adenomyosis and assisted conception
TRANSCRIPT
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Adenomyosisand Assisted Conception
Marwan Alhalabi MD PhDProfessor in Reproductive Medicine Faculty of Medicine Damascus University
And
Medical Director Orient Hospital Assisted Reproduction Center Damascus – Syria
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AdenomyosisANeglectedDisease
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Karl, baron von Rokitansky( 1804 – 1878)
In1860GermanPathologist
The1st descriptionon“Adenomyosis”
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Thomas Stephen Cullen1896
• Gynecologist.
• In his book “Adenomyosisof the uterus” publishedin 1908 was the firstsystematic description ofwhat is today known asadenomyosis
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DefinitionAdenomyosis is a benign disease of the uterus characterizedby ectopic endometrial glands and stroma within themyometrium.
It is associated with myometrial hypertrophy and may beeither diffuse or focal. (Bird et al, 1972)
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Definition
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DefinitionofAdenomyosis
1- Presence.
2- DepthOfPenetration.
3- DegreeOfSpread.
4- ConfigurationofLesions(diffuseornodular/Focal).
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Adenomyosis:Epidemiology
§ About 1%offemalepatients.
§ 5- 70%ofhysterectomyspecimens.
§ Moreofteninmultiparous women.
§ HistoryofUterineSurgery.
§ Lessinsmokers(LowE2).
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Adenomyosis:Epidemiology
• Theprevalenceofadenomyosisisunknown:
Theavailabledata?isbasedonhistologicaldiagnosisfollowinghysterectomy.
Pathologistsdonotadheretoclearsetofcriteriasincethereisnoclinicalimpactontheindividualpatient.
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Thetypicalsymptomsinclude
• Pelvicpain.
• Dysmenorrhea.
• Andmenorrhagiaunresponsivetohormonaltherapyoruterinecurettage.
• Dyspareunia.
• Subfertility.Andpregnancytermination.
Cyclic,crampinguterinepainbeginninglaterinreproductivelife(generallyafterage35)andoftenassociatedwithprolongedandheavymenses
classicpresentation
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Adenomyosis
PossibleAssociationwith:
• Infertility
• EarlyPregnancyLoss
• PretermLabor
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DiagnosisFirstSteptoSuccessfulTherapy
• Achieving the right diagnosis is probably the mostimportant task of the physician!
• Without the right diagnosis the choice of treatment isinadequate and “guess work”.
• The right diagnosis allows the physician to present to thepatient the choice of available treatments and todetermine together the right therapy for the rightpatient – a prerequisite for success!
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DiagnosisMajorProblemoftreatmentof
Adenomyosis• Differential diagnosis with a major and very common
“other” uterine disease:
- uterine leiomyomas 35 – 55 % coexistence).
• Knowledge and use of radiological diagnosis (TVUS,MRI) not yet routine.
• Definitive diagnosis is in the hands of the pathologist!
- many diagnosis (post hysterectomy!)
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Diagnosis
Thediagnosiscanonlybeprovenbythepathologists
Agoodgynecologistmaysuspectadenomyosis basedontheclinicalfactors,butthefinaldiagnosisusuallyhastowait
untilhysterectomyisperformed.
(Discepoli S,Leocata P,Giangregorio F).examined1500surgicalbitshadbeenhistologically examined..Inalltheyhavefound310casesofadenomyosis (20,6%);
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If you do not think “adenomyosis”,
you will not find “adenomyosis”
Diagnosis
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transvaginalsonography(TVS)thesensitivity80%–86%,thespecificity50%–96%,overallaccuracy68%–86%
MRimagingsensitivity andspecificityof86%–100%overall
accuracyof85%–90.5%
MRimagingishighlyaccurate indiagnosisofadenomyosis,
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UltrasoundDiagnosis
Thetechniqueisstronglyoperatordependent
TVUS
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Adenomyosis:TVUSMorphology
Asymmetricaluterineenlargement(orglobularappearinguterus)
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Adenomyosis:TVUSMorphology
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Adenomyosis:TVUSMorphology
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Signfoundin75%ofpatients
Adenomyosis:TVUSMorphology
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Asymmetricaluterineenlargementdefinedhyperechoic &hypoechoic areas(heterogeneousmyometrial echotexture)
Adenomyosis:TVUSMorphology
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Adenomyosis:TVUSMorphology
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Asymmetricaluterineenlargementdefinedhyperechoic &hypoechoic areasSmallanechoiccysts.
Adenomyosis:TVUSMorphology
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Adenomyosis:TVUSMorphology
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Thepresenceofdilatedcysticglandsorhemorrhagic fociwithintheheterotopicendometrialtissueresultsinthe presenceofsmallmyometrialcysts(usually<5mmindiameter) inapproximately50%ofpatients
Adenomyosis:TVUSMorphology
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Adenomyosis:TVUSMorphology
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Myometrial Veins
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Asymmetricaluterineenlargement.Illdefinedhyperechoic &hypoechoic areas.Smallanechoiccysts.Indistinctendometrial-myometrialborder.
Adenomyosis:TVUSMorphology
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Adenomyosis:TVUSMorphology
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LinearStriationsfromEndometrium(Kepkep etat.UltrasoundObstet Gynecol,inpress)
Adenomyosis:TVUSMorphology
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Subendometrialstripes
Adenomyosis:TVUSMorphology
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4D Ultrasound
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MRI
widening ofthejunctional zone.
brightfoci.
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•Thenormalwidthofthejunctionalzoneisupto8mm.•Wideningofthejunctionalzonefrom8mmupto12mmissuggestiveoffocaladenomyosis•ajunctionalzonethatis12mmwideorgreaterisdiagnosticofdiffuseadenomyosis
5mm 16mm
MRI
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Thelow-signalintensitythickeningofthejunctionalzonerepresentspathologichypertrophyofsmoothmusclesurroundingislandsofheterotropicendometrialglands
MRI
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Bright,tinyfociareoftennoticedonT1- orT2-weightedimages
MRI
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DiagnosisofAdenomyosis
• InaCochraneReview
• MRIwassuperiorthanTVUSinthediagnosis.
• ThecombinationofMRIandTVUSproducehigherlevelofaccuracy.
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Junctional Zone(JZ)
• The junction between the endometrial mucosa andmyometrium“interface”.
• In recent years this interface “JZ” has proven to becritically governs many reproductive functions.
• Its smooth muscle cells is under ovarian hormonescontrol and shows cyclic changes (fujii S et al 1989).
• JZ almost disappear on MRI during OC, GnRh, Post-menopausal and reappear with HRT.
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Junctional Zone(JZ)
A disruption of Endometrial – Myometrial interface may leadto adenomyosis and mayoccur after mechanical damage.
(Mori et al 1984, Azziz 1989, Levgure et al 2000)
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Junctional ZoneFunction
JZ plays an important role in :
- Sperm transport.
- Implantation.
- Ectopic pregnancy.
- Recurrent miscarriages.
- Unexplained infertility.
(Evers JL, et al 1996, IjlandMM et al 1997)
- IVF/ET
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Uterotubal transportdisorderinadenomyosis--- acauseforinfertility
(kissler etal2006BJOC)
• MRI + HSG ( Hystero Salpingo Graphy)
in 41 infertility Patient Laparoscopically provenendometriosis and patent tube, 35 (85%) hadAdenomyosis.
• The data showed that adenomyosis is commonlyassociated with endometriosis and has direct effectson uterotubal transport capacity.
• The data explains the reduced fertility in subjectswith intact tubo-ovarian anatomy.
Wecall itUnexplainedinfertility!!!
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Hysteroscopic Diagnosis
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Hysterosalpingogram
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Adenomyosisandinfertility
ØStrong association between adenomyosis andlonglife infertility in the baboon (Barrier et al, 2005)
ØAssociation between pelvic endometriosis andadenomyosis 54% (de Souza et al, 1995) to 97-90% (Kuntzetal, 2005)
Ø Increased preterm labor (Juang et al, 2006)
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• Uterine hypermotility: alteration of sperm transport(Kissper et al, 2006)
• Alteredoxydative stress(Ota et al, 1998, 2000, 2001)
• Increased microvessel density(schindl et al, 2001)
• Alteredgene pattern expression(Heres et el, 2006)
Adenomyosisandinfertility
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Ø Fewerfolliclesandcorporalutea.
Ø MIIoocytes withscatteredchromosomes.
Ø Cytoplasmic fragmentation.
Ø Formationofpseudopronuclei.
Ø Spontaneousoocyte activation.
Ø Reducedfertilizationandabnormalpronuclei.
Ø Delayed-arrestedembryo cleavage.
Ø Nomicrotubulesinblastocysts.
Woods-Marshalletal.Reprod Sci 2007;14.
ARTandAdenomyosis
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ARTandAdenomyosis
• WhentoofferIVF?
• DoesitaffectIVFoutcome?
• IsmedicaltherapypreIVFuseful?
• ShouldICSIalwaysbeused?
• Ifsurgeryisneeded,whichtechnique?
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Variabla Healthy AdenomyosisCycles 33 25
Embryos 4.1 4Implantation (%) 16 14.8Pregnancy (%) 45.5 40Miscarriage (%) 16 20Live birth (%) 27.2 28
Healthy Recipient
Recipient With Severe Adenomyosis
Diaz et al, Fertil Steril 2000
ART and Adenomyosis
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Adenomyosis&oocyte donation
ADENOMYOSIS LOW RESPONDER Pvalue
Patients(cycles) 30(53) 54(68)
Age 36.9±5.8 37.0±0.5 NS
Yrsinfertility 4.8±0.6 3.8±1.0 NS
Embryosreplaced 3.1±1.2 3.6±0.8 NS
Implantation (%) 28/158(17.7) 59/246(24.0) NS
Clinicalpregn.(%) 18/53(33.9) 30/68(44.1) NS
Miscarriage(%) 6/53(11.3) 7/68(10.3) NS
Termpregn. (%) 12/53(22.6) 23/68(33.8) NS
Camargo et al, ESHRE 2000
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Adenomyosis&oocyte donation
ADENOMYOSIS CONTROL Pvalue
Patients(cycles) 40(60) 60(60)
Age 38.7±6.8 37.9±5.9 NS
Yrsinfertility 2.8±2.1 2.7±1.6 NS
Embryosreplaced 2.7±1.5 2.7±1.6 NS
Implantation (%) 27/160(16.9) 40/161(24.8) NS
Clinicalpreg. (%) 18/60(30.0) 23/60(38.3) NS
Miscarriage(%) 3/60(5.0) 5/60(8.3) NS
Termpregn. (%) 15/60(25.0) 18/60(30.0) NS
Camargo et al, ASRM 2001
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Junctional ZoneinIVF-ET
Ø The important of JZ contractility on pregnancy rate hasbeen studied in IVF-ET.
(Lesny P et al 1998, Fanchin et al 1998, Lensy et al 2004, Kido A et al 2005).
Ø ART may expose the embryo to a higher JZ activity asconsequence of :ü High hormone level associated with the ovarian hyperstimulation.ü Uterine manipulation during ET.
Ø Abnormal JZ as result of Adenomyosis.
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ART&Adenomyosis
• In largeMeta analysis (Barnhart 2002)
Women with adenomyosis undergoing ART have asignificant lower pregnancy rate compared withwomen with tubal factor infertility.
Moreover; women with stage 3 and 4endometriosis have much lower pregnancy ratethan stage 1 and 2
Barnhart k et al, Fertil Steril 2002;77:114-1155
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ImplantationinART
Embryoquality
EndometrialReceptivity
TransferEfficiency
Adenomyosis
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TreatmentOptions
• Medicaltreatment.
• Surgicaltreatment.
• CombinedsurgicalandMedicalTreatment.
• Vesselembolisation.
• High-intensityfocusedUltrasound(HIFU).
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MedicalTreatment
• GnRH agonist(Linetal,2000;Huarg etal,1999).
• Levonorgestrel – releasingintra-uterinesystem(LNG-IUS)Mirena.
• Danazol loadedintra-uterinedevice.
(igarishi etal2000)
• Aromatase inhibitors.
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MedicalTreatment
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Adenomyosis– IVFIsmedicaltherapypreIVFuseful?
Sallam,Garcia-velascoetal,Cochranedatabase2006
GnRHa reducesNKcellactivityinvitro
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conservativesurgeryforadenomyosis
The conservative surgery for adenomyoma can reducesymptom and raise pregnancy rate significantly, it canbe accepted by young women who want to preservetheir reproductive capacity.
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conservativesurgeryforadenomyosis
. Though the pregnancy rate of conservative surgeryfor diffused adenomyosis was low, it still hastherapeutic value
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Hysteroscopic management
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InSiteDistruction
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CombinedSurgicalandHormonaltreatment
• SurgicalcompleteresectionofthevisibleadenomyosisareafollowedbyGnRHa 2-6mresultedinthebirthof4cases.
(Hungetal,1998;Wangetal,2000;Ozakietal,1999)
• LaparoscopicexcisionofadenomyosisFollowedbylivebirth.(Linetal,2000)
• Laparoscopiccytoreductive surgeryresultedin2livebirths. (Wangetal,2006)
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VesselEmbolisation
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VesselEmbolisation
• Siskin et al, 2001 reported on 15 casesdiagnosed with MRI, improvement ofquality of life in 12 out of 13.
• The reported series are small and so farNo successful pregnancy has beenreported.
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UAEisaneffectiveandsafemethodinthetreatmentofAdenomyosis.BUTtherecurrencerateisnotyet
evaluated.
VesselEmbolisation
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High– IntensityFocusedUltrasound(HIFU)
HIFUgiveacombinationofCoagulationandtissuedestructioninanon-invasive,bloodlessmanner,underMRIguiding.
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High– IntensityFocusedUltrasound(HIFU)
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High– intensityFocusedUltrasound(HIFU)
• Pregnancy and live birth reported after HIFUfor symptomatic focal adenomyosis.
(Robinovici et al, Hum Reprod 2006).
• The early results indicate the safe andeffective ablation of adenomyosis tissue byHIFU the procedure also resulted in theimprovement in clinical symptoms during the6 month of follow – up.
(Fukunishi et al, 2008).
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Summary• Theprevalenceofadenomyosisininfertilityisnotknown.
• Theaetiology,pathogenesisareunclear.
• Thediagnosisbeforehysterectomyisdifficult.
• Theoptionsoftreatmentarelimited• Furtherstudiesareneededtoexplore:
- Therelationofunexplainedinfertilityandadenomyosis
- HowadenomyosiseffectIVFoutcome- Diagnostic,non-invasiveandreliabletools.
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Conclusion1
• Adenomyiosis is strongly associated with endometriosisand uterine fibromas, thus being frequently diagnosed ininfertile patients.
• In women with adenomyosis the receptivity of the eutopicendometrial to embryo implantation appears normal.
• Adenomyosis might impair the mechanism of directedsperm transport.
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Conclusion 2
• Adenomyosis might compromise the intrafolliculardevelopment of oocytes and thus represents acausal factor of subfertility.
• Alterations in the gene expression pattern of theendometrium of women with adenomyosis havebeen described.
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Conclusion 3
• The infertility in women with adenomyosis is
best treated by hormonal stimulation and IVF,
not by insemination.
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Conclusion 4
• There are novel “uterus-preserving”
treatment options for adenomyosis !
- LNG-IUS.
- Vessel embolisation .
- HIFU.
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Conclusion: take home Massage
• Before you make the diagnosis ofunexplained infertility, or you havefailure of assisted conception :Try to exclude the possibility ofAdenomyosis.
“ Particularly in infertility women with heavy periodsor chronic pelvic pain”
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AcknowledgementClinicalTeamS.SamawiN.KafriS.ModiM.Mousa
IVFLabJ.SharifR.DoghozA.KadriA.Konali
FetalMed.A.TahaM.KhalafM.Hazemah
Andrology LabW.HamadN.AssafM.OthmanN.MazzawiS.Sheko
Bio-Ginitic LabA.KhatibM.KinjA.SakrA.Othman Administration
F.HamadR.QamarM.HajhasanN.OlabiE.FayadW.Saker
MedEngineeringY.KhaboriS.Khayat
AnesthesiaR.TarkoY.LakkisM.KhadraH.Sulaiman
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