Universidade de Lisboa Faculdade de Medicina de Lisboa Effects of Dehydroepiandrosterone on Cognition: an Electrophysiological Approach Sónia Isabel do Vale Fernandes Orientadores: Professor Doutor João Maria Martin Martins Professor Doutor Carles Enric Escera Micó Doctoral Program in Metabolic Disorders and Eating Behavior Tese especialmente elaborada para obtenção do grau de Doutor em Medicina, Especialidade Endocrinologia 2016 Universidade de Lisboa Faculdade de Medicina de Lisboa Effects of Dehydroepiandrosterone on Cognition: an Electrophysiological Approach Sónia Isabel do Vale Fernandes Orientadores: Professor Doutor João Maria Martin Martins Professor Doutor Carles Enric Escera Micó Doctoral Program in Metabolic Disorders and Eating Behavior Tese especialmente elaborada para obtenção do grau de Doutor em Medicina, Especialidade Endocrinologia Júri: Presidente: Doutor José Luís Bliebernicht Ducla Soares, Professor Catedrático em regime de tenure e Vice-Presidente do Conselho Científico da Faculdade de Medicina da Universidade de Lisboa (por subdelegação do Doutor José Augusto Gamito Melo Cristino, Professor Catedrático e Presidente do Conselho Científico da Faculdade de Medicina da Universidade de Lisboa) Vogais: - Professor Carles Enric Escera Micó, Full Professor (Catedràtic d´Universitat) da University of Barcelona; (co-Orientador) - Doutora Maria Helena Cardoso Pereira da Silva, Professora Associada Convidada do Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto; - Doutor Valeriano Alberto Pais Horta Leite, Professor Auxiliar Convidado da Faculdade de Ciências Médicas da Universidade Nova de Lisboa; - Doutor Rui Manuel Martins Victorino, Professor Catedrático da Faculdade de Medicina da Universidade de Lisboa; - Doutor Manuel Diamantino Pires Bicho, Professor Catedrático da Faculdade de Medicina da Universidade de Lisboa; - Doutor Manuel Augusto de Castro Pereira Barbosa, Professor Associado com Agregação da Faculdade de Medicina da Universidade de Lisboa; - Doutor João Maria Martin Martins, Professor Auxiliar Convidado da Faculdade de Medicina da Universidade de Lisboa; (Orientador). This work has been supported by the Spanish Ministry of Economy and Knowledge (CDS2007-00012), the Catalan Government (SGR2009-11 and SGR2014-177), ICREA (Catalan Institution for Research and Advanced Studies) Academia Distinguished Professorship awarded to Carles Escera, the Portuguese Calouste Gulbenkian Foundation (116503, 2011), Lisbon Medical School (Metabolic Disorders and Eating Behavior course and Endocrinology University Clinic), Hospital Association of Endocrinology and Diabetes (HEID) and Merck SA. 2016 As opiniões expressas nesta publicação são da exclusiva responsabilidade do seu autor. A impressão desta dissertação foi aprovada em Conselho Científico da Faculdade de Medicina de Lisboa em reunião de 19 de Abril de 2016. Dissertação apresentada à Faculdade de Medicina de Lisboa para obtenção do grau de Doutor em Medicina À minha família: aos que sucedo, aos que precedo e em especial ao meu marido. Liberdade Aqui nesta praia onde Não há nenhum vestígio de impureza, Aqui onde há somente Ondas tombando ininterruptamente, Puro espaço e lúcida unidade, Aqui o tempo apaixonadamente Encontra a própria liberdade. Sophia de Mello Breyner Andresen, in “Mar” “We know accurately only when we know little; doubt grows with knowledge.” Johann Wolfgang von Goethe Acknowledgements To Professor João Martin Martins for everything he taught me in endocrinology, for showing me the beauty of behavioral endocrinology, for teaching and letting me participate in his research, for the liberty and incentive to pursue the present research, for the active participation in the initial steps of this research and for the supervision of this thesis. To Professor Carles Escera, who kindly received me at the laboratory and the team he leads, allowing the present research. His outstanding expertise in electrophysiology and psychophysiology were fundamental for the present work. I also thank his invaluable help, support and friendly words along these years. To Lenka Selinger, whose work and friendship were fundamental. She actively participated in the research performed in Barcelona, taught me many practical aspects regarding electrophysiology research and shared some of my headaches while trying to solve research problems. To Professor Isabel do Carmo, for challenging me to pursue this doctoral program and for the positive and supportive attitude during its performance. To Professor Manuel Bicho, who kindly allowed me the use of the Genetics’ laboratory for the performance of the endocrine measurements and kindly followed the development of the present works and thesis. To Professor Rui Victorino, for his vote of confidence and supportive attitude. To Professor Manuel Barbosa for his support, friendship and incentive words. To Dr. Anabela Oliveira, the head of my emergency room team, for understanding and allowing my absence from that work while in Barcelona and for the positive attitude towards the professional development of the team elements. To Dr. Nelson de Melo, for the English corrections and his good will and friendship at all times. To José Valenzuela who programmed the computer sequences used in the experimental protocols and Francisco Diaz, who solved other informatics issues. To the other colleagues at the Barcelona Brainlab, namely to Irene Romero, who made me feel at home while abroad. To the study participants. To the unnamed ones who somehow contributed to the present works. To my friends and good colleagues. And Especially, to my lovely family, that really allowed my everyday work and happiness, without whom this thesis would not be possible. This work has been carried out in the Endocrinology University Clinic, led by Professor João Martin Martins and in the Genetics Laboratory, led by Professor Manuel Bicho, at the Lisbon Medical School, University of Lisbon (Lisbon, Portugal); in Santa Maria University Hospital (Lisbon, Portugal) led by Professor Isabel do Carmo; in the Institute for Brain, Cognition and Behavior (IR3C) and the Cognitive Neuroscience Research Group (Centre of Excellence established by the Generalitat de Catalunya) at the Department of Psychiatry and Clinical Psychobiology, Faculty of Psychology, University of Barcelona (Barcelona, Catalonia, Spain), led by Professor Carles Escera. Index Summary ....................................................................................................................... i Resumo ........................................................................................................................ v List of Original Publications in Relation to the Present Thesis ........................................ xi Abbreviations ............................................................................................................. xiii Introduction/Literature Review: Dehydroepiandrosterone and Dehydroepiandrosterone-sulphate as Neuroactive Steroids .......................................... 1 Synthesis and distribution ................................................................................................. 3 Changes along the life span and regulation .................................................................... 20 Mechanisms of action and cellular effects ...................................................................... 29 Cognitive and neuropsychiatric effects ........................................................................... 44 Electrophysiological and neuroimaging correlates ......................................................... 56 Aims and Hypothesis .................................................................................................. 83 Study I ........................................................................................................................ 87 Study II ...................................................................................................................... 107 Study III ..................................................................................................................... 141 Study IV .................................................................................................................... 173 Discussion ................................................................................................................. 205 Conclusions ............................................................................................................... 233 Future research and clinical perspectives ................................................................... 235 References ................................................................................................................ 237 Annex: Published articles included in the Thesis ........................................................ 299 Figure index Figure 1: Cyclopentanoperhydrophenanthrene structure, dehydroepiandrosterone and dehydroepiandrosterone-sulphate chemical structure. ....................................................... 3 Figure 2: Biochemical pathway for DHEA synthesis.. ............................................................ 5 Figure 3: Adrenal steroidogenesis.. ....................................................................................... 5 Figure 4: Steroidogenic pathway in the ovary.. .................................................................... 6 Figure 5: Steroidogenesis in human testis. ..........................................................................