Ovulation Induction and Controlled Ovarian Stimulation: A Practical Guide

224 Pages·2014·2.308 MB·English

by  Roy Homburg (auth.)

Roy 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
© Springer International Publishing Switzerland 2014
This work is subject to copyright. All rights are reserved by the Publisher,
whether the whole or part of the material is concerned, specifi cally the rights of
translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction
on microfi lms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or
dissimilar methodology now known or hereafter developed. Exempted from this
legal reservation are brief excerpts in connection with reviews or scholarly
analysis or material supplied specifi cally for the purpose of being entered and
executed on a computer system, for exclusive use by the purchaser of the work.
Duplication of this publication or parts thereof is permitted only under the
p rovisions of the Copyright Law of the Publisher's location, in its current version,
and permission for use must always be obtained from Springer. Permissions for
use may be obtained through RightsLink at the Copyright Clearance Center.
Violations are liable to prosecution under the respective Copyright Law.
The use of general descriptive names, registered names, trademarks, service
marks, etc. in this publication does not imply, even in the absence of a specifi c
statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
While the advice and information in this book are believed to be true and accu-
rate at the date of publication, neither the authors nor the editors nor the pub-
lisher can accept any legal responsibility for any errors or omissions that may be
made. The publisher makes no warranty, express or implied, with respect to the
material contained herein.
Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)
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