The Endometrial Factor A Reproductive Precision Medicine Approach

275 Pages·2017·11.714 MB·English

by  Giudice, Linda C., Simón, Carlos

The Endometrial Factor
A Reproductive Precision Medicine Approach
Edited by
Carlos Simón MD, PhD and
Linda C. Giudice MD, PhD
CRC Press
Taylor & Francis Group
7 6000 Broken Sound Parkway NW, Suite 300
1
0 Boca Raton, FL 33487-2742
2
r
e
b © 2017 by Taylor & Francis Group, LLC
o
ct CRC Press is an imprint of Taylor & Francis Group, an Informa business
O
6 No claim to original U.S. Government works
2
4
3 Printed on acid-free paper
3:
0
at International Standard Book Number-13: 978-1-4987-4039-5 (Hardback)
]
L) This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish
D reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that
C
( may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors
uz are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is
Cr intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s
a own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guide-
nt lines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently
a
S verified. The reader is strongly urged to consult the drug companies’ printed instructions, and their websites, before administering any of the
a, drugs recommended in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual.
ni
r Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients
o
f appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and
ali apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged
C
f please write and let us know so we may rectify in any future reprint.
o
y
rsit E elxeccetprot naisc ,p emremcihtatendic uanl,d oerr Uot.hSe. rC mopeyarnigs,h tn oLwaw k, nnoow pna rot ro fh ethreisa fbteoro kin mveanyt ebde, rienpcrliundteindg, rp ehporotodcuocpeydi,n tgr,a nmsmicriottfeildm, oinr g u, tailnizde dre icno radniyn gfo, romr biny aannyy
e
v information storage or retrieval system, without written permission from the publishers.
ni
U
[ For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or
y contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization
b
d that provides licenses and registration for a variety of users. For  organizations that have been granted a photocopy license by the CCC, a separate
e
d system of payment has been arranged.
a
o
nl Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation
w
without intent to infringe.
o
D
Library of Congress Cataloging-in-Publication Data
Simón, Carlos, editor ; Giudice, Linda, editor.
The endometrial factor : a reproductive precision medicine approach / edited by Carlos Simón, Linda C. Giudice.
Boca Raton, FL : CRC Press/Taylor & Francis Group, [2017]
Includes bibliographical references and index.
LCCN 2016041251| ISBN 9781498740395 (hardback : alk. paper) | ISBN 9781498740401 (ebook)
Subjects: | MESH: Uterine Diseases--diagnosis | Endometrium--physiopathology | Uterine Diseases--complications | Uterine
Diseases--therapy
Classification: LCC RG316 | NLM WP 440 | DDC 618.1/4--dc23
LC record available at https://lccn.loc.gov/2016041251
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
Contents
Preface v
Foreword: An eye to the future vii
Contributors ix
1 Highlights on the dynamism and multifunctionality of human endometrium in the era of precision medicine 1
Linda C. Giudice
Section i DiAGnoSiS oF tHe enDoMetRiAL FActoR
2 New imaging diagnostics 15
7
1 Sanja Kupesic Plavsic
0
2 3 Molecular diagnosis of endometrial receptivity 36
r
e
b Jose Miravet-Valenciano, Nuria Balaguer, Felipe Vilella, and Carlos Simón
o
ct 4 Molecular diagnosis of endometriosis 50
O
6 Lusine Aghajanova and Linda C. Giudice
4 2 5 Microbiological diagnosis: The human endometrial microbiome—Endometritis 65
3:3 Inmaculada Moreno and Carlos Simón
0 6 Hysteroscopy: An invasive diagnosis 78
at
] Natasha Pritchard, Shavi Fernando, and Luk Rombauts
)
L
D
C
(
z Section ii PeRSonALiZAtion oF tHe enDoMetRiAL FActoR
u
r
C 7 The endometrium in polycystic ovary syndrome 97
nta Terhi T. Piltonen
Sa 8 Obesity and the endometrium 111
a, Ioanna A. Comstock, Sun H. Kim, and Ruth B. Lathi
ni
r 9 Uterine fibroids and the endometrium 120
o
f
ali Deborah E. Ikhena and Serdar E. Bulun
C 10 New knowledge about adenomyosis 130
f
o Giuseppe Benagiano, Beatrice Ermini, Marwan Habiba, and Ivo Brosens
y
sit
r
e
v
ni Section iii tHeRAPeUtic oPtionS oF tHe enDoMetRiAL FActoR
U
y [ 11 Hormonal regulation of the endometrium and the effects of hormonal therapies 161
b Gulcin Sahin Ersoy, Monica Modi, Myles Alderman, and Hugh S. Taylor
d
e 12 Abnormal uterine bleeding (the old dysfunctional uterine bleeding): How to manage? 177
d
a
o Hilary O. D. Critchley and Lucy Whitaker
nl
w 13 Inflammation of the endometrium in reproduction 190
o
D John Groth, Dana McQueen, and Mary Stephenson
14 Empirical treatments to improve receptivity: Why not? 201
Nick S. Macklon
15 Endometrial scratching 208
Claire Bourgain, Samuel Santos-Ribeiro, and Christophe Blockeel
16 Stem cell therapies for atrophic endometrium and Asherman’s syndrome 217
Benjamin J. Seifer, Hanyia Naqvi, Elham Neisani Samani, Graciela Krikun, and Hugh S. Taylor
17 Gestational surrogacy 228
Molly Quinn and Heather Huddleston
18 Uterine transplantation 234
Mats Brännström
iii
iv Contents
Section iV tHe ULtiMAte GoAL
19 Embryo/fetal–maternal cross talk 243
Nuria Balaguer, Francisco Dominguez, Carlos Simón, and Felipe Vilella
20 Embryo transfer: Fresh, deferred, personalized? Reproductive and obstetrical outcomes 256
Siladitya Bhattacharya
Index 265
Preface
The relevance of the endometrial factor in repro- Hilary Critchley, to immunological treatment by Mary
ductive medicine is gradually gaining momentum. Stephenson, analysis of empirical unproven treatments
The Endometrial Factor was carefully conceived with world by Nick S. Macklon, and endometrial scratching by Claire
experts to be a compendium of critically evaluated, state- Bourgain. New stem cell therapies in the atrophic endo-
of-the-art basic and clinical knowledge about the human metrium and Asherman’s syndrome are addressed by
endometrium that impacts or will impact clinical practice. Hugh S. Taylor. Finally, we discuss what to do when the
This new text updates the advances in the diagno- uterus is absent or not functional, including surrogacy
sis and treatment of the uterine or endometrial factor in by Molly Quinn and Heather Huddleston and uterine
the management of the infertile patient in the context of transplantation by Mats Brännström.
precision medicine. Section I is devoted to the description Section IV addresses the ultimate function of the
7
1 of “all you need to know” about the human endometrium, endometrium—modulating and facilitating embryonic
0
2
r by Linda C. Giudice, coeditor of this book. It is f ollowed implantation. The interaction between the endometrium
e
b by an update of diagnostic possibilities: noninvasive and the preimplantation embryo is presented by Felipe
o
ct diagnosis using imaging, by Sanja Kupesic Plavsic; Vilella, and the establishment of pregnancy through differ-
O
6 molecular diagnosis of endometrial receptivity, by Jose ent embryo transfer strategies by Siladitya Bhattacharya.
2
4 Miravet-Valenciano; molecular diagnosis of endome- The book is introduced by the views of a pioneer,
3
3: triosis, by Lusine Aghajanova; microbiological diagnosis Peter A. W. Rogers, in pursuit of a better understand-
at 0 of the human endometrial microbioma—endometritis, ing of endometrial function on the hoped-for pathway to
] by Inmaculada Moreno; and invasive diagnosis through precision medicine.
)
L hysteroscopy, by Luk Rombauts. We express our utmost appreciation to all of our inter-
D
C Section II focuses on specific reproductive and medi- national best-in-class colleagues who have graciously
(
z cal disorders and their clinical impact on the endometrial contributed to the realization of this publication; we are
u
r
C factor in a personalized manner. The endometrium is grateful for the time and effort they devoted. We hope
a
nt analyzed in polycystic ovary syndrome patients by Terhi that readers will find the contents of this book useful as a
Sa T. Piltonen, in obesity by Ruth B. Lathi, in the presence of reference and a valuable tool for continued advancement
a, fibroids by Serdar Bulun and adenomyosis by Ivo Brosens. in the understanding and management of the endometrial
ni
r Section III updates current therapeutic options for factor in reproductive medicine.
o
f
ali the endometrial factor in a critical manner: from effects
C of classical hormonal treatments by Hugh S. Taylor and Carlos Simón and Linda C. Giudice
f
o the management of dysfunctional uterine bleeding by 2016
y
sit
r
e
v
ni
U
[
y
b
d
e
d
a
o
nl
w
o
D
v

Foreword: An eye to the future
PETER A. W. ROGERS
The advent of in vitro fertilization (IVF) more than molecular profiling of endometrial gene expression.
35  years ago revolutionized reproductive medicine. Future potential developments around the endometrial
While the goal was to treat infertile couples, the tech- receptivity assay are discussed in detail in Chapter 9. The
niques that were developed generated a huge amount of limited mechanistic and evidence-based understanding
new information on reproductive endocrinology, ovarian that we have of endometrial function is highlighted in two
function, ovulation, fertilization, preimplantation embry- chapters toward the end of the book, where the clinical
ology, implantation, and early pregnancy. This knowledge value of “endometrial scratching” to increase endometrial
dividend from IVF continues today, as exemplified by receptivity is questioned. Many of the current treatments
chapters in this book covering advances in areas such as for endometrial factors in subfertile patients are based on
7
1 pelvic ultrasound, the impact of obesity on the endome- empirical approaches due to our incomplete understand-
0
2
r trium, and the rapidly emerging field of the microbiome. ing of the molecular regulation of endometrial receptivity.
e
b The importance of this reproductive medicine research is The chapters in this book cover advances in the diagnosis
o
ct brought sharply into focus by a recent analysis of data from and treatment of uterine and endometrial factors in the
O
6 the 2010 Global Burden of Disease Study (1). This work management of women with gynecological disorders,
2
4 reported a systematic analysis of “years lived with dis- including infertility. In many sections, there is an increas-
3
3: ability” (YLD) for 1160 sequelae of 289 diseases and inju- ing focus on a personalized or individualized approach,
at 0 ries. Within the list, gynecological diseases contribute 146 as part of an overall vision that sees precision medicine as
] YLD per 100,000 years, with major diseases being fibroids an integral component of healthcare (3). However, there is
)
L (44 YLD), polycystic ovary syndrome (40 YLD), genital still much to be done before the goal of precision medicine
D
C prolapse (26 YLD), premenstrual syndrome (18 YLD), and in gynecology becomes the norm. When looking to the
(
z endometriosis (8 YLD). To put this gynecological disabil- future, it can be instructive to look at the past as a guide
u
r
C ity burden in perspective, the same study reports 161 YLD to the challenges we face and the progress we might expect
a
nt per 100,000 years for HIV/AIDS and tuberculosis com- to make in solving them.
Sa bined, 99 YLD for Alzheimer’s and other dementias, and When reviewing what we have learned about endo-
a, 55 YLD for rheumatoid arthritis. Most would agree that metrial function since the advent of IVF more than 35
ni
r the investment by government into improving outcomes years ago, it is not that unfair to suggest that we have
o
f
ali for gynecological diseases does not match that for these learned more about what we do not know than what we
C other higher-profile diseases with similar YLD impacts. do. This comment is made in the context of the limited
f
o This is an issue that requires ongoing lobbying of govern- number of new gynecological treatment paradigms that
y
sit ment by all patients, clinicians, and researchers with an have reached clinical practice in this time. Over the past
r
e interest in gynecological medicine. This book will help to decade, there have been important publications that have
v
ni raise awareness and understanding of these problems. illustrated the gaps in our knowledge and, as a conse-
U
[ A significant proportion of gynecological disease is quence, dramatically changed our understanding of how
y
b directly linked to uterine pathophysiology, including much more there still is to discover about the complex-
d
e heavy menstrual bleeding, endometriosis, adenomyosis, ity of uterine function. A study that significantly altered
d
a
o polyps, endometrial cancer, endometritis, pelvic pain, my thinking involved genome-wide analysis of estrogen
wnl reduced uterine receptivity leading to failed implanta- receptor binding sites (4). While the researchers used a
Do tion, and early pregnancy loss. Many of these disorders breast cancer cell line for this work, the findings were
are addressed by leading experts in this book. Uterine generalizable to all sex steroid–responsive tissues. The
research, and in particular endometrial research, has major finding was that only 4% of estrogen receptor
taken something of a backseat when compared with the binding sites mapped as expected to the 1 kb promoter-
advances made in improving oocyte, sperm, and embryo proximal regions of genes. In other words, 96% of in vivo
quality over the past 35 years. While we understood many estrogen receptor binding events occurred in regions pre-
years ago that both a viable embryo and a receptive uterus viously unannotated as cis- regulatory elements within
were required for successful implantation (2), much of the the genome. To put this s imply, this work published in
focus since then has been on improving embryo viability 2006 demonstrated that our previous concept of estro-
rather than uterine receptivity. The lack of investment gen regulation through estrogen response elements in
in uterine and endometrial research is perplexing given gene promoters did not account for the vast majority of
the pressing need for improved patient outcomes both in regulatory events that occur in response to estrogen. At
infertility specifically and in gynecology more generally. that time, this paper emphasized to me just how little we
Recently, a clinical test for uterine receptivity has been understood about the molecular mechanisms by which
developed harnessing earlier basic studies that undertook the uterus responds to estrogen.
vii
viii Foreword
Another fascinating insight into the complexity of of endometrial function on the hoped for pathway to
endometrial function came from investigation of the evo- precision medicine? All is not bleak, and some major
lution of pregnancy in mammals (5,6). This work initially advances in both fundamental understanding and new
identified 1532 genes that had been recruited into endome- treatment paradigms for gynecological disease are in the
trial expression in the evolution of pregnancy in placental pipeline. Many of these ideas are contained in the excellent
mammals. Many of these genes, including ones that medi- chapters in this book, which should serve to both inform
ate maternal–fetal communication and immunotolerance, and inspire readers to continue pushing the boundaries of
contain cis-regulatory elements derived from ancient endometrial research.
mammalian transposable elements. The authors suggest
that mammalian pregnancy evolved from these DNA ReFeRenceS
sequences being co-opted into hormone-responsive regu- 1. Vos T, Flaxman AD, Naghavi M et al. Years lived with
latory elements distributed throughout the genome. How disability (YLDs) for 1160 sequelae of 289 diseases
and why this first occurred as a coordinated process is dif- and injuries 1990–2010: A systematic analysis for
ficult to comprehend; however, it has resulted in a large the Global Burden of Disease Study 2010. Lancet
number of endometrial genes being “rewired” to perform 2012;380(9859):2163–96.
functions unique to reproduction and pregnancy. As a 2. Rogers PA, Milne BJ, Trounson AO. A model
consequence of this work, we can begin to understand why to show human uterine receptivity and embryo
gene function and pathway analysis based on data from viability following ovarian stimulation for in
genes in nonreproductive tissues is often of little value vitro fertilization. J In Vitro Fert Embryo Transf
when trying to work out what is happening in the same 1986;3(2):93–8.
genes that have been rewired for reproductive function. 3. Aronson SJ, Rehm HL. Building the founda-
The third and final example of the depth of our tion for genomics in precision medicine. Nature
ignorance is not confined to just reproductive function. 2015;526(7573):336–42.
Genome-wide association studies (GWASs) have played 4. Carroll JS, Meyer CA, Song J et al. Genome-wide
an important part in identifying genomic loci that influ- analysis of estrogen receptor binding sites. Nat Genet
ence phenotype, with most interest being on loci that con- 2006;38(11):1289–97.
fer increased susceptibility to complex diseases. However, 5. Lynch VJ, Leclerc RD, May G, Wagner GP.
approximately 88% of GWAS loci turn out to be in noncod- Transposon-mediated rewiring of gene regulatory
ing (intergenic or intronic) regions of the DNA (7), which networks contributed to the evolution of pregnancy
begs the question as to how they exert their influence on in mammals. Nat Genet 2011;43(11):1154–9.
phenotype. The fact that parts of what was previously 6. Lynch VJ, Nnamani MC, Kapusta A et al. Ancient
considered “junk DNA” have functional roles has forced transposable elements transformed the uterine
a reexamination of our understanding of how gene expres- regulatory landscape and transcriptome during
sion is regulated. If we hope to harness the full power of the evolution of mammalian pregnancy. Cell Rep
genetic and genomic information in precision medicine 2015;10(4):551–61.
approaches, a far better understanding of the underlying 7. Edwards SL, Beesley J, French JD, Dunning AM.
molecular mechanisms is required. Beyond GWASs: Illuminating the dark road
So, where does this newfound lack of knowledge about from association to function. Am J Hum Genet
the uterus leave us in our pursuit of a better understanding 2013;93(5):779–97.
Contributors
Lusine Aghajanova MD PhD Ioanna A. Comstock MD
Department of Obstetrics, Gynecology, and Reproductive Department of Obstetrics and Gynecology
Sciences George Washington University
University of California, San Francisco Washington, DC
San Francisco, California
Hilary O. D. Critchley MBcHB(Hons) MD FRcoG
Myles Alderman BS MRC Centre for Reproductive Health
Yale School of Medicine The Queen’s Medical Research Institute
Yale University University of Edinburgh
New Haven, Connecticut Edinburgh, United Kingdom
17 Nuria Balaguer BS Francisco Dominguez PhD
20 Fundación Instituto Valenciano de Infertilidad (FIVI) Fundación Instituto Valenciano de Infertilidad (FIVI)
er Valencia University and Instituto Universitario Valencia University and Instituto Universitario
b
cto IVI/INCLIVA IVI/INCLIVA
O Valencia, Spain Valencia, Spain
6
4 2 Giuseppe Benagiano MD PhD FAcoG FicoG FRcoG Beatrice Ermini MD
3 Department of Gynecology, Obstetrics, and Urology
3: Department of Gynecology, Obstetrics, and Urology
at 0 URonmiveer, sItitayly of Rome University of Rome
] Rome, Italy
)
DL Siladitya Bhattacharya MD FRcoG Gulcin Sahin Ersoy MD
C Institute of Applied Health Sciences
( Yale School of Medicine
z School of Medicine, Medical Sciences and Nutrition
u Yale University
Cr University of Aberdeen
nta Aberdeen, United Kingdom New Haven, Connecticut
Sa Christophe Blockeel MD PhD Shavi Fernando MBBS(hon) BMedSc(hon) FRAnZcoG
nia, Centre for Reproductive Medicine TDheep aRrittcmheien tC oenf Otrbestetrics and Gynecology
or Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel
f Monash University
ali Brussels, Belgium
C and
of Claire Bourgain MD PhD Hudson Institute of Medical Research
sity DUnepivaerrtsmitye nHto fsopr iPtaalt hLeoulovgeyn and
r Monash Health
e
v Leuven, Belgium
ni Department of Obstetrics and Gynaecology
U and Clayton, Australia
[
y
d b Department for Pathology Linda C. Giudice MD PhD
e Imelda Hospital Department of Obstetrics, Gynecology, and Reproductive
d
oa Bonheiden, Belgium Sciences
nl
w Mats Brännström MD PhD University of California, San Francisco
o
D Department of Obstetrics and Gynecology San Francisco, California
University of Gothenburg
John Groth MD PhD
Gothenburg, Sweden
Department of Pathology
and University of Illinois at Chicago
Chicago, Illinois
Stockholm IVF
Stockholm, Sweden Marwan Habiba PhD FRcoG
Ivo Brosens MD PhD FRcoG Department of Health Sciences
Leuven Institute for Fertility and Embryology University of Leicester
Leuven, Belgium Leicester, United Kingdom
Serdar E. Bulun MD Heather Huddleston MD
Department of Obstetrics and Gynecology Department of Obstetrics, Gynecology, and Reproductive
Prentice Women’s Hospital Sciences
Northwestern Memorial Hospital University of California
Chicago, Illinois San Francisco, California
ix