ........................................................................................................... 14 Part I: Hormonal fluctuation studies in multiple sclerosis ............................................. 14 Pregnancy ................................................................................................................. 14 Clinical trials mimicking pregnancy .................................................................. 15 Menstrual cycle ........................................................................................................ 16 Oral contraception .................................................................................................... 18 Clinical trials of oral contraceptives .................................................................. 21 Part I: Summary ........................................................................................................ 21 Part II: Impact and mechanisms of ethinylestradiol and progestin in female animal models of neuroinflammation and degeneration ................................................... 22 Ethinylestradiol ........................................................................................................ 22 Progestin ................................................................................................................... 25 Part II: Summary ...................................................................................................... 26 Part III: Another approach to study oral contraceptives in multiple sclerosis ............... 27 A model of multiple sclerosis ................................................................................... 27 Optic neuritis ............................................................................................................ 28 Evaluating optic neuritis ........................................................................................... 29 High and low contrast acuity ............................................................................. 29 vi Optical coherence tomography .......................................................................... 30 Visual evoked potentials .................................................................................... 32 Magnetic resonance imaging ............................................................................. 33 Evidence that sex steroids may influence optic neuritis characteristics ................... 34 Sex differences in retinal nerve fiber layer thickness after optic neuritis .......... 34 Exogenous estradiol protects retinal ganglion cells in models of optic atrophy34 States
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