Diagnosis and Management of Polycystic Ovary Syndrome (eBook)

Part I The Syndrome 11
to 1 Clinical Manifestations of PCOS 12
1.1 Introduction 12
1.2 How to Approach the Patient 12
1.3 Clinical Picture of PCOS 12
1.4 Family History 13
1.5 Evaluation of Clinical Hyperandrogenism 13
1.6 Evaluation of Menstrual Irregularity and Chronic Anovulation 14
1.7 Evaluation of Infertility 15
1.8 Evaluation of Overweight and Obesity 15
1.9 Additional Information: Insulin Resistance, Metabolic Syndrome, T2DM and Risk for CVD 16
1.10 The Impact of Obesity on Insulin Resistance, Metabolic Syndrome, T2DM and Risk for CVD 17
1.11 Sleep Disorders 17
1.12 Diet History and Food Intake 17
1.13 Psychological Aspects and Quality of Life 18
1.14 PCOS After Menopause 18
1.15 Physical Examination 19
1.15.1 Anthropometry 19
1.15.2 Skin 19
1.15.3 Reproductive System 20
1.15.4 General 20
1.15.5 Differential Diagnosis 20
to 2 The Menstrual Cycle in PCOS 23
2.16 The Normal Menstrual Cycle 23
2.17 Dynamics of Hypothalamic Secretion During the Normal Menstrual Cycle 23
2.18 Feedback During the Normal Menstrual Cycle 24
2.3.1 Normal Folliculogenesis 25
2.19 Menstrual Dysfunction in PCOS 25
2.20 Gonadal Steroids in PCOS 25
2.21 Follicular Development in PCOS 26
2.22 Neuroendocrine Abnormalities in PCOS 27
2.7.1 Impact of Hyperandrogenemia 27
2.7.2 Impact of BMI 28
2.7.3 Impact of Hyperinsulinemia 28
2.23 Summary 28
to 3 The Radiology of Polycystic Ovaries 31
3.24 Introduction 31
3.25 Historical Perspective 31
3.26 Ultrasound 32
3.27 Some Practical Facts 32
3.4.1 Transabdominal and Transvaginal Ultrasound 33
3.4.2 Timing of the Ultrasound Scan 33
3.28 Ultrasound Assessment of the Ovaries 34
3.5.1 Multifollicular Ovaries 35
3.5.2 Doppler Studies 36
3.5.3 Other Ultrasound Findings 36
3.29 Technical Recommendations for Ultrasound Assessment of Ovaries in PCOS 36
3.30 MRI 38
3.31 Key Points 38
Part II Origins 40
to 4 Insulin Resistance in PCOS 41
4.32 Introduction: Definition of Insulin Resistance 41
4.33 Prevalence of Insulin Resistance in Women with PCOS 41
4.34 Determinants of Heterogeneity of IR in PCOS 44
4.3.1 Factors Specific to PCOS 44
4.3.1.1 Diagnostic Criteria -- PCOS Phenotypes 44
4.3.1.2 Obesity--Dietary Factors 47
4.3.1.3 Family History PCOS -- Family History of Type 2 Diabetes 47
4.3.2 Factors Independent of PCOS 48
4.3.2.1 Methodological Issues 48
4.3.2.2 Race/Ethnicity 49
4.35 Target Tissues of Insulin Action in PCOS 49
4.4.1 Insulin Action in Peripheral Tissues 50
4.4.1.1 Skeletal Muscle 50
4.4.1.2 Adipose Tissue 50
4.4.2 Insulin Action in the Ovarian Tissue: Clinical Aspects and Molecular Insights into the Paradox 51
4.4.3 Insulin Action in the Cardiovascular System 53
4.36 Insulin Resistance in PCOS: The Aggravating Role of the Endocrine and Inflammatory Milieu 53
4.5.1 The Role of Androgens 54
4.5.2 The Role of Inflammation, Adipokines, Oxidative Stress 55
4.37 Genetics of Insulin Resistance in PCOS 56
4.38 Conclusions 57
to 5 Genetics of Metabolic Syndrome and Genetic Lipodystrophies 68
5.39 Introduction 68
5.40 Complex VS. Monogenic Traits 68
5.41 Metabolic Syndrome 69
5.3.1 Clinical Features and Epidemiology 69
5.3.2 Pathophysiology of Mets 69
5.3.3 Genetic Features 72
5.3.4 Linkage Analysis 72
5.3.5 Genetic Association Studies 73
5.3.5.1 Adipokine Candidate Genes 73
5.3.5.2 Candidate Genes in Inflammation 73
5.3.5.3 Candidate Genes in Adipose Distribution 76
5.3.5.4 Candidate Genes in Insulin and Glucose Metabolism 76
5.3.5.5 Candidate Genes from Sex Hormone Metabolism 77
5.42 Genetic Lipodystrophies 77
5.4.1 Definition 77
5.4.2 Congenital Generalized Lipodystrophy (Berardinelli--Seip Syndrome) 78
5.4.2.1 Clinical Features 78
5.4.2.2 Pathophysiology and Molecular Genetics 78
5.4.3 Familial Partial Lipodystrophy 78
5.4.3.1 Clinical Features 78
5.4.3.2 Pathophysiology and Molecular Genetics 79
5.43 Genetics of Mets and Genetic Lipodystrophies: Relation to PCOS 79
5.44 Conclusions 80
to 6 The Genetics of Polycystic Ovary Syndrome 87
6.45 Introduction 87
6.46 Methods for Identifying PCOS Genes 88
6.2.1 Linkage and Association 88
6.2.2 Markers Used in Linkage and Association Studies 89
6.2.3 Candidate Gene Analysis 89
6.2.4 Genome-Wide Screens 89
6.47 Genes Associated with PCOS 90
6.3.1 Genes Associated with Sex Hormone Regulation 90
6.3.1.1 FBN3 90
6.3.1.2 SHBG 90
6.3.1.3 The AR Gene 91
6.3.1.4 CYP21 91
6.3.1.5 Dopamine D3 Receptor 91
6.3.1.6 FSH-Beta 92
6.3.2 Genes Associated with Insulin Resistance 92
6.3.2.1 CAPN10 92
6.3.2.2 IGF2 92
6.3.2.3 IRS1 and IRS2 92
6.48 Conclusion 93
to 7 Uterine Origins and Evolution in Childhood 96
7.49 Introduction 96
7.50 Prenatal Androgen Excess Evidence for the Fetal Origins of PCOS 96
7.2.1 Clinical Observations 97
7.2.2 Experimental Animal Research 97
7.2.3 Potential Origin of Prenatal Androgen Excess in Humans 98
7.2.4 Plausible Biological Mechanisms 99
7.51 Prenatal Growth and PCOS 100
7.52 Pubarche and PCOS 102
7.53 Conclusion 102
Part III Consequences 105
to 8 Hyperandrogenism in PCOS 106
8.54 Introduction 106
8.55 Clinical Evaluation of Hyperandrogenism 106
8.2.1 Hirsutism 106
8.2.2 Acne 107
8.2.3 Male-Pattern Alopecia 107
8.56 Laboratory Evaluation of Hyperandrogenism 107
8.57 Biochemical Features of Hyperandrogenism 108
8.4.1 Ovarian Hyperandrogenism 108
8.4.2 Adrenal Hyperandrogenism 109
8.58 The Molecular Basis of Hyperandrogenism 109
to 9 The Risk of Diabetes and Metabolic Syndrome in PCOS 112
9.59 Adverse Metabolic Features and Cardiovascular Risk in PCOS 112
9.60 Prevalence of Metabolic Syndrome in PCOS 112
9.2.1 Diagnostic Criteria for Metabolic Syndrome 113
9.2.2 Diagnostic Criteria for PCOS 114
9.2.3 Distribution of BMI and Age 114
9.61 Aetiology of Metabolic Dysfunction in PCOS 115
9.3.1 Insulin Resistance 115
9.3.2 Abnormal Abdominal Adiposity 116
9.3.3 Abnormal -Cell Function 116
9.62 Screening and Management of T2D and Dysglycaemia in PCOS 116
9.63 Practice Points 117
to 10 The Risks of Cardiovascular Disease and Diabetes in the Polycystic Ovary Syndrome 121
10.64 Overview 121
10.65 Insulin Resistance and PCOS 121
10.66 Risk for Impaired Glucose Tolerance and Type 2 Diabetes Mellitus in PCOS 122
10.67 Risk for Cardiovascular Disease in PCOS 123
10.68 Clinical Significance of Insulin Resistance in PCOS 124
10.5.1 Oral Contraceptives for Chronic Treatment of PCOS 125
10.5.2 Insulin-Sensitizing Drugs for Chronic Treatment of PCOS 125
10.69 Insulin-Sensitizing Drugs 125
10.6.1 Metformin 126
10.6.2 Thiazolidinediones 127
10.70 Areas of Future Research 128
10.71 Recommendations 128
to 11 Pregnancy Complications in PCOS 134
11.72 PCOS and Miscarriage 134
11.73 Prevalence 134
11.74 Etiology 135
11.3.1 Fertility Treatment 135
11.3.2 Obesity 135
11.3.3 Hyperinsulinaemia 135
11.3.4 Hypersecretion of LH 135
11.3.5 Endometrial Dysfunction 136
11.75 Treatment Modes 136
11.4.1 Metformin 137
11.4.2 Weight Loss 137
11.4.3 Reduction of LH Concentrations 137
11.76 Gestational Diabetes 138
11.77 Pregnancy-Related Hypertension 138
11.78 Small-for-Gestational-Age Babies 138
11.79 Summary 139
to 12 Polycystic Ovary Syndrome, Sleep Apnea, and Daytime Sleepiness and Fatigue 142
12.80 Introduction 142
12.81 Sleep Apnea, Inflammation, Insulin Resistance, and Central Adipocity 142
12.82 Visceral Fat is the Predominant Fat Problem in Sleep apnea 144
12.83 Sleep Apnea is Very Frequent in Women with PCOS 146
12.84 PCOS is Associated with Sleep Apnea and EDS Independent of Obesity 146
12.85 Insulin Resistance is the Strongest Predictor of Sleep Apnea in PCOS 147
12.86 Excessive Daytime Sleepiness: Prevalence and its Association with Metabolic Disorders 147
12.87 Daytime Sleepiness in PCOS 148
12.88 Summary 150
to 13 Polycystic Ovarian Syndrome and Gynaecological Cancer 154
13.89 Introduction 154
13.90 Endometrial Cancer 154
13.2.1 Epidemiology 154
13.2.2 Pathogenesis 155
13.2.3 Screening for Endometrial Cancer 157
13.2.4 Prevention and Treatment of Endometrial Hyperplasia 157
13.2.5 Management of Endometrial Cancer 160
13.91 Non-Endometrioid Carcinoma of Uterus 161
13.3.1 Breast Cancer 161
13.3.2 Ovarian Cancer 161
13.92 Conclusion 162
to 14 PCOS, Depression, and Alzheimer0s Disease 165
14.93 Introduction 165
14.94 Depressive Disorders in Women with PCOS 165
14.2.1 Psychosocial Aspects of PCOS: Additional Contribution to Depression 167
14.95 Cardiovascular Disease and PCOS 167
14.3.1 Obesity 168
14.3.2 Insulin Resistance (IR) 168
14.3.3 Elevated Immunological Response 169
14.3.4 Risk of CVD in Women with PCOS 169
14.96 PCOS and Alzheimers Disease 170
14.4.1 Cognitive Performance in Women with PCOS 170
14.4.2 Associated Conditions of PCOS may also Confer Risk of AD 171
14.97 Conclusion 172
to 15 Psychological Issues and Their Treatment 178
15.98 Psychological Consequences 178
15.1.1 Depression 178
15.1.2 Body Dissatisfaction and Eating Disorders 179
15.1.3 Other Mental Health Correlates 179
15.99 Treating Psychological Aspects of PCOS 180
15.2.1 Screening for Psychological Symptoms 180
15.2.2 Management of Depression 180
15.2.3 Management of Body Dissatisfaction and Eating Disorders 181
15.2.4 Lifestyle Modification 181
15.100 Conclusions 182
Part IV Management 185
to 16 Dietary Management of PCOS 186
16.101 Introduction 186
16.102 Obesity and Weight Loss in PCOS 186
16.103 Lifestyle Changes Effective in Women with PCOS 187
16.104 Dietary Management of PCOS More Than Just Weight Loss 187
16.105 What Should You Recommend to Your Patients with PCOS? 187
16.5.1 Encourage the Use of Low GI, Wholegrain Breads and Cereals Over High GI, Processed Grain Products 188
16.5.2 Advise Limiting Intake of Saturated and Trans Fats and Favouring Monounsaturated and Omega-3 Fats 189
16.5.3 Caution Against High-Protein Diets and Favour Plant Protein Over Animal Protein 189
16.5.4 Promote Low Energy Density 190
16.106 Evidence in Support of These Recommendations 190
16.107 Conclusion 191
16.108 Practice Points 191
to 17 Exercise in the Treatment of PCOS 198
17.109 Introduction 198
17.110 Exercise and Weight Loss 198
17.111 Exercise and Insulin Resistance 199
17.112 Exercise, Diet and PCOS 199
17.113 Other Potential Benefits of Exercise in PCOS Patients 200
17.114 Practical Recommendations 201
17.115 Conclusions 201
to 18 Medical Treatment 203
18.116 Introduction 203
18.117 Role of Insulin Resistance and Insulin Action in Polycystic Ovary Syndrome 203
18.2.1 PCOS Insulin Resistance 203
18.2.2 Role of Insulin Action in PCOS Hyperandrogenemia 204
18.2.3 PCOS: A Syndrome of Androgenic Insulin Hypersensitivity? 204
18.118 Insulin Sensitization Through Weight Loss and Exercise 204
18.3.1 Obesity and PCOS 205
18.3.2 Benefits of Weight Loss and Exercise in Women with PCOS 205
18.119 Insulin-Sensitizing Drugs 208
18.4.1 Agents 209
18.4.1.1 Metformin 209
18.4.1.2 Thiazolidinediones (TZDs) 210
18.4.2 Clinical Benefits in Women with PCOS 210
18.4.2.1 Improving Menstrual Cyclicality and Fertility 210
18.4.2.2 Benefits on Clinical Hyperandrogenism 212
18.4.2.3 Management of Long-Term Risks of Type 2 Diabetes and Cardiovascular Diseases 215
18.4.3 Indications 215
18.4.4 Monitoring of Clinical Outcomes 216
18.120 Insulin Sensitization During Pregnancy 217
18.121 Take Home Messages 217
to 19 Therapy of Hirsutism 227
19.122 Physical Methods of Hair Removal 227
19.1.1 Depilation and Creams 228
19.1.2 Particular Creams 228
19.1.3 Epilation 229
19.123 Pharmacological Treatment 231
19.2.1 Inhibition of Ovarian Steroidogenesis 231
19.2.2 Antagonism on Androgen Receptors 232
19.124 Inhibition of 5-Reductase 233
to 20 Ovulation Induction in PCOS 237
20.125 Introduction 237
20.126 Treatment of Anovulation 237
20.127 Lifestyle Modification 239
20.128 Surgical Intervention 239
20.129 Induction of Ovulation 240
20.5.1 Anti-estrogens (Clomiphene Citrate) 240
20.5.2 Follicle Stimulating Hormone (FSH) 240
20.5.3 Insulin-Sensitizing Drugs (Metformin) 242
20.5.4 Aromatase Inhibitors (Letrozole) 243
20.130 Recommendations and Conclusions 243
to 21 IVF in Polycystic Ovary Syndrome 247
21.131 Introduction 247
21.132 Preconception Care in Women with PCOS 247
21.133 Pre-treatment with Metformin 248
21.134 Monitoring Response to Stimulation 249
21.135 Prevention of OHSS 250
to 22 The Surgical Management of Polycystic Ovarian Syndrome 253
22.136 Introduction 253
22.137 Obesity and PCOS 253
22.138 PCOS and Other Gynaecological Disorders 254
22.139 Surgical Options for PCOS 254
22.140 Mechanisms by Which LOD Induces Ovulation 255
22.141 Effects of PCOS in Pregnancy 255
22.142 Conclusion 256
to 23 When Periods Stop: Long-Term Consequences of PCOS 258
23.143 Introduction 258
23.144 Menopausal Age in Women with Polycystic Ovary Syndrome 258
23.145 Increased Cardiovascular Risk in Women with PCOS 258
23.146 Cardiovascular Disease in Postmenopausal PCOS Women 259
23.147 Changes in Polycystic Ovaries and Androgens with Age 260
23.148 Body Weight and Diabetes in Postmenopausal PCOS Women 261
23.149 Cancer in Postmenopausal PCOS 261
23.150 Therapeutic Approaches in Postmenopausal PCOS 261
23.151 Conclusions 262