Adenomyosis and Assisted Conception

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

AdenomyosisANeglectedDisease

Karl, baron von Rokitansky( 1804 – 1878)

In1860GermanPathologist

The1st descriptionon“Adenomyosis”

Thomas Stephen Cullen1896

• Gynecologist.

• In his book “Adenomyosisof the uterus” publishedin 1908 was the firstsystematic description ofwhat is today known asadenomyosis

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)

Definition

DefinitionofAdenomyosis

1- Presence.

2- DepthOfPenetration.

3- DegreeOfSpread.

4- ConfigurationofLesions(diffuseornodular/Focal).

Adenomyosis:Epidemiology

§ About 1%offemalepatients.

§ 5- 70%ofhysterectomyspecimens.

§ Moreofteninmultiparous women.

§ HistoryofUterineSurgery.

§ Lessinsmokers(LowE2).

Adenomyosis:Epidemiology

• Theprevalenceofadenomyosisisunknown:

Theavailabledata?isbasedonhistologicaldiagnosisfollowinghysterectomy.

Pathologistsdonotadheretoclearsetofcriteriasincethereisnoclinicalimpactontheindividualpatient.

Thetypicalsymptomsinclude

• Pelvicpain.

• Dysmenorrhea.

• Andmenorrhagiaunresponsivetohormonaltherapyoruterinecurettage.

• Dyspareunia.

• Subfertility.Andpregnancytermination.

Cyclic,crampinguterinepainbeginninglaterinreproductivelife(generallyafterage35)andoftenassociatedwithprolongedandheavymenses

classicpresentation

Adenomyosis

PossibleAssociationwith:

• Infertility

• EarlyPregnancyLoss

• PretermLabor

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!

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!)

Diagnosis

Thediagnosiscanonlybeprovenbythepathologists

Agoodgynecologistmaysuspectadenomyosis basedontheclinicalfactors,butthefinaldiagnosisusuallyhastowait

untilhysterectomyisperformed.

(Discepoli S,Leocata P,Giangregorio F).examined1500surgicalbitshadbeenhistologically examined..Inalltheyhavefound310casesofadenomyosis (20,6%);

If you do not think “adenomyosis”,

you will not find “adenomyosis”

Diagnosis

transvaginalsonography(TVS)thesensitivity80%–86%,thespecificity50%–96%,overallaccuracy68%–86%

MRimagingsensitivity andspecificityof86%–100%overall

accuracyof85%–90.5%

MRimagingishighlyaccurate indiagnosisofadenomyosis,

UltrasoundDiagnosis

Thetechniqueisstronglyoperatordependent

TVUS

Adenomyosis:TVUSMorphology

Asymmetricaluterineenlargement(orglobularappearinguterus)



Signfoundin75%ofpatients


Asymmetricaluterineenlargementdefinedhyperechoic &hypoechoic areas(heterogeneousmyometrial echotexture)



Asymmetricaluterineenlargementdefinedhyperechoic &hypoechoic areasSmallanechoiccysts.



Thepresenceofdilatedcysticglandsorhemorrhagic fociwithintheheterotopicendometrialtissueresultsinthe presenceofsmallmyometrialcysts(usually<5mmindiameter) inapproximately50%ofpatients



Myometrial Veins

Asymmetricaluterineenlargement.Illdefinedhyperechoic &hypoechoic areas.Smallanechoiccysts.Indistinctendometrial-myometrialborder.



LinearStriationsfromEndometrium(Kepkep etat.UltrasoundObstet Gynecol,inpress)


Subendometrialstripes


4D Ultrasound

MRI

widening ofthejunctional zone.

brightfoci.

•Thenormalwidthofthejunctionalzoneisupto8mm.•Wideningofthejunctionalzonefrom8mmupto12mmissuggestiveoffocaladenomyosis•ajunctionalzonethatis12mmwideorgreaterisdiagnosticofdiffuseadenomyosis

5mm 16mm

MRI

Thelow-signalintensitythickeningofthejunctionalzonerepresentspathologichypertrophyofsmoothmusclesurroundingislandsofheterotropicendometrialglands

MRI

Bright,tinyfociareoftennoticedonT1- orT2-weightedimages

MRI

DiagnosisofAdenomyosis

• InaCochraneReview

• MRIwassuperiorthanTVUSinthediagnosis.

• ThecombinationofMRIandTVUSproducehigherlevelofaccuracy.

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.

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)

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

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!!!

Hysteroscopic Diagnosis

Hysterosalpingogram

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)

• 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

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

ARTandAdenomyosis

• WhentoofferIVF?

• DoesitaffectIVFoutcome?

• IsmedicaltherapypreIVFuseful?

• ShouldICSIalwaysbeused?

• Ifsurgeryisneeded,whichtechnique?

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

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

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

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.

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

ImplantationinART

Embryoquality

EndometrialReceptivity

TransferEfficiency

Adenomyosis

TreatmentOptions

• Medicaltreatment.

• Surgicaltreatment.

• CombinedsurgicalandMedicalTreatment.

• Vesselembolisation.

• High-intensityfocusedUltrasound(HIFU).

MedicalTreatment

• GnRH agonist(Linetal,2000;Huarg etal,1999).

• Levonorgestrel – releasingintra-uterinesystem(LNG-IUS)Mirena.

• Danazol loadedintra-uterinedevice.

(igarishi etal2000)

• Aromatase inhibitors.

MedicalTreatment

Adenomyosis– IVFIsmedicaltherapypreIVFuseful?

Sallam,Garcia-velascoetal,Cochranedatabase2006

GnRHa reducesNKcellactivityinvitro

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.

conservativesurgeryforadenomyosis

. Though the pregnancy rate of conservative surgeryfor diffused adenomyosis was low, it still hastherapeutic value

Hysteroscopic management

InSiteDistruction

CombinedSurgicalandHormonaltreatment

• SurgicalcompleteresectionofthevisibleadenomyosisareafollowedbyGnRHa 2-6mresultedinthebirthof4cases.

(Hungetal,1998;Wangetal,2000;Ozakietal,1999)

• LaparoscopicexcisionofadenomyosisFollowedbylivebirth.(Linetal,2000)

• Laparoscopiccytoreductive surgeryresultedin2livebirths. (Wangetal,2006)

VesselEmbolisation

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.

UAEisaneffectiveandsafemethodinthetreatmentofAdenomyosis.BUTtherecurrencerateisnotyet

evaluated.

VesselEmbolisation

High– IntensityFocusedUltrasound(HIFU)

HIFUgiveacombinationofCoagulationandtissuedestructioninanon-invasive,bloodlessmanner,underMRIguiding.

High– IntensityFocusedUltrasound(HIFU)

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).

Summary• Theprevalenceofadenomyosisininfertilityisnotknown.

• Theaetiology,pathogenesisareunclear.

• Thediagnosisbeforehysterectomyisdifficult.

• Theoptionsoftreatmentarelimited• Furtherstudiesareneededtoexplore:

- Therelationofunexplainedinfertilityandadenomyosis

- HowadenomyosiseffectIVFoutcome- Diagnostic,non-invasiveandreliabletools.

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.

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.

Conclusion 3

• The infertility in women with adenomyosis is

best treated by hormonal stimulation and IVF,

not by insemination.

Conclusion 4

• There are novel “uterus-preserving”

treatment options for adenomyosis !

- LNG-IUS.

- Vessel embolisation .

- HIFU.

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”

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

Health & Medicine

Adenomyosis and Assisted Conception