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The Role of Kisspeptin in Reproduction

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The Role of Kisspeptin in Reproduction The Role of Kisspeptin in Reproduction Thesis submitted for the degree of Doctor of Philosophy Imperial College London Alexander Comninos 2014 Section of Investigative Medicine Division of Diabetes, Endocrinology & Metabolism Imperial College London 1 Declaration of Copyright ___________________________________________ 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 Abstract ___________________________________________ Kisspeptin is a recently identified hypothalamic neuropeptide hormone which is a critical regulator of mammalian reproductive physiology. In addition, kisspeptin administration stimulates gonadotrophin release in all species tested. Kisspeptin may therefore serve as a potential therapy for reproductive pathologies. The role of kisspeptin has been studied extensively within the hypothalamus but little is known about its extra-hypothalamic effects. Using manganese-enhanced MRI to detect neuronal activity, I demonstrate marked decreases in neuronal activity in the amygdala of adult mice after kisspeptin administration. This data reveals a novel effect of kisspeptin with pharmacological implications. The human kisspeptin peptides kisspeptin-10, -13, -14, and -54 are named according to their constituent amino acids. Kisspeptin-10 is the smallest and most easily synthesised peptide from a pharmacological point of view. By investigating the effects of the kisspeptin-10 peptide in healthy men and women, I uncover a sexual dimorphism in gonadotrophin response to kisspeptin-10 as well as a greater potency of kisspeptin-54 over kisspeptin-10 in healthy women. Having established the effects of acute kisspeptin administration in healthy women, I investigated the effects of chronic administration of kisspeptin on reproductive function. Using biochemical and radiological parameters of menstrual cyclicity, I demonstrate that 7 days of kisspeptin administration advances the menstrual cycle in healthy women. In summary, in this thesis I have identified a novel effect of kisspeptin in rodents involving the amygdala. My clinical studies have identified for the first time the acute and chronic effects of kisspeptin administration in humans. Combined, these data have important implications for the development of kisspeptin as a potential therapy for reproductive pathologies. 3 Declaration of Contributors ___________________________________________ Declaration of Originality: The work described in this thesis is my own. Any collaborations and assistance are detailed below. Contributors are within the Section of Investigative Medicine (Imperial College London) unless stated otherwise. Radioimmunoassays were established and maintained by Professor Mohammad Ghatei. Chapter 2: I designed the study with the assistance of Professor Waljit Dhillo, Professor Jimmy Bell (Metabolic and Molecular Imaging Group, Imperial College London) and Professor Paul Matthews (Division of Brain Sciences, Imperial College London). I performed the animal studies with the assistance of Dr. Jelena Anastasovska and Dr. Meliz Sahuri-Arisoylu (both from the Metabolic and Molecular Imaging Group, Imperial College London). Chapter 3: The study was designed in collaboration with Professor Waljit Dhillo, Dr. Channa Jayasena and Dr. Monica Nijher. Recruitment and studies were carried out by myself with assistance from Dr. Channa Jayasena, Dr. Monica Nijher, Dr. Ali Abbara, Dr. Adam Januszewki, Ms. Meriel Vaal and Ms. Zohreh Farzad. Assays were performed by myself together with Dr. Channa Jayasena and Dr. Monica Nijher. Chapter 4: The study was designed in collaboration with Professor Waljit Dhillo and Dr. Channa Jayasena. Study visits were carried out by myself with assistance from Dr. Channa Jayasena, Dr. Monica Nijher, Dr. Ali Abbara, Dr. Akila de Silva, Dr. Risheka Ratnasabapathy and Dr. Chioma Izzi-engbeaya. The ultrasound scans were performed by Dr. Adrian Lim and Ms. Daksha Patel. Professor Johannes Veldhuis performed the pulsatility analyses. Assays were performed by myself together with Dr. Channa Jayasena and Dr. Monica Nijher. 4 Acknowledgements ___________________________________________ Firstly, I would like to thank Professor Waljit Dhillo for the opportunity to conduct research on kisspeptin in his research group and for his constant support and enthusiasm throughout my research studies. I am extremely grateful to the senior researchers Dr. Channa Jayasena, Professor Sir Stephen Bloom, Professor Jimmy Bell, Professor Paul Matthews and Professor Mohammad Ghatei for their advice and help with various technical aspects of the work. For the animal studies, I am indebted to Dr. Jelena Anastasovska and Dr. Meliz Sahuri- Arisoylu for teaching me many new techniques and being so generous with their time. For the clinical studies, I am indebted to my colleagues Dr. Ali Abbara, Dr. Monica Nijher, Dr. Akila de Silva, Dr. Risheka Ratnasabapathy, Dr. Chioma Izzi-engbeaya Ms. Meriel Vaal and Ms. Zohreh Farzad for all their help and moral support. Special thanks are due to the staff at the Imperial College Clinical Research Facility for providing invaluable support during the screening of study participants for the clinical studies. I am grateful to the Wellcome Trust and GlaxoSmithKline for awarding me a Translational Medicine Training Fellowship which allowed me to pursue my PhD research studies. Finally I would like to thank the study participants, without whom none of the clinical studies would have been possible. This thesis is dedicated to my parents and Georgia for all their love and support. 5 Table of Contents ___________________________________________ ABSTRACT ................................................................................................................................... 3 DECLARATION OF CONTRIBUTORS ......................................................................................... 4 ACKNOWLEDGEMENTS ............................................................................................................. 5 TABLE OF CONTENTS ................................................................................................................ 6 INDEX OF FIGURES ................................................................................................................... 10 INDEX OF TABLES ..................................................................................................................... 12 LIST OF ABBREVIATIONS ........................................................................................................ 13 CHAPTER 1: GENERAL INTRODUCTION ................................................................................ 15 1.1 THE REPRODUCTIVE AXIS: AN OVERVIEW ............................................................................... 16 1.2 THE REPRODUCTIVE AXIS: THE GNRH PULSE GENERATOR ..................................................... 20 1.3 KISSPEPTIN: THE PEPTIDE PRODUCT OF THE KISS1 GENE ..................................................... 23 1.4 KISS1 EXPRESSION: CNS DISTRIBUTION .............................................................................. 24 1.4.1 Mouse ......................................................................................................................... 24 1.4.2 Rat ............................................................................................................................... 24 1.4.3 Primates (including humans) ...................................................................................... 25 1.5 KISS1 EXPRESSION: PERIPHERAL DISTRIBUTION ................................................................... 25 1.6 THE KISSPEPTIN RECEPTOR (KISS1R) .................................................................................. 27 1.7 KISS1R EXPRESSION: CNS DISTRIBUTION ............................................................................ 28 1.7.1 Mouse ......................................................................................................................... 28 1.7.2 Rat ............................................................................................................................... 28 1.7.3 Primates (including humans) ...................................................................................... 29 1.8 KISS1R EXPRESSION: PERIPHERAL DISTRIBUTION ................................................................ 29 1.9 THE IMPORTANCE OF THE KISS1/KISS1R SYSTEM IN THE REPRODUCTIVE AXIS ..................... 30 1.9.1 KISS1R ....................................................................................................................... 30 1.9.2 KISS1 .......................................................................................................................... 31 1.10 KISSPEPTIN ADMINISTRATION CAN INDUCE PUBERTY IN ANIMALS .......................................... 32 1.11 KISSPEPTIN STIMULATES THE RELEASE OF GNRH WHICH IN TURN STIMULATES GONADOTROPHIN RELEASE .................................................................................................................................... 33 1.12 DIRECT EFFECTS OF KISSPEPTIN ON PITUITARY GONADOTROPHIN SECRETION
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