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Thischaptershouldbecitedasfollows:
Davis,J,Segars,J,Glob.libr.women'smed.,
(ISSN:17562228)2009DOI10.3843/GLOWM.10296

Thischapterwaslastupdated:
May2009

MenstruationandMenstrualDisorders:Anovulation
JosephB.Davis,DO
AkronGeneralMedicalCenter,Akron,Ohio,USA
JamesHSegars,MD
ReproductiveBiologyandMedicalBranch,EuniceKennedyShriver,NationalInstituteofChildHealthandHumanDevelopment,NationalInstitutesof
Health,Bethesda,Maryland,USA
INTRODUCTION
ETIOLOGY
DIAGNOSISANDTREATMENT
REFERENCES

INTRODUCTION

Anovulationisthefailureoftheovarytoreleaseovaoveraperiodoftimegenerallyexceeding3months.Thenormal
functioningovaryreleasesoneovumevery2528days.Thisaveragetimebetweenovulationeventsisvariable,especially
duringpubertyandtheperimenopauseperiod.1 Fornonpregnantwomenaged1640anovulationisconsideredabnormaland
acauseofinfertilityin30%offertilitypatients.2
Oneofthecardinalsignsofanovulationisirregularorabsentmenstrualperiods.Oligomenorrheaisdefinedasmorethan36
daysbetweenmenstrualcyclesorfewerthaneightcyclesperyear.3 Intheabsenceofpregnancy,menstruationfollows
ovulationbyapproximately14days.Becausemenstruationislinkedtoovulation,theclinicalfindingofoligomenorrhea
correlateswitholigoovulation.Thispredictablepatternofovulationandmenstruationisregulatedbyacyclicchangein
hormones.Consequently,thediagnosisofovulationdysfunctionincludestheassessmentofthehormonesandsystemsinvolved
inovulationandnotjustthesymptomofamenorrhea.
Thischapterincludesabasicreviewoftheprocessofovulationandtheprimarymechanismsofanovulation.Anovulationis
coveredusingasystemsapproach.Thisapproachincludeshypothalamicandbrain,pituitary,ovarian,andsystemicbased
anovulation.Eachsystemreviewincludesdiagnosisandtreatmentoptions.

Theprocessofovulation
Tounderstandanovulation,onemustfirstunderstandovulation.Ovulationinvolvesaprogressionofcellularchangesin
folliclesthatoccurfromfetallifeuntilmenopause.4 Atanygiventimeintheovaryfolliclesareatdifferentstagesofmaturity.
Primordialfolliclesprogresstoimmaturefolliclesandacquiredhormoneresponsivenessbyaprocessthatremainsunclear.5 ,6
Thesesmallimmaturefollicles,calledrestingfolliclesorantralfollicles,areacteduponbyseveralhormonestoeitherprogress
toagrowthphaseorregressbyatresia.4 Granulosaandthecacellsofthefolliclemakeupthetwocellsystemthatisresponsible
forfolliculargrowth.5 Gonadotropinhormonesfromthepituitaryeffectastructuralchangeinthesecellsthatcausesthe
folliclestoenlarge.Thenumberofgranulosacellsandthecacellswithineachfollicleincreasesandafollicularfluidcontaining
hormoneproductsisaccumulatedinthefollicleasitprogressesthroughthegrowthphase.
Folliclestimulatinghormone(FSH)istheprimarygonadotropinresponsibleforthisprogression.4 Asthefolliclesenlarge,FSH
stimulatestheproductionofmoreFSHreceptorsonthegranulosacells.Thisallowsthefollicletobecomemoresensitiveto
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FSHandgrowmorerapidly.Thelargerfolliclesrecruitmorethecacells,whichproduceandrostenedione.Thisandrogenpasses
throughthebasementmembraneandisconvertedtoestradiolbyFSHdrivenaromatizationintheincreasingnumberof
granulosacells.7 Oncethefolliclebecomeslargeenough,cellgrowthslowsandthecellularenergyresourcesareusedalmost
exclusivelytoproducethesesteroids.TheincreasingamountofestradiolproducedinturninhibitsthereleaseofFSHfromthe
pituitary.WithoutFSH,thesmallerfolliclesthatcontainfewerFSHreceptorsarenolongerstimulatedtogrowandinstead
regress,leavingthedominantfollicleforovulation.
FolliculardevelopmentisdrivenbyFSH,butlutenizinghormone(LH)isresponsibleforovulation.FSHactsonthecacellsto
induceLHreceptorexpressionandrenderthecellssensitivetoLH.4 LHalsostimulatesthethecacellstoproduce
androstenedione,whichisconvertedtoestradiolbygranulosacellsasdescribedabove.Theestradiolproducedfurther
stimulatesLHreleasefromthepituitary.WhenacriticallevelofLHisreached,ovulationoccursandthefolliclerapidly
changestoacorpusluteum.Progesterone,producedbythecorpusluteum,increasesfollowingovulationandinhibitsLH
secretionbyaneffectonthehypothalamus.8 Withoutfertilizationoftheova,thecorpusluteumregresses,progesteroneand
estradiollevelsdrop,andFSHisagainreleasedtopromotedevelopmentofanewdominantfollicle.4
Thegonadotropinsresponsibleforthisseriesofevents(FSHandLH)arereleasedfromthepituitaryandaredirectlyregulated
bygonadotropinreleasinghormone(GnRH).8 GnRHissecretedinapulsatilepatternthatbecomesregularaswomenprogress
throughpuberty.ThisregularpatternisessentialforproperproductionandreleaseofLHandFSH.Severalconditionsof
anovulationmimictheirregularGnRHpulsepatternseeninprepubescentgirlsfurtherdemonstratingtheimportanceofthe
cyclicreleaseofGnRHinnormalovulation.Estradiolandprogesterone,whichareproducedasthedominantfollicledevelops,
furtherregulatethereleaseofGnRH.ThehormonefeedbackandregulationofGnRHismediatedbycatecholaminesand
endogenousopioids.9 ,10
Inadditiontothesystemicgonadotropins,follicledevelopmentisalsoregulatedbylocalhormones.7 Activinandinhibinare
producedinthegranulosacellsinresponsetoFSHstimulation.ActivinaugmentstheFSHeffectsongranulosacellsand
suppressesandrogensynthesis,allowingforfolliclegrowth.Inhibinisproducedasthefollicledevelopsandenhancesandrogen
synthesisinthecacells.11 Theincreasedandrostenedioneisthesubstrateforestradiolproduction.Thecacellsalsorespondto
insulinlikegrowthfactorIIthatfurtheraugmentsLHaction.7
Anovulationcanresultfromdisruptionofthisseriesofeventsanywherealongthepathway.4 Severalexternalfactorssuchas
stressandnutritionalsocauseanovulationbyaffectingthehypothalamusandthecentralnervoussystem.Disruptionatthe
levelofthepituitarycausesreducedgonadotropinsecretion.Polycysticovarysyndromecanbeconsideredaphysiologicstateof
anovulationthatmaybecausedbydisorderinoneormoreorgansystems.Systemicdiseasehasbeenshowntoaffectovulation
aswell.Thischapterreviewsthecausesofanovulationandhowtotreatthiscommonproblem.

ETIOLOGY
Anovulationcanresultfromdisruptionatanylevelinthehypothalamicpituitaryovarian(HPO)axis.Consequently,
categorizingthedifferentmechanismsofanovulationlogicallyfollowsasystemsapproach.Asystemsapproachbreaksdown
thecausesofanovulationintofourcategories:
Hypothalamicandbrain
Pituitary
Ovarian
Systemic

Itisimportanttorememberthatanovulationisaffectedbythehealthoftheentirepatient,therefore,somedisorderscan
involvemultiplelevelsoftheHPOaxis.

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Anovulationduetodisorderofthehypothalamusandbrain
ThehypothalamiccausesofanovulationresultfromdecreasedordysfunctionalproductionofGnRH.Pharmacologicalstudies
haveshownGnRHreleaseisregulateddirectlyandindirectlybyendogenousopioids,catecholamines,anddopamine.9
DopaminestimulatesthereleaseofGnRH,whereasendogenousopioidsblockdopamineandconsequentlydecreaseGnRH.In
patientswithconditionsofelevatedendogenousopioids,treatmentwithnaloxoneblocksopioidreceptorsandresultsina
returnofLHlevelstonormal.10
Corticotropinreleasinghormone(CRH)isproducedbythehypothalamusandblocksGnRHrelease.CRHisalsoproducedin
theamygdala.12 ThecentralnucleusoftheamygdalamediatesfearandanxietybyCRHproducingneurons.Theseneurons
projecttoseverallimbicstructuresandhavebeenshowntodecreaseserotoninandincreasebetaendorphinproduction
therebydecreasingGnRHrelease.Highlevelsofcortisolfromtheadrenalglandshavealsobeenassociatedwithhighlevelsof
CRHimplicatingstressinanovulation.13
STRESSINDUCEDANOVULATION
Stresshasbeendefinedasastateofthreatenedhomeostasis.14 Thestresssystemisthemechanismbywhichthebodytriesto
maintainhomeostasis.Stressincludesphysical,emotional,andnutritionalchanges.Reproductivestatusmirrorsthe
physiologicstateandtheexternalenvironment.15 Whenstressissignificantreproductivefunctiondecreasesinaneffortto
maintainhomeostasis.16 Stresshasalsobeenshowntodecreasepregnancyratesandincreasemiscarriagerates.17

Thestresssystemiscomprisedofthehypothalamicpituitaryadrenal(HPA)axis,arousal,andtheautonomicsystem.18 The
mainchemicalmediatorsofstressincludeCRH,glucocorticoids,andbetaendorphins.CRHhasreceptorsinmanydifferent
tissuesincludingovary,endothelium,hypothalamus,andinflammatorytissues.Producedinthehypothalamus,CRHand
argininevasopressinstimulateadrenocorticotropichormone(ACTH)productioninthepituitary.Thisincreasescortisol
productionintheadrenalglands.CortisolisaglucocorticoidthatactsonmultiplebodysystemsandreducesLH,estradiol,and
progesteroneeffects.ManyoftheeffectsofglucocorticoidsandCRHinastressresponseinvolvesystematicallyinhibitingT
helper(Th1)proinflammatoryresponsesandinductionofaTh2shift.14
BetaendorphinsaresecretedfromnerveterminalsinresponsetoCRHandproducetheinitialeuphoriaofacutestress,
necessaryforsurvival.14 Dopaminehasalsobeenshowntoincreaseduringstressinapatterncorrelatingtocortisollevels.19
EstrogenhasadirecteffectonCRHreleaseinstressandpromotesCRHsynthesis.20 ElevatedlevelsofCRHandcortisol
suppressGnRHsecretionandconsequentlydecreaseovulation.15 Stressisacommonprobleminpatientsundergoingfertility
workupandtreatment.Techniquesarecurrentlybeingstudiedtoreducestressincludingacupuncture,yoga,and
meditation.21
FUNCTIONALHYPOTHALAMICAMENORRHEA
Functionalhypothalamicamenorrhea(FHA)isdefinedascessationofmensesandovulationwithoutanidentifiableorganic
cause.22 Examplesoforganiccausesofanovulationincludeclinicaleatingdisordersandsignificantweight.23 FHAthereforeisa
diagnosisofexclusionwithareportedincidenceof1535%.22 Asfurtherunderstandingofanovulationdevelops,thenumberof
patientsdiagnosedasFHAdecreases.
AnovulationinFHAresultsfromadecreaseinGnRHreleaseandconsequentlydecreasedgonadotropinrelease.Suchpatients
alsofailtomenstruateaftertreatmentwithprogesteronedemonstratinglowestrogenlevelscorrelatingtochroniclackof
gonadotropinstimulation.24 Slightlyincreasedcortisollevelsaretypicalwithlowtonormalgonadotropins.Suchpatientsdo
respondtopulsatileGnRHtreatmentfurtheridentifyingthehypothalamusasthemaincauseforanovulation.LHpulse
frequencyisreducedandtheintervalbetweenpulsesisprolonged.25

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OnehypothesisforFHAisasynergisticmetabolicandpsychosocialdysfunctionsimilartoastateofchronicstress.22 FHA
patientshavebeenreportedtohaveahigherlikelihoodofmooddisorders,increasedamountofexercise,mildweightloss,and
dietswithlowerfatcontent,increasedfiber,andincreasedcarbohydrates.22 ,23 Personalitytraitsincludeperfectionism,lowself
esteem,andpoorstressmanagementability.23
AnotherevolvingtheoryisthatFHAisaspectrumofreducedgonadotropinsecretionduetovariableexpressionofagenetic
formofanovulation.26 Thishasbeenseeninmaleswhoshowreversiblehypothalamichypogonadismandanidentifiable
geneticmutation(seebelow).27 Atthepresenttime,similargeneshavenotbeenidentifiedinwomen.Thisconditionrepresents
astateofGnRHresistancesimilartoinsulinresistance.Duetothelowestrogenandelevatedcortisollevels,patientswithFHA
areatincreasedriskofbonelossandsystemicdisease.22 Treatmentshouldinvolvenutritionalandpsychologicalcounseling,
however,thisformofanovulationoftenresolvesspontaneously.
PSYCHOGENICTRAUMAANDSTRESS
Studieshaveshowntheimpactofexternalfactorsintheenvironmentonmenstruationandconsequentlyovulation.13 ,28 ,29
Menstrualcyclesincollegewomenlivingtogetherwillbegintosynchronize.28 Thesesamewomenwillhavelongercycleswhen
spendingincreasingtimewithmalestudents.Thesechangesarelikelytheresultofpheromonesinfluencingthehypothalamus.
Furtherstudiesnotetheinfluenceofpsychologicalstateonmenstruation.Inpatientswithclinicaldepression,cortisollevels
werefoundtobesignificantlyelevated.29 Otherhormonesincludingprolactin,gonadotropins,andestrogenareallnormalin
patientswithpsychologicaldistress.WhengivenexogenousGnRH,thesepatientshaveanormalreleaseofLHandFSH
suggestingasuppressionofGnRHasthecauseofanovulationassociatedwithdepression.
ANOREXIANERVOSA
Anorexianervosaisaneatingdisorderstemmingfromadisorderedbodyimageresultinginmalnutritionandsevereweight
loss.30 ThediagnosticcriteriaincludesamenorrheaimplyingafunctionalabnormalityoftheHPOaxis.31 Theprevalenceis
reportedtobe0.51%inadolescents.Complicationsofanorexianervosaincludeamortalityrateof210%mostoftendueto
suicideandsevereelectrolytedisturbance.Bonedensitylossoccursasaresultoflowestrogenlevels.31 ,32 Anorexiadiffersfrom
otherformsofpsychogenicanovulation.Theovulatoryfailureinanorexiaisduetometabolicchangesthatoccurwithweight
loss,whiletheunderlyingproblemispsychological.

Gonadotropinlevelsarereducedinanorexia,asareleptinandestradiol.32 Thishypoestrogenicstateresultsinathin
endometrialliningthatdoesnotshedafterprogesteronetreatment.Leptinlevels,whichcorrelatewithbodyfatandnutrition
status,havebeenfoundtoplayaroleinovulationandarediscussedlaterinthischapter.33 Triiodothyronine(T3)isdecreased
andreverseT3iselevated,resultinginhypothyroidsymptomsincludingdryskinandbradycardia.32 Growthhormoneisalso
increasedduetoperiodsofstarvation.

Severalfindingsindicatethatanovulationassociatedwithanorexiaarisesatthelevelofthehypothalamus.30 ,32 ,34 Thepulse

frequencyofgonadotropinreleaseissimilartothepulsefrequencyseeninchildhood.30 Starvationhasbeenshowntodecrease
GnRHreleaseandsubsequentlydecreasegonadotropins.WhenexogenousGnRHisadministeredinaphysiologicpatternthe
gonadotropinpulsefrequencynormalizesandovulationoccurs.34 LevelsofCRHarealsoelevated,correlatingwithelevated
cortisolandsuppressionofGnRHrelease.32 ,35
Anovulationwithanorexiaandhypothalamicsuppressionisnotonlyduetolowbodyfat.Nutritionalstatusandphysical
activityplayakeyroleinovulationandtreatment.Amenorrheawasnotedtooccurwhenweightdroppedbelow90%ofideal
bodyweight,independentofbodyfatpercentage.36 Inpatientswhogainappropriateamountsofweight,someremain
anovulatoryandshowdecreasedgonadotropinlevels.Anovulatoryanorexicswhoweighedthesameasovulatinganorexics
werefoundtohavehigherlevelsofphysicalactivity.35 Lowlevelsofleptinarealsofoundinpatientswhohavepooreating
habitswhencontrollingforweight.33 Asaresult,treatmentrequiresnutritionalimprovement,weightgain,andpsychiatric
care.Thissyndromeisseriousandcarriesmortalconsequences.
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BULIMIANERVOSA
Bulimianervosaisanothereatingdisorderassociatedwithanovulation.Bulimianervosaisdefinedasbingeeatingwith
subsequentcompensatorybehavior(purging)andapoorbodyimage.31 Unlikeanorexia,bulimicsarenotunderweight.Fifty
percentofbulimicshaveamenorrhea.37 BulimicsdohavedecreasedlevelsofLHsecretionmuchlikepatientswithanorexia.
LowLHinbulimiaisfoundwhenbodyweightislessthan85%ofprevioushighestweightindependentoftotalbodyfat.
Patientswithbulimiaarenothypoestrogenicandareatlessriskforosteoporosis.However,persistentlyamenorrheicbulimics
dohaveanelevatedriskofendometrialcancerduetocontinuousestrogenstimulationoftheuterus.31 Leptinlevelsinbulimic
patientscanbenormal,butdodecreasewithpoornutrition.33
PHARMACOLOGICAGENTS
Estrogenandprogesteroneeffectgonadotropinreleaseindirectlyusingbiogenicaminesasintermediaries.Norepinephrineand
epinephrineareresponsibleforsignaltransductionbetweenthehypothalamusandthepituitary.38 Theseaminesincrease2
dayspriortotheLHsurge.39 DopamineregulatesprolactinandGnRHreleaseandisblockedbyendogenousopioids.11 ,40
DrugsthataffectmetabolismandreleaseoftheseamineswillconsequentlyeffectchangesintheHPOaxis.Examplesofthese
medicationsaregiveninTable1.ThesedrugswilloftencauseelevatedLHandprolactin.FSHisgenerallynotaffected.
Table1.Medicationscausinganovulation
Phenothiazines
Tricyclicantidepressants
Metoclopramide
Antipsychotics
Morphine
Dextroamphetamine
Alphamethyldopa
Verapamil
Cimetidine

Oneadditionalclassofdrugsthatmayaffectovulationisnonsteroidalantiinflammatorydrugs(NSAIDs).41 Prostaglandinsare
importantforovulationandreleaseoftheovafromtheovary.Preovulatoryfolliclesproduceprostaglandinsinresponsetothe
LHsurge.NSAIDsblockprostaglandinsynthesistherebypreventingovulation.41
POSTPILLANOVULATION
Hormonalcontraceptionhasbeenassociatedwithamenorrheaandaslowreturntofertilityafterstoppingtherapy.Thepost
pillanovulationsyndromeishistoricallydefinedasafailuretomenstruatewithin1yearofdiscontinuinghormonal
contraception.42 Muchofthedatasupportingaslowreturntofertilitywasbasedonhighdosehormonecontraceptivepills.43
Additionally,manypatientstakinghormonecontraceptionmayhaveunderlyinganovulationorsubfertility.Currentlythereare
severaldifferentvehiclesforadministeringcontraception.Currentdatasupportasimilarreturntofertilitybetweenmost
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modalities.42 Patientswithanovulationexceeding36monthsfollowingdiscontinuationoforalcontraceptivepills(OCPs)
shouldhaveaworkupforothercausesofamenorrhea.

Thepregnancyrateat1yearafterdiscontinuingcombinedoralcontraceptivepills(COCPs)isthesameasthepregnancyrate
forpeoplenotpreviouslytakingbirthcontrol.42 SomedatasuggestwomenwhohadtakenCOCPshadmorepregnanciesthan
womenwhohadnottakenCOCPs.44 Thehormonecontainingintrauterinedevice(IUD)andthenonhormonecontainingIUD
donotsignificantlydifferfromCOCPsinreturntofertilityrates.42 Fertilityafterdiscontinuingprogesteroneonlycontraceptive
pillsdidnotdifferfromnonhormoneusers.Dataarenotavailableforcontinuoususeoralcontraception,however,
extrapolatingfromimplantableandintrauterinedevicedatatherewerenodifferencesinpregnancyratesafterdiscontinuation
comparedtononcontraceptionpatients.Theonlymodalitythathadalowerpregnancyrateat1yearwhencomparedto
noncontraceptionusersissubcutaneousdepomedroxyprogesterone.Insummary,pregnancyrates1yearafterstoppingbirth
controlarethesameaspregnancyratesforwomenwhodonotusebirthcontrol.However,anevaluationworkupshouldbe
performedinpatientswhohaveamenorrheaformorethan36monthsafterdiscontinuingOCPs.
HYPOTHALAMICLESIONS
Tumors,inflammation,anddegenerationofthehypothalamuscanaffectovulatoryfunction.Generallytheseeventswillleadto
areductioningonadotropinreleasefromthepituitaryduetothetumorcompressingthepituitarystalk.45 Otherhypothalamic
tumorsaffectovulationbysecretinghormones.46 Inflammatorylesionswithinthehypothalamushavebeenshowntodecrease
functionbyincreasinglevelsofcortisol.47
Themostcommonhypothalamictumoristhecraniopharyngioma.45 Othertumorsincludegliomas,dermoids,meningiomas,
andgerminomas.48 Incraniopharyngiomas,growthhormone,thyroxin,andgonadotropinsaregenerallydecreased.45
StimulationwithGnRHdoesnotproduceanincreaseingonadotropinssuggestingadysfunctioninthebloodsupplytothe
pituitaryduetothetumor.Whenhormonallyactivetumorsareremoved,thesymptomsofhormoneexcessrapidlyimprove.48
Inflammatorylesionshavebeenseenintuberculosisandsarcoidosiscausinglowgonadotropins.47 ,49 Treatmentforanatomic
defectsinvolvestreatmentoftheunderlyingcause.
CONGENITALDEFECTS
Hypothalamichypogonadismcanbeassociatedwithageneticsyndromeorseveralsinglegenemutations.Kallmanns
syndromeisadeficiencyofGnRHandconcurrentanosmia.50 Thisraredisorderhasanincidenceof1:50,000.51 Thesepatients
haveamigrationdefectofGnRHsecretingneuronsfromthethalamusandagenesisofolfactoryneurons.50 Severalmutations
oftheKAL1genehavebeenassociatedwiththeXlinkedformofthissyndrome,however,mostcasesaresporadic
mutations.50 ,52 BothLHandFSHaredecreasedasexpectedduetotheGnRHdeficiency.Folliclesareseeninearlystagesof
maturationandsuccessfulpregnancyhasoccurredusinggonadotropintherapy.51
Idiopathichypogonadotropichypogonadism(IHH)isacollectionofgeneticmutationsthatresultindelayofpuberty,
infertility,andlowgonadotropins.53 OneXlinkedrecessivemutationisadrenalhypoplasiacongenita(AHC),whichissimilar
tocongenitaladrenalhyperplasia(CAH)butdoesnothavehyperandrogenism.AHCgenemutationresultsinproductionofan
abnormalDAX1proteinthatregulatesgonadotropinsecretioninthehypothalamusandpituitary.Severalothergenes
associatedwithIHHincludeKAL1,FGFR1,GNRHR,andNELF.26 Mutationsinthesegenesshowincompletepenetranceand
variablephenotypeinmenandresolutionhasbeenreorted.27 Itremainstobeshownifwomenalsohaveareversiblesubtype
ofIHH.WomenwithIHHhavehypoestrogenism,amenorrhea,andlowgonadotropinlevels.Leptinmutationsandleptin
receptormutationsareanothercauseofIHH.53 Mutationshavealsobeenfoundinthebetasubunitsofseveralpituitary
hormonesincludingLH,FSH,andthyrotropinandarediscussedlaterinthischapter.
AnothercongenitalcauseforhypothalamichypogonadismisBardetBiedlorLaurenceMoonsyndrome.Recentliterature
supportsthatthesetwosyndromesarevariantsofthesamegeneticabnormalities.54 Thesepatientspresentwithavariable
phenotypeincludingobesity,polydactyly,retinalandrenalabnormalities,andhypogonadism.Thisisarareautosomal
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recessivesyndromewithanincidenceof1:125,000to1:160,000.Severalgenemutationshavebeenisolatedinthesepatients
thatencodeforciliarymovementwhichisessentialfornormalorgandevelopment.55 LHandFSHlevelscanbevariable.56
WhengivenGnRHstimulation,thesepatientshaveaLHresponsesimilartopubertalgirls.57 Whengiventhyrotropinreleasing
hormone,theTSHsecretionofthesepatientsisnormal,suggestinganovulationisduetohypothalamicdysfunction.

Pituitaryanovulation
Normalovulationrequirescommunicationbetweenthehypothalamus,pituitary,andovary.TheHPOaxisiscomplexandis
influencedbyseveralotherprocessesinthebody.Thepituitaryglandactstoenablecommunicationbetweenthehypothalamus
andtheovary.Theglandiscomposedofananteriorandaposteriorlobe.Theanteriorlobesecretesgonadotropinsinresponse
toGnRHfromthehypothalamustoproduceaneffectontheovary.Bythismeans,thepituitaryactsasanendocrine
intermediarybetweenthebrainandthegonads.Hormonefeedbackregulatestherateofsecretiontomaintainregular
ovulationandcoordinatesexualfunction.Overgrowthofpituitarycellsorvascularinjurycanoccuranddisruptoralter
productionofhormones.Additionally,abnormalhormonescanbeproducedbythepituitaryresultinginineffectivepituitary
function.
PITUITARYTUMORS
Pituitarytumorscomprise1020%ofallbraintumors.58 Theyareclassifiedasmacroadenomasifthesizeisgreaterthan10
mmormicroadenomasiflessthan10mm.Clinically,pituitarytumorscanbeeitherfunctionalornonfunctionaldependingon
whetherornotthetumorproduceshormones.Seventypercentofpituitarytumorsarefunctional.Fortyfivepercentof
adenomassecreteprolactin.59 Mostfunctionalpituitarytumorsaremicroadenomas,however,manypatientswith
macroadenomashavemenstrualabnormalities.58 Duetothelackofhormoneproduction,macroadenomasmaybediagnosed
onlywhentheycausevisualproblemsfromcompressionofopticnerves.Microadenomasmostcommonlypresentwith
hormoneabnormalities.

Macroadenomascauseanovulationduetocompressionofthepituitaryasthemassenlarges.58 Thebloodsupplytothe
pituitaryfromthehypothalamusisthemeansforhormonecontrolofgonadotropinrelease.60 Compressionofthevessels,the
gland,orbothresultsindecreasedproductionofpituitaryhormonesandsubsequentanovulation.Asthemassgrowsand
compressesthepituitary,endocrinologistshaveoftenobservedthatthefirsthormonetobelostisgrowthhormone,followedby
gonadotropins.58 Somepatientswithmacroadenomasignoremenstrualirregularitiesforyearsbeforeseekingcare.Inpatients
seekingfertilitytreatment,pituitarytumorsareoftendetectedearlieronmagneticresonanceimaging(MRI).

Microadenomasoftenproduceelevatedlevelsofprolactin,whichcausesanovulation.61 Ofpatientswithhyperprolactinemia,
2025%willhavegalactorrhea.Elevatedlevelsofprolactincauseapositivefeedbacktodopaminerelease.Dopamineincreases
causeadecreasedreleaseofGnRH.Therearealsodirecteffectsofprolactinontheovaryandpituitarydecreasingovulation.62 ,
63 Gonadotropinsecretingtumorshavebeenreportedaswell.60 SerumLHandFSHlevelsareabnormalinsuchpatients,

indicatinggonadotropinreleaseisnotunderthecontrolofGnRH.

Sarcoidosisisachronicinflammatorydisease,whichresultsintheformationofgranulomasinmultipleorgansystems.64
Sarcoidosishasbeenfoundinthepituitaryandcancauseanovulation.65 Themechanismofanovulationfromsarcoidosisis
believedtobeacompressionoftheglandbythegranulomas,muchlikemacroadenomas.Treatmentinvolvessteroid
replacementandradiationtherapy,butduetotheprogressivenatureofthediseasethesetherapieshavenotbeenvery
successful.
ISCHEMIA
Vascularcompromisetothepituitarybloodsupplycanresultinanovulation.Thisisknownaspituitaryapoplexy.66 Several
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situationscanleadtovascularinjuryincludingtumorcompressionofbloodsupply,cerebralvascularaccident,hemorrhage
causingshuntingofbloodfromthepituitary,anddiabetes.Sheehanssyndromeisischemicdamagetothepituitaryresulting
fromvascularchangesatthetimeofparturition.67 Sicklecelldiseasehasalsobeenseenwithhypopituitarism.68 Infectionscan
alsoleadtodamagetothepituitarygland.69 Ischemiaofthepituitaryglandmostoftenresultsinlossofallhormones,unlike
thesequentiallossseenwithtumorexpansion.Emptysellasyndromeisanotherconditioninwhichthepituitaryisnot
visualizedwithinthesellaturcicaandresultsinpartiallossofpituitaryfunction.
PITUITARYHORMONEDEFECTS
Anotherpituitarycauseofanovulationisabnormalitiesinthepituitaryhormonestructure.LHandFSHhavetwosubunits,
alphaandbeta.Thealphasubunitstructureisveryconsistent,whilethebetasubunitcanvary.70 Mutationsinthestructureof
thebetasubunitcaninterferewithbindingtothealphasubunitandconsequentlycauseaninabilitytofunction.71 Patientswith
FSHabnormalitieshavedelayedpubertyanddecreasedsexhormonesalongwithanovulation.Becausethebetasubunitdiffers
foreachhormonetheseabnormalitiesonlyaffectonegonadotropin.72 Thediagnosiscanbedeterminedbyadministering
GnRH,whichresultsinnormalelevationofonlyonehormone,generallyLH.73
Onecharacteristicofgonadotropinsthatmaycontributetoabnormalhormonestructureisvariablebioactivity.74 LHhasa
bioactivetypeandanimmunologicorinactivetype.Inpatientswithanovulationthereappearstobeahigherconcentrationof
bioactiveLHwhenstimulatedwithGnRH.ThetypesofFSHaremorevariableandconsequentlymaybemoreproneto
abnormalproduction.70

Ovariancausesofanovulation
Theovarianfolliclerequireshormonestimulationtodevelop.4 Gonadotropinsactontheovarytopromotegrowthand
maturationofprimordialfolliclesintoadominantfollicle.Inreturn,steroidhormonesareproducedbytheovaryandactas
feedbacktoregulatetheovulationsystem.Defectsinovarianfunctionaffectingovulationincludealackoffolliclestodevelop,
anabnormalityinsteroidsecretion,orlackofcommunicationbetweenthegonadotropinsandtheovarianreceptors.
Gonadotropinsareelevatedinovariandysfunctionbecauseestrogenlevelsarelow.75 Thenormalfeedbacksignaltothe
hypothalamusisabsent.InhibinisanothersubstanceproducedbythefolliclethatinhibitsFSHrelease.76 Althoughestrogen
replacementisimportanttoreducehealthrisksassociatedwithhypoestrogenemia,estrogenalonedoesnotcorrectthe
gonadotropinelevationwheninhibinisdeficient.
POLYCYSTICOVARYSYNDROME
Oneofthemorecomplexconditionsassociatedwithanovulationispolycysticovarysyndrome(PCOS).Thecriteriadefinedby
thePCOSConsensusWorkshopGroup(Rotterdam)requiretwoofthreefeaturesforthediagnosisofPCOS.77 Thesefeatures
includeclinicalorbiochemicalevidenceofhyperandrogenemia,oligoovulationoranovulation,andpolycysticappearing
ovaries.77 Usingthesecriteria,theincidenceofPCOSisgreaterthan5%inwomenofreproductiveage.78 Commonlaboratory
findingswithPCOSincludeelevatedLH,androgens,andestrogen,withnormalorlowFSH.79 Inmanybutnotallpatientswith
PCOS,insulininsensitivityandobesityareseen.
Theoccurrenceofpolycysticovariesinthegeneralpopulationiscommon.79 Twentytwopercentofovulatingwomenwillhave
polycysticappearingovariesonultrasound.However,73%ofanovulatorywomenwillhavepolycysticovaries.Thepresenceof
polycysticovariesdoesnotincreasetheriskofdevelopingPCOSinthefuture.80 However,ifpresentwitholigomenorrheathere
isanincreasedriskofdevelopingPCOS.79
ThecauseofanovulationinPCOSinvolvesdysfunctionofthenormalcyclicnatureofthemenstrualcycleandcanariseby
severaldifferentmechanisms.Abnormalantralfollicledevelopmentandfunctionisafundamentalfeature.78 Thecystic
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appearanceoftheovariesresultsfromseveralfolliclesfailingtomatureproperlywithoutdevelopmentofadominantfollicle.
Themultiplefolliclesproducelargeamountsofestradiol,whichinhibitsFSHreleasetherebypreventingfurtherfollicular
development.Antimullerianhormone(AMH)maybeinvolvedinregulatingtheprogressionoffolliclesintogrowthphase,and
abnormalitiesinAMHhavealsobeenproposedascontributorstotheetiologyofPCOS.
HalfofPCOSpatientsareobese.77 ObesepatientswithPCOSaremorelikelytobeanovulatoryandhavesymptomsofexcess
androgens.78 Excessadiposetissueincreasesperipheralconversionofandrogenstoestrone,whichinhibitsovulationatthe
hypothalamus.ObesepatientswithPCOShaveahigherincidenceofinsulinresistancethanobesepatientswithoutPCOS.
Elevatedinsulinandinsulininsensitivityplayaroleinanovulationandhyperandrogenemia.Highlevelsofinsulinstimulate
thethecacellstoincreaseandrogenproductionviainsulinlikegrowthfactors.77 Elevatedandrogensfurtherarrestfollicular
developmentandresultinanovulation.Weightlossof510%ofbodyweightinobesepatientswillincreaseovulation.Obesity
andhyperinsulinemiaincreasetheriskofdevelopingmetabolicsyndromeandsubsequentlysignificantlyincreasemortality
fromcardiovascularevents.81 Hyperestrogenemiafromchronicanovulationincreasestheriskofdevelopinguterineandbreast
canceraswell.82
TreatmentofPCOSrequiresunderstandingofthegoalsofthepatient.Chronicanovulationwithunopposedestrogenshouldbe
treatedwithcyclicprogesteronewithdrawal.82 Symptomsofhirsutismcanbemanagedwithantiandrogensandoral
contraceptiveswithantiandrogenattributes.Forpatientsdesiringpregnancy,thefirstlineoftreatmentshouldbeweight
loss.83 Weightlossof510%ofbodyweighthasa50%returntoovulationanda33%pregnancyratewithin6months.Ifweight
lossaloneisnotsuccessful,clomiphenecitratecanbeused.84 TheASRM2008guidelinesstateglucophagecanbeaddedto
clomiphenecitrateifnotsuccessful,butthereisnobenefittoglucophagealoneforovulationinduction.AllPCOSpatients
shouldbescreenedfordiabetesmellituswitha2hourglucosetolerancetest(GTT)andhyperinsulinemiashouldbetreated.85
Laparoscopicovariandrilling(LOD)84 hasbeenusedhowever,theprocedurecausesdestructionofprimordialfolliclesand
mostspecialistseschewthistreatmentinwomeninterestedinfuturefertility.Finally,gonadotropintherapyorIVFareoptions
ifotherstrategiesforovulationinductionarenotsuccessful.
NONPSYCHOGENICWEIGHTDISTURBANCES
In15%ofwomen,amenorrheaisrelatedtotheirbodyweight.86 Amenorrheaoccurswhenwomenlose1015%oftheirnormal
bodyweight.87 However,absolutebodymassorfatcontentisnotasimportantinovulationasenergybalance.Energybalance
involvestheamountofenergysupplyandtheamountofusage.Inastudyofnonathletes,43%becameanovulatorywhenthey
startedaggressivelyexercising.88 Thesepatientshadarapidincreaseinenergyexpenditureaccompaniedbyweightloss.In
trainedathletes,cortisolandCRHlevelsareelevatedimplyingasuppressionofGnRHandsubsequentdecreaseinLHcausing
anovulation.89 SimilardecreasesinLHareseeninweightlossalonewhichresolvewithweightgain.88 ,90 Thestateof
gonadotropinsuppressionseeninwomenwithanegativeenergybalanceresultsinhypoestrogenemiaandincreasestheriskof
decreasedbonedensity.91 Thislowestrogenstateisfurtherseenbythepresenceofvaginalatrophyinnonanorexic
malnourishedwomen.92

Theotherweightrelatedanovulatoryconditionisobesity.ObesityiscurrentlyofepidemicproportionsintheUSwitha
prevalenceof21%ofthepopulationincreasingby16%annually.87 Unlikeundernourishedpatients,obesepatientshavea
stateofenergysurplus.Mostcommonlyobesityisaresultofasedentarylifestyle,butgeneticsmayplayarole.Anovulationin
obesityresultsfromexcessandrogensandestrogencausingdecreasedprogesterone.93 TheLHpulseamplitudeisalso
diminished.94 Adiposetissueishighlymetabolicallyactiveandproduces50%ofpremenopausaltestosterone.87 Further
metabolicchangesseeninobesityincludedecreasedsexhormonebindingglobulin,FSH,prolactin,andcortisol.93 Estroneis
significantlyincreasedbyperipheralconversioninadipocytes.Inadditiontoanovulation,obesepatientshaveincreasedrisksof
spontaneousabortion,IVFfailure,andrequirehigherdosesofclomiphenecitrateandgonadotropins.87 Modestweightlossof
10%ofbodyweightdoesincreaseovulationrates.Bariatricsurgeryhasalsobeensuccessfulinimprovingovulation.95 The
improvedovulationfollowinggastricbypassisdirectlyproportionaltotheamountofpostoperativeweightloss.
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ROLEOFLEPTININANOVULATION
Leptinisaproteinproducedbyadiposecellsthatactsasahormoneonthereproductiveaxis.96 Serumlevelsofleptinfluctuate
witheatingandareindicatorsofenergystores.ReproductionrequiresenergyandleptinactsasasignaltotheHPOaxiswhen
adequateenergyispresentforovulation.97 Leptinreceptorshavebeenfoundinseveralendocrinetissuesincluding
hypothalamus,anteriorpituitary,granulosaandthecacells,andinterstitialcellsoftheovary.Insulinandestrogenstimulate
leptinproductionwhileandrogensdecreaseproduction.
TheeffectsofleptinonhormonesoftheHPOaxisvarywithdifferentphysiologicstates.GnRHpulsatilityisincreasedindirectly
viaafferentinterneuronsofthehypothalamusinresponsetoleptin.98 LHreleaseisdirectlystimulatedasisFSHtoalesser
amount.97 Sinceleptinisanindicatorofenergyavailability,itisunderstandablethatleptinlevelswillbelowinstarvationsuch
asanorexiaandunderweightwomen.Thisisalsopresentinhypothalamicamenorrhea.Consequently,ovulationisinhibitedby
theabsenceofleptinstimulationofGnRHrelease.ExogenousadministrationofleptinincreasesLHpulsefrequencyinthese
patientsindependentofbodymass.99 Conversely,inobesityandPCOSleptinlevelsaresignificantlyincreased.97 ,100 Veryhigh
levelsofleptinantagonizefactorsinvolvedinLHandFSHreleaseandsuppressestradiolproductiontherebypreventing
ovulation.97 Leptinactsasaregulatoryhormoneanddecreasesovulationinconditionsofextremeenergyimbalance.Therole
ofleptininthediagnosisandtreatmentofanovulationisstillbeingstudied.
PSEUDOOVULATION/LUTEINIZEDUNRUPTUREDFOLLICLE
Luteinizedunrupturedfolliclesyndrome(LUF)maybeararecausefortransientanovulationandhasbeenlinkedtoNSAID
use.101 Prostaglandinsareimportantforfollicleruptureandovulation.Indomethacin,anNSAID,induceda50100%
occurrenceofLUF.FertilityreturnsaftercessationofNSAIDs.Duetolowrecurrencerates,fertilityratesweresimilarbetween
patientswithLUFandcontrols.Becauseofthehighprevalenceandtransientnature,currentthinkingisthatLUFisnotatrue
causeofinfertility.
OVARIANTUMORS
Neoplasmsoftheovarycancauseanovulationbyseveralmechanisms.Tumorsintheovarycandisruptthestromaand
decreasenormaloocyterelease.102 Somenonhormonesecretingtumorsreleaseadditionalsubstancesthatincreaseandrogen
production.Thisexcessandrogenisconvertedbyaromataseintheperipheraltissuestoestrogen,whichprohibitsovulation.
Ovariantumorscanalsoproducehormones.103 Abnormallevelsofgonadotropinsdisruptthenormalovulatorycycleand
preventovulation.
PRIMARYOVARIANINSUFFICIENCY
Menopauseisthecessationofmensesformorethan1yearsignifyingacompletionofovarianfunction.Theaverageageof
menopauseis50yearsold.104 Lossofovarianfunctionresultsfromthedepletionoffolliclesandthereforemaybemistakenfor
anovulation.Primaryovarianinsufficiency(POI)isthedepletionoffolliclereservepriortoage40.105 Thiscanbeduetoeither
absenceoffolliclesorabnormalovarianfunction.106 POIoccursinapproximately1%ofallwomen.107 MostoftenPOIis
spontaneousandthecauseisunknown.POIisreviewedherebecauseinsomecasesthesyndromeistransient,withresulting
ovarianfunctionandbecausePOImustbedistinguishedfromothercausesofanovulation.
ThemostaccepteddefinitionofPOIisdisorganizedmensesoranovulationformorethan4monthspriortoage40.105 Included
areserumFSHmeasurementsinthemenopausalrangeontwooccasionsmorethan1monthapart.PatientswithPOIhavelow
estrogenlevelsoftenatanearlyageandhormonereplacementisimportantforboneandcardiovascularhealth.108 Theterm
POIhasreplacedthemorefinitetermprematureovarianfailurebecausethissyndromeoccursasacontinuumandasmall
numberofpatientsmayconceiveafterthediagnosisofPOI.105

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SeveralabnormalitiesinovarianfunctioncancausePOI.MutationsinthegenecodingfortheFSHreceptorpreventFSHfrom
bindingtothesignalingreceptor.75 FSHisrequiredforfolliclematurationandestrogenproduction,consequently,these
patientshaveanovulationandhypoestrogenemia.Thesereceptorgenemutationsarecalledinactivatingmutationsduetothe
effectiveblockofFSHactivity.109 Activatinggenemutationsalsooccur.Thesemutationspresentwithincreasedfunctionofthe
FSHreceptoroftenbindingotherligands.110 FSHreceptorfunctioncanalsobeaffectedbyautoantibodiesbindingreceptor
sites.76
AconditionpreviouslycalledSavagesyndrome,orovarianresistance,ismarkedbyanovulationwithelevatedFSHanda
normalkaryotype.TheovarieswillshowmultipleprimordialfolliclesfromthelackofFSHstimulation.UnlikeFSHreceptor
mutations,successfulpregnancieshavebeenachievedwithhormonereplacementinpatientswithSavagesyndrome.111
Currentstudieshaveexaminedovarianresistanceatamolecularlevel,therebydrawingdoubtontotheexistenceofSavage
syndromeasanindependentdisorder.
AutoantibodieshavebeenassociatedwithPOIand3361%ofunexplainedinfertilitycases.111 ,112 Autoimmunepolyglandular
syndrome(APS)isaconditionwithautoantibodiesaffectingmultiplesystems.111 ThreetypeshavebeenidentifiedwithAPS
type1havingthehighestcorrelationtoPOI.Autoantibodieshavebeenfoundtobindgonadotropinreceptorsleadingto
anovulation.Addisonsdiseasehasthebestknownassociationwithautoimmuneovarianinsufficiency.113 POIoccursin10
20%ofpatientswithautoimmuneadrenalinsufficiency.114 Autoantibodiestargetingadrenalcellsalsotargetthecacellsand
steroidproducingcellsleadingtoanovulation.ViralinfectionssuchasmumpscauseoophoritisandPOI.115 Theamountof
ovarianfunctiondependsontheageatwhichthepatientwasexposedtothemyxovirus.
AbsenceoffollicledevelopmentalsoleadstoPOIandismostlyduetogeneticabnormalities.Thesepatientshavestreak
ovariesduetotheearlylossoffolliclesinuteroorbeforetheonsetofpuberty.Puregonadaldysgenesis,alsocalledXXGD,isa
poorlyunderstoodcondition.116 Theetiologyofthisgeneticabnormalityisnotknown,butoccurrencehasbeenassociatedwith
consanguinity.Thisautosomalrecessivedisorderisrarewithanestimatedincidenceof1:8300.Othergenemutationsinclude
FOXL2andNR5A1.117 ,118 FOXL2mutationisassociatedwithblepharophimosis/ptosis/epicanthusinversus(BPE)syndrome
type1.117 MutationsinFOXL2geneproduceabnormalproteinsontheforkheaddomainresultinginabnormalsignal
transduction.NR5A1inactivationcausesovarianhypoplasia.118 DIA,ZFT,andXISTgenemutationsarealsolinkedtoPOI.119 ,
120

RapidfollicleatresiaresultsinvariableonsetPOI.ThemostcommongeneticdefectisTurnersyndrome.Thesepatientshave
rapidfollicleatresiabeforetheonsetofpubertyresultinginstreakovaries.106 Becausetherateofatresiaisrapidandfollicles
areinitiallypresentintheovaries,2030%ofthesepatientswillreachspontaneouspuberty.Ofthisgroup,510%willbe
fertilepriortocompletelossoffollicles.Therehavebeenreportsofsuccessfulpregnanciesusingdonoreggsinpatientswith
Turnersyndrome.Patientswithearlierovarianfailureshouldbegivenhormonereplacementtopreventbonedensityloss.
FMR1genemutationisassociatedwithacceleratedfollicleatresiaandfragileXsyndrome.121 Themutationoccursin2%of
spontaneous46,XXPOIand14%ofspontaneous46,XXPOIwithafamilyhistory.105 Additionally,1325%offragileX
syndromecarriershavePOI.119 BecauseFMR1mutationoccursfrequentlywithPOI,andbecausetheXlinkedcondition
carriesariskofmentalretardationinmales,thisgenemutationshouldbescreenedforintheworkupofanonsyndromic
patientwithPOI.GalactocemiaisanothergeneticdisorderwithahighriskofPOI.122 POIhasalsoresultedfromexposureto
chemicalsolventscontaining2bromopropane.123 Thisexposureresultedinarrestoffolliculardevelopmentwithrecoveryof
ovarianfunctionandpregnancyintwopatients.

Systemicanovulation
ACUTEANDCHRONICDISEASE
Chronicanovulationisseeninillnessandstresscausedbychronicillness.124 Thisresultsfromeitherthediseasedorgansystem
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alteringreproductivehormonelevelsorelevatedstresshormonesaffectingtheHPOaxisasnotedabove.Cytokinesareelevated
insystemicdisease,whichcandirectlyinhibitreproductivehormoneproducingorgans.125 Ashealthstatusimproves,
reproductivefunctionoftenresumes.Withmanychronicdiseases,however,asfertilityreturns,pregnancymaynegatively
impactapatientshealth.
RENALDISEASE
Earlyrenalinsufficiencyresultsindecreasedfertilityandlowlibido.Inchildren,onsetofpubertyisdelayed.126 With
developmentofchronicrenalfailure,anovulationoccurs.LHpulsefrequencydecreasesresultinginlossoftheLHsurgeand
subsequentanovulation.TheLHtoFSHratioisslightlyincreasedbuttheLHresponsetoGnRHstimulationisdelayed.
Hyperprolactinemiaisoftenseenduetoincreasedprolactinsecretionanddecreasedrenalclearance.Menstruationresumes
withdialysisorrenaltransplant.124 Ovulationisseenin82.1%ofpatientsfollowingrenaltransplant.126
LIVERDISEASE
Theeffectofliverdiseaseonfertilitydependsontheageofonsetandetiology.Childrenwithliverdiseasewillhavedelayed
pubertyby1.1yearsonaverage.126 Fullsexualdevelopmentreturnswithin3yearsoftransplant.Gonadotropinmeasurements
arenormalinviralhepatitis,however,anovulationisseen.Hyperestrogenemiaoccursduetoaromatizationofweakandrogens
fromtheportalcirculationandconsequentlyovulationisprevented.Womenwithalcoholichepatitishaveearlymenopause.In
alcoholics2040yearsold,decreasednumbersoffolliclesareseenandnocorporaluteaareseen.Cirrhosisisassociatedwith
obesityandconsequentlyestrogenlevelsmaybeelevatedfromperipheralconversion.124
Secondaryamenorrheaoccursin50%ofwomenwithendstageliverdisease(ESLD).126 Menstrualirregularityisoftenthe
presentingcomplaintleadingtothediagnosisofliverdisease.InpremenopausalpatientswithESLD,gonadotropinlevelsare
decreasedasareestrogenandtestosterone.ThesepatientsdonotrespondwelltoGnRHstimulationorclomiphenecitrate.
Followinglivertransplant95%ofpatientsunder45yearsoldwillresumemenses.Infertilityinthispopulationis2550%
followingtransplant.
THYROIDDISEASE
Thyroiddiseaseisacommoncauseofmenstrualcycleirregularity.Oligomenorrheaandamenorrheaoccurin58%ofpatients
withhyperthyroidism.127 Anovulationoccursinsevereuntreateddisease.Gonadotropinsareelevatedinhyperthyroidism,asis
sexhormonebindingglobulin(SHBG).TheelevationinSHBGleadstoanincreaseintotaltestosterone.Hypothyroidism
presentswithmenorrhagia.Anovulationresultsfromelevatedthyroidstimulatinghormone,whichactsasareleasingfactorfor
prolactin,andelevatedlevelsofprolactininturncontributetoanovulationasdescribedpreviously.
ADRENALDISEASE
Adrenalhormonesareinvolvedintheregulationofovulation.Inacquiredadrenalinsufficiencyautoantibodiesalsomayblock
FSHreceptors.113 Congenitaladrenalhyperplasiaisassociatedwithdelayedpubertyandamenorrhea.128 Glucocorticoidsare
decreasedandandrogenicprecursorsareincreased.Folliclesarepresentintheovariesbutovulationdoesnotoccurbecauseof
theexcessivelevelsofandrogens.
HIV
OvulationstudiesinHIVareconflicting.PatientswithHIVareexposedtoseveralmedicationsandoftenhaveconcomitant
infections.SomestudiesshowanovulationinHIVpositivewomencorrelatestothenormalpopulation.Otherstudiesreport
worseningovarianfunctionwithdecreasedCD4cellcounts.2 Consensusmaintainsthatthereiscurrentlynodifferencein
ovulationratesinHIVpositivewomencomparedtononinfectedwomen.

DIAGNOSISANDTREATMENT
Themostimportantconsiderationintheworkupofanovulationistodeterminethepatientsgoals.Treatmentofthepatient
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whowantstogetpregnantdiffersfromthatofthepatientwhoisconcernedabouttherisksofearlymenopause.Inpatientswho
desirepregnancy,theclinicianneedstodetermineiftheyareactivelytryingforpregnancy,orareplanningforpregnancy
severalyearsinthefuture.Theapproachoutlinedbelowbeginswiththepatientwhoisactivelytryingforpregnancy.

History
Manypatientswithanovulationwillpresentwithamenorrhea.Primaryamenorrheaisfailuretomenstruateandnosecondary
sexualcharacteristicsbyage14ornomenstruationbyage16withnormalsexualdevelopment.129 Secondaryamenorrheaisthe
cessationofmenstruationformorethan3months.130 Theetiologiesofprimaryandsecondaryamenorrheadiffer.Primary
amenorrheaisoftenseenincongenitaldisorders.131 Themostcommoncauseofsecondaryamenorrheainwomenof
childbearingageispregnancy,consequentlytheworkupforanovulationshouldbeginwithapregnancytest.
Detailsofapatientspreviousmedicalhistorycandirecttheevaluationofanovulation.Chronicdiseasecanaffectovulationand
mayincreaserisksduringpregnancy.132 Psychiatricproblemsarealsooftenassociatedwithovulationdysfunction.Theuseof
anyantipsychoticmedicationsshouldbenoted.40 Detailsofpreviouspregnanciesarelikewiseimportantintheevaluationof
ovulationandcanhelpdistinguishgeneticdisordersfromlateronsetanovulation.

Physical
Thephysicalexamshouldincludeanevaluationofvitalsigns,height,weight,BMI,andappearance.Obesityiscommonly
associatedwithanovulationandPCOS.77 Verythinpatientsmayhaveanorexiaornutritionaldeficits.Hirsutismmaysuggest
PCOS,CAHoranandrogensecretingtumor.Visualfieldtestingisusefulinpatientswhoreportvisualchangessuggestinga
pituitarytumor.Palpationofthethyroidandabdomenshouldalsobeperformedtoevaluateformasses.Evaluationofthe
patientwithprimaryamenorrheashouldincludeabimanualexamtodeterminethepresenceofapatentoutflowtractand
uterus.
Laboratorytests

Inpatientswithamenorrhea,pregnancyshouldbeconsideredandapregnancytestperformedearlyintheworkup.Evaluation
oftheHPOaxisshouldbeperformedinastepwisefashion.Serumestradiolandgonadotropinsdetermineovarianfunction.
FSHmeasurementshavebeenstandardizedforday3ofthemenstrualcycle.However,inpatientswithamenorrheaarandom
FSHisappropriate.MeasurementofLHhaslimitedclinicaluse.TheratioofLHtoFSHhasbeenstudiedforPCOSbutisnot
includedinthedefinitionofthesyndromeandisthereforenotnecessary.77
ElevatedFSHindicatesanovarianproblem.Inpatientsunder30yearsoldwithanelevatedFSH,akaryotypeshouldbe
performed.AnincreasedriskofovariancancerisseeninXYfemaleswithgonadaldysgenesis.133 Turnersyndrome(45,XO)is
associatedwithincreasedriskforcardiovascular,thyroid,andrenaldisease.134 Forthesepatients,akaryotypeisveryusefulin
theworkupparticularlyrelatingtofuturepregnancyandhealth.InpatientswithelevatedFSHandanormalkaryotype,ovarian
resistanceandPOIareconsidered.Atrialofovulationinductionmaybeperformedusingclomiphenecitrateasdescribedlater.
Ifthereisnobenefitofclomiphene,exogenousgonadotropinsmaybeeffective.
NormalordecreasedFSHvaluessuggestdysfunctionoftheHPOaxis.Subsequenttestingincludesprolactin,TSH,andT4.
Thyroidabnormalitiesareverycommonandmaybeseeninupto4%ofpatientswithinfertility.135 Treatmentforthyroid
diseaseoftenrestoresHPOaxisfunction.HyperprolactinemiashoulddirectthecliniciantoobtainanMRIofthepituitary.
Serumprolactinlevelsgreaterthan250g/Lareseeninprolactinsecretingmacroadenomas.136 Macroadenomasmayrequire
surgery,whilemanymicroadenomascanbesuccessfullytreatedwithmedicaltherapy.137
Inpatientswithsignsofhirsutism,serumandrogensincludingtestosteroneanddehydroepiandrosterone(DHEAS)canbe
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evaluated.Atestosteronelevelisausefulandrogentestindeterminingthecauseofhirsutisminwomen.138 Elevatedfree
testosteroneisseenin70%ofwomenwithPCOS.Duetotechnicallimitationsintestingforfreetestosterone,measurementof
totaltestosteronecanbeused.DHEASisproducedprimarilyfromtheadrenalglandandelevatedlevelssuggestanadrenal
tumor.Manyandrogensecretingtumors,however,causeseveresignsofhyperandrogenismincludingvirilizationand
clitoromegally.139 AnormalDHEASlevelshoulddirectattentiontotheovaryastheoriginofexcessandrogens.Anotheruseful
hormonetestinhirsutismis17hydroxyprogesterone.Thisisproducedintheadrenalglandandtheovary,andiselevatedin
CAH.MostpatientswithhirsutismandPCOSwillhaveelevatedtestosteronelevels,whileonly2535%willhaveelevated
DHEAS.138
AnadditionallaboratorytestforpatientswithPCOSisa2hourGTT.85 Thistestinvolvesexamininginsulinandglucoselevels
followingadministrationofa75gglucosebolus.140 Theglucosetolerancetestisusefulfordetermininginsulinresistance.
Additionally,obesePCOSpatientsareatincreasedriskfordyslipidemiaandmetabolicsyndromeandaserumlipidprofileis
appropriate.141 Elevatedlipidlevels,particularlyinyoungpatients,mayincreasetheriskofcardiovasculardiseaselaterinlife.
Diet,weightloss,andlifestylemodificationsshouldberecommendedtopatientswithmetabolicsyndromerisks.

Imagingtests
Ultrasoundisaninvaluabletoolfortheevaluationofgynecologicproblemsincludingtheassessmentofovarianarchitecture,
whichisacriterionforthediagnosisofPCOS.Transvaginalultrasoundprovidesareliablemeasurementofthethicknessofthe
endometriallining.142 Athickenedendometrialliningsuggesysthepresenceandeffectofestrogen.Longtermanovulation
leadstochronicestrogenstimulationoftheuterusandincreasestheriskofuterinecancer.143 Sincethereisnotgood
correlationbetweenthicknessandabsenceofendometrialhyperlasiaorcancer,144 itisjustifiedtosampletheendometrial
lininginchronicanovulatorypatientsindependentoftheendometrialthickness.Ultrasoundcanalsobeusedtoevaluatethe
ovariesandmeasurethenumberantralfollicles.Antralfolliclecountisasensitivetestfordeterminingovarianreserveand
responsetoovarianstimulation.145 Alownumberofantralfolliclesduringthefollicularphaseofthemenstrualcycleisan
indicationofpoorovarianreserve.UltrasoundevaluationoftheovaryisusefulinthediagnosisofPCOS.Tosatisfythe
definitionofpolycysticovaries,eachovarymustcontainmorethan12follicles29mminsizeoracalculatedovarianvolume
morethan10mL.146

Combinedapproach
Withanovulationitisimportanttocombineseveraltestsinordertocompletelyevaluatethepatient.Anexampleofthisisthe
evaluationofdiminishedovarianreserve.CombiningpatientdemographicssuchasagewithserumFSH,antimullerian
hormoneandantralfolliclecountgivesamoreaccurateassessmentofapatientschancesofsuccessfulpregnancy.147
Counselingpatientsaboutpropernutrition,weightmanagement,andstressreductioncanenhancefertilityevenwhenother
causesofanovulationaredetermined.

Somepatientsplantodelaypregnancyeitherforweightmanagementorbecausetheyareundergoingtherapyforothermedical
conditions.Forwomenwhoarechronicallyanovulatoryandhaveunopposedestrogenstimulationoftheuterus,itisimportant
totreatwithprogesteroneonaregularbasistoreducetheriskofendometrialcancer.142 Foranovulatorywomenwithout
estrogen,hormonereplacementshouldbeconsideredforbonehealth.148

Ovulationinduction
Thetreatmentforanovulatorywomenwhodesirepregnancyvariesbasedonthecauseoftheiranovulation.Ifanovulationis
duetoatumorormedicalcondition,treatmentoftheunderlyingcausemayimproveovulation.Forexample,patientswith
hyperprolactinemiaoftenresumeovulationaftertreatmentwithadopamineagonist,andthisshouldbeevaluatedbefore
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treatingwithovulationinducingagents.149
Clomiphenecitrateisthefirstlinemedicaltreatmentforovulationinduction.150 Itisaselectiveestrogenreceptormodulator
thatincreasesovulationbybindingestrogenreceptorsinthehypothalamus.151 ThisblockadecausesincreasedGnRHrelease
andincreasesovulation.Thestartingdoseofclomipheneis50mgdailyfor5daysbeginningonday2ofthemenstrualcycle.152
Thiscanbeincreasedby50mgperdayforeachsubsequentcycleifpregnancydoesnotoccur.Themaximumdosageof
clomipheneis200mgperday.ClomiphenecitrateisusefulforincreasingGnRHrelease,however,itrequiresendogenous
hormoneproduction.
Incasesofclomiphenefailuregonadotropintherapyisoftenusedtoinduceovulation.Gonadotropinsincludehuman
menopausalgonadotropins(hMG)orrecombinantsyntheticFSHandLH.153 ForPCOSpatientswhofailclomiphene,FSH
treatmentisofteneffectiveduetotheendogenouslyhighlevelsofLHpresentinPCOS.84 Inhypothalamichypogonadotropic
anovulationbothFSHandLHreplacementarerequiredanditisadvisabletobeginwithverylowdosesofLHforseveralweeks
beforeFSHisadded.Dosingregimensvary,butmanycentersstartwithalowdosesuchas37.575IUperdayfor712days
untiladominantfollicle1618mmispresent.150 Afterdevelopmentofadominantfollicle,humanchorionicgonadotropin
(hCG)oraGnRHagonistisadministeredtoinduceoocyterelease.Progesteronesupportduringtheinducedlutealphase
shouldbeconsideredbecauseendogenoushormoneproductionmaybeinsufficient.
Severalconsiderationsapplywithovulationinductionforcertainanovulatoryetiologies.Manystudieshaveevaluatedtheuseof
metforminforovulationinductioninPCOS.152 ,154 Theredoesnotappeartobeabenefittousingmetforminalonefor
ovulationinductioninPCOSpatients,however,itisbeneficialinmanaginginsulininsensitivityinthesepatients.152 In
addition,manypatientswithhypothalamicanovulationdonotovulatewithclomiphenecitrate.Itisreasonabletobeginusing
gonadotropinstotreatsuchpatientswithoutatrialofclomiphene.Inconclusion,therearemanycausesofanovulation.Proper
treatmentmustincludecorrectassessmentoftheunderlyingcauseofanovulation,treatmentofanyidentifiableconditions,and
ifappropriateovulationinductionusingclomiphenecitrateorgonadotropins.

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