The effect of the hormonal milieu of pregnancy on deep infiltrating endometriosis: serial ultrasound assessment of changes in size and pattern of deep endometriotic lesions.

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The

effect

of

the

hormonal

milieu

of

pregnancy

on

deep

inﬁltrating

endometriosis:

serial

ultrasound

assessment

of

changes

in

size

and

pattern

of

deep

endometriotic

lesions

Maria

Elisabetta

Coccia

a,

*

,

Francesca

Rizzello

b

,

Antonio

Palagiano

c

,

Gianfranco

Scarselli

a

DepartmentofSciencefortheWomanandChild’sHealth,UniversityofFlorence,viaIppolitoNievo,2,50100Florence,Italy

b

DepartmentofMedicalPathophysiology,SapienzaUniversityofRome,Rome,Italy

c

DepartmentofObstetrics,Gynecology,andReproductiveSciences,SecondUniversityofNaples,Italy

1. Introduction

Endometriosisisaverycommondiseaseaffectingupto10%of

reproductiveagewomen[1].Ahigherprevalenceofendometriosis

isreportedininfertilewomen,withestimatesrangingfrom25to

50% [2]. Although endometriosis is one of the most studied

conditionsingynaecologytoday,itstillrepresentsanenigmatic

disease[3].Inaddition,therearecontradictoryopinionsaboutthe

overallclinicalmanagement.

Deep inﬁltratingendometriosis (DIE)is a particular formof

endometriosisthatpenetratesintotheretroperitonealspaceorthe

wallofthe pelvicorgans toa depth of atleast 5mm,strongly

associatedwithseverepelvicpainanddeepdyspareunia[4].Its

distribution is typically multifocal and represents a complex

managementchallenge.

Thebeneﬁtsofpregnancyontheprogressionandrecurrenceof

endometriosisarewidelyrecognized.Someevidencesuggeststhat

earlypregnancymaybeprophylacticagainstthedevelopmentof

endometriosisandcouldactuallyreducetheriskofrecurrenceof

suchlesions[5].Otherreportsshowthepotentialoccurrenceof

serious and unexpected complications of the disease during

pregnancy[6].Thepurposeofthis studywastoreporttheﬁrst

seriesshowingtheeffectofpregnancyonDIElesionsandrelated

symptomatology.

2. Materialsandmethods

Aspartofalongitudinalstudyperformedoverthepast3years

to determine the efﬁcacy of hormonal treatment in treating

women with DIE,we identiﬁed three cases of advanced pelvic

endometriosis,allwithDIE(deeprecto-vaginalandrecto-sigmoid

involvement)wherepatientsachievedspontaneouspregnancies.

Theywerefollowedupbytransvaginalultrasound(TV-US).The

mainoutcomemeasureswereanalysisofthesizeandechographic

patternofdeepinﬁltratinglesionsofendometriosisandevaluation

ofclinicalsymptomsduringpregnancy.

The maximum longitudinal, anteroposterior and transversal

axesoftheimplantsweremeasured.Painfulsymptomswererated

onthebasisofa10-cmvisualanaloguescale(VAS).

ARTICLE INFO

Articlehistory: Received31May2011

Receivedinrevisedform28August2011 Accepted12October2011

Keywords:

Deepinﬁltratingendometriosis(DIE) Ultrasound

Pregnancy

Recto-vaginalendometriosis

ABSTRACT

Background: Deep inﬁltratingendometriosis (DIE) is associated withsevere painful symptoms and representsacomplexmanagementchallenge.

Objective: Toanalysetheeffectofpregnancyondeepinfiltratinglesionsandrelatedsymptomatology. Studydesign:Aspartofalongitudinalstudyperformedoverthepast3yearstodeterminetheefficacyof hormonal treatment in treating women with DIE, we identified three cases of advanced pelvic endometriosis,allwithDIE(deeprecto-vaginalandrecto-sigmoidinvolvement)wherepatientsachieved spontaneouspregnancies.Theywerefollowedupbytransvaginalultrasound(TV-US).Themainoutcome measureswereanalysisofthesizeandechographicpatternofdeepinfiltratinglesionsofendometriosis andevaluationofclinicalsymptomsduringpregnancy.

Results: Weobservedmodiﬁcationsinlesionsizeandpattern.Inthetwopatientsobservedinthethird trimester,thelesionsweremorehomogeneouswithlessevidentlimitsofnodulesandband-likeechoes, lessﬁbrotic-like.Allpatientsshowedcompleteresolutionofsymptomsduringpregnancy.

Conclusions: The hormonal environment produced by pregnancy might determine significant modificationsofendometrioticlesionsandreducepainful symptoms.AssurgeryforDIEisdifficult, complexandcanleadtomajorcomplications,theachievementofapregnancy-specifichormonalstate, throughpregnancyorhormonaltreatment,maybeavalidoptioninselectedcases.

ß2011ElsevierIrelandLtd.Allrightsreserved.

*Correspondingauthor.Tel.:+393356346293;fax:+3905588431171. E-mailaddress:cocciame@tin.it(M.E.Coccia).

ContentslistsavailableatSciVerseScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology

j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / e j ogr b

0301-2115/$–seefrontmatterß2011ElsevierIrelandLtd.Allrightsreserved. doi:10.1016/j.ejogrb.2011.10.004

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3. Results

3.1. Case1

A 33-year-oldCaucasianwoman wasreferredtothe

Gynae-cologicalUltrasoundCentreoftheDepartmentofScienceforthe

Woman and Child’s Health, University of Florence, with a

complaint of severe painful symptomatology (dysmenorrhoea:

VAS 9–10; dyspareunia: Biberoglu & Behrman Scale score 3;

persistent dyschezia) with associated headaches. In her past

medicalhistory shereported appendicectomyat theageof 24.

Fromtheageof14–29shetookestroprogestins.Shesmoked20

cigarettesperdayandherintestinalhabitswereirregular.

Apreviousscanperformed7monthsbeforeinanothercentre

had revealed a hydroureteronephrosis (II–III level) of theright

kidney,and invasion of the lower ureteral junction and

recto-sigmoidbydeependometrioticlesionswassuspected.Aureteral

stenthadbeenplacedintherightureteranda6-monthtreatment

withGnRHagonistswassuggested.

Shecameunderourobservationaftersixmonthsoftreatment

with GnRH agonists reporting only a slight relief of painful

symptomsandshowingadesireforpregnancy.Weperformeda

transvaginal ultrasound (TV-US) and observed an irregular

hypoechoicmassattachedtotherecto-sigmoidwallandspreading

down to therecto-vaginal septum measuring30mm20mm,

withthinband-likeechoesdepartingfromthelesion.Thesevere

pain provoked during the TV-US examination induced the

interruptionoftheTV-USscan.Atrans-abdominalscan showed

regressionofthehydroureteronephrosis.

Onthebasisofherdesireforpregnancywesuggestedthepatient

thediscontinuationofherhormonaltreatment.Endocrine

investi-gationperformedtwomonths latershowed day 3FSH

(follicle-stimulatinghormone),LH(luteinizingstimulatinghormone)and

estradiolof6.7IU/L,4.6IU/L,29pg/ml,respectively.Herpartner’s

semenanalysis was normal.Ultrasound monitoringof follicular

growthduringnaturalcycleswasofferedtooptimisethechanceof

gettingpregnantspontaneouslyineachcycle.Anti-inﬂammatory

treatmentwassuggestedforpelvicpainordysmenorrhea.

Six months after the discontinuation of GnRH agonists, a

spontaneouspregnancyoccurred.ATV-USwasperformedat5+4_,

7+5,14and24+4weeks.Weobservedaprogressivechanginginsize

ofthelesion,increasinginlengthandreducinginthickness(last

scan 36mm9mm). After the end of the ﬁrst trimester the

plaque appeared less ﬁbrotic with ill-deﬁned contours. With

pregnancy,painwaspracticallyabsent.Duetotheriskofpreterm

deliveryand living a longdistanceaway, thepatientcouldnot

attendthesubsequentscansatourCentre.Acaesareansectionwas

performedat36+5_weeks._During_a_scan_performed₅_months_after

delivery,thelesionappearedlongerandthinner,andmoreoverit

dividedintotwoparts(Figs.1and2).

3.2. Case2

A 33-year-old Caucasian woman presented with severe

dysmenorrhoea, dyschezia and hematochezia arising after the

discontinuation of estroprogestins. Her past history included

surgery for left pyeloureteral junction stenosis (renal calculi).

Whenshecametoourattention,herperiodswereregularandshe

hadbeentryingforapregnancyfor4months.Oneyearpreviously

shehadexperiencedabiochemicalpregnancy.

TV-USshowedaleftovarianendometriomaof48mm35mm

and plaque of deep recto-vaginal endometriosis measuring

44mm12mmwithobliterationofrectal-uterinespace.

Colo-noscopy revealed an inﬂammatory pattern of sigmoid-rectal

mucosa.Histologyofabiopsysampledemonstratedanon-speciﬁc

inﬂammation.Abdominalmagneticresonanceimaging(MRI),22

Fig.1.Case1.Length,thicknessandmeandiameterchanges(inmm)duringTV-US follow-up.

Fig.2.(a)Beforepregnancy:medianrecto-vaginal‘IndianHeaddress’;(b)24+4

weeks:longer,thinner,andlessﬁbrotic;(c)5monthsafterdelivery.Thelesion appeareddoubledintotwothinplaqueswithmoreﬁbroticpatterns.

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dayslater,conﬁrmedtheovariancystandaﬁbroticthicknesson

the left side of the rectal-uterine space with a complete

obliterationofthesame.

Atlaparoscopyone monthlater, theleft endometriomawas

completelyexcisedwithastrippingprocedure,andafterextensive

pelvicadhesiolysisdeeprecto-sigmoidandrecto-vaginallesions

wereremovedasmuchas possible,butnot theentirelesionin

ordertoavoid anybowelinjuries.TV-USperformedonemonth

afterthelaparoscopyshowedaresiduallesionintherecto-vaginal

septummeasuring37mm12mm.A pregnancyoccurred two

monthsaftersurgeryandthepatientwasfollowedbyTV-US.

Duringfollow-upﬁrstlyweobservedareductionofthelesion,

thenaslightincreaseinthesizewitha maximumat24weeks.

Thenthelesionsizereduced(Fig.3).Inthis casetoo,thelesion

patternwaslessﬁbroticandthemarginappearedmoreregular.No

painfulsymptomswerecomplainedofthroughoutthepregnancy.

Weobservedthepatientfourmonthsafterdeliveryandfound

thatthedeeprecto-vaginallesionwasthinneranddividedintotwo

plaques.Nopainwasarousedbycompressionwiththeprobeandit

appearedtobereducedinconsistency(Fig.4).

3.3. Case3

A34-year-oldCaucasian womanwasreferred foroutpatient

carewithahistoryofseveredysmenorrhoeaforthelast2yearsand

primaryinfertilityforthelast1.5years.Shehadhadhermenarche

attheageof14.Thereaftershehadirregularmenstrualcycles.In

herpastmedicalhistoryshereportedacystectomyforleftovarian

endometriomaviaalaparotomicapproach,twoyearspreviously.

TV-USrevealed,ontheleftside,aretrocervicallinearthickening

of15mm10mmwithirregularcontourslikean‘Indian head

dress’,continuingwithasupra-cervicalnoduleof15mm18mm

withrectosigmoidinvolvement.Acolonoscopywasperformedand

excluded bowel involvement. On routine infertility evaluation,

bilateraltubalpatencyandnormaluterine cavityby

hysterosal-pingography were observed and male factor infertility was

excluded.Thepatientwasscheduledforaninvitrofertilization

andembryotransfer(IVF-ET)programme.

DuringthewaitingperiodbeforethestartofIVF-ET,anongoing

pregnancywithoutanytreatmentoccurred.TheTV-USrepeatedat

7+4weeksofgestationalagerevealedareductioninthesizeofthe

lesions.Theretrocervical linearthickeningwas12mm7mm,

and thenodule 20mm7mm. Thepatient reported complete

resolutionofsymptomssincetheﬁrstmonthofpregnancy.At14+3

weeksboththelesionsappeareddistended.Probablyduetothe

highlocalization,scans performed duringthe secondand third

trimesterwewereunabletodetectthelesions.

At37weeks,shedeliveredahealthyfemaleinfantbycaesarean

sectionforbreechpresentation.Onemonthafterdeliveryshewas

submitted to a further scan. Two retrocervical plaques were

observed10mm5mmand 15mm7mmand a hypoechoic

nodulemeasured21mm19mm.

4. Comment

Traditionally the treatment of ﬁrst intention for DIE is

considered tobesurgical,andmedicaltreatmentis indicatedin

veryfewcases.Radicalsurgeryfordeependometriosisiscomplex

and oftenrequires amultidisciplinary team approachincluding

inputfromcolorectalsurgeonsandurologists[7].

Eventhoughoperationsareassociatedwithpainrelief,therisk

ofmajorcomplicationsandtherecurrence,orpersistence,rateare

veryhighinthesepatients.

Incasesofsurgeryforrectovaginalendometriosis,theincidence

of rectovaginal ﬁstula formation, anastomotic leakage, and

postoperativeureteralﬁstulaformationisintherangeof2–10%,

1–2%and 0.5–1%, respectively[7]. Whencolorectal resection is

performed,post-operativecomplicationsincludeahigherrateof

functionaldigestiveandurinaryoutcomes[8].Inoneseries,major

complications requiring further surgery occurred in 10.4% of

patients and included: anastomoticleakage (4.7%),rectovaginal

ﬁstula(2.7%),anastomoticﬁstula(2%),perforation(0.5%),bowel

obstruction (0.5%), uroperitoneum (1.5%), ureteral ﬁstula (1%),

bladder ﬁstula (0.5%), pelvic abscess (0.5%), sepsis (0.5%),

hemoperitoneum(2%),heterologousbloodtransfusion(6%),and,

after 30 days, urinary retention (4.7%), constipation (2.6%) and

peripheralsensorydisturbance(1.5%)[9].

These issues can create a conﬂict between the radicality of

excision and the patient’s needs and desires (pregnancy and

relieving painful symptoms). Therefore a major conservative

approach,centredonthepatient’ssymptomsandneedshasbeen

advocatedforendometriosisingeneral,andfordeep

endometri-osisinparticular[8,10].

Fig.3.Case2.Length,thicknessandmeandiameterchanges(inmm)duringTV-US follow-up.

Fig.4.Case2.(a)35+3

weeksofgestation,recto-vaginalendometriosisappearedasa homogeneouslesion,lessﬁbroticappearanceand(b)after deliverythelesion appearedasdividedintotwoplaques.

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TheconceptexpressedbyAboulgharaboutsurgicaltreatment

ofovarianendometriomamightbeextendedtoDIE[11].Surgery

fordeepinﬁltratingendometriosisshouldbeperformedonlyby

highlyexperiencedsurgeonstoreducetheriskofcomplications.

They should avoid too-radical surgery in patients with the

diagnosisofDIEwhodesirepregnancies[11].

Actually,decidualizationwiththeresultantdecreaseinsizeofa

transmural endometriotic nodule may lead to perforation, by

weakeningoftheintestinalwall,mainlyduringthethirdtrimester

[6].Ontheotherhand,transmuralbowelwallinvolvementisnotso

common,theintestinalmucosausuallyremainsintact,and

perfora-tionoftheaffectedintestinaltractisaveryrarecomplication[6].

In our case series we observed spontaneous pregnancies

occurringinthreepatients. DuringTV-USfollow-upwedidnot

observe a worsening in endometriotic lesions. This ﬁnding

conﬁrmsotherpreviouslypublisheddata[5,12].

The effect of surgery for DIE on fertility is controversial.

Vercellinishowedthatexcisionofrectovaginalendometriosisdid

notimprovethelikelihoodofpregnancynorreducethetime to

conception in women with endometriosis-associated infertility

[13].Thereproductiveoutcomeinoperatedpatientsappearedto

be similar to that observed in women undergoing expectant

management,with15pregnanciesamong44women(34.1%)in

womenwhounderwentresectionofrectovaginalendometriosis

bylaparotomycomparedwith22pregnanciesamong61patients

(36.1%) deciding on expectant management. The 12 month

cumulative probability of conception was 20.5% in the former

groupand34.7%inthelatter(p=0.12)[13].

Inallpatientsweobservedthecompleteresolutionofpainful

symptomatologyfromtheﬁrstweeksofpregnancyonwards.As

size changes occurred in different ways in the patients, the

beneﬁcialeffectofpregnancyonpainfulsymptoms,suchasdeep

dyspareunia and rectal tenesmus, may be due not only to a

reductioninthesizeof DIEplaquesand nodulesbut alsomost

probablytoadecreaseintheintra-andperi-lesionalinﬂammatory

condition and to reduced production of prostaglandins and

cytokines [8]. Amenorrhoea and the consequent reduction in

cyclicbleeding atectopicendometrial sitescouldalsoinducea

regressionofactivityoftheendometrioticimplants.

Thedifferentchangesinsizewithtimemightbeexplainedbya

numberoffactors:differentlocationofthelesions,consequentlya

differenteffecton thelesiondue tothevariationof cervixand

uterussizeoccurringinthecourseofpregnancy,mechanismsof

oedemaabsorption,ﬁbrosisretractionanddecidualization.

TV-USallowedfollow-upofthelesionsduringpregnancy.Many

studieshavevalidatedthenon-surgicaldiagnosisofendometriomas

anddeep endometriosisthroughTV-US [14–17]. Theultrasound

patternshowedsimilarmodiﬁcationinallpatients:DIEplaquesand

nodulesappeared less ﬁbroticandmorehomogeneous, with

ill-deﬁnedcontours.Suchcommonchangesmightbedirectlyrelatedto

theeffectofprogesteroneonthelesions.Ithasbeenproventhatthe

actionofprogesteroneonendometrioticimplantscouldbebasedon

a receptor-mediated effect that can reach lesions through the

circulationorthroughdirectdiffusionfromtheproducing organ

[17].During pregnancy,increasing amountsof progesteroneare

produced:atﬁrst,thesourceisthecorpusluteum,andafterthe8th

week,productionofprogesteroneshiftstotheplacenta.Attermthe

placenta produces about 250mg progesterone per day. The

hormonalenvironmentthatcharacterisespregnancymight

deter-mine profound modiﬁcations of the sonographic appearance of

lesions.Thesonographicappearanceofdeeplesionsdependsonthe

degree of ﬁbrosis. Thus, it might be argued that also the

histopathologyofthelesionismodiﬁed.

Thepresentreportconﬁrmedthebeneﬁcialroleofpregnancy

on endometriosis-related symptomatology already reported by

others[18–20].Someevidencesuggeststhatearlypregnancymay

be prophylacticagainst thedevelopment of endometriosisand

could actually cause regression of established lesions. The

mechanisms postulated include production of anovulation and

amenorrhea, decidual change and eventual necrosis induced

withinthelesions[21].

Endometriosisisachronicdisease.Thiscomplexillnessimpacts

patients’livesinwaysthatcannotbequantiﬁedonamedicalchart.

Over the last few decades, new concepts have emerged and

changed classical approaches to endometriosis. The

decision-makingprocesseschangedfroma‘diseasecentred’approachintoa

‘patient-centred’approach.Thisensuresthatallpatientsreceivea

thoroughandcomprehensiveevaluation,treatmentandfollow-up

care taking into consideration their needs, symptoms, and

expectations.

Ourexperiencesupportsthe‘patient-centredcaremodel’.Each

ofourpatientsavoidedthecomplicationofsurgeryandobtaineda

spontaneouspregnancythatﬁnallyresultedinapositiveeffecton

bothsymptomatologyandendometrioticlesions.Previousauthors

have observed the sonographic characteristics of decidualized,

hypervascularizedendometriomasduringpregnancy[22–27]but

thisistheﬁrstreportonultrasoundpatternmodiﬁcationofDIE

occurringduringaspontaneouspregnancy.

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