Polycystic Ovary Syndrome (eBook)

Preface 7
Contents 9
Contributors 11
List of Color Plates 14
1 Folliculogenesis in Polycystic Ovaries 15
CONTENTS 15
1. INTRODUCTION 15
2. ANTRAL FOLLICLE FUNCTION IN POLYCYSTIC OVARIES 16
3. MECHANISMS OF ARRESTED ANTRAL FOLLICLE GROWTH IN PCOS 16
4. EARLY FOLLICULAR DEVELOPMENT IN PCOS 18
REFERENCES 20
2 Accounting for the Follicle Population in the Polycystic Ovary 22
CONTENTS 22
1. INTRODUCTION 22
2. NORMAL FOLLICULAR GROWTH 23
3. INCREASED FOLLICLE RECRUITMENT 24
3.1. Hyperandrogenism 25
3.2. Hyperinsulinemia 26
3.3. Anti-Mullerian Hormone Deficiency 27
4. FOLLICULAR ARREST 28
4.1. Elevated 5a-Reduced Androgens 29
4.2. Premature Follicle Luteinization 29
4.3. Inhibins, Activins, and Follistatin 30
5. IMPAIRED FOLLICULAR GROWTH 31
ACKNOWLEDGMENTS 31
REFERENCES 32
3 What Is the Appropriate Imaging of the Polycystic Ovary 38
CONTENTS 38
1. INTRODUCTION 38
2. 2-D ULTRASONOGRAPHY 39
2.1. Technical Aspects and Recommendations 39
2.2. The Consensus Definition of PCO 39
2.3. Other Criteria and Other Definitions 41
3. OTHER TECHNIQUES FOR IMAGING PCO 43
3.1. 3- D Ultrasonography 43
3.2. Doppler Ultrasonography 44
3.3. Magnetic Resonance Imaging 45
4. CONCLUSIONS AND FUTURE AVENUES OF INVESTIGATION 45
REFERENCES 46
4 Polycystic Ovary Versus Polycystic Ovary Syndrome 49
CONTENTS 49
1. INTRODUCTION 49
2. POLYCYSTIC OVARIES IN THE ABSENCE OF HYPERANDROGENISM 51
3. POLYCYSTIC OVARIES IN THE ABSENCE OF MENSTRUAL DYSFUNCTION 52
4. OVARIAN DYSFUNCTION IN PCOS 56
5. EXPRESSION OF PCOS IN WOMEN WITH PCO 57
5.1. Insulin Resistance and Expression of PCOS 58
6. CONCLUSIONS 59
REFERENCES 59
5 Genetic Analyses of Polycystic Ovary Syndrome 62
CONTENTS 62
1. POLYCYSTIC OVARY SYNDROME 63
2. FAMILIAL BASIS OF PCOS 63
3. CURRENT STATUS OF PCOS GENETIC STUDIES 63
3.1. Phenotyping 79
3.2. Sample Sizes 80
3.3. Variant Choice 81
4. PCOS CANDIDATE GENES 81
4.1. CYP11A 81
4.2. Insulin Gene VNTR 82
4.3. Calpain-10 83
4.4. SHBG 83
4.5. AR and X-inactivation 84
4.6. Chromosome 19p13.2 PCOS susceptibility locus (D19S884) 86
5. FUTURE DIRECTIONS 87
REFERENCES 87
6 Fetal Origins of Polycystic Ovary Syndrome 98
CONTENTS 98
1. INTRODUCTION 99
2. PCOS IN PRENATALLY ANDROGENIZED FEMALE RHESUS MONKEYS 101
3. PCOS METABOLIC DEFECTS IN PRENATALLY ANDROGENIZED MALE RHESUS MONKEYS 108
4. FETAL OR DEVELOPMENTAL ORIGINS HYPOTHESIS FOR PCOS 108
ACKNOWLEDGMENTS 110
REFERENCES 110
7 Pubertal Precursors of the Polycystic Ovarian Syndrome 118
CONTENTS 118
1. INTRODUCTION 119
2. GONADOTROPIN SECRETION DURING OVULATORY CYCLES AND IN WOMEN WITH PCOS 119
2.1. Gonadotropin Secretion During Ovulatory Cycles 119
2.2. GnRH and Gonadotropin Secretion in Adult Women with PCOS 120
2.3. Etiology of Abnormal Gonadotropin Secretion 121
3. GONADOTROPIN SECRETION IN NORMAL PUBERTY AND ADOLESCENTS WITH HYPERANDROGENEMIA 124
3.1. Regulation During Normal Pubertal Maturation 124
3.2. The Origin and Role of Excess Androgens and the Pubertal Evolution of PCOS 126
ACKNOWLEDGMENTS 128
REFERENCES 128
8 Variations in the Expression of the Polycystic Ovary Syndrome Phenotype 133
CONTENTS 133
1. INTRODUCTION 134
2. CLASSIC PCOS PHENOTYPE 134
3. OVULATORY PCOS PHENOTYPE 136
4. NORMOANDROGENIC PCOS PHENOTYPE 138
5. DIFFERENCES BETWEEN THE HYPERANDROGENIC PCOS PHENOTYPES AND FACTORS THAT PROMOTE PHENOTYPE SHIFT 139
REFERENCES 140
9 Acquired Polycystic Ovary Syndrome 143
CONTENTS 143
1. INTRODUCTION 143
2. EPILEPSY AND MENSTRUAL DISORDERS 144
2.1. PCOS and Epilepsy 145
2.2. Epilepsy, AEDs, and PCOS 145
3. PCOS AND BIPOLAR DISEASE 148
4. ARE ORAL CONTRACEPTIVE PILLS PROTECTIVE? 151
5. VALPROATE-ASSOCIATED PCOS: CURRENT THEORIES 152
6. CONCLUSION 154
REFERENCES 154
10 Recommendations for the Early Recognition and Prevention of Polycystic Ovary Syndrome 156
CONTENTS 156
1. EARLY RECOGNITION 156
1.1. Onset of PCOS 156
1.2. Hirsutism 157
1.3. Irregular Bleeding 158
1.4. Obesity 159
1.5. Insulin Resistance 160
1.6. Ovarian Morphology 160
1.7. Acne 161
2. LABORATORY EVALUATION 161
3. PREVENTION 162
3.1. Life-Style Modification 162
3.2. Oral Contraceptives 162
3.3. Anti-Androgens 163
3.4. Insulin-Lowering Drugs 163
REFERENCES 164
11 Insulin Action and Secretion in Polycystic Ovary Syndrome 167
CONTENTS 167
1. INTRODUCTION 167
2. INSULIN RESISTANCE IN PCOS 168
2.1. Definition of Insulin Resistance and Methods of Measurement 168
2.2. In vivo Insulin Action in Adult Women with PCOS 168
2.3. In vivo Insulin Action: Studies in Pediatric PCOS 169
2.4. Relationship Between Insulin Sensitivity and Insulin Secretion 170
3. INSULIN SECRETION IN PCOS 172
3.1. In vivo Insulin Secretion in Adult Women with PCOS 172
3.2. In vivo Insulin Secretion and Glucose Metabolism in Adolescents with PCOS 172
4. IN VITRO INSULIN ACTION IN PCOS 173
4.1. Ovary 174
4.2. Skeletal Muscle 175
4.3. Endothelium 176
4.4. Adipocyte 176
5. PCOS-ASSOCIATED CO-MORBIDITIES OF INSULIN RESISTANCE 177
5.1. Type 2 Diabetes 177
5.2. Metabolic Syndrome 177
5.3. CVD Risk and Outcomes 178
5.4. Sleep Apnea 179
5.5. Fatty Liver Disease 180
6. THERAPEUTIC APPROACHES TARGETING INSULIN SENSITIZATION 180
7. CONCLUSION AND FUTURE DIRECTION 182
ACKNOWLEDGMENTS 182
REFERENCES 182
12 Polycystic Ovary Syndrome and the Metabolic Syndrome Long- Term Risks 198
CONTENTS 198
1. INTRODUCTION 199
2. REPRODUCTIVE HEALTH 199
2.1. Menstruation 199
2.2. Fecundity 199
2.3. Hysterectomy 200
3. HIRSUTISM 200
4. BONE METABOLISM 201
5. RISK OF CANCER 201
5.1. PCOS and Endometrial Carcinoma 201
5.2. PCOS and Breast Cancer 201
5.3. PCOS and Ovarian Carcinoma 202
6. OBESITY AND ANTHROPOMETRY 202
7. THE METABOLIC SYNDROME 203
7.1. Definitions 203
7.2. Insulin Resistance in Women with PCOS 203
7.3. Hypertension 204
7.4. Risk for CVD in Women with PCOS 204
REFERENCES 205
13 Insulin Sensitizers Targeting Metabolic and Reproductive Consequences in Polycystic Ovary Syndrome 210
CONTENTS 210
1. INTRODUCTION 210
2. INSULIN SENSITIZERS TARGETING METABOLIC CONSEQUENCES 212
2.1. Carbohydrate Abnormalities and Insulin Resistance 212
2.2. Conclusion 217
3. INSULIN SENSITIZERS AND REPRODUCTIVE CONSEQUENCES 217
3.1. Metformin 217
3.2. TZDs: Menstrual Cycle, Ovulation, Ovulation Induction, and Pregnancy 220
3.3. DCI: Ovulation 221
3.4. Conclusions 221
REFERENCES 222
14 Mechanisms and Treatment of Obesity in Polycystic Ovary Syndrome 229
CONTENTS 229
1. INTRODUCTION 230
2. EPIDEMIOLOGY OF PCOS 230
3. EPIDEMIOLOGY OF OBESITY 231
4. PREVALENCE OF OBESITY IN PCOS 232
5. THE ABDOMINAL OBESITY PHENOTYPE IS PREVALENT IN PCOS WOMEN 233
6. THE INFLUENCE OF OBESITY ON THE PHENOTYPE OF PCOS 234
6.1. Clinical Hyperandrogenism and Androgen Blood Levels 234
6.2. Menses Abnormalities and Infertility 234
6.3. Metabolic Abnormalities: Insulin Resistance and Hyperinsulinemia 235
6.4. Metabolic Abnormalities: Glucose Intolerance and T2DM 236
6.5. Metabolic Abnormalities: Lipid Abnormalities 236
6.6. The Metabolic Syndrome 236
6.7. Other Cardiovascular Risk Factors 237
7. PATHOPHYSIOLOGICAL ROLE OF OBESITY ON PCOS 238
7.1. Insulin 238
7.2. Androgens and SHBG 238
7.3. Estrogens 239
7.4. Gonadotropins 239
7.5. The Growth Hormone–IGF-1 Axis 239
7.6. The Hypothalamic–Pituitary–Adrenal Axis 240
7.7. The Opioid System 240
7.8. Leptin 241
7.9. Other Potential Factors 241
8. BENEFITS INDUCED BY LIFESTYLE INTERVENTION EMPHASIZE THE PATHOPHYSIOLOGICAL ROLE OF OBESITY IN PCOS 242
8.1. Metabolic and Hormonal Effects 243
8.2. Effects on Menses, Ovulation, and Fertility 244
9. SUMMARY AND PERSPECTIVES 245
REFERENCES 246
15 Metabolic and Endocrine Effects of Statins in Polycystic Ovary Syndrome 253
CONTENTS 253
1. INTRODUCTION 254
2. HORMONAL DYSREGULATION IN PCOS 254
3. PCOS AND OXIDATIVE STRESS 255
4. STATINS AND THE MEVALONATE PATHWAY 256
5. MECHANISM OF STATIN ACTION 258
6. RATIONALE FOR THE USE OF STATINS IN PCOS 258
7. EFFECTS OF STATINS ON OVARIAN FUNCTION 260
8. TREATMENT OF PCOS WITH STATINS 261
9. CONCLUSION 263
REFERENCES 264
16 Recommended Therapies for Metabolic Defects inPolycystic Ovary Syndrome 271
CONTENTS 271
1. INTRODUCTION 272
2. THE METABOLIC BASIS FOR ABNORMALITIES IN PCOS 272
3. METABOLIC SYNDROME DEFINITIONS AND PREVALENCE 273
4. METABOLIC RISK FACTORS IN PCOS 276
4.1. Hypertension 276
4.2. Dyslipidaemia 276
4.3. Hyperandrogenism 276
4.4. Insulin Resistance 276
4.5. Disorders of Glucose Metabolism 277
4.6. Inflammatory Markers 277
4.7. Coagulation Markers 277
4.8. The Effects of Therapy 277
5. CLINICAL DISEASE RELATED TO METABOLIC RISK FACTORS IN PCOS 279
5.1. Hypertension 279
5.2. Obesity 279
5.3. Vascular Lesions 279
5.4. Ischaemic Heart Disease 279
6. INTERVENTIONS 280
6.1. Lifestyle Change including Diet and Exercise 280
6.2. Management of Hirsutism 284
REFERENCES 285
17 Pathogenesis of Hyperandrogenism in Polycystic Ovary Syndrome 292
CONTENTS 292
1. INTRODUCTION 292
2. ABNORMAL HYPOTHALAMIC PITUITARY FUNCTION AND HYPERANDROGENISM 294
3. OVARIAN HYPERANDROGENISM 295
3.1. Excessive Theca Cell Proliferation and Androgen Production in PCOS 295
3.2. Abnormal Granulosa Cell Function in PCOS 296
4. ADRENOCORTICAL HYPERANDROGENISM 296
4.1. Adrenocortical Hyper-Responsivity in PCOS 297
4.2. Altered Cortisol Metabolism in PCOS 298
4.3. Adrenal AE in PCOS: Acquired Trait? 299
5. INSULIN RESISTANCE AND HYPERANDROGENISM 300
REFERENCES 301
18 Recommended Treatment Modalities for Hyperandrogenism 306
CONTENTS 306
1. INTRODUCTION 306
2. CLINICAL APPROACH TO HYPERANDROGENISM 307
2.1. Hirsutism 307
2.2. Acne 307
2.3. Baldness 307
2.4. Symptoms of Virilization 307
2.5. Other Symptoms Related to Androgen Excess 308
3. PRINCIPLES OF HYPERANDROGENISM TREATMENT 308
3.1. Androgen Excess 308
3.2. Increased Testosterone Bioavailability 308
3.3. Increased Sensitivity to Androgens 308
3.4. Antiandrogen Prescription 308
3.5. Cosmetic Measures 308
4. COMBINED ESTROGEN–PROGESTIN THERAPY 309
5. GLUCOCORTICOIDS 309
6. ANTIANDROGENS 309
6.1. Principle 309
6.2. Spironolactone 309
6.3. Cyproterone Acetate 311
6.4. Effectiveness of Cyproterone Acetate Versus Spironolactone 312
6.5. Flutamide and Derivatives 312
6.6. Comparative Studies of Flutamide 313
6.7. Finasteride 314
7. INSULIN SENSITIZERS AS TREATMENT OF HYPERANDROGENISM 314
7.1. Principle 314
7.2. Metformin or Antiandrogen 314
8. ANTIANDROGENS AND METABOLIC DISORDERS IN HYPERANDROGENIC PATIENTS 314
8.1. Metabolic Consequences of Antiandrogens 314
8.2. Improved Insulin Resistance 315
9. CONCLUDING REMARKS 315
REFERENCES 315
19 Effective Regimens for Ovulation Induction in Polycystic Ovary Syndrome 318
CONTENTS 318
1. INTRODUCTION 319
2. WEIGHT LOSS AND LIFESTYLE MODIFICATIONS 319
3. CLOMIPHENE CITRATE 319
4. GONADOTROPINS 320
5. INSULIN-LOWERING AGENTS 321
5.1. Metformin 321
5.2. Metformin and Additive Treatment 322
5.3. True Insulin Sensitizers: Troglitazone, Pioglitazone, Rosiglitazone 323
5.4. Others 324
6. AROMATASE INHIBITORS 324
7. OVARIAN DRILLING 324
8. TREATMENT RECOMMENDATIONS FOR AN ANOVULATORY WOMAN WITH PCOS 325
9. CONCLUSIONS 325
REFERENCES 326
20 Pregnancy in Polycystic Ovary Syndrome 332
CONTENTS 332
1. INTRODUCTION 332
2. PCOS AND MISCARRIAGE 333
2.1. Prevalence 333
2.2. Etiology 334
2.3. Treatment Modes 336
3. GESTATIONAL DIABETES 338
4. PREGNANCY-RELATED HYPERTENSION 339
5. SMALL FOR GESTATIONAL AGE BABIES 339
6. SUMMARY 339
REFERENCES 340
21 Impact of Diagnostic Criteria 344
CONTENTS 344
1. INTRODUCTION 345
2. DEFINITION OF PCOS: 1990 NIH VERSUS 2003 ROTTERDAM 346
3. COMMON CRITERIA SHARED BY BOTH 1990 NIH AND 2003 ROTTERDAM 348
3.1. Androgen Excess 348
3.2. Oligo-Anovulation 349
4. DIFFERENCES BETWEEN 1990 NIH AND 2003 ROTTERDAM 350
4.1. Polycystic Ovaries 350
4.2. Two Newly Introduced PCOS Phenotypes by the 2003 Rotterdam Criteria 351
5. CONCLUSION 352
REFERENCES 352
Subject Index 356