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Impact of Hyperandrogenism and Diet on the Development of Polycystic Ovary Syndrome

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Impact of Hyperandrogenism and Diet on the Development of Polycystic Ovary Syndrome Impact of hyperandrogenism and diet on the development of polycystic ovary syndrome Valentina Rodriguez Paris A thesis in fulfilment of the requirements for the degree of Doctor of Philosophy School of Women’s & Children’s Health Faculty of Medicine University of New South Wales 2020 ii Thesis/Dissertation Sheet Surname/Family Name : Rodriguez Paris Given Name/s : Valentina Abbreviation for degree as give in the University calendar : PhD Faculty : Medicine School : Women’s & Children’s Health Impact of Hyperandrogenism and Diet on the development of Polycystic Ovary Thesis Title : Syndrome Abstract 350 words maximum: (PLEASE TYPE) Polycystic ovary syndrome (PCOS) is a heterogeneous disorder featuring reproductive, endocrine and metabolic abnormalities. Hyperandrogenism is a defining characteristic of PCOS and evidence supports a role for androgen driven actions in the development of PCOS. The aetiology of PCOS is poorly understood and current management is symptom based. Therefore, defining the ontogeny of PCOS traits and the factors impacting their development, is important for developing early PCOS detection markers and new treatment strategies. The aims of this research were to determine the temporal pattern of development of PCOS features in a hyperandrogenic environment, define the impact of dietary macronutrient balance on hyperandrogenic PCOS traits and evaluate the impact of diet and a hyperandrogenic PCOS pathology on the gut microbiome using a mouse model. The first study characterised the temporal pattern of development of PCOS features after excess androgen exposure. Findings identified that acyclicity, anovulation and increased body weight are early predictors of developing PCOS. The second study utilized the geometric framework for nutrition and reports the first systematic analysis of dietary protein, carbohydrate and fat on the evolution of reproductive and metabolic PCOS traits in a PCOS mouse model. Results revealed that reproductive PCOS features of acyclicity and anovulation were ameliorated on low protein, medium carbohydrate and fat consumption. In contrast, diet had minimal effect on PCOS metabolic features. Specifically, PCOS mice were significantly heavier compared to controls due to an increased sensitivity to caloric intake, implying differences in post-ingestive responses to diet. Therefore, the third study investigated the interplay between diet and PCOS pathology on gut microbiota and revealed that diet exerted a stronger influence over gut microbial composition than PCOS. However, a PCOS environment did decrease levels of an obesity associated Bacteroides species. Overall, findings provide insights into the sequence of PCOS trait development, the impact of diet on PCOS features, and the interplay between diet and PCOS pathology on the gut microbiome, and support the addition of body weight criteria to the early diagnosis of PCOS and future research into the development of evidence-based nutritional and microbiome-mediated strategies for the treatment of PCOS. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents a non-exclusive licence to archive and to make available (including to members of the public) my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known. I acknowledge that I retain all intellectual property rights which subsist in my thesis or dissertation, such as copyright and patent rights, subject to applicable law. I also retain the right to use all or part of my thesis or dissertation in future works (such as articles or books). …………………………………………………………… ……….……………………...…….… Signature Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years can be made when submitting the final copies of your thesis to the UNSW Library. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. iv ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. v COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents a non-exclusive licence to archive and to make available (including to members of the public) my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known. I acknowledge that I retain all intellectual property rights which subsist in my thesis or dissertation, such as copyright and patent rights, subject to applicable law. I also retain the right to use all or part of my thesis or dissertation in future works (such as articles or books).’ ‘For any substantial portions of copyright material used in this thesis, written permission for use has been obtained, or the copyright material is removed from the final public version of the thesis.’ Signed ……………………………………………........................... Date …………………………………………….............................. AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis.’ Signed ……………………………………………........................... Date …………………………………………….............................. INCLUSION OF PUBLICATIONS STATEMENT UNSW is supportive of candidates publishing their research results during their candidature as detailed in the UNSW Thesis Examination Procedure. Publications can be used in their thesis in lieu of a Chapter if: • The candidate contributed greater than 50% of the content in the publication and is the “primary author”, ie. the candidate was responsible primarily for the planning, execution and preparation of the work for publication • The candidate has approval to include the publication in their thesis in lieu of a Chapter from their supervisor and Postgraduate Coordinator. • The publication is not subject to any obligations or contractual agreements with a third party that would constrain its inclusion in the thesis Please indicate whether this thesis contains published material or not: This thesis contains no publications, either published or submitted for publication ☒ (if this box is checked, you may delete all the material on page 2) Some of the work described in this thesis has been published and it has been documented in the relevant Chapters with acknowledgement ☐ (if this box is checked, you may delete all the material on page 2) This thesis has publications (either published or submitted for publication) ☐ incorporated into it in lieu of a chapter and the details are presented below CANDIDATE’S DECLARATION I declare that: • I have complied with the UNSW Thesis Examination Procedure • where I have used a publication in lieu of a Chapter, the listed publication(s) below meet(s) the requirements to be included in the thesis. Candidate’s Name Signature Date (dd/mm/yy) Valentina Rodriguez Paris viii This thesis is dedicated to my mom, Yolanda, my dad, Roberto and my husband, Carlos ix "It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions; who spends himself in a worthy cause; who at the best knows in the end the triumph of high achievement, and who at the worst, if he fails, at least fails while daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat." Theodore Roosevelt x Acknowledgments Acknowledgements Words will never be enough to express my immense gratitude to everyone who has made this journey so amazing. You are all incredible human beings with whom I would not have been able to get through the rollercoaster that is a PhD. I would like to thank the University of New South Wales and the School of Women’s & Children’s Health for funding my PhD. I would like to start by thanking my supervisor Dr. Kirsty Walters, and co-supervisors Dr. Robert Gilchrist and Dr. Michael Bertoldo. Kirsty, thank you for giving me the opportunity to work with you and for always believing in me. Thank you for always being there looking after me with kind encouraging words and chocolate, and for being my mentor and role model. Kirsty, you are an amazing scientist but an even more amazing person with a kind heart and I am truly grateful for having you in my life. Rob and Michael thank you for your help, advice, encouragement and endless enthusiasm throughout my PhD. Thank you to everyone in the Ovarian and Oocyte Biology Research Unit at UNSW for making my time during my PhD amazing. Together, we have all created a fantastic environment to learn and enjoy doing research. Special thanks to Melissa Edwards, for being there since the beginning helping me, and being my friend throughout this journey. Madeleine Cox, thank you for your help and endless enthusiasm. To my fellow PhD students who I began this journey with Adriana Krysta and Ali Aflatounian, thank you for your great support and good times.
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