Manual of Oocyte Retrieval and Preparation in Human Assisted Reproduction

133 Pages·2022·8.391 MB·English

by  Rachel Cutting

Manual of Oocyte Retrieval and
Preparation in Human Assisted
Reproduction
Published online by Cambridge University Press
Published online by Cambridge University Press
Manual of Oocyte Retrieval and
Preparation in Human Assisted
Reproduction
Edited by
Rachel Cutting
HumanFertilisationandEmbryologyAuthority,London
Mostafa Metwally
RoyalHallamshireHospital,Sheffield
Published online by Cambridge University Press
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DOI:10.1017/9781108891646
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Contents
List of Contributors vi
9 Laboratory Design, Equipment and
Consumables forOocyte Retrieval 65
1 The Ovary:AGeneral Overview of Follicle Stephen Harbottle
Formationand Development 1
10 QualityManagement Requirements for
Mark A. Fenwick Oocyte Collection 76
2 Monitoring ofOvarianStimulation 10 Lucy Wood andRachelCutting
Lewis Nancarrow andAndrew Drakeley 11 Morphological Assessment of
3 TheatreDesign,EquipmentandConsumables Oocyte Quality 85
for Oocyte Retrieval 18 Basak Balaban,İpek Keles and Thomas Ebner
Lukasz Polanski and Alka Prakash 12 Oocyte Preparation for Conventional In Vitro
4 Conscious Sedation and Analgesia for Fertilisation andIntracytoplasmic
Oocyte Retrieval 24 Sperm Injection 98
Jennifer M. Ulyatt and Sarah J. Martins da Silva Bryan Woodward
5 Practical Clinical Aspectsof 13 Oocyte Retrieval: The
Oocyte Retrieval 37 Patient’sPerspective 108
Peter I.Kerecsenyi andRajMathur Kate Brian
6 Challenges during OocyteRetrieval 46
Stephen Davies and Mostafa Metwally
7 ComplicationsofOocyteRetrieval 52 Index 114
Hajeb Kamali and Valentine Akande
Colorplatesaretobefoundbetweenpages57and
8 The Nurse’sRole duringOocyteRetrieval 58
58.
Alison McTavish
v
Published online by Cambridge University Press
Contributors
Valentine Akande, Bristol Centre for Reproductive Peter I. Kerecsenyi, Manchester Fertility, Amelia
Medicine, 135 Aztec W, Almondsbury, Bristol BS32 House, Cheadle Royal Business Park, 3 Oakwood
4UB, UK. Email: [email protected] Square, Cheshire, Cheadle SK8 3SB, UK. Email:
[email protected]
Basak Balaban, Assisted Reproduction Unit, VKF
American Hospital Istanbul, Turkey. Email: basak- Sarah J. Martins da Silva, Reproductive and
[email protected] Developmental Biology, Ninewells Hospital and
Medical School, University of Dundee, Dundee DD1
KateBrian,FertilityNetworkUK,TrafalgarRd,London
9SY,UK. Email:[email protected]
SE109EQ,UK.Email:[email protected]
RajMathur,ManchesterUniversityNHSFoundation
Rachel Cutting, Jessop Fertility, Tree Root Walk,
Trust, Oxford Road, Manchester M13 9WL, UK.
Sheffield Teaching Hospital NHS Foundation Trust,
Email: [email protected]
SheffieldS102SF,UK.Email:[email protected]
Alison McTavish, Aberdeen Fertility Centre,
StephenDavies(retired),TheJessopWingandRoyal
University of Aberdeen, Aberdeen, UK. Email: a.r.
Hallamshire Hospital, The University of Sheffield,
[email protected]
Tree Root Walk, Sheffield S10 3HY, UK.
Andrew Drakeley, Liverpool Women’s NHS Mostafa Metwally, The Jessop Wing and Royal
HallamshireHospital,UniversityofSheffield, TreeRoot
Foundation Trust, Crown Street, Liverpool L8 7SS,
Walk,SheffieldS103HY,UK.Email:[email protected]
UK; Edge Hill University, St Helens Rd, Ormskirk
L394QP, UK. Email:[email protected] Lewis Nancarrow, Hewitt Fertility Centre, Liverpool
Women’s NHS Foundation Trust, Crown Street,
Thomas Ebner, Kepler University, Kinderwunsch
Liverpool L8 7SS, UK. Email: lewis.nancarrow@doc-
Zentrum, Linz, Austria. Email: Thomas.
tors.org.uk
[email protected]
Lukasz Polanski, Guy’s Hospital, Great Maze Pond,
Mark A. Fenwick, Academic Unit of Reproductive
London SE1 9RT, UK. Email: Lucas.polanski@hot-
and Developmental Medicine, Department of
mail.com
Oncology and Metabolism, University of Sheffield,
Beech Hill Road, Sheffield S10 2RX, UK. Email: m.a. AlkaPrakash,CambridgeIVF,KeffordHouse,Maris
[email protected] Lane, Trumpington, Cambridge CB2 9LG, UK.
Email: [email protected]
Stephen Harbottle, Cambridge IVF, Maris Lane,
Trumpington, Cambridge CB2 9LG, UK. Email: Jennifer M. Ulyatt, Assisted Conception Unit,
[email protected] Ninewells Hospital, Dundee DD1 9SY, UK. Email:
[email protected]
Hajeb Kamali, Bristol Centre for Reproductive
Medicine, 135 Aztec W, Almondsbury, Bristol BS32 Lucy Wood, Jessop Fertility, Tree Root Walk,
4UB, UK. Email: [email protected] Sheffield Teaching Hospital NHS Foundation Trust,
İpek Keles, Assisted Reproduction Unit, VKF Koc Sheffield S102SF,UK.Email:[email protected]
University Hospital Istanbul,Turkey. Email:ikeles@- Bryan Woodward, X&Y Fertility, 144a New Walk,
kuh.ku.edu.tr LeicesterLE17JA,UK.Email:[email protected]
vi
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Chapter The Ovary: A General Overview of Follicle
1
Formation and Development
MarkA.Fenwick
1.1 Introduction known as the paramesonephric) ducts, which all
togetherconstituteabipotentialreproductivesystem.
In the context of reproduction, the key functions of
Subsequentdifferentiationofthegonadsisgener-
the ovary are to provide an environment that sup-
ally dependent on the genetic constitution of the
ports the maturation of oocytes for ovulation along-
embryo. In males, brief and timely expression of the
side adequate production of sex steroids to prepare
sex-determining region on the Y chromosome (SRY
forandsustainapotentialpregnancy.Thesefunctions
gene) in somatic cells, together with other transcrip-
arenotmutuallyexclusive,aseachdependsonfollicle
tion factors (e.g. SF1 and WT1), drives expression of
and oocyte growth and maturation progressing in a
SRY-box transcription factor 9 (SOX9). This tran-
coordinated and timely manner. Our current under-
scription factor in turn activates the expression of an
standingof how the ovary is formed, with its limited
arrayofgenesthatdrivesapre-Sertolicellphenotype,
supply of follicles, and how individual follicles
including cues that amplify and propagate the
developandachievethesefunctionsofoocytesupport
molecular programme along adjacent somatic and
and steroidogenesis are summarised briefly this
germ cells (e.g. FGF9 and PTGDS), leading to the
chapter.
differentiation of the fetal testis. PGCs, now called
spermatogonia, undergo further proliferation before
arresting in mitosis. The production of testosterone
1.2 SexDeterminationandEarly from newly differentiated Leydig cell precursors
stimulates the Wolffian ducts to develop into com-
GonadalDevelopment
ponents of the male reproductive tract – the vas
In humans, male and female embryos are morpho- deferens, epididymis and seminal vesicles – while
logically similar until around week 6 of development the production of anti-Müllerian hormone (AMH),
when activation of the molecular programme from drivenbySOX9inpre-Sertolicells,causesregression
sex chromosomes allocated at fertilisation sets in of the Müllerian ducts.
motion the formation of a sex-specific gonadal Female XX embryos lack SRY, and therefore
phenotype.Priortothis,asmallclusterofpluripotent SOX9expressionremains lowinsomaticcells within
primordial germ cells (PGCs), first identified in the the developing gonad. These cells, thought to be
posterioryolksacendoderm,beginstoproliferateand derived from the mesenchyme or coelomic epithe-
migratealongthehindgut,throughthedorsalmesen- liumoverlyingthegonadalridge,additionallyexpress
tery,toeventuallysettleoneithersideofthedevelop- factorsthatactivelyrepressSOX9anditstargets.Such
ingaortaintheemerginggonads,or‘gonadalridges’. factors, including RSPO1, WNT4, CTNNB, FST and
This migration of PGCs, driven by chemotactic sig- FOXL2, are necessary to promote and maintain the
nals(e.g.KIT/KITLG),occursalongsideproliferation differentiationofthesecellsinto‘pre-granulosa’cells.
and inward migration of somatic cells to create a Adequate expression of these proteins is fundamen-
bulge on the ventromedial aspect of each mesone- tallyimportantformaintainingthephenotypeofthis
phros called the gonadal ridge. The gonadal ridges, lineage, even into adulthood, with experimental
covered by coelomic epithelium, develop alongside examples of mutations shown to precipitate a partial
thetwo adjacentembryonic ducts, theWolffian(also gonadalsexreversalorthedevelopmentofanovotes-
known as the mesonephric) and Müllerian (also tisphenotype.Secretedsignalsfromthepre-granulosa
1
https://doi.org/10.1017/9781108891646.001 Published online by Cambridge University Press
MarkA.Fenwick
cells are important for (1) stimulating PGCs (now vitro [5]. More recent studies in mice have shown
called oogonia) to arrest in meiosis (see Section 1.3), that adult somatic cells of non-ovarian lineages can
and (2) promoting differentiation of nearby somatic be ‘reprogrammed’ in vitro to generate new oocytes
cells,fromanalternativelineage,into‘pre-theca’cells. capableoffertilisationandgenerationofoffspring[6,
Thus,thepre-granulosacellsinitiateaseriesofdevel- 7]. Thus, research efforts are being directed towards
opmental events to define the tissue that will eventu- developing novel fertility preservation strategies
ally become the ovary. In comparison with the fetal throughartificialamplificationoftheovarianreserve,
testis, the relatively low levels of testosterone and althoughthemedicalpotentialofthesefindingsisstill
AMH cause the Wolffian ducts to regress and the farfrom being realised.
Müllerian ducts to persist, the latter of which will
form the precursor structures to the oviduct, uterus
1.4 FollicleDevelopment
anduppervaginain the female[1].
1.4.1 PrimordialFollicles
1.3 FollicleFormation:Establishment
Primordial follicles, situated in the cortex of the
oftheOvarianReserve
ovary, constitute the most numerous population of
Asthefetalovaryisbeingestablished,thegermcells– follicles at any one time. Each primordial follicle
now called oogonia – continue to proliferate by consistsofasmall,primaryoocyte(~20μmindiam-
mitosistoformdenseoogonialcellclusters;however, eter)arrestedinprophaseIofmeiosis,surroundedby
cell division is incomplete, and many of the oogonia a layer of squamous pre-granulosa cells and
remain connected to each other with a shared cyto- enveloped by a basement membrane. Within the
plasm. Retinoic acid, which is produced by the som- oocyte, the nucleus, also known as the germinal ves-
atic cells of the ovary and the adjacent mesonephros, icle, contains chromosomes in the dictyate state, a
bindstostimulatedbyretinoicacid8(STRA8)recep- configurationconduciveforactivegenetranscription.
tors on oogonia to initiate the process of meiosis, Both the oocyte and pre-granulosa cells are tightly
whileatthesametimeinhibitingfurtherproliferation connectedbyjunctionalcomplexestoallowforbidir-
of these cells. Oogonia proceed relatively slowly ectionalcommunicationandpreservationofaviable,
through the early stages of meiosis to arrest in the yet relatively quiescent phenotype. Thus, although
diplotenestageofprophaseI,atwhichpointtheyare primordialfolliclesareoftenreferredtoas‘dormant’,
called oocytes. In humans, arrested oocytes are iden- it is important to note that they are still intrinsically
tifiable in fetal ovaries between 10 and 24 weeks of active, with the oocyte and surrounding pre-
gestation.Itisduringthistimethatprimordialfollicle granulosa cells undergoing normal cellular metabol-
formation occurs, a process whereby pre-granulosa ism and homeostasis.
cells invade and interpose between the germ cells in Fromthetimethereserveisestablishedwithinthe
their clusters to envelop individual oocytes. Germ fetal ovary, the number of primordial follicles pro-
cells that fail to enter meiosis or become completely gressively decreases; in other words, the ovarian
encapsulated in pre-granulosa cells degenerate by reservebeginsasteadytrajectoryofdecline.Formost
apoptosis [2]. females, the main reason why the ovary eventually
It is generally believed that the net effect of these runs out of follicles is because they are continuously
mitotic and apoptotic processes throughout this recruited to grow. In adults, this continuous acti-
period leads to the final establishment of the ovarian vation eventually leads to the menopause, a natural
reserve. Based on a relatively small number of histo- event that occurs in women at an average age of
logical studies, the average number of follicles in the 51 years, when fewer than 1,000 viable primordial
human ovarian reserve (i.e. in both ovaries) is esti- follicles remain. Interestingly, it has been proposed
matedtobe500,000–1,000,000atthetimeofbirth[3, that the initial size of the ovarian reserve formed
4].Evidencefordenovosynthesisofoocytesafterthis during fetal development is a predictor of the timing
timeisstillamatterofdebate,althoughrecentstudies ofmenopause,asthereisastrongassociationbetween
have identified a small population of ‘oogonial stem the rate of follicle loss and the advancement of
cells’ that persist into adulthood, and these can be chronological age [3]. Genetic variation, which can
isolated and differentiated into oocyte-like cells in influencetheinitialsizeoftheovarianreservebutalso
2
https://doi.org/10.1017/9781108891646.001 Published online by Cambridge University Press
Chapter1:TheOvary:AGeneralOverviewofFollicleFormationandDevelopment
the rate of primordial follicle activation, can also granulosa cells. Once this layer is complete, these
impact the timing of menopause, which, if it occurs primary-stage follicles require adequate expression
before the age of 40, is termed premature ovarian of oocyte-derived factors for further development,
insufficiency.Regardlessofgeneticinfluence,thereisa specifically growth differentiation factor 9 (GDF9)
continuous departure of primordial follicles from the and bone morphogenetic protein 15 (BMP15),
ovarianreserveastheyactivateandenteratrajectoryof members of the transforming growth factor β
irreversiblegrowth.Theremainingnon-growingprim- (TGFβ) family. These molecular signals act on sur-
ordialfolliclesmayberetainedinarelativelyquiescent rounding somatic cells, which in turn signal back to
but potentially vulnerable state for up to 40–50 years the oocyte – possibly by KIT/KITL – to ensure both
beforebeingactivated.However,thisprotractedperiod cell types develop in synchrony. The oocyte also
of suspended animation makes them particularly sus- developsaglycoprotein-richzonapellucida(ZP)coat,
ceptibletochronicandacuteexposurestoenvironmen- which remains throughoutthe lifeof theoocyte. The
tal toxicants. Products of cigarette smoking, diet and ZPisimportantforfertilisationandpre-implantation
alcoholconsumptionarealllifestylefactorsreportedto development and is only shed just prior to implant-
affect the viability or rate of decline of the ovarian ation. Despite the presence of this relatively thick
reserve. Therefore, it is not only the quantity of prim- barrier, granulosa cells develop long thread-like pro-
ordial follicles that becomes diminished with age but cesses, called transzonal projections, which extend
also the quality. This is important in the context of through the ZP to the surface of the oocyte where
femalefertility,especiallynowthattheageoffirst-time they connect to gap junctions. The existence of gap
parentshassteadilyincreasedoverthepast40years[8]. junctionsbetweentheoocyteandgranulosacells,and
Thequestionofwhysomeprimordialfolliclesare also between adjacent granulosa cells, is vital for
activatedtogrowwhileothersstayarrestedisamajor allowing bidirectional molecular communication.
areaofinterestinreproductivescienceandmedicine. It is also during the primary stage when stromal
Numerous molecular signals havebeen implicated in stem cells begin to differentiate into a layer of theca
a range of models; however, an intricate balance of cells and associate with the basement membrane. As
stimulatory and inhibitory factors (e.g. KL, BMP4, preantral follicle development progresses, granulosa
BMP7,bFGF,LIFandKGF)alongwithspatialaccess andthecacellscontinuetoproliferateundertheinflu-
tothesefactorsarelikelytobeimportant.Transgenic ence of local growth factors – principally originating
mouse modelshaveestablishedthatadequateexpres- from the oocyte (e.g. GDF9, BMP15) but also from
sion of key transcription factors (e.g. Nobox, Sohlh1, the surrounding cells and tissues. Several signalling
Sohlh2, Foxo3a and Lhx8) are essential for oocyte pathways play key roles at this stage, including the
activation. Studies have also found that AMH, pro- TGFβ (e.g. activin), insulin-like growth factor (IGF)
duced by developing preantral follicles, exerts an and epidermal growth factor (EGF) pathways;
inhibitory influence on the primordial pool, while however, many others are also implicated. The com-
factors that activate the PI3K/AKT/mTOR signalling binationofthesemitogenicsignalscausesmultilayer-
pathways in pre-granulosa cells and oocytes have a ing of the somatic cells and further growth of the
stimulatory effect on growth. Identifying how these oocyte, leading to overall expansion of the follicle
pathways are regulated in this context is now the into a secondary-stage or multilayered preantral
subjectofmanyresearchgroups.Inmostmammalian follicle [11].
species, an increase in the rate of pre-/granulosa cell Importantly,theseearlystagesofpreantralfollicle
division, accompanied by morphological changes in development occur independently of gonadotrophins
shape of these cells from a squamous to a cuboidal andsteroidhormones.Assuch,earlyfollicledevelop-
form, as well as a relatively abrupt increase in oocyte ment occurs throughout pre-pubertal life – even in
growth, are all morphological features characteristic the fetal ovary – although fetal preantral/small antral
of follicle activation [9,10]. follicleswillneverdevelopmuchfurtherduetoinsuf-
ficient levels of follicle-stimulating hormone (FSH).
1.4.2 PreantralFollicles In the post-pubertal ovary, FSH from the pituitary
bindstofunctionalFSHreceptorsexpressedongran-
Follicles committed to activate and grow eventually ulosa cells of preantral follicles. FSH augments the
establish a tightly packed single layer of cuboidal actions of local growth factors to mainly stimulate
3
https://doi.org/10.1017/9781108891646.001 Published online by Cambridge University Press