Premature ovarian insufficiency in eshre/mrcog point of view

1. premature ovarian insuffeciency
on eshre-mrcog backgrounds
by:dr.Ahmed Abdolmotaleb kamal-fertility specialist
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p.o.i :lossof ovarianactivitybefore the age of 40 years.
characterizedbymenstrual disturbance (amenorrheaoroligomenorrhea)withraised
gonadotrophinsandlowestradiol.
prevalence:1%.Populationcharacteristicssuchasethnicitymayaffectthe prevalence
In viewof the long-termhealthconsequencesof POI,effortsshouldbe made toreduce the incidence of
POI.Modifiable factorsmayinclude:1- gynaecological surgical practice
2- lifestyle—smoking 3- modifie treatmentregimensformalignantandchronicdiseases.
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background
as a womanapproachesmenopause,there isagradual cessationof ovarianfunction,leadingto
estrogendeficiencyanda reductioninfertility.Thisisassociatedwitharise ingonadotrophinlevels.The
meanage forthisnatural phenomenonis50 years(standarddeviation 4 years).Whenthe menopause
occurs before the age of 40 years,itisconsideredpremature andisknownaspremature ovarianfailure
(POF).A widelyuseddefinitionof POFis4 monthsof amenorrhoeaandtwofshlevels 30 iu/ml atan
interval of at least1 month(25iu/l accordingtoeshre).
The termpremature ovarianfailure suggeststhatthe state of ovarianfailure isirreversible,whichisnot
strictlytrue.The ovarianfollicularfunctionfluctuatesinabout50% of womenwithPOFand5–10% of
womenwiththe diagnosismayeventuallyconceive,Moreover,the term‘failure’hasanegative
connotationandconveysasense of hopelessnesswhichdoesnothelpwhentryingtocounsel awoman
and herfamilyina sensitivemanner.
Irrespective of aetiology,there are twomainmechanismsof POi:dysfunctionof follicularmaturation
and depletioninthe follicularpool.Inearlyfetal life,the germcells(oogonia) reachtheirmaximum
numberas a resultof rapidmitoticmultiplication,These
oogoniasubsequentlyformthe follicularpool.Thereisacontinuousdeclineinthispool beforeandafter
birth(due to follicularatresia,whichisaprocessof supposedlyfolliculardegradation) andbythe time of
pubertyonly0.5 millionare present.

2. ----------------------------------------------------------------------------------------------------------------
Diagnosis
---Cliniciansshouldenquireaboutsymptomsof estrogendeficiencyinwomenpresentingwith
oligomenorrheaoramenorrhea.
---POIneedstobe excludedinwomenwithamenorrhea/oligomenorrheaorestrogen-deficiency
symptomsbelowthe age of 40 years.
---The diagnosisPOIisbasedonthe presence of menstrualdisturbance andbiochemical confirmation.
---AlthoughproperdiagnosticaccuracyinPOI islacking,the GDG recommendsthe followingdiagnostic
criteria:(i) oligo/amenorrheaforatleast4 months,and (ii) anelevatedFSHlevel .25IU/l on two
occasions.4 weeksapart.
so diagnosisinclude a.diagnosisof condition.
b.diagnosisof sequlae.
c.implicationsonrelatives.
licitationof adetailedhistorywouldsuggestthe diagnosisof POFbyexcludingothercommoncausesof
amenorrhoea.These include pregnancy,hypothalamic amenorrhoea(causedbyanorexianervosa,
exercise,stressandweightloss),hyperprolactinaemia(symptomsinclude headachesandgalactorrhoea)
and polycysticovarysyndrome (symptomsincludehirsutismandacne).A historyof chemotherapy,
radiotherapyorpelvicsurgeryinthe pastisclearlyrelevant.A historyof obstetriccatastrophe,severe
bleeding,dilatationandcurettage orinfectionindicatesauterine cause (Ashermansyndrome).A history
pertinenttoautoimmune disorders,includinghypothyroidismor adrenal insufficiency,shouldalsobe
elicited.A familyhistoryof POFcan be recordedin14–31% of cases2,20 anda definitefamilialdisorder
can be identifiedinsome of these.Perraultsyndrome(XXgonadal dysgenesiswithsensorineural
deafness),FSHreceptormutationsandfragile Xpremutationsare relativelymore commonamong
womenwithafamilial historyof POF.A physical examination,includingheight,weightandbodymass
index,isessential andthe recognitionof anydysmorphicfeaturessuggestinga chromosomal orgenetic
cause of POFis important.Breastexaminationisindicatedif there isanyevidence of galactorrhoea.The
skinshouldbe examinedforhirsutism,acne,striae,acanthosisnigransandvitiligo.
Once the diagnosisof POFisconfirmed,second-lineinvestigations canbe considered:•Karyotypingand
FMR-1 premutationanalysisare useful.
• Screeningforautoimmunediseases(anti-adrenal,anti-21-hydroxylase,anti-thyroid
peroxidase andanti-thyroglobulinantibodies) is indicated.Ovarianantibodyscreeningisalso
recommended,asmanyovarianantigenshave the potential forantibodyformation.Besides

3. providingaclearexplanationforthe womanasto the cause of herPOF,thismay helpidentifythose at
highriskfor otherautoimmune conditions.
• Anti-Müllerianhormone (AMH) estimationcanbe done to assessovarianreserve.
• Ovarianbiopsyhasbeenperformedbutitsclinical significance isuncertain,aspregnancy
has beenreportedevenwhenaspecimenhasshownanabsence of follicles.
• A dual-emissionX-rayabsorptiometry(DEXA) scanshouldbe consideredforbaseline
assessment,aswomenwithPOFhave ariskof almost50% for osteopenia.
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causes
The cause of POi is largelyunknown:inthe largestclinical series,adefinitiveaetiologywasidentified
among(11.8%) of women.
a.idiopathic;majorityof cases.
b.Xchromosome abnormalities
• Turner/Turnersyndrome-like karyotype.
inTurnersyndrome there isacceleratedatresiaof the primordialfolliclesduringlaterfetal
life.Consequentlythe ovarianfollicle pool isdepletedbythe time of pubertyamongthose withthe 45
XO genotype andtheypresentwithprimaryamenorrhoea.10Amongthose withamosaicgenotype such
as 45XO/46XX (whenthe X chromosome ismissinginsome cellsbutnotinothers),the rate of atresia,
althoughaccelerated,isrelativelyslowerandthese womenpresentwithsecondaryamenorrhoea.
• FMR-1 premutation(Xq27.3)
prevalence of POFis13–26%.
unlike the classical fragile Xsyndrome,where the FMR-1gene contains>200 repeatsof the
CGG codon,inpremutationthe individual isphenotypicallynormal andthere are 55–200
repeats.The mechanismsbywhichFMR-1premutationcausesPOFare not clearly
understood.One hypothesisisthatthe increase inFMR-1 transcriptionresultsinexcessRNA
proteinclusters,causingprematuredegradationof ovarianfollicles.
• Bone morphogeneticprotein
• OtherXchromosome abnormalities(deletion,translocation,others)

4. 46XY gonadal dysgenesis
c.Autosomal causes
• FSH receptormutation
• Blepharophimosisptosisepicanthusinversussyndrome
d.Iatrogeniccauses
• Chemotherapy/radiotherapy
e.Autoimmune cause
Premature ovarianfailure isalsofrequentlyassociatedwithautoimmunedisorders,including
hypothyroidism(13.8%),insulindependentdiabetesmellitus(1.7%) andantibodies,includingparietal
cell antibodies(3.7%)andthe acetylcholine esteraseantibodiesseeninmyastheniagravis(2.7%).
N.Brare causesin additionincludetrisomyX,luteinisinghormone receptormutations,Perrault
syndrome,galactosaemia,surgicalinjuriesorextirpationandviral infections.
---Chromosomalanalysisshouldbe performedinall womenwithnon-iatrogenicPOI.
---Gonadectomyshouldbe recommendedforall womenwithdetectable Ychromosomal material.
---Fragile-XpremutationtestingisindicatedinPOIwomen.
---The implications of the fragile-Xpremutationshouldbe discussedbefore the testisperformed.
---Autosomalgenetictestingisnotat presentindicatedinwomenwithPOI,unlessthereisevidence
suggestingaspecificmutation(e.g.BPES:blepharophimosis–ptosis–epicanthusinversussyndrome).
---Screeningfor21OH-Ab(oralternativelyadrenocortical antibodies(ACA))shouldbe consideredin
womenwithPOIof unknowncause orif an immune disorderissuspected.
Screeningfor21OH-Ab(or alternativelyadrenocortical antibodies
(ACA)) shouldbe consideredinwomenwithPOIof unknowncause orif animmune disorderis
suspectedReferPOIpatientswithapositive 21OH-Ab/ACA testtoanendocrinologistfortestingof
adrenal functionandtorule out Addison’sdisease.
---Screeningforthyroid(TPO-Ab) antibodiesshouldbe performedinwomenwithPOIof unknowncause
or if an immune disorderissuspected.
In patientswithapositive TPO-Abtest,thyroidstimulatinghormone(TSH) shouldbe measuredevery
year.

5. ---There isinsufficient evidence torecommendroutinelyscreeningPOIwomenfordiabetes.
---There isnoindicationforinfectionscreeninginwomenwithPOI.
---The possibilityof POIbeingaconsequenceof amedical orsurgical interventionshouldbe discussed
withwomenaspart of the consentingprocessforthattreatment.
---Althoughnocausal relationhasbeenprovedforcigarette smokingandPOI,there isarelationtoearly
menopause.Therefore,womenwhoare prone toPOI shouldbe advisedtostopsmoking.
---If 21OH-Ab/ACA andTPO-Abare negative inwomenwithPOI,there isnoindicationforre-testinglater
inlife,unlesssignsorsymptomsof these endocrinediseasesdevelop.
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implications for relatives
---Relativesof womenwiththe fragile-Xpremutationshouldbe offeredgeneticcounsellingandtesting.
---Relativesof womenwithnon-iatrogenicPOIwhoare concernedabouttheirriskfordevelopingPOI
shouldbe informedthat:(i) currentlythere isnoprovedpredictivetesttoidentifywomenthatwill
developPOI,unlessamutationknowntobe relatedtoPOIwasdetected,(ii) there are noestablishedPOI
preventingmeasures,(iii) fertilitypreservationappearsasa promisingoption,althoughstudiesare
lacking (iv) theirpotential riskof earliermenopauseshouldbe takenintoaccountwhenplanninga
family.
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Sequelae
---lifeexpectancy
UntreatedPOIisassociatedwithreducedlifeexpectancy,largelydue tocardiovasculardisease.
---fertility
WomenwithPOIshouldbe informedthatthere isasmall chance of spontaneouspregnancy.(5-10%).
WomenwithPOIshouldbe advisedtouse contraceptionif theywishtoavoidpregnancy.
there are no interventionsthathave beenreliablyshowntoincrease ovarianactivityandnatural
conceptionrates.
InwomenwithestablishedPOI,the opportunityforfertilitypreservationismissed.

6. or those whoactivelydesire parenthood,the optionsinclude eitheradoptionorachievinga
pregnancybyoocyte or embryodonation.Inoocyte donationitisnecessarytoprepare the
endometriumforimplantation.Thiscanbe successfullyachievedbyincremental dosesof
estradiol valerate,from2–6 mg overa 2-weekperiod,andthenprogesterone therapy,whichisusually
startedas pessaries,400 mg twice daily.Thiscreatesanendometriumreceptivetoembryoimplantation.
Anothertreatmentoptionthatprovidessome hope forwomenwithPOFisestrogensuppression
followedbyexogenousgonadotrophins.41Women
withPOFhave chronicallyhighgonadotrophinlevelswhichdownregulate FSHreceptorson
granulosacells,sothatthe remainingfolliclesbecome refractorytoexogenousstimulation.
PretreatmentwithestrogenssuppressesFSHserumlevelsandallowsthe restorationof FSH
receptorsinthe remainingfollicles.Whenthispretreatmentwasfollowedbyexogenous
gonadotrophinstimulation,ovulationoccurredin32% of casesand,among these,pregnancywas
achievedin50%.
---obstetricrisks
Womenshouldbe reassuredthatspontaneouspregnanciesafteridiopathicPOIormost formsof
chemotherapydonotshowany higherobstetricorneonatal riskthaninthe general population.
Oocyte donationpregnanciesare highriskandshouldbe managedinan appropriate obstetric
unit.Womenandtheirpartners shouldbe encouragedtodisclose the originof theirpregnancywiththeir
obstetricteam.
Antenatal aneuploidyscreeningshouldbe basedonthe age of the oocyte donor.
Pregnanciesinwomenwhohavereceivedradiationtothe uterusare at highriskof obstetric
complicationsandshouldbe managedinanappropriate obstetricunit.
PregnanciesinwomenwithTurnerSyndromeare atveryhighriskof obstetricandnon-obstetric
complicationsandshouldbe managedinanappropriate obstetricunitwithcardiologist involvement.
A cardiologistshouldbe involvedincare of pregnantwomenwhohave receivedanthracyclinesand/or
cardiac irradiation.
---fitnessforpregnancy
Womenpresentingforoocyte donationwhoare suspectedof havingPOIshouldbe fullyinvestigated
priorto oocyte donation,includingthyroidandadrenal functionaswell askaryotype.

7. Womenpreviouslyexposedtoanthracyclines,high-dose cyclophosphamide ormediastinalirradiation
shouldhave anechocardiogrampriorto pregnancy,andreferral toa cardiologistif indicated.
WomenwithTurnerSyndrome shouldbe assessedbyacardiologistwithaspecialistinterestinadult
congenital heartdiseaseandshouldhave ageneral medical andendocrineexamination.
WomenwithPOIshouldhave theirbloodpressure,renal functionandthyroidfunctionassessedpriorto
pregnancy.
Pregnancyinsome womencanbe of such highriskthat cliniciansmayconsideroocyte donationtobe
life threateningandtherefore inappropriate.
---bone health
POIis associatedwithreducedbone mineral density(BMD)
ReducedBMD is verylikelytoindicatethatPOIisassociatedwithanincreasedriskof fracture laterin
life,althoughthishasnotbeenadequatelydemonstrated.
treatmentoptionsforbone protectionandimprovement:
Womenshouldmaintainahealthylifestyle,involvingweight-bearingexercise,avoidance of smoking,
and maintenance of normal bodyweighttooptimize bonehealth.
A balanceddietwill containthe recommendedintake of calciumandvitaminD.Dietary
supplementationmaybe requiredinwomenwithinadequate vitaminDstatusand/orcalciumintake,
and maybe of value inwomenwithlowBMD.
Estrogenreplacementisrecommendedtomaintainbone healthandpreventosteoporosis;itisplausible
that itwill reduce the riskof fracture,till age of natural menooause.
The combinedoral contraceptive pillmaybe appropriate forsome womenbuteffectsonBMD are less
favourable.
Otherpharmacological treatments,includingbisphosphonates,shouldonlybe consideredwithadvice
froman osteoporosisspecialist.Particularcautionappliestowomendesiringpregnancy.
howbone healthtobe monitored
MeasurementofBMDatinitial diagnosisof POIshouldbe consideredforall women,butespeciallywhen
there are additional riskfactors.
If BMD is normal and adequate systemicestrogenreplacementiscommenced,the valueof repeated
DEXA scan islow.
If a diagnosisof osteoporosisismade andestrogenreplacementorothertherapyinitiated,BMD
measurementshouldbe repeatedwithin5years.A decrease inBMDshouldpromptreview of estrogen

8. replacementtherapyandof otherpotentialfactors.Review byaspecialistinosteoporosismaybe
appropriate.
---cardiovascularsystem
WomenwithPOIare at increasedriskof cardiovasculardiseaseandshouldbe advisedof riskfactors
that theycan modifythroughbehavioural change (e.g.stoppingsmoking,takingregularweight-bearing
exercise,healthyweight).
All womendiagnosedwithTurnerSyndrome shouldbe evaluatedbya cardiologistwithexpertisein
congenital heartdisease.
estrogenreplacementcardio-protective?
Despite lackof longitudinal outcome data,hormone replacementtherapy(HRT) with earlyinitiationis
stronglyrecommendedinwomen withPOItocontrol future riskof cardiovasculardisease;itshouldbe
continuedatleastuntil the average age of natural menopause
cardiovascularriskfactors monitoring
Cardiovascularriskshouldbe assessedinwomendiagnosedwithPOI.Atleast bloodpressure,weight
and smoking status shouldbe monitored annuallywithotherriskfactorsbeingassessedif indicated.
In womenwith TurnerSyndrome,cardiovascularriskfactorsshouldbe assessedatdiagnosisand
annually monitored(atleast bloodpressure,smoking,weight,lipidprofile,fastingplasmaglucose,
HbA1c).
---psychological wellbeingandqualityof life
A diagnosisof POIhasa significantnegative impactonpsychological wellbeingandqualityof life.
Psychological andlifestyleinterventionsshouldbe accessibletowomenwithPOI.
---sexuality
Routinelyinquire aboutsexual wellbeingandsexual functioninwomenwithPOI.
Adequate estrogenreplacementisregardedasa startingpointfornormalizingsexual function.Local
estrogenmay be requiredto treat dyspareunia.
WomenwithPOIshouldreceive adequate counsellingaboutthe possibilityof usingtestosterone
supplementationsothattheycan make an informedchoice,inthe knowledgethatlong-termefficacy
and safety are unknown.
---genito-urinarysymptoms
Local estrogensare effective intreatmentof genito-urinarysymptoms.

9. Cliniciansshouldbe aware thatdespite seeminglyadequate systemicHRT,womenwithPOImay
experience genito-urinarysymptoms.Local estrogensmay be giveninadditiontosystemicHRT.
Lubricants are useful fortreatmentof vaginal discomfortanddyspareuniaforwomennotusingHRT.
---neurological function
The possible detrimentaleffectoncognitionshouldbe discussedwhenplanninghysterectomy and/or
oophorectomyunderthe age of 50 years,especiallyforprophylacticreasons.
Estrogenreplacementtoreduce the possible riskof cognitive impairmentshouldbe consideredin
womenwithPOIat leastuntil the average age of natural menopause.
WomenwithPOIshouldbe advisedtotake lifestylemeasures(e.g.exercise,cessationof smoking,
maintainingahealthyweight) toreduce possible risksforcognitive impairment.
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Treatment
HRT
HRT isindicatedforthe treatmentof symptomsof low estrogeninwomenwithPOI.
Womenshouldbe advisedthatHRT mayhave a role inprimarypreventionof diseasesof the
cardiovascularsystemandforbone protection.
WomenwithPOIshouldbe informedthatHRThas not beenfound toincrease the risk of breast cancer
before the age of natural menopause.
Progestogenshouldbe givenincombinationwithestrogentherapytoprotectthe endometriumin
womenwithanintact uterus.
17-bestradiol is preferredtoethinylestradiol orconjugatedequine estrogensforestrogenreplacement.
Womenshouldbe informedthatwhilstthere maybe advantagestomicronizednatural progesterone,
the strongestevidenceof endometrial protectionisfororal cyclical combinedtreatment.
Patientpreference forroute andmethodof administrationof eachcomponentof HRTmust be
consideredwhenprescribing,asshouldcontraceptive needs.
Once establishedontherapy,womenwithPOIusingHRTshouldhave a clinical reviewannually,paying
particularattentiontocompliance.
No routine monitoringtestsare requiredbutmaybe promptedbyspecificsymptomsorconcerns.
androgens

10. Womenshouldbe informedthatandrogentreatmentisonlysupportedbylimiteddata,andthat long-
term healtheffectsare not clear yet.
If androgentherapyiscommenced,treatmenteffectshould be evaluatedafter3–6 months and should
possiblybe limitedto 24 months.
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HRT inWomenwithTurnerSyndrome
Girlsand womenwithPOIdue toTurner Syndrome shouldbe offeredHRTthroughoutthe normal
reproductive lifespan.
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BRCA gene mutationorafterbreastcancer
HRT isgenerallycontra-indicatedinbreastcancersurvivors.
HRT isa treatmentoptionforwomencarryingBRCA1/2 mutationsbutwithoutpersonal historyof
breastcancer afterprophylacticbilateral salpingo-oophorectomy.
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POIand endometriosis
For womenwithendometriosiswhorequiredoophorectomy,combinedestrogen/progestogentherapy
can be effective forthe treatmentof vasomotorsymptomsandmayreduce the riskof disease
reactivation.
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POIand migraine
Migraine shouldnotbe seenasa contraindicationtoHRTuse bywomenwithPOI.
Considerationshouldbe giventochangingdose,route of administrationorregimenif migraine worsens
duringHRT.
Transdermal deliverymaybe the lowest-riskroute of administrationof estrogenformigraine sufferers
withaura.
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POIand hypertension
Hypertensionshouldnotbe consideredacontraindicationtoHRTuse by womenwithPOI.
In hypertensivewomenwithPOI,transdermal estradiolisthe preferredmethodof delivery.

11. --------------------------------------------------
POIand a historyof priorvenousthromboembolism
WomenwithPOIand a historyof prior VTEor thrombophilicdisordershouldbe referredtoa
haematologistpriortocommencingHRT
Transdermal estradiol isthe preferredroute of deliveryforwomenwithPOIatincreasedriskof VTE.
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POIand obesity
Transdermal estradiol isthe preferredmethodof deliveryforwomenwithPOIrequiringHRTwhoare
obese oroverweight.
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POIand fibroid
Fibroidsare nota contraindicationtoHRTuse by womenwithPOI
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Puberty induction
Puberty should be induced or progressed with 17-estradiol,b starting with a low dose at the age of 12
years with a gradual increase over 2–3 years
In cases of late diagnosis and for those girls in whom growth is not a concern, a modified regimen of
estradiol can be considered
Evidence for the optimum mode of administration (oral or transdermal) is inconclusive. Transdermal
estradiol results in more physiological estrogen levels and is therefore preferred
The oral contraceptive pill is contra-indicated for puberty induction
Begin cyclical progestogens after at least 2 years of estrogen or when breakthrough bleeding occurs