Evaluation of Clinical Efficacy and Investigation of Mechanism of Action of Acupuncture Treatment in the Management of Polycystic Ovarian Syndrome Scholarship Candidate: Dr Chi Eung Danforn Lim BSs(Med) MBBS (UNSW), BHltSc(Complementary Med)(CSU), DCH(USyd), Clin Dip Pall Med(RACP) MMed(Repro Health & Hum Genetics)(USyd), MAppSc(Acupuncture)(RMIT), MAppMgt(Health)(Newcastle), RCMP(Acupuncture & Chinese Herbal Medicine), AFRACMA, AFCHSM, MACNEM, MACE, JP Scholarship support awarded for this doctoral study: South Western Sydney Clinical School Scholarship, University of New South Wales, Australia (2008-2011) Principal Supervisor: Professor Felix WS Wong MBBS MD MMed FRANZCOG FRCOG FRCS Ed FRCS Glas FHKCOG FHKAM Co-Supervisor: Associate Professor Anthony J O’Sullivan MBBS MD FRACP This thesis is submitted in 2012 to fulfil the requirement for the award of degree of Doctor of Philosophy (Medicine) at the Faculty of Medicine, University of New South Wales, Australia 2 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.’ Copyright Statement ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Authenticity Statement ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Dr Chi Eung Danforn Lim 28th August, 2012 DECLARATION I declare that this thesis contains no material that has been accepted for the award of any other degree or diploma in any university. And that, to the best of my knowledge and belief, this thesis contains no material previously published or written by any other persons, except where due reference is made in the text of the thesis or the article has been published under my name at the peer reviewed journals. The content of the thesis is the result of work that has been carried out since the official commencement date of the approved research program. I declare that all the work performed in this thesis are all my own work, except where due references and acknowledgment are made. I declare that I have received formal education in Chinese medicine and acupuncture through my postgraduate studies at RMIT University. I declare that I am a Registered Chinese Medicine Practitioner in Victoria, Australia with good standing throughout this doctoral study period and able to perform acupuncture without any restriction in Australia. Chi Eung Danforn Lim Registered Medical Practitioner, Medical Board of Australia Registered Chinese Medicine Practitioner, Chinese Medicine Board of Australia _______________________________ Date: __________________ 3 ACKNOWLEDGEMENTS At the outset, I thank God for His abundant grace benevolent blessings and counsel that made this research possible. Becoming a competent and mature doctor is a long and challenging process. I have been very lucky to be tutored under Professor Felix Wong and Associate Professor Anthony O’Sullivan, in particularly since when I was an undergraduate medical student at the UNSW. First of all, I must thank my supervisors, Professor Felix Wong and Associate Professor Anthony O’Sullivan for their invaluable time and supervision throughout this study. In particular, I would like to further extend my appreciation towards Professor Felix Wong for his inspiration, encouragement, guidance, advice and friendship throughout my study for this degree. I am heartily thankful to him for offering me to commence my doctoral study since my internship and also the ample opportunities that he has given me to view medicine and research in many different ways. Without all their support, this thesis would not have been possible. Being a medical graduate of the University of New South Wales, I am very fortunate to be able to continue my PhD(Med) study at my alma mater. I would like to take this opportunity to express my sincere gratitude towards South Western Sydney Clinical School for their generous support throughout my candidateship by offering me a full scholarship. Furthermore, I would like to thank all the clinical teachers and staff for their invaluable constructive comments throughout my internal reviews within the School and enrolments each year, in particular to Professor Minoti Apte and Ms Claudia Calero. Throughout the studies, I have been given a lot of assistance from my colleagues regarding to research issues and publication matters. I would like to thank all my colleagues and friends for their patience and 4 help throughout my studies, in particular to all the co-authors of my papers published in various journals, as well as to my brother in law Professor Charlie Xue for his advice at the early stage of this research study. I would also like to thank all the teaching, clinical and laboratory staff at the Guangdong Women’s and Children’s Hospital of the Guangzhou Medical University, China, for their countless support and assistance in this collaboration to recruit subjects throughout this study. All these would not be possible without the leadership of Professor Xiping Luo and Dr Xinlin Zhan throughout this study. In particularly, I thanked Prof Xiping Luo’s participation in subject’s clinical visits, follow ups, and allocation of research assistant. Furthermore, I thanked Dr Xinlin Zhan for performing the acupuncture for the subjects recruited in their hospital. Most importantly, I would like to take this opportunity to thank my parents, Dr Long Kiat Lim and Dr Mee Led Hung, for their invaluable love, support and teaching throughout my life. They taught me how to be a good doctor and also lead me to my Lord in heaven. They give me all they have and also the most power that lines up my courage to face the various difficulties of life. Without their substantial and unstinting love and support, nothing would have been possibly achieved. There were a lot of changes in my life throughout this doctoral study. I have gone from a bachelor to being a husband and later on becoming a father. I would also like to thank my wife, Dr Nga Chong Lisa Cheng, for her unlimited support, patience, understandings and love throughout my studies. I am thankful to my little boy, Enoch Lim, for his understanding throughout my studies that being a father I was not able to spend a lot of time with him while preparing this thesis. I would like to thank my siblings, Dr Ki 5 Fong Bailey Lim and Dr Ki Yuk Lam, for their devoted care which is always an excellent patronage to me. Last but not least, I convey my heartfelt thanks to all participants in this project for their understanding and co-operation in providing sample amidst their physical and psychological impacts from PCOS and making this a success. 6 ABBREVIATIONS ACTH Adrenocorticotrophic hormone AES Androgen Excess Society ASRM American Society of Reproductive Medicine BBT Basal body temperature b-hCG Beta - human chorionic gonadotropin BMI Body mass index CAH Congenital adrenal hyperplasia CAM Complementary and alternative medicine CM Chinese medicine CMCRC Chinese Medicine Clinical Research Centre, Liverpool Hospital Sydney CRF Corticotrophin-releasing factor CV Conception vessel / Meridian in Acupuncture CVD Cardiovascular disease DHEAS Dehydroepiandrosterone sulphate E2 Estradiol (Oestrogen) ESHRE European Society of Human Reproduction and Embryology FAI Free Androgen Index FSH Follicular stimulating hormone GIT Gastrointestinal tract GnRH Gonadotropin-releasing hormone hMG Human menopausal gonadotrophin HPA axis Hypothalamic-pituitary-adrenal axis HPG Hypothalamic-pituitary-gonadal HPO Hypothalamic-pituitary-ovarian 7 LH Luteinising hormone MSG Monosodium glutamate NIDDM Non-insulin dependent diabetes mellitus NIH National Institute of Health OCP Oral contraceptive pills OGTT Oral glucose tolerance test OHS Ovarian Hyperstimulation Syndrome PCO Polycystic ovaries PCOS Polycystic Ovarian Syndrome RANZCR Royal Australian and New Zealand College of Radiologists RCOG Royal College of Obstetricians and Gynaecologists, United Kingdom RCTs Randomised controlled trials r-FSH Recombinant follicular stimulating hormone RUQ Right upper quadrant SD Standard deviation SHBG Sex hormone-binding globulin SMD Standardised mean difference T2DM Type 2 diabetes mellitus TCM Traditional Chinese Medicine u-FSH Purified follicular stimulating hormone VAS Visual Analogue Scale WHO World Health Organisation 8 Related Publications / Conference Proceedings generated from this Thesis: Published in SCI Journals: 1. LIM DCE, Chen W, Cheng LNC, Xue CC, Wong FWS, O'Sullivan AJ, Liu JP. Acupuncture for polycystic ovarian syndrome. Cochrane Database of Systematic Reviews 2011, Issue 8. Art. No.: CD007689. DOI: 10.1002/14651858.CD007689.pub2 2. LIM CED, Xue C, Liu, J, Wong WSF, O’Sullivan A. Acupuncture and PCOS, Cochrane Collaboration Systematic Review, Issue 2, 2009 (Protocol) 3. LIM, CED, WONG, F. Current evidence of Acupuncture on PCOS. Gynecological Endocrinology. 2010, Vol. 26, (6): 473-478 4. LIM, CED. Liu, JP, Cheng, N. Traditional Chinese Medicine for Gynaecological Diseases. Australian Traditional Medicine Society Journal. 2011:17(1): 17-20 5. Zhang J, Zhou L, Tang L, Wu T, Lim CED. Chinese Herbal Medicine for sub fertile women with PCOS, Cochrane Collaboration Systematic Reviews 2010, Issue 9. Art. No.: CD007535. DOI: 10.1002/14651858.CD007535.pub2.. 6. Zhu X, Proctor M, Lim CED. Cochrane review of Acupuncture for female subfertility. Cochrane Collaboration Systematic Review (Protocol Stage) 7. YII MF, LIM, CED, WONG F. PCOS in Adolescence. Gynaecological Endocrinology. 2009 25(10): 634-639 8. LIM, CED, WONG, F – Evaluation of Clinical Efficacy of Acupuncture Treatment on the Management of Polycystic Ovarian Syndrome: A Pilot Study. J Alt & Comp Med Jan 08 S: 54 9. LIM, CED, WONG, F, CHENG, L – Traditional Chinese Medicine and Female Infertility: A Review of Literature. J Alt & Comp Med Jan 08 S: 55 Published in Conference Proceedings: 1. (Abstract No. 28) LIM, CED, WONG, Wu Shun Felix. A study of Mechanism of Acupuncture on the treatment of Polycystic Ovarian Syndrome (PCOS), Australian Acupuncture & Chinese Medicine Association Conference 2005, Melbourne 13-15 May, 2005 2. (Abstract No. 47) LIM, CED, WONG, Wu Shun Felix. A study of Mechanism of Acupuncture on the treatment of Polycystic Ovarian Syndrome (PCOS), Harmonisation of Traditional and Modern Medicine An international symposium, Melbourne, Australia 12 – 14 December 2005 3. LIM, D, WONG, Felix. Effect of Acupuncture and Traditional Chinese Herbal Medicine on the Treatment of Female Infertility, World Congress on Chinese Medicine, Hong Kong 23-25 Nov, 2006 4. LIM, D. Acupuncture & PCOS: RCT. First International Asia Pacific PCOS Meeting. University of Hong Kong, Hong Kong (17-18 Jan, 2009) 5. LIM, D. Insulin Resistance in Chinese women with PCOS. Guangdong Maternal & Child Health Conference, Guangdong Maternal & Child Health Hospital, Guangzhou Medical University, China (July 2008) 6. WONG, Felix. LIM, D. Acupuncture & PCOS. RANZCOG Scientific Meeting. New Zealand 2009 7. Lim, D. Acupuncture & PCOS: RCT. Inaugural Chinese Medicine Academic Conference. Sydney Australia. 2011 9 Published in Australian Doctors’ newsletter as featured article: 1. Lim, D. Acupuncture promising for infertility in PCOS. Chinese Medicine Clinical Research Centre, Liverpool Hospital. Available: http://www.mydr.com.au/womens-health/acupuncture- promising-for-infertility-in-pcos via the Internet. Accessed 2009 Apr 23 Pending to be submitted for publication from this thesis once the degree is awarded: 2. LIM, CED, WONG, WSF. et al Acupuncture & PCOS: A RCT. 3. LIM, CED, WONG, WSF. et al A pilot experience of using acupuncture in PCOS. 4. LIM, CED, WONG, WSF. et al PCOS: What does Chinese women worry about ? 5. LIM, CED, WONG, WSF, et al Standardisation of PCOS Diagnosis in Chinese Medicine – A diagnostic tool study 10
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