COMPLEMENTARY AND ALTERNATIVE MEDICINE USE AND THE MENOPAUSAL TRANSITION: THE EFFECT OF A CHINESE HERBAL FORMULA ON VASOMOTOR SYMPTOMS AND BONE TURNOVER Corinne Patching van der Sluijs, B.Sc, B.Hlth Sc, Dip Ed This thesis is submitted for the degree of Doctor of Philosophy, University of Western Sydney Centre for Complementary Medicine Research November 2007 © C. van der Sluijs 2007 ii CERTIFICATION The work presented in this thesis is, to the best of my knowledge and belief, original except as acknowledged in the text. I hereby declare that I have not submitted this material, either in full or in part, for a degree at this or any other institution. Corinne Patching van der Sluijs iii DEDICATION To Byron Edward Patching Without your loving support and patience, this work would not have been possible And To our two beautiful young children who entered the world during this time Micah Robert (1st January 2005) Grace Elisabeth (23rd June 2006) iv ACKNOWLEDGEMENTS I wish to take this opportunity to express my sincere thanks to the many people who supported and assisted me during this research project; without whose help this thesis would not have eventuated. I am grateful to the many survey respondents and clinical trial participants who graciously gave their time to take part in this research. Thank you to the general practice clinics, the menopause clinics, the New South Wales Government and the University of Western Sydney who gave permission to allow for the distribution of the questionnaire. To my principal supervisor Professor Alan Bensoussan, I am extremely grateful for your guidance, expertise, patience and understanding throughout this journey; and to my co- supervisors Drs Smita Shah and Liwan Liyanage who encouraged and supported me during this time. I am grateful for the assistance and support of Dr Rod Baber and staff at the Royal North Shore Menopause Clinic, Professors Felix Wong and Markus Seibel. In addition, I wish to acknowledge the support of Professor Seibel and the ANZAC Research Centre for providing the bone marker assay kits and for testing the samples. Sungwon Chang, I am grateful for your statistical guidance and assistance. Your support has been invaluable. I wish to also sincerely thank practitioners Nadine Licht, Christine Guirguis and Tuyet Tran for your considerable help in consulting trial participants. I am grateful for financial support and the PhD scholarship granted to me by the University of Western Sydney. I also wish to thank staff at CompleMED for their ongoing support for this project. Finally, I would like to express my sincere gratitude for the financial and technical assistance received from Global Therapeutics for the clinical trial. v ABSTRACT Although Hormone Therapy (HT) is the most effective treatment for alleviating menopausal vasomotor symptoms and reducing bone loss, many women are reluctant to take this treatment due to side effects and concerns about safety. Epidemiological studies suggest that a significant proportion of women use Complementary and Alternative Medicine (CAM) therapies to alleviate vasomotor symptoms and improve quality of life. Anecdotal and clinical evidence indicate a number of CAM therapies, such as herbal medicine, may be effective in alleviating symptoms and modulating bone metabolism. Hence, in the context of concerns over the safety of HT and the extensive history of the clinical use of herbal medicine, this thesis investigated issues pertinent to CAM use and the menopausal transition. The aims of this thesis were to: • Examine the nature and extent of CAM use by women transitioning through menopause • Evaluate the effectiveness of a herbal formula containing Chinese herbs and Cimicifuga racemosa for alleviating vasomotor symptoms, improving quality of life and modulating bone turnover markers. From July 2003 until July 2004 the Women’s Health during Midlife Survey recruited 1,296 women aged 45-65 who were symptomatic when transitioning through menopause or asymptomatic but taking menopause specific treatments. A validated 19-item survey instrument assessed the use of CAM modalities and menopause vi specific products. The instrument was completed voluntarily and anonymously by women recruited from three strata; menopause clinics, clinics of general practice and government agencies. Approximately 54% of respondents had visited a CAM practitioner and/or used a CAM product during the previous 12 months. The most popular practitioners were the naturopath (7.2%) and acupuncturist (4.8%), while soy (25.4%) and evening primrose oil (EPO, 18.4%) were the most popular products. Massage and chiropractic were considered the most effective therapies, while phytoestrogen tablets and EPO were the most efficacious products. Although 26.4% of respondents indicated their doctor asked about CAM use, 71% of CAM users said they informed their physician about using CAM. Of the 60% of women using pharmaceutical medicines, 62.5% reported using a CAM product during the preceding 12 months. The survey results confirm the continued popularity of CAM use amongst women transitioning through menopause. A number of treatments were perceived to be effective in relieving symptoms. However, communication between medical practitioners and patients about CAM use is inadequate, and given the high use of pharmaceutical medicines this oversight may unnecessarily expose women to drug- herb interactions. A randomised, double-blind, placebo controlled clinical trial was conducted to evaluate the effectiveness of a herbal formula derived from two traditional Chinese herbal formulae with the addition of Cimicifuga in alleviating vasomotor symptoms. The trial recruited 93 healthy women who reported at least six vasomotor symptoms vii per day. After a four week baseline period, women were randomly allocated to receive either herbal treatment or identical looking placebo tablets for 16 weeks. During the trial women recorded the number and severity of their flushes on a Daily Flush Diary, and at each monthly consultation two quality of life scales were completed. Forty nine eligible trial women were entered into a pilot study to assess the effect of the formula on bone turnover markers; bone specific alkaline phosphatase and deoxypyridinoline (corrected for creatinine). The herbal formula was found to be no more effective than placebo in reducing the frequency of flushing and the composite hot flush score or in improving quality of life. The pilot study found the formula had no effect on bone turnover markers after 16 weeks of treatment. Therefore, this formula cannot be recommended as a treatment for vasomotor symptoms and is unlikely to have any long term effect on bone. The use of CAM during the menopausal transition is very popular. Although this thesis found the current herbal formula to be an ineffective treatment, the scientific evaluation of potential CAM therapies is imperative so that health care professionals and consumers can make informed decisions concerning treatment options for the alleviation of symptoms. viii TABLE OF CONTENTS CERTIFICATION II DEDICATION III ACKNOWLEDGEMENTS IV ABSTRACT V TABLE OF CONTENTS VIII LIST OF FIGURES XIII LIST OF TABLES XIV LIST OF ABREVIATIONS XVI LIST OF APPENDICES XVIII CHAPTER 1 INTRODUCTION 1 1.1 General Background to the Study 1 1.2 Aim and Scope 5 1.3 Significance of the Study 8 1.4 Thesis Overview 9 SECTION ONE COMPLEMENTARY AND ALTERNATIVE MEDICINE USE FOR MENOPAUSAL COMPLAINTS 11 CHAPTER 2 CAM AND THE MENOPAUSAL TRANSITION 12 2.1 Introduction 12 2.2 Defining CAM 13 2.3 Economic Impact of CAM 15 2.4 The CAM Consumer 19 2.5 CAM Use and the Menopausal Transition 23 ix 2.6 CAM Use by Middle Aged Women 32 2.7 Summary and Conclusions 42 CHAPTER 3 SURVEY: RESEARCH DESIGN 44 3.1 Introduction 44 3.2 Study Objectives 45 3.3 Participants and Setting 46 3.4 Survey Instrument 49 3.5 Statistical Analyses 53 3.6 Summary 54 CHAPTER 4 SURVEY: RESULTS 56 4.1 Introduction 56 4.2 Survey Instrument Reliability 57 4.3 Demographics and Health Characteristics 57 4.4 Use of CAM 62 4.5 Use of Pharmaceuticals 69 4.6 Determinants of CAM Use 71 4.7 Discussion 72 CHAPTER 5 SURVEY: DISCUSSION AND CONCLUSIONS 75 5.1 Introduction 75 5.2 CAM Use by Women Aged 45-65 75 5.3 CAM and Pharmaceutical Use 80 5.4 Determinants of CAM Use 81 5.5 Methodological Considerations 83 5.6 Conclusions 86 x SECTION TWO THE EFFECT OF FF-01 ON VASOMOTOR SYMPTOMS AND BONE TURNOVER 87 CHAPTER 6 MENOPAUSE AND VASOMOTOR SYMPTOMS 88 6.1 Introduction 88 6.2 A Definition of the Menopause 89 6.3 Epidemiology of the Menopause 92 6.4 Changes during the Menopausal Transition 94 6.5 Symptoms of the Menopause 99 6.6 Pharmacological Treatments for Vasomotor Symptoms 116 6.7 Summary and Conclusion 124 CHAPTER 7 CHINESE HERBAL MEDICINE FOR VASOMOTOR SYMPTOMS 126 7.1 Introduction 126 7.2 TCM and Menopause 127 7.3 Systematic Review on CHM for Vasomotor Symptoms 131 7.4 Discussion and Conclusions 153 CHAPTER 8 TRIAL FORMULA: FF-01 155 8.1 Introduction 155 8.2 FF-01: the Clinical Trial Formula 156 8.3 Constituent Herbs of the Formula 158 8.4 CHM Pharmacological Research 189 8.5 Summary and Conclusions 191 CHAPTER 9 MENOPAUSE AND BONE METABOLISM 193 9.1 Introduction 193 9.2 Definition of Osteoporosis 194 xi 9.3 Risk Factors for Osteoporosis 195 9.4 Burden of Osteoporotic Fractures 196 9.5 Skeletal Changes Associated with Menopause 198 9.6 Biochemical Markers of Bone Turnover 199 9.7 Pharmacological Treatments for Osteoporosis 203 9.8 The Effect of Herbs on Bone Metabolism 217 9.9 Summary and Conclusions 222 CHAPTER