Table Of ContentRoy Homburg
Ovulation Induction
and Controlled
Ovarian Stimulation
A Practical Guide
Second Edition
123
Ovulation Induction
and Controlled Ovarian
Stimulation
Roy Homburg
Ovulation Induction
and Controlled Ovarian
Stimulation
A Practical Guide
Second Edition
Roy Homburg
Homerton Fertility Centre
Homerton University Hospital
London
United Kingdom
ISBN 978-3-319-05611-1 ISBN 978-3-319-05612-8 (eBook)
DOI 10.1007/978-3-319-05612-8
Springer Cham Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014939003
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Contents
1 A Potted History of Ovulation Induction . . . . . . . . . 1
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2 Physiology of Ovulation. . . . . . . . . . . . . . . . . . . . . . . . 7
2.1 Hypothalamic-Pituitary-Ovarian Axis. . . . . . . . 8
2.1.1 Gonadotrophin Releasing
Hormone (GnRH) . . . . . . . . . . . . . . . . . . 9
2.1.2 FSH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.1.3 LH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1.4 Two Cells: Two Gonadotrophins . . . . . . . 14
2.1.5 Oestradiol. . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.1.6 Progesterone . . . . . . . . . . . . . . . . . . . . . . . 17
2.2 Ovarian Morphology . . . . . . . . . . . . . . . . . . . . . . 17
2.3 Selection of the Dominant Follicle. . . . . . . . . . . 19
2.4 Ovulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.5 Fine Tuning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.5.1 Inhibin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.5.2 Activin and Follistatin. . . . . . . . . . . . . . . . 21
2.5.3 Growth Factors . . . . . . . . . . . . . . . . . . . . . 21
2.5.4 Anti-Mullerian Hormone (AMH) . . . . . 22
2.6 Ovarian Steroidogenesis . . . . . . . . . . . . . . . . . . . 22
3 Diagnosis and Causes of Anovulation . . . . . . . . . . . . 25
3.1 Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.2.1 Following the Diagnosis
of Anovulation. . . . . . . . . . . . . . . . . . . . . . 31
3.3 Causes of Anovulation. . . . . . . . . . . . . . . . . . . . . 32
v
vi Contents
3.3.1 Hypothalamic-Pituitary Failure
(WHO Group I) . . . . . . . . . . . . . . . . . . . . 32
3.3.2 Hypothalamic-Pituitary Dysfunction
(WHO Group II). . . . . . . . . . . . . . . . . . . . 33
3.3.3 Ovarian Failure (WHO Group III). . . . . 36
3.3.4 Hyperprolactinaemia
(WHO Group IV). . . . . . . . . . . . . . . . . . . 37
3.4 Diagnostic Schemes . . . . . . . . . . . . . . . . . . . . . . . 38
3.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4 General Factors Influencing Ovarian Function
and the Prognosis for Ovulation Induction . . . . . . . . 43
4.1 Influence of Female Age . . . . . . . . . . . . . . . . . . . 44
4.1.1 Ovarian Reserve . . . . . . . . . . . . . . . . . . . . 45
4.1.2 Prognosis for Conception. . . . . . . . . . . . . 46
4.2 Influence of Obesity and Weight Loss. . . . . . . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
5 Assessment of Ovarian Reserve . . . . . . . . . . . . . . . . . 51
5.1 Female Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5.2 Day 3 FSH. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5.3 Antral Follicle Count . . . . . . . . . . . . . . . . . . . . . . 54
5.4 Anti-Mullerian Hormone (AMH) . . . . . . . . . . . 54
5.5 Other Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
6 Management of Hypogonadotrophic-
Hypogonadism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
6.1 Pulsatile Gonadotrophin-Releasing
Hormone Therapy. . . . . . . . . . . . . . . . . . . . . . . . . 61
6.2 Gonadotrophin Therapy . . . . . . . . . . . . . . . . . . . 63
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
7 Understanding the Problems of Treating PCOS. . . . 65
7.1 Definition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
7.2 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . 67
7.3 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
7.3.1 Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . 69
Contents vii
7.4 Anti-oestrogens. . . . . . . . . . . . . . . . . . . . . . . . . . . 69
7.5 Insulin Sensitisers . . . . . . . . . . . . . . . . . . . . . . . . . 70
7.6 Gonadotrophin Therapy . . . . . . . . . . . . . . . . . . . 71
7.7 Laparoscopic Ovarian Drilling . . . . . . . . . . . . . . 71
7.8 In-Vitro Fertilization (IVF). . . . . . . . . . . . . . . . . 71
7.8.1 Long-Term Health Implications
of PCOS . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
8 Anti-oestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
8.1 Clomifene Citrate. . . . . . . . . . . . . . . . . . . . . . . . . 74
8.1.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . 74
8.1.2 Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
8.1.3 Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
8.1.4 Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . 76
8.1.5 Possible Adjuvants to Clomifene
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . 77
8.1.6 Unexplained Infertilty . . . . . . . . . . . . . . . 79
8.2 Aromatase Inhibitors. . . . . . . . . . . . . . . . . . . . . . 80
8.2.1 Mode of Action . . . . . . . . . . . . . . . . . . . . . 81
8.2.2 Possible Advantages of Letrozole. . . . . . 81
8.2.3 Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
8.2.4 Use of Letrozole in Controlled
Ovarian Hyperstimulation . . . . . . . . . . . . 82
8.2.5 Questions Remaining . . . . . . . . . . . . . . . . 83
8.2.6 Safety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
9 L ow-Dose Gonadotrophin Therapy
for Ovulation Induction . . . . . . . . . . . . . . . . . . . . . . . . 87
9.1 Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
9.2 Chronic Low-Dose Regimen. . . . . . . . . . . . . . . . 90
9.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
9.4 Variations on a Theme . . . . . . . . . . . . . . . . . . . . . 92
9.5 Starting Dose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
9.6 Incremental Dose Rise. . . . . . . . . . . . . . . . . . . . . 92
9.7 Patience Is a Virtue. . . . . . . . . . . . . . . . . . . . . . . . 93
9.8 Gonadotrophin Preparations . . . . . . . . . . . . . . . 94
9.9 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
viii Contents
10 Insulin Lowering Agents. . . . . . . . . . . . . . . . . . . . . . . 97
10.1 Weight Loss. . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
10.2 Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
10.3 Restoration of Ovulation. . . . . . . . . . . . . . . . . 102
10.3.1 Metformin Alone. . . . . . . . . . . . . . . . . 102
10.3.2 Metformin + Clomiphene. . . . . . . . . . 103
10.3.3 Metformin + Low-Dose FSH. . . . . . . 103
10.3.4 Metformin in IVF . . . . . . . . . . . . . . . . 104
10.3.5 Metformin During Pregnancy . . . . . . 104
10.4 The Treatment of PCOS in Adolescence. . . . 104
10.5 Other Insulin Lowering Drugs . . . . . . . . . . . . 105
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
11 Laparoscopic Ovarian Drilling . . . . . . . . . . . . . . . . . 109
11.1 Surgical Methods . . . . . . . . . . . . . . . . . . . . . . . 110
11.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
11.3 Patient Selection and Mechanism
of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
11.4 How Does It Work? . . . . . . . . . . . . . . . . . . . . . 112
11.5 The Order of Treatment Options . . . . . . . . . . 113
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
12 Management of Hyperprolactinaemia . . . . . . . . . . . 115
12.1 Aetiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
12.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
12.3 Indications for Treatment . . . . . . . . . . . . . . . . 118
12.4 Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
12.5 Results of Treatment . . . . . . . . . . . . . . . . . . . . 120
13 Gonadotrophins for Ovulation Induction . . . . . . . . 121
13.1 Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
13.2 Preparations. . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
13.3 Urinary vs Recombinant: Safety. . . . . . . . . . . 124
13.4 Urinary FSH vs Recombinant
FSH: Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . 124
13.5 FSH vs hMG . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
13.6 Treatment Protocols for Ovulation
Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Contents ix
14 Unexplained Infertility. . . . . . . . . . . . . . . . . . . . . . . . 129
14.1 Diagnostic Tests. . . . . . . . . . . . . . . . . . . . . . . . . 130
14.2 Definition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
14.3 When to Intervene . . . . . . . . . . . . . . . . . . . . . . 131
14.4 Treatment Options . . . . . . . . . . . . . . . . . . . . . . 132
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
15 Controlled Ovarian Stimulation
for Intra-uterine Insemination. . . . . . . . . . . . . . . . . . 137
15.1 Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
15.2 Treatment Regimes for IUI. . . . . . . . . . . . . . . 139
15.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
16 Controlled Ovarian Stimulation for IVF/ICSI . . . . 143
16.1 Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
16.2 Gonadotrophins in COH. . . . . . . . . . . . . . . . . 145
16.2.1 The Choice of Gonadotrophin
Preparation. . . . . . . . . . . . . . . . . . . . . . 145
16.2.2 LH Content. . . . . . . . . . . . . . . . . . . . . . 147
16.2.3 Starting Doses . . . . . . . . . . . . . . . . . . . 148
16.2.4 Patient Comfort . . . . . . . . . . . . . . . . . . 148
16.2.5 Triggering Ovulation. . . . . . . . . . . . . . 148
16.3 GnRH Agonists. . . . . . . . . . . . . . . . . . . . . . . . . 149
16.3.1 Protocols. . . . . . . . . . . . . . . . . . . . . . . . 149
16.3.2 Oral Contraceptives and the Long
GnRH Protocol . . . . . . . . . . . . . . . . . . 151
16.3.3 Doses. . . . . . . . . . . . . . . . . . . . . . . . . . . 152
16.4 GnRH Antagonists. . . . . . . . . . . . . . . . . . . . . . 152
16.4.1 Principles. . . . . . . . . . . . . . . . . . . . . . . . 152
16.4.2 Protocols. . . . . . . . . . . . . . . . . . . . . . . . 153
16.4.3 Single or Multiple Doses,
Fixed Day or Flexible? . . . . . . . . . . . . 156
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
17 Management of Poor Responders. . . . . . . . . . . . . . . 159
17.1 Definition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
17.2 Aetiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
