Approaches to a Thin Resistant Endometrium Prior to Embryo Transfer.ppt

Approaches to a
Thin/Resistant Endometrium
Prior to Embryo Transfer
Dr Ndjapa-Ndamkou

1. Approaches to a
Thin/Resistant Endometrium
Prior to Embryo Transfer
DR NDJAPA-NDAMKOU

2. Theimpactandmanagementofthinendometriumisacommonchallengeforpatientsundergoing
assistedreproduction.
Assessmentoftheendometriumisanessentialcomponentinassistedreproduction.Endometrial
thicknesshasbeenidentifiedasaprognosticfactorforsuccessinassistedreproduction.Whenthe
endometriumisassessedtobe‘thin’,physiciansandpatientsfaceadecisionofwhetherornotto
proceedwiththetreatmentcycle.
Variousfactorscanlimittheaccuracyofendometrialmeasurementssuchasfibroids,adenomyosis,
polyps,uterineorientation,bodyhabitus,previoussurgeries,uterinecontractions,ultrasoundmachine
quality,interobserverandintra-observervariability,andpatientintolerance.
TheCanadianFertilityandAndrologySociety(CFAS)guidelinehaveprovidesomeevidence-based
recommendationsusingtheGRADE(GradingofRecommendations,Assessment,Developmentand
Evaluations)frameworkontheassessment,impactandmanagementofthinendometriuminassisted
reproduction.
Iwilladdresstheeffectofendometrialthicknessonpregnancyandlivebirthoutcomesinovarian
stimulationandIVF(freshandfrozencycles)isaddressed.
Inaddition,recommendationsontheuseofadjuvantstoimproveendometrialthicknessandpregnancy
outcomeswillbeprovided.

3. Thin/Resistant Endometrium
•no agreement has been reached on
endometrial thickness..
•available evidence does not support any
specific cut-off
•Pregnancies from 5 mm to > 15 mm EMT have
been reported
Caiet al, 2011; Remohíet al, 1997

4. •Leukemia patient in remission
•Successful live birth in the pesenceof ‘very
thin’ endometrium (3 mm) despite use of
several methods
•ERA indicated receptive endometrium
Cruz and Bellver2014

5. •14 included studies with 4922 cycles
•mean EMT is higher in
pregnantsthan those non
pregnants(p <0.001)
•mean difference of 0.4 mm
•OR for pregnancy: 1.40(95%
CI 1.24–1.58)
Momeniet al 2011

6. •22 RCT/cohort studies were included in all
ages (30-35.5 years)
•EMT cut-off was 7 mm (6-27 mm) (as in
majority of trials)
•Pregnancy outcomes and ROC analysis were
reported
Kasiuset al 2014

7. CPRs
OR: 0,42

8. Age?
•Kasiuset al
In the group with EMT < 7mm, mean age is higher and mean no of
retrieved oocytes are lower when compared to EMT > 7mm

9. Yes
•Al-Ghamdiet al., 2008;
•Chen et al.,2010;
•Noyeset al., 1995;
•Richter et al., 2007;
•Rinaldiet al.,1996
No
•Basiret al., 2002
•De Geyteret al., 2000;
•Dietterichet al.,2002;
•Rashidiet al., 2004
•Endometrial Pattern & Pregnancy rate

10. Endometrial Pattern
•Triple-line >homogen,
heterogen, intermediate
pattern on the day of hCG
Zhao et al 2014, Hock et al 1997
•confirmed it only in a
subset of patients with
EMT of 7–14 mm
Rashidiet al 2005
•No clear association
between patterns
Chen et al 2010, Zhao et al 2012

11. •277 patients undergoing
fresh or frozen ET
•EuploidET
•Endometrial patterns 1,2
or 3
•EMT or pattern were not
found suggestive of clinical
outcomes of euploid
embryos
•Type 3 pattern: suggestive
of closed WOI
Gingoldet al 2015

12. •FET cycles that HRT
was used
•EMT >8 mm
revealed higher
clinical pregnancies
El Toukhyet al 2007

13. Bu et al 2016
•Clinical pregnancies and LBRs are improved when EMT > 8mm
•This is valid for both young (< 35) and advanced age (>35) women

14. EMT; Summary
•there is no solid conclusion on the optimal
EMT cut-off
•It appears that at least 7 mm EMT;
Fresh
cycles
Frozen-
thaw ET
cycles

15. The mechanism by which a ‘thin’ endometrium may affect
implantation
is not known, but several theories have been suggested.
1.Estrogen receptor abnormality/dysfunction
hypothesis (Lessey2011)
2.Oxygen tension theory (R. Casper 2011)
3.Impaired angiogenesis and altered blood
flow (Miwa 2007)

16. Oxygen Tension
Spiral arteries
with high
oxygenated
blood flow
Casper 2011

17. Embryo
Casper 2011

18. Miva2007
•Uterine and radial artery
RI increased
•Glandular epithelium
area and no of blood
vessels are decreased in
thin endometrium group
Impaired Angiogenesis Theory
Miwa proposed that in thin endometirum
cases: angiogenesis was severely
compromised, resulting with decreased
glandular and vascular texture

19. Etiology of Thin Endometrium
•Surgical (DD&C and post abortion obstetric curettage Ablation Aggressive myomectomy)
•Radiotherapy (dose dependant)
•Infections (chronic endometritis)
•Prolonged OCP use (>10 years)
•Clomiphene cycles (repeated cycles)
•Congenital MullerianAnomalies
•Idiopathic

20. THINENDOMETRIUMINOVARIANSTIMULATION(NON-IVF)
Thinendometriumiscommonlyencounteredduringcontrolledovarian
stimulationcycles(non-IVF).Whenpatientsundergoingovarianstimulationhavea
thinendometrium,cliniciansmayconsiderwhethertoproceedwiththetreatment
cycleandintrauterineinsemination(IUI)ifplannedorcancelthecycle.
Theeffectofendometrialthicknessontreatmentoutcomeshasbeendescribedin
manystudies;however,mostofthesestudieshavebeenretrospectiveandsmall.
Moststudieshavenotshownaneffectofthinendometriumonoutcomes(Chenet
al.,2012;Kolibianakisetal.,2004;Weissetal.,2017),althoughonestudy(Jeonet
al.,2013)showedaverylowpregnancyratewithendometrialthickness≤7mm.In
aprospectivestudyof168patients,Kolibianakisetal.(2004)foundcomparable
pregnancyratesinclomiphenecitratecyclesforendometrialthicknessconceive.
Studiesusingclomiphenecitrate,letrozoleandgonadotropinswereincludedin
theanalysis.Theauthorsacknowledgedthatthismaynotaccountforcycleswhich
werecancelledduetothinendometrium.

21. Inreviewingtheliteratureonthinendometriumandovarian
stimulationIUI,itshouldbenotedthatabsolutepregnancyand
livebirthratesaremuchlowerwithovarianstimulationIUI
comparedwithIVF,whichmayaccountforthelackofeffect
Inpatientswiththinendometrium,theprognosisforachievinga
thickerendometriuminsubsequentovarianstimulationcyclesis
unclear.Clinicianswilloftenswitchstimulationmedicationsafter
encounteringathinendometrium.

22. Inasystematicreviewandmeta-analysis,clomipheneandletrozolewereboth
associatedwithathinnerendometriumcomparedwithgonadotropinsinovarian
stimulationcycles(Weissetal.,2017).Onlyonestudywasfoundwhichcompared
stimulationmedicationsforpatientswithahistoryofthinendometriuminovarian
stimulation(Wangetal.,2008).Inthisprospectivecohortstudy,160patientswith
ahistoryofendometrium<8mmwithovarianstimulationweretreatedwitheither
tamoxifenorclomiphenefollowedbyhumanmenopausalgonadotropins.
Pregnancyrateswerehigher,andspontaneousabortionratesandendometrial
thickness<8mmwerelowerinthetamoxifengroup.
Theuseofadjuvantstoimprovepregnancyratesinpatientswithahistoryofthin
endometriumhasnotbeenwellstudied.Onenon-blindedRCTof136patients
evaluatedtheuseofaspirininpatientswithahistoryofendometrialthickness<8
mminaprecedingcycle(Hsiehetal.,2000).Althoughtherewasatrendtowardsa
thickerendometriumandhigherpregnancyrateswithaspirin,neithertrendwas
statisticallysignificant.Theuseofsildenafilcitrateasanadjuvantinovarian
stimulationhasbeendescribedinacasereport(Zingeretal.,2006)butnot
evaluatedinaresearchstudy

23. THINENDOMETRIUMINIVF(FRESHORFROZENEMBRYOTRANSFER)
TheimpactofathinendometrialliningonIVF-embryotransferoutcomeshasbeen
studiedextensively.Thequalityoftheavailabledataisoftenlow,andthestudiesare
fairlyheterogeneous.Moststudiesonthistopicareretrospectiveandexaminefresh
IVF-embryotransfercycles,withonlyasmallsubsetlookingatfrozenembryotransfer
cycles.
ObservationalstudiesoffreshIVFcycleshaveindicatedadecreasedchanceofclinical
pregnancyorlivebirthwiththinendometrium;however,theyalluseddifferentcut-
offstodefinethinendometrium(Kovacsetal.,2003;Kumbaketal.,2009;Vaegteret
al.,2017;Yuanetal.,2016;Zhaoetal.,2014).Vaegteretal.(2017)foundsignificantly
reducedlivebirthrateswithendometrialthickness<7mmand7–10mmcompared
withcaseswithathickerendometrium.

24. Kumbaketal.(2009)showedsignificantlyreducedclinicalpregnancy
andlivebirthrateswhenendometrialthicknesswas<7mm;however,
theydidnotroutinelyevaluatetheuterinecavitypriortoembryo
transfer.Theyalsohadsubstantial
variabilityinthenumberofembryostransferred.Kovacsetal.(2003)
foundthatendometrialthickness<10mmwasassociatedwithalower
pregnancyrate,butonlysixcaseswithendometrialthickness<8mm
wereincludedinthisstudyoutofatotalof1228cycles.
AverylargestudybyYuanetal.(2016)examinedover10,000freshIVF
cycles,includingover500embryotransferswithendometrialthickness
<8mm.Theyfoundthattheclinicalpregnancyratewassignificantly
lowerinpatientswithendometrialthickness<8mm(23%versus37.2%
forendometrialthicknessof8–11mm).Zhaoetal.(2014)foundthatthe
clinicalpregnancyratewassignificantlylowerwithendometrial
thicknesscut-offsofboth7mmand≤8mm.

25. Onesmall,olderstudyfoundthatendometrialthickness<7mmwasnot
significantlyassociatedwithalowerpregnancyrate(Noyesetal.,1995).
Anothersmallstudyofeuploidembryosfoundthattheclinicalpregnancy
ratewasnotsignificantlydifferentwithendometrialthickness≤7mm
comparedwithendometrialthickness>7mm(Gingoldetal.,2015);
however,thisstudymayhavebeenunderpowered.
ArecentsystematicreviewbyKasiusetal.(2014)didnotfindadifference
inlivebirthandongoingpregnancyratesforthinendometrium,definedas
≤7mm,althoughthiswaslikelytobeduetoaverysmallsamplesize.
However,theclinicalpregnancyratewassignificantlyreducedwith
endometrialthickness≤7mm,withanoddsratioof0.42andanarrow
confidenceinterval.Thereviewhadlowheterogeneity,butthestudies
wereamixofprospectiveandretrospectivestudies,andmostofthe
studieshadselectionbias.Manyofthestudiesalsouseddifferentcut-offs
forthedefinitionofthinendometrium.

26. IntheCanadianstudyofalmost22,000freshIVF-embryotransfer
cyclesusingtheBORN/CARTR+database,clinicalpregnancyand
livebirthratesareprogressivelylowerwithdecreasing
endometrialthickness.InfreshIVF-embryotransfercycles,the
livebirthratedecreasedprogressivelypermillimetrebelow8
mm:33.7%,25.5%,24.6%and18.1%inpatientswithendometrial
thickness≥8mm,7–7.9mm,6–6.9mmand5–5.9mm,
respectively(Liuetal.,2018).
WhenpatientspresentwiththinendometriumduringafreshIVF-
embryotransfercycle,adecisionmustbemaderegarding
whethertoproceedwithtreatmentorfreezealltheembryosto
allowfordifferentendometrialpreparationprotocols.Thereare
nostudiesavailabletoassesstheimpactofdifferentIVF
stimulationprotocolsforpatientswiththinendometrium.These
studiesareunlikelytobeconductedascurrentcryopreservation
techniquesallowembryostobefrozenfortransferinafuture
cyclewithminimalimpactonpregnancyoutcomes.

27. Treatment Strategies
Veolascoet al 2016
Preventing adhesions
Avoiding Asherman’sS.
Surgical option/Medical options
Bone Marrow studies
Transplantation

28. Medical Treatment
•Estradiol
•hCG
•Local plasma rich
platelet (PRP)
•Local G-CSF
•GnRH-a
•Acetyl Salysilic
acid
•Vitamins
•Nitroglycerin
•Vitamin-E
•Pentoxifylline
•sildenafil

29. Estrogen Administration
•Spiral artery
contraction
•Proliferation
•Reducing
oxygen
tension
Young et al 2014, Velasco et al 2016
•Oral
•Transdermal
•Vaginal

30. Vaginal Estrogen
•Avoids first pass effect
•High local and systemic E2 concentrations
•2 mg/day E2; vaginal vsoral
•Better uterinperfusion
•Better endometrial proliferation Fanchinet al 2001

31. No of
patients
Treatment
and duration
outcomes discussion
Liu et al 2015101with
thin EMT
18 mg/day E2
potill EMT >8
mm
Mean duration
was 96 days,
longer duration
ineffective
Prolonged therapy
seems effective
If achieved, pregnancy
outcomes are similar
Tourgeman
2001
10
refractory
to poE2
6mg/day po
E2 and 4
mg/day
vaginal till
EMT >7 mm
4 weeks 7 out of them had EMT >
7mm and concieved
Shenet al 20131 with
refractory
thinEMT
18 mg/day
starting from
2
nd
day for 9
days
9 days Max EMT 10 mm, live
birth
Demiret al
2013
57 with
thin EMT,
60
controls
4 mg/day
starting from
the day of
hCG
Till pregnancy
test
No differences in terms
of EMT and pregnancies

32. Medical Treatment
•High doses of E2
•Prolonged E2
•Local E2
•hCG
•Local plasma rich
platelet (PRP)
•Local G-CSF
•GnRH-analogues
•Aspirin
•Vitamins
•Nitroglicerin
patches
•Vitamin-E
•L-arginine
•Pentoxifylline
•sildenafil

33. hCG
Lichtet al demonstrated hCG/LH receptor mRNA during
both proliferative and secretory phase
Result:
•VEGF expression
•Tissue remodelling
•Plays role in receptivity
Lichtet al 2007
Paivaet al 2011

34. EMT
E2E2
E2
hCG150 IU sc
Day 8
•17 infertile patients (RIF) with refractory endometrium
resistant to other treatments
•Recipientsof fresh donor or frozen embryos
Day 2
Prog.
ET
Papanikolauet al 2013
7 days

35. •52% revealed 10%
•35% revealed 20% Improvement in EMT
Papanikolauet al 2013

36. Higher hCGDoses
•Prapaset al:
•Oocytes donor recipents, no thin EMT history
•750 IU hCGinj. every 3 days concommitantto
E2 compared to no hCGgroup
•Revealed significantly thin EMT
•Study prematurely discontinued due to
ethical reasons (13% vs45% pregnancy rate in
hCGarm)
•dose dependantlyaltered receptivity?
Prapaset al 2009

37. Medical Treatment
•High doses of E2
•Prolonged E2
•Local E2
•hCG
•Local G-CSF
•Local plasma rich
platelet (PRP)
•GnRH-analogues
•Aspirin
•Vitamins
•Nitroglicerin
patches
•Vitamin-E
•L-arginine
•Pentoxifylline
•sildenafil

38. Granulocyte-colony stimulating factor
(G-CSF)
•Glycoprotein and cytokinproduced by many
tissues and cells
•Endometrial cell regeneration by mobilizing stem
cells to the endometrial injury location
•Endometrial vascular re-modelling, local immune
regulation and cell adhesion
Endometrial improvement
Rahmatiet al 2014
Zhao et al 2013

39. •4 cases with thin EMT
prior to ET despite
oral+vaginalE2 and
vaginal sildenafil
•All received in-utero G-
CSF perfusion (1ml=300
IU)(2-9 days before ET)
•Growth in EMT can be
observed within 48 h of G-
CSF administration
•4 successful pregnancies
•2 of them were >40 yrs
Gleicheret al
2011

40. 




✖
✖

41. •G-CSF and Plasebosignificantly
increased EMT
•Is this an impact of G-CSF or
endogenous mechanisms taking
action following hCGadministration?
•No effect in terms of implantation..
Baradet al 2014

42. Medical Treatment
•High doses of E2
•Prolonged E2
•Local E2
•hCG
•Local G-CSF
•Local plasma rich
platelet (PRP)
•GnRH-analogues
•Aspirin
•Vitamins
•Nitroglicerin
patches
•Vitamin-E
•L-arginine
•Pentoxifylline
•sildenafil

43. Autologous Platelet Rich Plasma
•has been widely applied in orthopedics, ophthalmology
and wound healing

45. •5 women who had cancelled cycles due to
refractory thin endometrium
•In new cycle: 12mg/day E2 and on 10
th
day PRP
was obtained
•2 centrifugations of 15 ml peripheral blood
•1 ml PRP immediately given into the cavity with
catheter
Chang et al 2015

46. Acetyl SalisilicAcid
•might enhance endometrial growth and
embryo implantation via:
1.reducing sub-endometrial contractility
2.minimizing inflammation by inhibiting
cyclooxygenase and prostaglandin biosynthesis
3.improving uterine endometrial blood flow
•80 or 100 mg ASA orally
Wada et al 1994

47. No of cases Outcomes Notes
Weckstein
1997
•Oocyte
donation
cycles
28patients
with thin EMT,
15 ASA 80
mg/day po
13 controls
EMT 7 vs6,8
mm (NS)
•Pregnancies
were better
with ASA
Hsieh 2000
•IUI cycles
114 received
100 mg
ASA/day po,
122 controls
7 vs5,8 mm
(NS)
•Pregnancies
were better
with ASA
•Triple line
patternwas
more likely
with ASA
Pregnancies rather than thickness
seems to be improved

48. Vitamin E ±pentoxifylline
Pentoxifylline
•Vasodilatation
•Decreases blood
viscosity
•Inflammatory
response
•Decreasing
fibroblast
proliferation
Vitamin E (α-
Tocopherol)
•Anti-oxidant
•Vasodilatation
•Used along with
pentoxifylline
•Decrease the
radiation related

49. No of casesOutcomes Notes
Bataille200218 oocyte
recipents
whose EMT
reminedthin
despite vaginal
E2
800 mg PTX
and 1000 IU
vit-E per day till
ET
•72% of cases
revealed
increased
EMT (4,9 to
6,2 mm)
•6 months
Acharya200920 women with
refractory thin
EMT despite
several
attempts
800 mg PTX
and 1000 IU
vit-E per day till
ET
•Overall
increase in
EMT:4,3 to
6,0 mm
•8 months
Prolonged
duration..

50. Sildenafil
•PDE-5 selective inhibitor
•Vasodilatation via NO release
•Regulating vascular structure, growth and
tone
Pulmonary
hypertension
Erectile
dysfunction
Placental
insufficiency

51. •4 women with
refractory thin EMT
•25 mg/6 hrs
vaginal sildenafil
during proliferative
phase concurrent
with E2
•All patients
demonstrated
increased blood flow
and EMT
Sheret al 2000

52. No of cases Treatment Outcome
Sher2002 105 cases with >2
IVF failures due to
thin EMT
25 mg vaginal
sildenafil,4 times a
day, beginning from
day 2 to until hCG
%70of cases had
EMT of >9 mm
45% ongoing
pregnancies vs0%
in controls
Zinger 2006 2 Asherman’s
Syndrome cases
following D/C
1: vaginal sildenafil
25 mg X4 in thaw-
ET cycle
2: same in
clomiphene-coitus
cycle
Bothdelivered
healthy infants
Firouzabadi2013
(RCT)
80 cases with thin
EMT history
undergoing thaw-ET
cycles
40 received oral 50
mg sildenafil, 50
controls
Sildenafil group
revealed higher
EMT: 8 vs9,8 mm
Pregnancies were
similar

53. Surgical Management
•Hysteroscopy
•Regeneration using stem cells
•Uterus transplantation

54. Hysteroscopy
•A possible validity of H/S in thin-unresponsive
endometrium: previously unrecognized uterine
pathologies
•Pathologies have been detected in up to 50%of
women undergoing ART with no prior detected
abnormalities
Correction
Scratching
Faciliating
future
succesfulET

55. a.Thickadhesionband
b.Thinendometrium
c.Partialobliterationof thecavity
Amin et al, 2015

56. Hysteroscopic adhesiolysis is a safe and
effective procedure for restoring the normal
menstrual pattern and fertility.
Pabuçcu R et al. Fertil Steril 1997

57. •638 patients
diagnosedwith
Asherman’s
Syndrome
•Adhesiolysiswas
successfulin 95 %
•Recurrence(%27.3)
Hanstedeet al 2015

58. H/S
•Adhesions may be underlying as an
etiology of thin EMT
•Systematic approach should be
considered
•After max 3 attempts, successful
outcomes could be achieved

59. Surgical Management
•Hysteroscopy
•Stem-cell
•Uterus transplantation

60. Sources
•Clonogeniccells (epithelial or stromal)
•Bone marrow derived stem cells
•Human embryonic puliripotentstem cells
•Induced puliripotentstem cells

61. Bone Marrow Derived Cells
Case Intervention Outcome
Nagori2011 33 yroldAsherman
case following D/C
Bonemarrow
derived CD 9, CD
44 and CD 90
angiogenicstem
cells were infused
into endometrium
Ongoing pregnancy
was achieved 6-
monthslater
following oocyte
donation
Singh 2014 6 refractory AS
cases
Bonemarrow
derived CD 34 cells
were infused into
myometrium by
OPU needle
Following 3-6-9
monthsoffollow-
up, EMT
significantly
increased

62. Bone Marrow Derived Stem Cells
•Up to date, promising results have been
revealed
•Needs further validation…

63. Uterine Transplantation

64. Conclusion
•Management of thin endometrium is still
challenging
•Successful pregnancies were reported even
with 3 mm EMT
•Several approaches have been proposed but
none have been validated
•There is a paucity of solid evidence that
supports one intervention versus the other
•No such consensus on medical strategies

65. Conclusion…
Avoiding iatrogenic complications is outmost important
a hysteroscopicevaluation of the uterine cavity
should be a priority
Angiogenicstem cell studies needs to be standardized
Thinendometriumisaninfrequentbutchallengingoccurrence
inassistedreproduction.Physiciansmustbalancetheprognosis
forpatientsiftheyproceedwithtreatmentwithathin
endometriumorconsideralternativetreatments.Currently,
thereisminimalevidencetosupportanyspecificprotocolsor
adjuvantstosignificantlyimprovepregnancyoutcomesin
patientswiththinendometrium.

66. Thank You