Menstruation and Menstrual Disorders_ Anovulation

2/9/2015 MenstruationandMenstrualDisorders:Anovulation

http://www.glowm.com/section_view/heading/Menstruation%20and%20Menstrual%20Disorders:%20Anovulation/item/295 1/25

PrintThisPage

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

May2009

MenstruationandMenstrualDisorders:Anovulation

JosephB.Davis,DOAkronGeneralMedicalCenter,Akron,Ohio,USA

JamesHSegars,MDReproductiveBiologyandMedicalBranch,EuniceKennedyShriver,NationalInstituteofChildHealthandHumanDevelopment,NationalInstitutesofHealth,Bethesda,Maryland,USA

INTRODUCTIONETIOLOGYDIAGNOSISANDTREATMENTREFERENCES

INTRODUCTION

Anovulationisthefailureoftheovarytoreleaseovaoveraperiodoftimegenerallyexceeding3months.Thenormalfunctioningovaryreleasesoneovumevery2528days.Thisaveragetimebetweenovulationeventsisvariable,especiallyduringpubertyandtheperimenopauseperiod.1Fornonpregnantwomenaged1640anovulationisconsideredabnormalandacauseofinfertilityin30%offertilitypatients.2

Oneofthecardinalsignsofanovulationisirregularorabsentmenstrualperiods.Oligomenorrheaisdefinedasmorethan36daysbetweenmenstrualcyclesorfewerthaneightcyclesperyear.3Intheabsenceofpregnancy,menstruationfollowsovulationbyapproximately14days.Becausemenstruationislinkedtoovulation,theclinicalfindingofoligomenorrheacorrelateswitholigoovulation.Thispredictablepatternofovulationandmenstruationisregulatedbyacyclicchangeinhormones.Consequently,thediagnosisofovulationdysfunctionincludestheassessmentofthehormonesandsystemsinvolvedinovulationandnotjustthesymptomofamenorrhea.

Thischapterincludesabasicreviewoftheprocessofovulationandtheprimarymechanismsofanovulation.Anovulationiscoveredusingasystemsapproach.Thisapproachincludeshypothalamicandbrain,pituitary,ovarian,andsystemicbasedanovulation.Eachsystemreviewincludesdiagnosisandtreatmentoptions.

Theprocessofovulation

Tounderstandanovulation,onemustfirstunderstandovulation.Ovulationinvolvesaprogressionofcellularchangesinfolliclesthatoccurfromfetallifeuntilmenopause.4Atanygiventimeintheovaryfolliclesareatdifferentstagesofmaturity.Primordialfolliclesprogresstoimmaturefolliclesandacquiredhormoneresponsivenessbyaprocessthatremainsunclear.5,6

Thesesmallimmaturefollicles,calledrestingfolliclesorantralfollicles,areacteduponbyseveralhormonestoeitherprogresstoagrowthphaseorregressbyatresia.4Granulosaandthecacellsofthefolliclemakeupthetwocellsystemthatisresponsibleforfolliculargrowth.5Gonadotropinhormonesfromthepituitaryeffectastructuralchangeinthesecellsthatcausesthefolliclestoenlarge.Thenumberofgranulosacellsandthecacellswithineachfollicleincreasesandafollicularfluidcontaininghormoneproductsisaccumulatedinthefollicleasitprogressesthroughthegrowthphase.

Folliclestimulatinghormone(FSH)istheprimarygonadotropinresponsibleforthisprogression.4Asthefolliclesenlarge,FSHstimulatestheproductionofmoreFSHreceptorsonthegranulosacells.Thisallowsthefollicletobecomemoresensitiveto



FSHandgrowmorerapidly.Thelargerfolliclesrecruitmorethecacells,whichproduceandrostenedione.ThisandrogenpassesthroughthebasementmembraneandisconvertedtoestradiolbyFSHdrivenaromatizationintheincreasingnumberofgranulosacells.7Oncethefolliclebecomeslargeenough,cellgrowthslowsandthecellularenergyresourcesareusedalmostexclusivelytoproducethesesteroids.TheincreasingamountofestradiolproducedinturninhibitsthereleaseofFSHfromthepituitary.WithoutFSH,thesmallerfolliclesthatcontainfewerFSHreceptorsarenolongerstimulatedtogrowandinsteadregress,leavingthedominantfollicleforovulation.

FolliculardevelopmentisdrivenbyFSH,butlutenizinghormone(LH)isresponsibleforovulation.FSHactsonthecacellstoinduceLHreceptorexpressionandrenderthecellssensitivetoLH.4LHalsostimulatesthethecacellstoproduceandrostenedione,whichisconvertedtoestradiolbygranulosacellsasdescribedabove.TheestradiolproducedfurtherstimulatesLHreleasefromthepituitary.WhenacriticallevelofLHisreached,ovulationoccursandthefolliclerapidlychangestoacorpusluteum.Progesterone,producedbythecorpusluteum,increasesfollowingovulationandinhibitsLHsecretionbyaneffectonthehypothalamus.8Withoutfertilizationoftheova,thecorpusluteumregresses,progesteroneandestradiollevelsdrop,andFSHisagainreleasedtopromotedevelopmentofanewdominantfollicle.4

Thegonadotropinsresponsibleforthisseriesofevents(FSHandLH)arereleasedfromthepituitaryandaredirectlyregulatedbygonadotropinreleasinghormone(GnRH).8GnRHissecretedinapulsatilepatternthatbecomesregularaswomenprogressthroughpuberty.ThisregularpatternisessentialforproperproductionandreleaseofLHandFSH.SeveralconditionsofanovulationmimictheirregularGnRHpulsepatternseeninprepubescentgirlsfurtherdemonstratingtheimportanceofthecyclicreleaseofGnRHinnormalovulation.Estradiolandprogesterone,whichareproducedasthedominantfollicledevelops,furtherregulatethereleaseofGnRH.ThehormonefeedbackandregulationofGnRHismediatedbycatecholaminesandendogenousopioids.9,10

Inadditiontothesystemicgonadotropins,follicledevelopmentisalsoregulatedbylocalhormones.7ActivinandinhibinareproducedinthegranulosacellsinresponsetoFSHstimulation.ActivinaugmentstheFSHeffectsongranulosacellsandsuppressesandrogensynthesis,allowingforfolliclegrowth.Inhibinisproducedasthefollicledevelopsandenhancesandrogensynthesisinthecacells.11Theincreasedandrostenedioneisthesubstrateforestradiolproduction.ThecacellsalsorespondtoinsulinlikegrowthfactorIIthatfurtheraugmentsLHaction.7

Anovulationcanresultfromdisruptionofthisseriesofeventsanywherealongthepathway.4Severalexternalfactorssuchasstressandnutritionalsocauseanovulationbyaffectingthehypothalamusandthecentralnervoussystem.Disruptionatthelevelofthepituitarycausesreducedgonadotropinsecretion.Polycysticovarysyndromecanbeconsideredaphysiologicstateofanovulationthatmaybecausedbydisorderinoneormoreorgansystems.Systemicdiseasehasbeenshowntoaffectovulationaswell.Thischapterreviewsthecausesofanovulationandhowtotreatthiscommonproblem.

ETIOLOGY

Anovulationcanresultfromdisruptionatanylevelinthehypothalamicpituitaryovarian(HPO)axis.Consequently,categorizingthedifferentmechanismsofanovulationlogicallyfollowsasystemsapproach.Asystemsapproachbreaksdownthecausesofanovulationintofourcategories:

HypothalamicandbrainPituitaryOvarianSystemic

Itisimportanttorememberthatanovulationisaffectedbythehealthoftheentirepatient,therefore,somedisorderscaninvolvemultiplelevelsoftheHPOaxis.



Anovulationduetodisorderofthehypothalamusandbrain

ThehypothalamiccausesofanovulationresultfromdecreasedordysfunctionalproductionofGnRH.PharmacologicalstudieshaveshownGnRHreleaseisregulateddirectlyandindirectlybyendogenousopioids,catecholamines,anddopamine.9

DopaminestimulatesthereleaseofGnRH,whereasendogenousopioidsblockdopamineandconsequentlydecreaseGnRH.Inpatientswithconditionsofelevatedendogenousopioids,treatmentwithnaloxoneblocksopioidreceptorsandresultsinareturnofLHlevelstonormal.10

Corticotropinreleasinghormone(CRH)isproducedbythehypothalamusandblocksGnRHrelease.CRHisalsoproducedintheamygdala.12ThecentralnucleusoftheamygdalamediatesfearandanxietybyCRHproducingneurons.TheseneuronsprojecttoseverallimbicstructuresandhavebeenshowntodecreaseserotoninandincreasebetaendorphinproductiontherebydecreasingGnRHrelease.HighlevelsofcortisolfromtheadrenalglandshavealsobeenassociatedwithhighlevelsofCRHimplicatingstressinanovulation.13

STRESSINDUCEDANOVULATION

Stresshasbeendefinedasastateofthreatenedhomeostasis.14Thestresssystemisthemechanismbywhichthebodytriestomaintainhomeostasis.Stressincludesphysical,emotional,andnutritionalchanges.Reproductivestatusmirrorsthephysiologicstateandtheexternalenvironment.15Whenstressissignificantreproductivefunctiondecreasesinanefforttomaintainhomeostasis.16Stresshasalsobeenshowntodecreasepregnancyratesandincreasemiscarriagerates.17

Thestresssystemiscomprisedofthehypothalamicpituitaryadrenal(HPA)axis,arousal,andtheautonomicsystem.18ThemainchemicalmediatorsofstressincludeCRH,glucocorticoids,andbetaendorphins.CRHhasreceptorsinmanydifferenttissuesincludingovary,endothelium,hypothalamus,andinflammatorytissues.Producedinthehypothalamus,CRHandargininevasopressinstimulateadrenocorticotropichormone(ACTH)productioninthepituitary.Thisincreasescortisolproductionintheadrenalglands.CortisolisaglucocorticoidthatactsonmultiplebodysystemsandreducesLH,estradiol,andprogesteroneeffects.ManyoftheeffectsofglucocorticoidsandCRHinastressresponseinvolvesystematicallyinhibitingThelper(Th1)proinflammatoryresponsesandinductionofaTh2shift.14

BetaendorphinsaresecretedfromnerveterminalsinresponsetoCRHandproducetheinitialeuphoriaofacutestress,necessaryforsurvival.14Dopaminehasalsobeenshowntoincreaseduringstressinapatterncorrelatingtocortisollevels.19

EstrogenhasadirecteffectonCRHreleaseinstressandpromotesCRHsynthesis.20ElevatedlevelsofCRHandcortisolsuppressGnRHsecretionandconsequentlydecreaseovulation.15Stressisacommonprobleminpatientsundergoingfertilityworkupandtreatment.Techniquesarecurrentlybeingstudiedtoreducestressincludingacupuncture,yoga,andmeditation.21

FUNCTIONALHYPOTHALAMICAMENORRHEA

Functionalhypothalamicamenorrhea(FHA)isdefinedascessationofmensesandovulationwithoutanidentifiableorganiccause.22Examplesoforganiccausesofanovulationincludeclinicaleatingdisordersandsignificantweight.23FHAthereforeisadiagnosisofexclusionwithareportedincidenceof1535%.22Asfurtherunderstandingofanovulationdevelops,thenumberofpatientsdiagnosedasFHAdecreases.

AnovulationinFHAresultsfromadecreaseinGnRHreleaseandconsequentlydecreasedgonadotropinrelease.Suchpatientsalsofailtomenstruateaftertreatmentwithprogesteronedemonstratinglowestrogenlevelscorrelatingtochroniclackofgonadotropinstimulation.24Slightlyincreasedcortisollevelsaretypicalwithlowtonormalgonadotropins.SuchpatientsdorespondtopulsatileGnRHtreatmentfurtheridentifyingthehypothalamusasthemaincauseforanovulation.LHpulsefrequencyisreducedandtheintervalbetweenpulsesisprolonged.25



OnehypothesisforFHAisasynergisticmetabolicandpsychosocialdysfunctionsimilartoastateofchronicstress.22FHApatientshavebeenreportedtohaveahigherlikelihoodofmooddisorders,increasedamountofexercise,mildweightloss,anddietswithlowerfatcontent,increasedfiber,andincreasedcarbohydrates.22,23Personalitytraitsincludeperfectionism,lowselfesteem,andpoorstressmanagementability.23

AnotherevolvingtheoryisthatFHAisaspectrumofreducedgonadotropinsecretionduetovariableexpressionofageneticformofanovulation.26Thishasbeenseeninmaleswhoshowreversiblehypothalamichypogonadismandanidentifiablegeneticmutation(seebelow).27Atthepresenttime,similargeneshavenotbeenidentifiedinwomen.ThisconditionrepresentsastateofGnRHresistancesimilartoinsulinresistance.Duetothelowestrogenandelevatedcortisollevels,patientswithFHAareatincreasedriskofbonelossandsystemicdisease.22Treatmentshouldinvolvenutritionalandpsychologicalcounseling,however,thisformofanovulationoftenresolvesspontaneously.

PSYCHOGENICTRAUMAANDSTRESS

Studieshaveshowntheimpactofexternalfactorsintheenvironmentonmenstruationandconsequentlyovulation.13,28,29

Menstrualcyclesincollegewomenlivingtogetherwillbegintosynchronize.28Thesesamewomenwillhavelongercycleswhenspendingincreasingtimewithmalestudents.Thesechangesarelikelytheresultofpheromonesinfluencingthehypothalamus.Furtherstudiesnotetheinfluenceofpsychologicalstateonmenstruation.Inpatientswithclinicaldepression,cortisollevelswerefoundtobesignificantlyelevated.29Otherhormonesincludingprolactin,gonadotropins,andestrogenareallnormalinpatientswithpsychologicaldistress.WhengivenexogenousGnRH,thesepatientshaveanormalreleaseofLHandFSHsuggestingasuppressionofGnRHasthecauseofanovulationassociatedwithdepression.

ANOREXIANERVOSA

Anorexianervosaisaneatingdisorderstemmingfromadisorderedbodyimageresultinginmalnutritionandsevereweightloss.30ThediagnosticcriteriaincludesamenorrheaimplyingafunctionalabnormalityoftheHPOaxis.31Theprevalenceisreportedtobe0.51%inadolescents.Complicationsofanorexianervosaincludeamortalityrateof210%mostoftenduetosuicideandsevereelectrolytedisturbance.Bonedensitylossoccursasaresultoflowestrogenlevels.31,32Anorexiadiffersfromotherformsofpsychogenicanovulation.Theovulatoryfailureinanorexiaisduetometabolicchangesthatoccurwithweightloss,whiletheunderlyingproblemispsychological.Gonadotropinlevelsarereducedinanorexia,asareleptinandestradiol.32Thishypoestrogenicstateresultsinathinendometrialliningthatdoesnotshedafterprogesteronetreatment.Leptinlevels,whichcorrelatewithbodyfatandnutritionstatus,havebeenfoundtoplayaroleinovulationandarediscussedlaterinthischapter.33Triiodothyronine(T3)isdecreasedandreverseT3iselevated,resultinginhypothyroidsymptomsincludingdryskinandbradycardia.32Growthhormoneisalsoincreasedduetoperiodsofstarvation.Severalfindingsindicatethatanovulationassociatedwithanorexiaarisesatthelevelofthehypothalamus.30,32,34Thepulsefrequencyofgonadotropinreleaseissimilartothepulsefrequencyseeninchildhood.30StarvationhasbeenshowntodecreaseGnRHreleaseandsubsequentlydecreasegonadotropins.WhenexogenousGnRHisadministeredinaphysiologicpatternthegonadotropinpulsefrequencynormalizesandovulationoccurs.34LevelsofCRHarealsoelevated,correlatingwithelevatedcortisolandsuppressionofGnRHrelease.32,35

Anovulationwithanorexiaandhypothalamicsuppressionisnotonlyduetolowbodyfat.Nutritionalstatusandphysicalactivityplayakeyroleinovulationandtreatment.Amenorrheawasnotedtooccurwhenweightdroppedbelow90%ofidealbodyweight,independentofbodyfatpercentage.36Inpatientswhogainappropriateamountsofweight,someremainanovulatoryandshowdecreasedgonadotropinlevels.Anovulatoryanorexicswhoweighedthesameasovulatinganorexicswerefoundtohavehigherlevelsofphysicalactivity.35Lowlevelsofleptinarealsofoundinpatientswhohavepooreatinghabitswhencontrollingforweight.33Asaresult,treatmentrequiresnutritionalimprovement,weightgain,andpsychiatriccare.Thissyndromeisseriousandcarriesmortalconsequences.



Phenothiazines

Tricyclicantidepressants

Metoclopramide

Antipsychotics

Morphine

Dextroamphetamine

Alphamethyldopa

Verapamil

Cimetidine

BULIMIANERVOSA

Bulimianervosaisanothereatingdisorderassociatedwithanovulation.Bulimianervosaisdefinedasbingeeatingwithsubsequentcompensatorybehavior(purging)andapoorbodyimage.31Unlikeanorexia,bulimicsarenotunderweight.Fiftypercentofbulimicshaveamenorrhea.37BulimicsdohavedecreasedlevelsofLHsecretionmuchlikepatientswithanorexia.LowLHinbulimiaisfoundwhenbodyweightislessthan85%ofprevioushighestweightindependentoftotalbodyfat.Patientswithbulimiaarenothypoestrogenicandareatlessriskforosteoporosis.However,persistentlyamenorrheicbulimicsdohaveanelevatedriskofendometrialcancerduetocontinuousestrogenstimulationoftheuterus.31Leptinlevelsinbulimicpatientscanbenormal,butdodecreasewithpoornutrition.33

PHARMACOLOGICAGENTS

Estrogenandprogesteroneeffectgonadotropinreleaseindirectlyusingbiogenicaminesasintermediaries.Norepinephrineandepinephrineareresponsibleforsignaltransductionbetweenthehypothalamusandthepituitary.38Theseaminesincrease2dayspriortotheLHsurge.39DopamineregulatesprolactinandGnRHreleaseandisblockedbyendogenousopioids.11,40

DrugsthataffectmetabolismandreleaseoftheseamineswillconsequentlyeffectchangesintheHPOaxis.ExamplesofthesemedicationsaregiveninTable1.ThesedrugswilloftencauseelevatedLHandprolactin.FSHisgenerallynotaffected.

Table1.Medicationscausinganovulation

Oneadditionalclassofdrugsthatmayaffectovulationisnonsteroidalantiinflammatorydrugs(NSAIDs).41Prostaglandinsareimportantforovulationandreleaseoftheovafromtheovary.PreovulatoryfolliclesproduceprostaglandinsinresponsetotheLHsurge.NSAIDsblockprostaglandinsynthesistherebypreventingovulation.41

POSTPILLANOVULATION

Hormonalcontraceptionhasbeenassociatedwithamenorrheaandaslowreturntofertilityafterstoppingtherapy.Thepostpillanovulationsyndromeishistoricallydefinedasafailuretomenstruatewithin1yearofdiscontinuinghormonalcontraception.42Muchofthedatasupportingaslowreturntofertilitywasbasedonhighdosehormonecontraceptivepills.43

Additionally,manypatientstakinghormonecontraceptionmayhaveunderlyinganovulationorsubfertility.Currentlythereareseveraldifferentvehiclesforadministeringcontraception.Currentdatasupportasimilarreturntofertilitybetweenmost



modalities.42Patientswithanovulationexceeding36monthsfollowingdiscontinuationoforalcontraceptivepills(OCPs)shouldhaveaworkupforothercausesofamenorrhea.Thepregnancyrateat1yearafterdiscontinuingcombinedoralcontraceptivepills(COCPs)isthesameasthepregnancyrateforpeoplenotpreviouslytakingbirthcontrol.42SomedatasuggestwomenwhohadtakenCOCPshadmorepregnanciesthanwomenwhohadnottakenCOCPs.44Thehormonecontainingintrauterinedevice(IUD)andthenonhormonecontainingIUDdonotsignificantlydifferfromCOCPsinreturntofertilityrates.42Fertilityafterdiscontinuingprogesteroneonlycontraceptivepillsdidnotdifferfromnonhormoneusers.Dataarenotavailableforcontinuoususeoralcontraception,however,extrapolatingfromimplantableandintrauterinedevicedatatherewerenodifferencesinpregnancyratesafterdiscontinuationcomparedtononcontraceptionpatients.Theonlymodalitythathadalowerpregnancyrateat1yearwhencomparedtononcontraceptionusersissubcutaneousdepomedroxyprogesterone.Insummary,pregnancyrates1yearafterstoppingbirthcontrolarethesameaspregnancyratesforwomenwhodonotusebirthcontrol.However,anevaluationworkupshouldbeperformedinpatientswhohaveamenorrheaformorethan36monthsafterdiscontinuingOCPs.

HYPOTHALAMICLESIONS

Tumors,inflammation,anddegenerationofthehypothalamuscanaffectovulatoryfunction.Generallytheseeventswillleadtoareductioningonadotropinreleasefromthepituitaryduetothetumorcompressingthepituitarystalk.45Otherhypothalamictumorsaffectovulationbysecretinghormones.46Inflammatorylesionswithinthehypothalamushavebeenshowntodecreasefunctionbyincreasinglevelsofcortisol.47

Themostcommonhypothalamictumoristhecraniopharyngioma.45Othertumorsincludegliomas,dermoids,meningiomas,andgerminomas.48Incraniopharyngiomas,growthhormone,thyroxin,andgonadotropinsaregenerallydecreased.45

StimulationwithGnRHdoesnotproduceanincreaseingonadotropinssuggestingadysfunctioninthebloodsupplytothepituitaryduetothetumor.Whenhormonallyactivetumorsareremoved,thesymptomsofhormoneexcessrapidlyimprove.48

Inflammatorylesionshavebeenseenintuberculosisandsarcoidosiscausinglowgonadotropins.47,49Treatmentforanatomicdefectsinvolvestreatmentoftheunderlyingcause.

CONGENITALDEFECTS

Hypothalamichypogonadismcanbeassociatedwithageneticsyndromeorseveralsinglegenemutations.KallmannssyndromeisadeficiencyofGnRHandconcurrentanosmia.50Thisraredisorderhasanincidenceof1:50,000.51ThesepatientshaveamigrationdefectofGnRHsecretingneuronsfromthethalamusandagenesisofolfactoryneurons.50SeveralmutationsoftheKAL1genehavebeenassociatedwiththeXlinkedformofthissyndrome,however,mostcasesaresporadicmutations.50,52BothLHandFSHaredecreasedasexpectedduetotheGnRHdeficiency.Folliclesareseeninearlystagesofmaturationandsuccessfulpregnancyhasoccurredusinggonadotropintherapy.51

Idiopathichypogonadotropichypogonadism(IHH)isacollectionofgeneticmutationsthatresultindelayofpuberty,infertility,andlowgonadotropins.53OneXlinkedrecessivemutationisadrenalhypoplasiacongenita(AHC),whichissimilartocongenitaladrenalhyperplasia(CAH)butdoesnothavehyperandrogenism.AHCgenemutationresultsinproductionofanabnormalDAX1proteinthatregulatesgonadotropinsecretioninthehypothalamusandpituitary.SeveralothergenesassociatedwithIHHincludeKAL1,FGFR1,GNRHR,andNELF.26Mutationsinthesegenesshowincompletepenetranceandvariablephenotypeinmenandresolutionhasbeenreorted.27ItremainstobeshownifwomenalsohaveareversiblesubtypeofIHH.WomenwithIHHhavehypoestrogenism,amenorrhea,andlowgonadotropinlevels.LeptinmutationsandleptinreceptormutationsareanothercauseofIHH.53MutationshavealsobeenfoundinthebetasubunitsofseveralpituitaryhormonesincludingLH,FSH,andthyrotropinandarediscussedlaterinthischapter.

AnothercongenitalcauseforhypothalamichypogonadismisBardetBiedlorLaurenceMoonsyndrome.Recentliteraturesupportsthatthesetwosyndromesarevariantsofthesamegeneticabnormalities.54Thesepatientspresentwithavariablephenotypeincludingobesity,polydactyly,retinalandrenalabnormalities,andhypogonadism.Thisisarareautosomal



recessivesyndromewithanincidenceof1:125,000to1:160,000.Severalgenemutationshavebeenisolatedinthesepatientsthatencodeforciliarymovementwhichisessentialfornormalorgandevelopment.55LHandFSHlevelscanbevariable.56

WhengivenGnRHstimulation,thesepatientshaveaLHresponsesimilartopubertalgirls.57Whengiventhyrotropinreleasinghormone,theTSHsecretionofthesepatientsisnormal,suggestinganovulationisduetohypothalamicdysfunction.

Pituitaryanovulation

Normalovulationrequirescommunicationbetweenthehypothalamus,pituitary,andovary.TheHPOaxisiscomplexandisinfluencedbyseveralotherprocessesinthebody.Thepituitaryglandactstoenablecommunicationbetweenthehypothalamusandtheovary.Theglandiscomposedofananteriorandaposteriorlobe.TheanteriorlobesecretesgonadotropinsinresponsetoGnRHfromthehypothalamustoproduceaneffectontheovary.Bythismeans,thepituitaryactsasanendocrineintermediarybetweenthebrainandthegonads.Hormonefeedbackregulatestherateofsecretiontomaintainregularovulationandcoordinatesexualfunction.Overgrowthofpituitarycellsorvascularinjurycanoccuranddisruptoralterproductionofhormones.Additionally,abnormalhormonescanbeproducedbythepituitaryresultinginineffectivepituitaryfunction.

PITUITARYTUMORS

Pituitarytumorscomprise1020%ofallbraintumors.58Theyareclassifiedasmacroadenomasifthesizeisgreaterthan10mmormicroadenomasiflessthan10mm.Clinically,pituitarytumorscanbeeitherfunctionalornonfunctionaldependingonwhetherornotthetumorproduceshormones.Seventypercentofpituitarytumorsarefunctional.Fortyfivepercentofadenomassecreteprolactin.59Mostfunctionalpituitarytumorsaremicroadenomas,however,manypatientswithmacroadenomashavemenstrualabnormalities.58Duetothelackofhormoneproduction,macroadenomasmaybediagnosedonlywhentheycausevisualproblemsfromcompressionofopticnerves.Microadenomasmostcommonlypresentwithhormoneabnormalities.Macroadenomascauseanovulationduetocompressionofthepituitaryasthemassenlarges.58Thebloodsupplytothepituitaryfromthehypothalamusisthemeansforhormonecontrolofgonadotropinrelease.60Compressionofthevessels,thegland,orbothresultsindecreasedproductionofpituitaryhormonesandsubsequentanovulation.Asthemassgrowsandcompressesthepituitary,endocrinologistshaveoftenobservedthatthefirsthormonetobelostisgrowthhormone,followedbygonadotropins.58Somepatientswithmacroadenomasignoremenstrualirregularitiesforyearsbeforeseekingcare.Inpatientsseekingfertilitytreatment,pituitarytumorsareoftendetectedearlieronmagneticresonanceimaging(MRI).Microadenomasoftenproduceelevatedlevelsofprolactin,whichcausesanovulation.61Ofpatientswithhyperprolactinemia,2025%willhavegalactorrhea.Elevatedlevelsofprolactincauseapositivefeedbacktodopaminerelease.DopamineincreasescauseadecreasedreleaseofGnRH.Therearealsodirecteffectsofprolactinontheovaryandpituitarydecreasingovulation.62,63Gonadotropinsecretingtumorshavebeenreportedaswell.60SerumLHandFSHlevelsareabnormalinsuchpatients,indicatinggonadotropinreleaseisnotunderthecontrolofGnRH.Sarcoidosisisachronicinflammatorydisease,whichresultsintheformationofgranulomasinmultipleorgansystems.64

Sarcoidosishasbeenfoundinthepituitaryandcancauseanovulation.65Themechanismofanovulationfromsarcoidosisisbelievedtobeacompressionoftheglandbythegranulomas,muchlikemacroadenomas.Treatmentinvolvessteroidreplacementandradiationtherapy,butduetotheprogressivenatureofthediseasethesetherapieshavenotbeenverysuccessful.

ISCHEMIA

Vascularcompromisetothepituitarybloodsupplycanresultinanovulation.Thisisknownaspituitaryapoplexy.66Several



situationscanleadtovascularinjuryincludingtumorcompressionofbloodsupply,cerebralvascularaccident,hemorrhagecausingshuntingofbloodfromthepituitary,anddiabetes.Sheehanssyndromeisischemicdamagetothepituitaryresultingfromvascularchangesatthetimeofparturition.67Sicklecelldiseasehasalsobeenseenwithhypopituitarism.68Infectionscanalsoleadtodamagetothepituitarygland.69Ischemiaofthepituitaryglandmostoftenresultsinlossofallhormones,unlikethesequentiallossseenwithtumorexpansion.Emptysellasyndromeisanotherconditioninwhichthepituitaryisnotvisualizedwithinthesellaturcicaandresultsinpartiallossofpituitaryfunction.

PITUITARYHORMONEDEFECTS

Anotherpituitarycauseofanovulationisabnormalitiesinthepituitaryhormonestructure.LHandFSHhavetwosubunits,alphaandbeta.Thealphasubunitstructureisveryconsistent,whilethebetasubunitcanvary.70Mutationsinthestructureofthebetasubunitcaninterferewithbindingtothealphasubunitandconsequentlycauseaninabilitytofunction.71PatientswithFSHabnormalitieshavedelayedpubertyanddecreasedsexhormonesalongwithanovulation.Becausethebetasubunitdiffersforeachhormonetheseabnormalitiesonlyaffectonegonadotropin.72ThediagnosiscanbedeterminedbyadministeringGnRH,whichresultsinnormalelevationofonlyonehormone,generallyLH.73

Onecharacteristicofgonadotropinsthatmaycontributetoabnormalhormonestructureisvariablebioactivity.74LHhasabioactivetypeandanimmunologicorinactivetype.InpatientswithanovulationthereappearstobeahigherconcentrationofbioactiveLHwhenstimulatedwithGnRH.ThetypesofFSHaremorevariableandconsequentlymaybemorepronetoabnormalproduction.70

Ovariancausesofanovulation

Theovarianfolliclerequireshormonestimulationtodevelop.4Gonadotropinsactontheovarytopromotegrowthandmaturationofprimordialfolliclesintoadominantfollicle.Inreturn,steroidhormonesareproducedbytheovaryandactasfeedbacktoregulatetheovulationsystem.Defectsinovarianfunctionaffectingovulationincludealackoffolliclestodevelop,anabnormalityinsteroidsecretion,orlackofcommunicationbetweenthegonadotropinsandtheovarianreceptors.Gonadotropinsareelevatedinovariandysfunctionbecauseestrogenlevelsarelow.75Thenormalfeedbacksignaltothehypothalamusisabsent.InhibinisanothersubstanceproducedbythefolliclethatinhibitsFSHrelease.76Althoughestrogenreplacementisimportanttoreducehealthrisksassociatedwithhypoestrogenemia,estrogenalonedoesnotcorrectthegonadotropinelevationwheninhibinisdeficient.

POLYCYSTICOVARYSYNDROME

Oneofthemorecomplexconditionsassociatedwithanovulationispolycysticovarysyndrome(PCOS).ThecriteriadefinedbythePCOSConsensusWorkshopGroup(Rotterdam)requiretwoofthreefeaturesforthediagnosisofPCOS.77Thesefeaturesincludeclinicalorbiochemicalevidenceofhyperandrogenemia,oligoovulationoranovulation,andpolycysticappearingovaries.77Usingthesecriteria,theincidenceofPCOSisgreaterthan5%inwomenofreproductiveage.78CommonlaboratoryfindingswithPCOSincludeelevatedLH,androgens,andestrogen,withnormalorlowFSH.79InmanybutnotallpatientswithPCOS,insulininsensitivityandobesityareseen.

Theoccurrenceofpolycysticovariesinthegeneralpopulationiscommon.79Twentytwopercentofovulatingwomenwillhavepolycysticappearingovariesonultrasound.However,73%ofanovulatorywomenwillhavepolycysticovaries.ThepresenceofpolycysticovariesdoesnotincreasetheriskofdevelopingPCOSinthefuture.80However,ifpresentwitholigomenorrheathereisanincreasedriskofdevelopingPCOS.79

ThecauseofanovulationinPCOSinvolvesdysfunctionofthenormalcyclicnatureofthemenstrualcycleandcanarisebyseveraldifferentmechanisms.Abnormalantralfollicledevelopmentandfunctionisafundamentalfeature.78Thecystic



appearanceoftheovariesresultsfromseveralfolliclesfailingtomatureproperlywithoutdevelopmentofadominantfollicle.Themultiplefolliclesproducelargeamountsofestradiol,whichinhibitsFSHreleasetherebypreventingfurtherfolliculardevelopment.Antimullerianhormone(AMH)maybeinvolvedinregulatingtheprogressionoffolliclesintogrowthphase,andabnormalitiesinAMHhavealsobeenproposedascontributorstotheetiologyofPCOS.

HalfofPCOSpatientsareobese.77ObesepatientswithPCOSaremorelikelytobeanovulatoryandhavesymptomsofexcessandrogens.78Excessadiposetissueincreasesperipheralconversionofandrogenstoestrone,whichinhibitsovulationatthehypothalamus.ObesepatientswithPCOShaveahigherincidenceofinsulinresistancethanobesepatientswithoutPCOS.Elevatedinsulinandinsulininsensitivityplayaroleinanovulationandhyperandrogenemia.Highlevelsofinsulinstimulatethethecacellstoincreaseandrogenproductionviainsulinlikegrowthfactors.77Elevatedandrogensfurtherarrestfolliculardevelopmentandresultinanovulation.Weightlossof510%ofbodyweightinobesepatientswillincreaseovulation.Obesityandhyperinsulinemiaincreasetheriskofdevelopingmetabolicsyndromeandsubsequentlysignificantlyincreasemortalityfromcardiovascularevents.81Hyperestrogenemiafromchronicanovulationincreasestheriskofdevelopinguterineandbreastcanceraswell.82

TreatmentofPCOSrequiresunderstandingofthegoalsofthepatient.Chronicanovulationwithunopposedestrogenshouldbetreatedwithcyclicprogesteronewithdrawal.82Symptomsofhirsutismcanbemanagedwithantiandrogensandoralcontraceptiveswithantiandrogenattributes.Forpatientsdesiringpregnancy,thefirstlineoftreatmentshouldbeweightloss.83Weightlossof510%ofbodyweighthasa50%returntoovulationanda33%pregnancyratewithin6months.Ifweightlossaloneisnotsuccessful,clomiphenecitratecanbeused.84TheASRM2008guidelinesstateglucophagecanbeaddedtoclomiphenecitrateifnotsuccessful,butthereisnobenefittoglucophagealoneforovulationinduction.AllPCOSpatientsshouldbescreenedfordiabetesmellituswitha2hourglucosetolerancetest(GTT)andhyperinsulinemiashouldbetreated.85

Laparoscopicovariandrilling(LOD)84hasbeenusedhowever,theprocedurecausesdestructionofprimordialfolliclesandmostspecialistseschewthistreatmentinwomeninterestedinfuturefertility.Finally,gonadotropintherapyorIVFareoptionsifotherstrategiesforovulationinductionarenotsuccessful.

NONPSYCHOGENICWEIGHTDISTURBANCES

In15%ofwomen,amenorrheaisrelatedtotheirbodyweight.86Amenorrheaoccurswhenwomenlose1015%oftheirnormalbodyweight.87However,absolutebodymassorfatcontentisnotasimportantinovulationasenergybalance.Energybalanceinvolvestheamountofenergysupplyandtheamountofusage.Inastudyofnonathletes,43%becameanovulatorywhentheystartedaggressivelyexercising.88Thesepatientshadarapidincreaseinenergyexpenditureaccompaniedbyweightloss.Intrainedathletes,cortisolandCRHlevelsareelevatedimplyingasuppressionofGnRHandsubsequentdecreaseinLHcausinganovulation.89SimilardecreasesinLHareseeninweightlossalonewhichresolvewithweightgain.88,90Thestateofgonadotropinsuppressionseeninwomenwithanegativeenergybalanceresultsinhypoestrogenemiaandincreasestheriskofdecreasedbonedensity.91Thislowestrogenstateisfurtherseenbythepresenceofvaginalatrophyinnonanorexicmalnourishedwomen.92

Theotherweightrelatedanovulatoryconditionisobesity.ObesityiscurrentlyofepidemicproportionsintheUSwithaprevalenceof21%ofthepopulationincreasingby16%annually.87Unlikeundernourishedpatients,obesepatientshaveastateofenergysurplus.Mostcommonlyobesityisaresultofasedentarylifestyle,butgeneticsmayplayarole.Anovulationinobesityresultsfromexcessandrogensandestrogencausingdecreasedprogesterone.93TheLHpulseamplitudeisalsodiminished.94Adiposetissueishighlymetabolicallyactiveandproduces50%ofpremenopausaltestosterone.87Furthermetabolicchangesseeninobesityincludedecreasedsexhormonebindingglobulin,FSH,prolactin,andcortisol.93Estroneissignificantlyincreasedbyperipheralconversioninadipocytes.Inadditiontoanovulation,obesepatientshaveincreasedrisksofspontaneousabortion,IVFfailure,andrequirehigherdosesofclomiphenecitrateandgonadotropins.87Modestweightlossof10%ofbodyweightdoesincreaseovulationrates.Bariatricsurgeryhasalsobeensuccessfulinimprovingovulation.95Theimprovedovulationfollowinggastricbypassisdirectlyproportionaltotheamountofpostoperativeweightloss.



ROLEOFLEPTININANOVULATION

Leptinisaproteinproducedbyadiposecellsthatactsasahormoneonthereproductiveaxis.96Serumlevelsofleptinfluctuatewitheatingandareindicatorsofenergystores.ReproductionrequiresenergyandleptinactsasasignaltotheHPOaxiswhenadequateenergyispresentforovulation.97Leptinreceptorshavebeenfoundinseveralendocrinetissuesincludinghypothalamus,anteriorpituitary,granulosaandthecacells,andinterstitialcellsoftheovary.Insulinandestrogenstimulateleptinproductionwhileandrogensdecreaseproduction.

TheeffectsofleptinonhormonesoftheHPOaxisvarywithdifferentphysiologicstates.GnRHpulsatilityisincreasedindirectlyviaafferentinterneuronsofthehypothalamusinresponsetoleptin.98LHreleaseisdirectlystimulatedasisFSHtoalesseramount.97Sinceleptinisanindicatorofenergyavailability,itisunderstandablethatleptinlevelswillbelowinstarvationsuchasanorexiaandunderweightwomen.Thisisalsopresentinhypothalamicamenorrhea.Consequently,ovulationisinhibitedbytheabsenceofleptinstimulationofGnRHrelease.ExogenousadministrationofleptinincreasesLHpulsefrequencyinthesepatientsindependentofbodymass.99Conversely,inobesityandPCOSleptinlevelsaresignificantlyincreased.97,100VeryhighlevelsofleptinantagonizefactorsinvolvedinLHandFSHreleaseandsuppressestradiolproductiontherebypreventingovulation.97Leptinactsasaregulatoryhormoneanddecreasesovulationinconditionsofextremeenergyimbalance.Theroleofleptininthediagnosisandtreatmentofanovulationisstillbeingstudied.

PSEUDOOVULATION/LUTEINIZEDUNRUPTUREDFOLLICLE

Luteinizedunrupturedfolliclesyndrome(LUF)maybeararecausefortransientanovulationandhasbeenlinkedtoNSAIDuse.101Prostaglandinsareimportantforfollicleruptureandovulation.Indomethacin,anNSAID,induceda50100%occurrenceofLUF.FertilityreturnsaftercessationofNSAIDs.Duetolowrecurrencerates,fertilityratesweresimilarbetweenpatientswithLUFandcontrols.Becauseofthehighprevalenceandtransientnature,currentthinkingisthatLUFisnotatruecauseofinfertility.

OVARIANTUMORS

Neoplasmsoftheovarycancauseanovulationbyseveralmechanisms.Tumorsintheovarycandisruptthestromaanddecreasenormaloocyterelease.102Somenonhormonesecretingtumorsreleaseadditionalsubstancesthatincreaseandrogenproduction.Thisexcessandrogenisconvertedbyaromataseintheperipheraltissuestoestrogen,whichprohibitsovulation.Ovariantumorscanalsoproducehormones.103Abnormallevelsofgonadotropinsdisruptthenormalovulatorycycleandpreventovulation.

PRIMARYOVARIANINSUFFICIENCY

Menopauseisthecessationofmensesformorethan1yearsignifyingacompletionofovarianfunction.Theaverageageofmenopauseis50yearsold.104Lossofovarianfunctionresultsfromthedepletionoffolliclesandthereforemaybemistakenforanovulation.Primaryovarianinsufficiency(POI)isthedepletionoffolliclereservepriortoage40.105Thiscanbeduetoeitherabsenceoffolliclesorabnormalovarianfunction.106POIoccursinapproximately1%ofallwomen.107MostoftenPOIisspontaneousandthecauseisunknown.POIisreviewedherebecauseinsomecasesthesyndromeistransient,withresultingovarianfunctionandbecausePOImustbedistinguishedfromothercausesofanovulation.

ThemostaccepteddefinitionofPOIisdisorganizedmensesoranovulationformorethan4monthspriortoage40.105IncludedareserumFSHmeasurementsinthemenopausalrangeontwooccasionsmorethan1monthapart.PatientswithPOIhavelowestrogenlevelsoftenatanearlyageandhormonereplacementisimportantforboneandcardiovascularhealth.108ThetermPOIhasreplacedthemorefinitetermprematureovarianfailurebecausethissyndromeoccursasacontinuumandasmallnumberofpatientsmayconceiveafterthediagnosisofPOI.105



SeveralabnormalitiesinovarianfunctioncancausePOI.MutationsinthegenecodingfortheFSHreceptorpreventFSHfrombindingtothesignalingreceptor.75FSHisrequiredforfolliclematurationandestrogenproduction,consequently,thesepatientshaveanovulationandhypoestrogenemia.ThesereceptorgenemutationsarecalledinactivatingmutationsduetotheeffectiveblockofFSHactivity.109Activatinggenemutationsalsooccur.ThesemutationspresentwithincreasedfunctionoftheFSHreceptoroftenbindingotherligands.110FSHreceptorfunctioncanalsobeaffectedbyautoantibodiesbindingreceptorsites.76

AconditionpreviouslycalledSavagesyndrome,orovarianresistance,ismarkedbyanovulationwithelevatedFSHandanormalkaryotype.TheovarieswillshowmultipleprimordialfolliclesfromthelackofFSHstimulation.UnlikeFSHreceptormutations,successfulpregnancieshavebeenachievedwithhormonereplacementinpatientswithSavagesyndrome.111

Currentstudieshaveexaminedovarianresistanceatamolecularlevel,therebydrawingdoubtontotheexistenceofSavagesyndromeasanindependentdisorder.

AutoantibodieshavebeenassociatedwithPOIand3361%ofunexplainedinfertilitycases.111,112Autoimmunepolyglandularsyndrome(APS)isaconditionwithautoantibodiesaffectingmultiplesystems.111ThreetypeshavebeenidentifiedwithAPStype1havingthehighestcorrelationtoPOI.Autoantibodieshavebeenfoundtobindgonadotropinreceptorsleadingtoanovulation.Addisonsdiseasehasthebestknownassociationwithautoimmuneovarianinsufficiency.113POIoccursin1020%ofpatientswithautoimmuneadrenalinsufficiency.114Autoantibodiestargetingadrenalcellsalsotargetthecacellsandsteroidproducingcellsleadingtoanovulation.ViralinfectionssuchasmumpscauseoophoritisandPOI.115Theamountofovarianfunctiondependsontheageatwhichthepatientwasexposedtothemyxovirus.

AbsenceoffollicledevelopmentalsoleadstoPOIandismostlyduetogeneticabnormalities.Thesepatientshavestreakovariesduetotheearlylossoffolliclesinuteroorbeforetheonsetofpuberty.Puregonadaldysgenesis,alsocalledXXGD,isapoorlyunderstoodcondition.116Theetiologyofthisgeneticabnormalityisnotknown,butoccurrencehasbeenassociatedwithconsanguinity.Thisautosomalrecessivedisorderisrarewithanestimatedincidenceof1:8300.OthergenemutationsincludeFOXL2andNR5A1.117,118FOXL2mutationisassociatedwithblepharophimosis/ptosis/epicanthusinversus(BPE)syndrometype1.117MutationsinFOXL2geneproduceabnormalproteinsontheforkheaddomainresultinginabnormalsignaltransduction.NR5A1inactivationcausesovarianhypoplasia.118DIA,ZFT,andXISTgenemutationsarealsolinkedtoPOI.119,120

RapidfollicleatresiaresultsinvariableonsetPOI.ThemostcommongeneticdefectisTurnersyndrome.Thesepatientshaverapidfollicleatresiabeforetheonsetofpubertyresultinginstreakovaries.106Becausetherateofatresiaisrapidandfolliclesareinitiallypresentintheovaries,2030%ofthesepatientswillreachspontaneouspuberty.Ofthisgroup,510%willbefertilepriortocompletelossoffollicles.TherehavebeenreportsofsuccessfulpregnanciesusingdonoreggsinpatientswithTurnersyndrome.Patientswithearlierovarianfailureshouldbegivenhormonereplacementtopreventbonedensityloss.

FMR1genemutationisassociatedwithacceleratedfollicleatresiaandfragileXsyndrome.121Themutationoccursin2%ofspontaneous46,XXPOIand14%ofspontaneous46,XXPOIwithafamilyhistory.105Additionally,1325%offragileXsyndromecarriershavePOI.119BecauseFMR1mutationoccursfrequentlywithPOI,andbecausetheXlinkedconditioncarriesariskofmentalretardationinmales,thisgenemutationshouldbescreenedforintheworkupofanonsyndromicpatientwithPOI.GalactocemiaisanothergeneticdisorderwithahighriskofPOI.122POIhasalsoresultedfromexposuretochemicalsolventscontaining2bromopropane.123Thisexposureresultedinarrestoffolliculardevelopmentwithrecoveryofovarianfunctionandpregnancyintwopatients.

Systemicanovulation

ACUTEANDCHRONICDISEASE

Chronicanovulationisseeninillnessandstresscausedbychronicillness.124Thisresultsfromeitherthediseasedorgansystem



alteringreproductivehormonelevelsorelevatedstresshormonesaffectingtheHPOaxisasnotedabove.Cytokinesareelevatedinsystemicdisease,whichcandirectlyinhibitreproductivehormoneproducingorgans.125Ashealthstatusimproves,reproductivefunctionoftenresumes.Withmanychronicdiseases,however,asfertilityreturns,pregnancymaynegativelyimpactapatientshealth.

RENALDISEASE

Earlyrenalinsufficiencyresultsindecreasedfertilityandlowlibido.Inchildren,onsetofpubertyisdelayed.126Withdevelopmentofchronicrenalfailure,anovulationoccurs.LHpulsefrequencydecreasesresultinginlossoftheLHsurgeandsubsequentanovulation.TheLHtoFSHratioisslightlyincreasedbuttheLHresponsetoGnRHstimulationisdelayed.Hyperprolactinemiaisoftenseenduetoincreasedprolactinsecretionanddecreasedrenalclearance.Menstruationresumeswithdialysisorrenaltransplant.124Ovulationisseenin82.1%ofpatientsfollowingrenaltransplant.126

LIVERDISEASE

Theeffectofliverdiseaseonfertilitydependsontheageofonsetandetiology.Childrenwithliverdiseasewillhavedelayedpubertyby1.1yearsonaverage.126Fullsexualdevelopmentreturnswithin3yearsoftransplant.Gonadotropinmeasurementsarenormalinviralhepatitis,however,anovulationisseen.Hyperestrogenemiaoccursduetoaromatizationofweakandrogensfromtheportalcirculationandconsequentlyovulationisprevented.Womenwithalcoholichepatitishaveearlymenopause.Inalcoholics2040yearsold,decreasednumbersoffolliclesareseenandnocorporaluteaareseen.Cirrhosisisassociatedwithobesityandconsequentlyestrogenlevelsmaybeelevatedfromperipheralconversion.124

Secondaryamenorrheaoccursin50%ofwomenwithendstageliverdisease(ESLD).126Menstrualirregularityisoftenthepresentingcomplaintleadingtothediagnosisofliverdisease.InpremenopausalpatientswithESLD,gonadotropinlevelsaredecreasedasareestrogenandtestosterone.ThesepatientsdonotrespondwelltoGnRHstimulationorclomiphenecitrate.Followinglivertransplant95%ofpatientsunder45yearsoldwillresumemenses.Infertilityinthispopulationis2550%followingtransplant.

THYROIDDISEASE

Thyroiddiseaseisacommoncauseofmenstrualcycleirregularity.Oligomenorrheaandamenorrheaoccurin58%ofpatientswithhyperthyroidism.127Anovulationoccursinsevereuntreateddisease.Gonadotropinsareelevatedinhyperthyroidism,asissexhormonebindingglobulin(SHBG).TheelevationinSHBGleadstoanincreaseintotaltestosterone.Hypothyroidismpresentswithmenorrhagia.Anovulationresultsfromelevatedthyroidstimulatinghormone,whichactsasareleasingfactorforprolactin,andelevatedlevelsofprolactininturncontributetoanovulationasdescribedpreviously.

ADRENALDISEASE

Adrenalhormonesareinvolvedintheregulationofovulation.InacquiredadrenalinsufficiencyautoantibodiesalsomayblockFSHreceptors.113Congenitaladrenalhyperplasiaisassociatedwithdelayedpubertyandamenorrhea.128Glucocorticoidsaredecreasedandandrogenicprecursorsareincreased.Folliclesarepresentintheovariesbutovulationdoesnotoccurbecauseoftheexcessivelevelsofandrogens.

HIV

OvulationstudiesinHIVareconflicting.PatientswithHIVareexposedtoseveralmedicationsandoftenhaveconcomitantinfections.SomestudiesshowanovulationinHIVpositivewomencorrelatestothenormalpopulation.OtherstudiesreportworseningovarianfunctionwithdecreasedCD4cellcounts.2ConsensusmaintainsthatthereiscurrentlynodifferenceinovulationratesinHIVpositivewomencomparedtononinfectedwomen.

DIAGNOSISANDTREATMENT

Themostimportantconsiderationintheworkupofanovulationistodeterminethepatientsgoals.Treatmentofthepatient



whowantstogetpregnantdiffersfromthatofthepatientwhoisconcernedabouttherisksofearlymenopause.Inpatientswhodesirepregnancy,theclinicianneedstodetermineiftheyareactivelytryingforpregnancy,orareplanningforpregnancyseveralyearsinthefuture.Theapproachoutlinedbelowbeginswiththepatientwhoisactivelytryingforpregnancy.

History

Manypatientswithanovulationwillpresentwithamenorrhea.Primaryamenorrheaisfailuretomenstruateandnosecondarysexualcharacteristicsbyage14ornomenstruationbyage16withnormalsexualdevelopment.129Secondaryamenorrheaisthecessationofmenstruationformorethan3months.130Theetiologiesofprimaryandsecondaryamenorrheadiffer.Primaryamenorrheaisoftenseenincongenitaldisorders.131Themostcommoncauseofsecondaryamenorrheainwomenofchildbearingageispregnancy,consequentlytheworkupforanovulationshouldbeginwithapregnancytest.

Detailsofapatientspreviousmedicalhistorycandirecttheevaluationofanovulation.Chronicdiseasecanaffectovulationandmayincreaserisksduringpregnancy.132Psychiatricproblemsarealsooftenassociatedwithovulationdysfunction.Theuseofanyantipsychoticmedicationsshouldbenoted.40Detailsofpreviouspregnanciesarelikewiseimportantintheevaluationofovulationandcanhelpdistinguishgeneticdisordersfromlateronsetanovulation.

Physical

Thephysicalexamshouldincludeanevaluationofvitalsigns,height,weight,BMI,andappearance.ObesityiscommonlyassociatedwithanovulationandPCOS.77Verythinpatientsmayhaveanorexiaornutritionaldeficits.HirsutismmaysuggestPCOS,CAHoranandrogensecretingtumor.Visualfieldtestingisusefulinpatientswhoreportvisualchangessuggestingapituitarytumor.Palpationofthethyroidandabdomenshouldalsobeperformedtoevaluateformasses.Evaluationofthepatientwithprimaryamenorrheashouldincludeabimanualexamtodeterminethepresenceofapatentoutflowtractanduterus.

Laboratorytests

Inpatientswithamenorrhea,pregnancyshouldbeconsideredandapregnancytestperformedearlyintheworkup.EvaluationoftheHPOaxisshouldbeperformedinastepwisefashion.Serumestradiolandgonadotropinsdetermineovarianfunction.FSHmeasurementshavebeenstandardizedforday3ofthemenstrualcycle.However,inpatientswithamenorrheaarandomFSHisappropriate.MeasurementofLHhaslimitedclinicaluse.TheratioofLHtoFSHhasbeenstudiedforPCOSbutisnotincludedinthedefinitionofthesyndromeandisthereforenotnecessary.77

ElevatedFSHindicatesanovarianproblem.Inpatientsunder30yearsoldwithanelevatedFSH,akaryotypeshouldbeperformed.AnincreasedriskofovariancancerisseeninXYfemaleswithgonadaldysgenesis.133Turnersyndrome(45,XO)isassociatedwithincreasedriskforcardiovascular,thyroid,andrenaldisease.134Forthesepatients,akaryotypeisveryusefulintheworkupparticularlyrelatingtofuturepregnancyandhealth.InpatientswithelevatedFSHandanormalkaryotype,ovarianresistanceandPOIareconsidered.Atrialofovulationinductionmaybeperformedusingclomiphenecitrateasdescribedlater.Ifthereisnobenefitofclomiphene,exogenousgonadotropinsmaybeeffective.

NormalordecreasedFSHvaluessuggestdysfunctionoftheHPOaxis.Subsequenttestingincludesprolactin,TSH,andT4.Thyroidabnormalitiesareverycommonandmaybeseeninupto4%ofpatientswithinfertility.135TreatmentforthyroiddiseaseoftenrestoresHPOaxisfunction.HyperprolactinemiashoulddirectthecliniciantoobtainanMRIofthepituitary.Serumprolactinlevelsgreaterthan250g/Lareseeninprolactinsecretingmacroadenomas.136Macroadenomasmayrequiresurgery,whilemanymicroadenomascanbesuccessfullytreatedwithmedicaltherapy.137

Inpatientswithsignsofhirsutism,serumandrogensincludingtestosteroneanddehydroepiandrosterone(DHEAS)canbe



evaluated.Atestosteronelevelisausefulandrogentestindeterminingthecauseofhirsutisminwomen.138Elevatedfreetestosteroneisseenin70%ofwomenwithPCOS.Duetotechnicallimitationsintestingforfreetestosterone,measurementoftotaltestosteronecanbeused.DHEASisproducedprimarilyfromtheadrenalglandandelevatedlevelssuggestanadrenaltumor.Manyandrogensecretingtumors,however,causeseveresignsofhyperandrogenismincludingvirilizationandclitoromegally.139AnormalDHEASlevelshoulddirectattentiontotheovaryastheoriginofexcessandrogens.Anotherusefulhormonetestinhirsutismis17hydroxyprogesterone.Thisisproducedintheadrenalglandandtheovary,andiselevatedinCAH.MostpatientswithhirsutismandPCOSwillhaveelevatedtestosteronelevels,whileonly2535%willhaveelevatedDHEAS.138

AnadditionallaboratorytestforpatientswithPCOSisa2hourGTT.85Thistestinvolvesexamininginsulinandglucoselevelsfollowingadministrationofa75gglucosebolus.140Theglucosetolerancetestisusefulfordetermininginsulinresistance.Additionally,obesePCOSpatientsareatincreasedriskfordyslipidemiaandmetabolicsyndromeandaserumlipidprofileisappropriate.141Elevatedlipidlevels,particularlyinyoungpatients,mayincreasetheriskofcardiovasculardiseaselaterinlife.Diet,weightloss,andlifestylemodificationsshouldberecommendedtopatientswithmetabolicsyndromerisks.

Imagingtests

Ultrasoundisaninvaluabletoolfortheevaluationofgynecologicproblemsincludingtheassessmentofovarianarchitecture,whichisacriterionforthediagnosisofPCOS.Transvaginalultrasoundprovidesareliablemeasurementofthethicknessoftheendometriallining.142Athickenedendometrialliningsuggesysthepresenceandeffectofestrogen.Longtermanovulationleadstochronicestrogenstimulationoftheuterusandincreasestheriskofuterinecancer.143Sincethereisnotgoodcorrelationbetweenthicknessandabsenceofendometrialhyperlasiaorcancer,144itisjustifiedtosampletheendometriallininginchronicanovulatorypatientsindependentoftheendometrialthickness.Ultrasoundcanalsobeusedtoevaluatetheovariesandmeasurethenumberantralfollicles.Antralfolliclecountisasensitivetestfordeterminingovarianreserveandresponsetoovarianstimulation.145Alownumberofantralfolliclesduringthefollicularphaseofthemenstrualcycleisanindicationofpoorovarianreserve.UltrasoundevaluationoftheovaryisusefulinthediagnosisofPCOS.Tosatisfythedefinitionofpolycysticovaries,eachovarymustcontainmorethan12follicles29mminsizeoracalculatedovarianvolumemorethan10mL.146

Combinedapproach

Withanovulationitisimportanttocombineseveraltestsinordertocompletelyevaluatethepatient.Anexampleofthisistheevaluationofdiminishedovarianreserve.CombiningpatientdemographicssuchasagewithserumFSH,antimullerianhormoneandantralfolliclecountgivesamoreaccurateassessmentofapatientschancesofsuccessfulpregnancy.147

Counselingpatientsaboutpropernutrition,weightmanagement,andstressreductioncanenhancefertilityevenwhenothercausesofanovulationaredetermined.Somepatientsplantodelaypregnancyeitherforweightmanagementorbecausetheyareundergoingtherapyforothermedicalconditions.Forwomenwhoarechronicallyanovulatoryandhaveunopposedestrogenstimulationoftheuterus,itisimportanttotreatwithprogesteroneonaregularbasistoreducetheriskofendometrialcancer.142Foranovulatorywomenwithoutestrogen,hormonereplacementshouldbeconsideredforbonehealth.148

Ovulationinduction

Thetreatmentforanovulatorywomenwhodesirepregnancyvariesbasedonthecauseoftheiranovulation.Ifanovulationisduetoatumorormedicalcondition,treatmentoftheunderlyingcausemayimproveovulation.Forexample,patientswithhyperprolactinemiaoftenresumeovulationaftertreatmentwithadopamineagonist,andthisshouldbeevaluatedbefore



treatingwithovulationinducingagents.149

Clomiphenecitrateisthefirstlinemedicaltreatmentforovulationinduction.150Itisaselectiveestrogenreceptormodulatorthatincreasesovulationbybindingestrogenreceptorsinthehypothalamus.151ThisblockadecausesincreasedGnRHreleaseandincreasesovulation.Thestartingdoseofclomipheneis50mgdailyfor5daysbeginningonday2ofthemenstrualcycle.152

Thiscanbeincreasedby50mgperdayforeachsubsequentcycleifpregnancydoesnotoccur.Themaximumdosageofclomipheneis200mgperday.ClomiphenecitrateisusefulforincreasingGnRHrelease,however,itrequiresendogenoushormoneproduction.

Incasesofclomiphenefailuregonadotropintherapyisoftenusedtoinduceovulation.Gonadotropinsincludehumanmenopausalgonadotropins(hMG)orrecombinantsyntheticFSHandLH.153ForPCOSpatientswhofailclomiphene,FSHtreatmentisofteneffectiveduetotheendogenouslyhighlevelsofLHpresentinPCOS.84InhypothalamichypogonadotropicanovulationbothFSHandLHreplacementarerequiredanditisadvisabletobeginwithverylowdosesofLHforseveralweeksbeforeFSHisadded.Dosingregimensvary,butmanycentersstartwithalowdosesuchas37.575IUperdayfor712daysuntiladominantfollicle1618mmispresent.150Afterdevelopmentofadominantfollicle,humanchorionicgonadotropin(hCG)oraGnRHagonistisadministeredtoinduceoocyterelease.Progesteronesupportduringtheinducedlutealphaseshouldbeconsideredbecauseendogenoushormoneproductionmaybeinsufficient.Severalconsiderationsapplywithovulationinductionforcertainanovulatoryetiologies.ManystudieshaveevaluatedtheuseofmetforminforovulationinductioninPCOS.152,154TheredoesnotappeartobeabenefittousingmetforminaloneforovulationinductioninPCOSpatients,however,itisbeneficialinmanaginginsulininsensitivityinthesepatients.152Inaddition,manypatientswithhypothalamicanovulationdonotovulatewithclomiphenecitrate.Itisreasonabletobeginusinggonadotropinstotreatsuchpatientswithoutatrialofclomiphene.Inconclusion,therearemanycausesofanovulation.Propertreatmentmustincludecorrectassessmentoftheunderlyingcauseofanovulation,treatmentofanyidentifiableconditions,andifappropriateovulationinductionusingclomiphenecitrateorgonadotropins.

REFERENCES

1 ShermanB,KorenmanS:Hormonalcharacteristicsofthehumanmenstrualcyclethroughoutreproductivelife.JClinInvest55:699,1975

2 CejtinH:GynecologicissuesintheHIVinfectedWoman.InfectiousDiseaseClinicsofNorthAmerica22:709,2008

3 LegroRS:Diagnosticcriteriainpolycysticovarysyndrome.SeminarsinReproductiveMedicine21(3):267,2003

4 GougeonA:Regulationofovarianfolliculardevelopmentinprimates:Factsandhypotheses.EndocrinRev17:121,1996

5 EricksonGF:Physiologicbasisofovulationinduction.SeminarsinReproductiveEndocrinology14(4):287,1996

6 MeduriG,BachelotA,CoccaMP,VasseurC,RodienP,KuttennF,TouraineP,MisrahiM:MolecularpathologyoftheFSHreceptor:newinsightsinFSHpathology.MolecularandCellularEndocrinology282:130,2008

7 KwintkiewiczJ,GiudiceLC:Theinterplayofinsulinlikegrowthfactors,gonadotropins,andendocrinedisruptorsinovarianfolliculardevelopmentandfunction.SeminarsinReproductiveMedicine27(1):43,2009

8 MarshallJ,KelchR:Gonadotropinreleasinghormone:Roleofpulsatilesecretionintheregulationofreproduction.NEnglJ



Med315:1459,1986

9 KalraS,KalraP:Opioidandrenergicsteroidconnectioninregulationofluteinizinghormonesecretionintherat.Neuroendocrinology38:418,1984

10 VeldhuisJ,RogolA,SamojlikEetal:Roleofendogenousopiatesintheexpressionofnegativefeedbackactionsofestrogenandandrogenonpulsatilepropertiesofluteinizinghormonesecretioninman.JClinInvest74:47,1984

11 ChangCL,WangTH,HorngSG,WuHM,WangHS,SoongYK:TheconcentrationoninhibinBinfollicularfluid:relationtooocytematurationandembryodevelopment.HumanReproduction17(7):1724,2002

12 CentenoML,SanchezRL,ReddyAP,CameronJL,BetheaCL:Corticotrophinreleasinghormoneandproopiomelanocortingeneexpressioninfemalemonkeyswithdifferencesinsensitivitytostress.Neuroendocrinology86:277,2007

13 BergaS,DanielsT,GilesD:Womenwithfunctionalhypothalamicamenorrheabutnototherformsofanovulationdisplayamplifiedcortisolconcentrations.FertilSteril67:1024,1997

14 ElenkovIJ,ChrousosGP:Stresssystemorganization,physiology,andimmunoregulation.Neuroimmunomodulation13:257,2006

15 BergaSL:Thebrainandthemenstrualcycle.GynecologicalEndocrinology24(10):537,2008

16 WilliamsNI,BergaSL,CameronJL:Synergismbetweenpsychosocialandmetabolicstressors:impactonreproductivefunctionincynomolgusmonkeys.AmJPhysiolEndocrinolMetab293:E270,2007

17 NakamuraK,ShepsS,ArckPC:Stressandreproductivefailure:pastnotions,presentinsightsandfuturedirections.JAssistReprodGenet25:47,2008

18 KalantaridouS,MakrigiannakisA,ZoumakisE,ChrousosGP:Reproductivefunctionsofcorticotrophinreleasinghormone.Researchandpotentialclinicalutilityofantalarmins.AmericanJournalofReproductiveImmunology51:269,2004

19 PruessnerJ,ChampagneF,MeaneyMJ,DagherA:Dopaminereleaseinresponsetoapsychologicalstressinhumansanditsrelationshiptoearlylifematernalcare.JNeurosci24(11):2825,2004

20 ChrousosG:OrganizationandIntegrationoftheEndocrineSystem.SleepMedClin2(2):125,2007

21 NgEHY,SoWS,GaoJ,WongYY,HoPC:Theroleofacupunctureinthemanagementofsubfertility.FertilityandSterility90(1):1,2008

22 MarcusMD,LoucksTL,BergaSL:Psychologicalcorrelatesoffunctionalhypothalamicamenorrhea.FertilityandSterility76(2):310,2001

23 LaughlinG,DominguezC,YenS:Nutritionalandendocrinemetabolicaberrationsinwomenwithfunctionalhypothalamicamenorrhea.JClinEndocrinolMetab83:25,1998



24 BombaM,GamberaA,BoniniL,PeroniM,NeriF,ScagliolaP,NacinovichR:Endocrineprofilesandneuropsychologiccorrelatesoffunctionalhypothalamicamenorrheainadolescents.FertilityandSterility87(4):876,2007

25 BergaS,MortolaJ,GirtonLetal:Neuroendocrineaberrationsinwomenwithfunctionalhypothalamicamenorrhea.JClinEndocrinolMetabol68:301,1989

26 PitteloudN,QuintonR,PearceS,RaivioT,AciernoJ,DwyerA,PlummerL,HughesV,SeminaraS,ChengY,LiW,MaccollG,EliseenkovaAV,OlsenSK,IbrahimiOA,HayesFJ,BoeppleP,HallJ,BoulouxP,MohammadiM,CrowleyW:Digenicmutationsaccountforvariablephenotypesinidiopathichypogonadotropichypogonadism.TheJournalofClinicalInvestigation117(2):457,2007

27 RaivioT,FalardeauJ,DwyerA,QuintonR,HayesFJ,HughesV,ColeLW,PearceSH,LeeH,BoeppleP,CrowleyWF,PitteloudN:Reversalofidiopathichypogonadotropichypogonadism.TheNewEnglandJournalofMedicine357(9):863,2007

28 McClintockM:Menstrualsyndromeandsuppression.Nature229:244,1971

29 GoldP,GoodwinF,ChrousosG:Clinicalandbiochemicalmanifestationsofdepression.NEnglJMed319:413,1988

30 BoyarR,KatzJ,FindelsteinJetal:Anorexianervosa:Immaturityofthe24hourluteinizinghormonesecretorypattern.NEnglJMed291:861,1974

31 SeidenfeldM,RickertV:Impactofanorexia,bulimia,andobesityonthegynecologicalhealthofadolescents.AmericanFamilyPhysician64(3):445,2001

32 StvingRK,HangaardJ,HansenNordM,HagenC:Areviewofendocrinechangesinanorexianervosa.JPsychiatrRes33(2):139,1999

33 NakaiY,HamagakiS,KatoS,SeinoY,TakagiR,KurimotoF:Roleofleptininwomenwitheatingdisorders.IntJEatDisord.26(1):29,1999

34 CorneliaJ,BinsbergenV,HerganJetal:Acomparativeandlongitudinalstudyonendocrinechangesrelatedtoovarianfunctioninpatientswithanorexianervosa.JClinEndocrinolMetabol71:705,1990

35 JacoangeliF,MasalaS,StaarMezzasalmaF,FioriR,MartinettiA,FiconeriC,NoviB,PierangeliS,MarchettiG,SimonettiG,BolleaMR:Amenorrheaafterweightrecoverinanorexianervosa:roleofbodycompositionandendocrineabnormalities.EatWeightDisord.11(1):e20,2006

36 GoldenNH,JacobsonMS,SchebendachJ,SolantoMV,HertzSM,ShenkerIR:Resumptionofmensesinanorexianervosa.ArchPediatrAdolescMed.151(1):16,1997

37 WeltzinTE,CameronJ,BergaS,KayeWH:Predictionofreproductivestatusinwomenwithbulimianervosabypasthighweight.AmJPsychiatry151(1):136,1994

38 CrowleyWR:Reproductiveneuroendocrineregulationinthefemaleratbycentralcatecholamineneuropeptideinteractions:alocalcontrolhypothesis.AnnNYAcadSci474:423,1986



39 ZuspanF,ZuspanJ:Ovulatoryplasmaamine(epinephrineandnorepinephrine)surgeinthewoman.AmJObstetGynecol117:654,1973

40 SmithS,WheelerMJ,MurrayR,OKeaneV:Theeffectsofantipsychoticinducedhyperprolactinaemiaonthehypothalamicpituitarygonadalaxis.JournalofClinicalPsychopharmacology22(2):109,2002

41 GaytnM,MoralesC,BellidoC,SnchezCriadoJE,GaytnF:Nonsteroidalantiinflammatorydrugs(NSAIDs)andovulation:lessonsfrommorphology.HistolHistopathol21(5):541,2006

42 BarnhartKT,SchreiberCA:Returntofertilityfollowingdiscontinuationoforalcontraceptives.FertilityandSterility91(3):659,2009

43 HassanMAM,KillickSR:Isprevioususeofhormonalcontraceptionassociatedwithadetrimentaleffectonsubsequentfecundity?HumanReproduction19(12):344,2004

44 FarrowA,HullMGR,NorthstoneK,TaylorH,FordWCL,GoldingJ:Prolongeduseoforalcontraceptionbeforeaplannedpregnancyisassociatedwithariskofdelayedconception.HumanReproduction17(10):2754,2002

45 JenkinsJ,GilbertC,AngV:Hypothalamicpituitaryfunctioninpatientswithcraniopharyngiomas.JClinEndocrinolMetabol43:394,1976

46 NeffF,WeirichG,HerzogP,SchlosserH,KiebachC,SchlegelJ:A35yearoldwomanwithanintrasellarandsuprasellarlesion.BrainPathol18(1):108,2008

47 BottassoO,BayML,BesedovskyH,delReyA:Theimmunoendocrinecomponentinthepathogenesisoftuberculosis.ScandJImmunol66(23):166,2007

48 HadjilambrisK,FahlbuschR,HeinzE:TrueprecociouspubertyofagirlwithhamartomaoftheCNSsuccessfullytreatedbyoperation.EurJPediatr145:148,1986

49 BihanH,ChristozovaV,DumasJL,JomaaR,ValeyreD,TaziA,ReachG,KrivitzkyA,CohenR:Sarcoidosis:clinical,hormonal,andmagneticresonanceimaging(MRI)manifestationsofhypothalamicpituitarydiseasein9patientsandreviewoftheliterature.Medicine(Baltimore)86(5):259,2007

50 GeorgopoulosN,ProlongF,SeidmanCetal:GeneticheterogeneityevidencedbylowincidenceofKAL1genemutationsinsporadiccasesofgonadotropinreleasinghormonedeficiency.JClinEndocrinolMetab82:213,1997

51 AharoniA,TalJ,PaltieliYetal:Kallmannsyndrome:Acaseoftwinpregnancyandreviewoftheliterature.ObstetGynecolSurv44:491,1989

52 BeckD,FrancoB,SherinsRetal:Briefreport:IntragenicdeletionoftheKalig1geneinKallmann'ssyndrome.NEnglJMed326:1752,1992

53 LaymanL:Geneticsofhypogonadotropichypogonadism.AmJMedGenet89:240,1999



54 MooreSJ,GreenJS,FanY,BhogalAK,DicksE,FernandezBA,StefanelliM,MurphyC,CramerBC,DeanJC,BealesPL,KatsanisN,BassettAS,DavidsonWS,ParfreyPS.ClinicalandgeneticepidemiologyofBardetBiedlsyndromeinNewfoundland:a22yearprospective,populationbased,cohortstudy.AmJMedGenetA132(4):352,2005

55 BlacqueOE,ReardonMJ,LiC,McCarthyJ,MahjoubMR,AnsleySJ,BadanoJL,MahAK,BealesPL,DavidsonWS,JohnsenRC,AudehM,PlasterkRH,BaillieDL,KatsanisN.LossofC.elegansBBS7andBBS8proteinfunctionresultsinciliadefectsandcompromisedintraflagellartransport.GenesDev200418:1630

56 GreenJ,ParfreyP,HarnettJetal:ThecardinalmanifestationsofBardetBiedlsyndrome,aformofLaurenceMoonBiedlsyndrome.NEnglJMed321:1002,1989

57 LeeCS,GallePC,McDonoughPG:TheLaurenceMoonBardetBiedlsyndrome.Casereportandendocrinologicevaluation.JReprodMed.31(5):353,1986

58 CaladoML,FernandesJC,MachadoHR,EliasLL,Moreira1AC,CastroM:Nonfunctioningpituitaryadenomas:clinicalfeature,laboratorialandimagingassessment,therapeuticmanagementandoutcome.ArqBrasendocrinolmetab53(1):31,2009

59 ArafahBM,NasrallahMP:Pituitarytumors:Pathophysiology,clinicalmanifestationsandmanagement.EndocrinerelatedCancer8:287,2001

60 WhiteM,NewlandD,ThompsonCetal:LHandFSHsecretionandresponsestoGnRHandTRHinpatientswithclinicallyfunctionlesspituitaryadenomas.ClinEndocrinol32:681,1990

61 FranksS,MurrayM,JeguierAetal:Incidenceandsignificanceofhyperprolactinemiainwomenwithamenorrhea.ClinEndocrinol4:597,1975

62 McNeillyAS,GlasierA,JonassenJ,HowiePW:Evidencefordirectinhibitionofovarianfunctionbyprolactin.JReprodFert65:559,1982

63 HendersonHL,TownsendJ,TortoneseDJ:DirecteffectsofprolactinanddopamineonthegonadotrophresponsetoGnRH.JournalofEndocrinology197:343,2008

64 TakanoK:Sarcoidosisofthehypothalamusandpituitary.InternalMedicine43(10):894,2004

65 LipnickRN,HungW,PandianMR:Neurosarcoidosispresentingassecondaryamenorrheainateenager.JournalofAdolescentHealth14:464,1993

66 SempleP,JaneJ,LawsE:Clinicalrelevanceofprecipitatingfactorsinpituitaryapoplexy.Neurosurgery61(5):956,2007

67 VeldhuisJD,HammondJM:Endocrinefunctionafterspontaneousinfarctionofthehumanpituitary.EndocrineReviews1(1):100,1980

68 PastoreRA,AndersonJW,HermanRH:Anteriorandposteriorhypopituitarismassociatedwithsicklecelltrait.Annalsof



InternalMedicine71(3):593,1969

69 PepeneCE,IlieI,MihuD,StanH,AlbuS,DunceaI:Primarypituitaryabscessfollowedbyemptysellasyndromeinanadolescentgirl.Pituitary2008[Epub]

70 HsuehA,BicsakT,JraXetal:Granulosacellsashormonetargets:Theroleofbiologicallyactivefolliclestimulatinghormoneinreproduction.RecentProgrHormRes45:209,1989

71 LaymanL,LeeE,PeekDetal:Delayedpubertyandhypogonadismcausedbyamutationinthefolliclestimulatinghormonesubunitgene.NEnglJMed337:607,1997

72 MatthewsC,BorgatoS,BeckPeccoyPetal:Primaryamenorrheaandinfertilityduetoamutationinthesubunitoffolliclestimulatinghormone.NatureGenet5:83,1993

73 RabinowitzD,BenvenisteR,LinderJetal:Isolatedfolliclestimulatinghormonedeficiencyrevisited.NEnglJMed300:126,1979

74 SuzinamiH,MasaokaH,KorzumiYetal:Biologicalandimmunologicalcharacterizationofhumanluteinizinghormonedischargebythestimulationofsyntheticluteinizinghormonereleasinghormoneinnormalandovulatingwomen.EndocrinolJpn29:523,1982

75 AiitomakiK,LucenaJ,PakarinenPetal:Mutationinthefolliclestimulatinghormonereceptorgenecauseshereditaryhypergonadotropicovarianfailure.Cell82:959,1995

76 AriciA,MatalliotakisI,KoumantakisG,GoumenouA,NeonakiM,KoumantakisE:DiagnosticroleofinhibinBinresistantovarysyndromeassociatedwithsecondaryamenorrhea.FertilityandSterility78(6):1324,2002

77 BroekmansFJ,KnauffEAH,LavenJS,EijkemansMJ,FauserBCJM:PCOSaccordingtotheRotterdamconsensuscriteria.BJOG113:1210,2006

78 FranksS,StarkJ,HardyK:Follicledynamicsandanovulationinpolycysticovarysyndrome.HumanReproductiveUpdate14(4):367,2008

79 FranksS:Polycysticovarysyndrome.NEnglJMed333:853,1995

80 MurphyMK,HallJE,AdamsJM,LeeH,WeltCK:Polycysticovarianmorphologyinnormalwomendoesnotpredictthedevelopmentofpolycysticovariansyndrome.JournalofClinicalEndocrinologyandMetabolism91(10):3878,2006

81 NestlerJ:Polycysticovarysyndrome:Adisorderforthegeneralist.FertilSteril70:811,1998

82 PapaioannouS,TafettasJ:AnovulationwithorwithoutPCO,hyperandrogenemia,andhyperinsulinemiaaspromotersofendometrialandbreastcancer.BestPracticeandResearchClinicalObstetricsandGynecology1,2009

83 CrosignaniPG,ColomboM,VegettiW,SomiglianaE,GessatiA,RagniG:Overweightandobeseanovulatorypatientswith



polycysticovaries:parallelimprovementsinanthropometricindices,ovarianphysiologyandfertilityrateinducedbydiet.HumanReproduction18(9):1928,2003

84 CristelloF,CelaV,ArtiniPG,GenazzaniAR:Therapeuticstrategiesforovulationinductionininfertilewomenwithpolycysticovarysyndrome.GynecologicalEndocrinology21(6):340,2005

85 NestlerJ,JakuowiczD:DecreaseinovariancytochromeP450c17aactivityandserumfreetestosteroneafterreductionofinsulinsecretioninpolycysticovarysyndrome.NEnglJMed335:617,1996

86 LaughlinG,DominguezC,YenS:Nutritionalandendocrinemetabolicaberrationsinwomenwithfunctionalhypothalamicamenorrhea.JClinEndocrinolMetab83:25,1998

87 TheESHRECapriWorkshopGroup:Nutritionandreproductioninwomen.HumanReproductionUpdate,12(3):193,2006

88 BullenB,ScreenerG,BeitinsIetal:Inductionofmenstrualdisordersbystrenuousexerciseinuntrainedwomen.NEnglJMed312:1349,1985

89 LoucksA,MortolaJ,GirtonLetal:Alterationsinthehypothalamicpituitaryovarianandthehypothalamicpituitaryadrenalaxisinathleticwomen.JClinEndocrinolMetabol68:402,1989

90 VigerskyR,AndersenA,ThompsonRetal:Hypothalamicdysfunctioninsecondaryamenorrheaassociatedwithsimpleweightloss.NEnglJMed297:1141,1977

91 LoucksA,VaitukaitisJ,CameronJetal:Thereproductivesystemandexerciseinwomen.MedSciSportExerc24(6suppl):S288,1992

92 McArthurJ,O'LaughlinK,BeitinsI,JohnsonL,HourihanJ,AlonsoC:Endocrinestudiesduringthefeedingofyoungwomenwithnutritionalamenorrheaandinfertility.MayoClinProc51:602,1976

93 ZhangY,SternB,RebarRW:Endocrinecomparisonofobesemenstruatingandamenorrheicwomen.JClinEndocrinolMetabol58:1077,1984

94 JainA,PolotskyA,RochesterD,BergaS,LoucksT,ZeitlianG,GibbsK,PolotskyH,FengS,IsaacB,SantoroN:Pulsatileluteinizinghormoneamplitudeandprogesteronemetaboliteexcretionarereducedinobesewomen.JournalofClinicalEndocrinologyandMetabolism92(7):2468,2007

95 TeitelmanM,GrotegutC,WilliamsNN,LewisJD:Theimpactofbariatricsurgeryonmenstrualpatterns.ObesitySurgery16(11):1457,2006

96 ChanJ,MantzorosS:Leptinandthehypothalamicpituitaryregulationofthegonadotropingonadalaxis.Pituitary4:87,2001

97 MoschosS,ChanJ,MantzorosC:Leptinandreproduction:areview.FertilityandSterility77(3):433,2002

98 QuennellJH,MulliganAC,TupsA,LiuX,PhippsSJ,KempCJ,HerbisonAE,GrattanDR,AndersonGM:Leptinindirectly



regulatesGnRHneuronalfunction.Endocrinology2009

99 WeltC,ChanJ,BullenJ,MurphyR,SmithP,DePaoliA,KaralisA,MantzorosC:Recombinanthumanleptininwomenwithhypothalamicamenorrhea.NewEnglandJournalofMedicine351:987,2004

100PehlivanovB,MitkovM:Serumleptinlevelscorrelatewithclinicalandbiochemicalindicesofinsulinresistanceinwomenwithpolycysticovarysyndrome.TheEuropeanJournalofContraceptionandReproductiveHealthCare14(2):153,2009

101 KatzE:Theluteinizedunrupturedfollicleandotherovulatorydysfunctions.FertilSteril50:839,1988

102MacDonaldP,GrodinJ,EdmanCetal:Originofestrogeninamenopausalwomanwithanonendocrinetumoroftheovaryandendometrialhyperplasia.ObstetGynecol46:644,1976

103RichardsonG:Weeklyclinicopathologicalexercises.NEnglJMed286:594,1972

104 vanNoordPAH,BoersmaH,DubasJS,teVeldeE,DorlandM:Ageatnaturalmenopauseinapopulationbasedscreeningcohort:theroleofmenarche,fecundity,andlifestylefactors.FertilityandSterility68(1):95,1997

105Nelson,L:PrimaryOvarianInsufficiency.NEnglJMed360:606,2009

106PienkowskiC,MenendezM,CartaultA,LorenziniF,LesourdF,TauberM:OvarianfunctionandTurnersSyndrome.GynecologieObstetriqueandFertilite36:1030,2008

107 CoulamC,AdamsonS,AmnegersJ:Incidenceofprematureovarianfailure.ObstetGynecol,67:604,1986

108AnastiJN,KalantaridouSN,KimzeyLM,DefensorRA,NelsonLM:Bonelossinyoungwomenwithkaryotypicallynormalspontaneousprematureovarianfailure.ObstetGynecol91(1):12,1998

109TapanainenJS,VaskivuoT,AittomakiK,HuhtaniemiIT:InactivatingFSHreceptormutationsandgonadaldysfunction.MolecularandCellularEndocrinology145:129,1998

110 LussianaC,GuaniB,MariC,RestagnoG,MassobrioM,RevelliA:MutationsandpolymorphismsoftheFSHreceptor(FSHR)gene.ObstetricalandGynecologicalSurvey63(12):785,2008

111 ForgesT,MonnierBarbarinoP,FaureGC,BeneMC:Autoimmunityandantigenictargetsinovarianpathology.HumanReproductionUpdate10(2):163,2004

112 CoulamC:Theprevalenceofautoimmunedisordersamongpatientswithprimaryovarianfailure.AmJReprodImmunol4:630,1984

113 HusebyeES,LovasK:ImmunologyofAddisonsdiseaseandprematureovarianfailure.EndocrinolMetabolClinNAm38:389,2009

114 WinquistO,GebreMedhinG,GustaffsonJetal:Identificationofthemaingonadalautoantigensinpatientswithadrenalinsufficiencyandassociatedovarianfailure.JClinEndocrinolMetabol80:1717,1995



115 MorrisonJC,GivensJR,WiserWL,FishSA:Mumpsoophoritis:Acauseofprematuremenopause.FertilityandSterility26(7):655,1975

116 AittomakiK:ThegeneticsofXXgonadaldysgenesis.AmJHumGenet54:844,1994

117 CrisponiL,DeianaM,LoriAetal:TheputativeforkheadtranscriptionfactorFOXL2ismutatedinblapharophemosis/ptosis/epicanthusinversussyndrome.NatureGenet27:159,2001

118 LourencoD,BraunerR,LinL,DePerdiloA,WeryhaG,MuredsanM,BoudjenahR,GuerraJuniorG,MacielGuerraA,AchermannJC,McElreaveyK,BashambooA:MutationsinNR5A1associatedwithovarianinsufficiency.NewEnglandJournalofMedicine360:1200,2009

119 DavidsonRM,DavisCJ,ConwayGS:TheXchromosomeandovarianfailure.ClinicalEndocrinologo51:673,1999

120VegettiW,MarozziA,ManfrediniEetal:Prematureovarianfailure.MolCellEndocrin61:53,2000

121 WieackerP:Geneticaspectsofprematureovarianfailure.JournalfurReproduktionsmedizinundEndokrinologie6(1):17,2009

122 GuerreroN,SighR,ManatungaAetal:Riskfactorsforprematureovarianfailureinfemaleswithgalactosemia.JPediatr137:833,2000

123 KohJ,KimC,HongS,Lee,K,KimY,KimO,KimG:Primaryovarianfailurecausedbyasolventcontaining2bromopropane.EuropeanJournalofEndocrinology138:554,1998

124 KaragiannisA,HarsoulisF:Gonadaldysfunctioninsystemicdiseases.EuropeanJournalofEndocrinology152:501,2005

125 BondanelliM,ZatelliMC,AmbrosioMR,degliUbertiEC:Systemicillness.Pituitary11:187,2008

126 DouglasNC,ShahM,SauerMV:Fertilityandreproductivedisordersinfemalesolidorgantransplantrecipients.SeminarsinPerinatology31:332,2007

127 KoutrasDA:Disturbancesofmenstruationinthyroiddisease.AnnalsNewYorkAcademyofSciences816:280,1997

128RabinoviciJ,BlanksteinJ,GoldmanBetal:Invitrofertilizationandprimaryembryoniccleavagearepossiblein17ahydroxylasedeficiencydespiteextremelylowintrafollicular17estradiol.JClinEndocrinolMetabol68:693,1989BondanelliM,ZatelliMC,AmbrosioMR,degliUbertiEC:Systemicillness.Pituitary11:187,2008

129 HeimanDL:Amenorrhea.PrimaryCareClinicsinOfficePractice36(1),1,2009

130 PetterssonF,FriesH,NilliusS:Epidemiologyofsecondaryamenorrhea.AmericanJournalofObstetricsandGynecology117:80,1973



131 MashchakCA,KletzkyOA,DavajanV,MishellDR:Clinicalandlaboratoryevaluationofpatientswithprimaryamenorrhea.JournalofObstetricsandGynecology57(6):715,1981

132 KaragionnisA,HarsoulisF:Gonadaldysfunctioninsystemicdisease.EuropeanJournalofEndocrinology152:501,2005

133 ZielinskaD,ZajaczekS,RzepkaGorskaI:TumorsofdysgeneticgonadsinSwyersyndrome.JPediatrSurg41(10):1721,2007

134 MorganT:Turnersyndrome:diagnosisandtreatment.AmericanFamilyPhysician76(3):405,2007

135 TrokoudesKM,SkordisN,PicolosMK:Infertilityandthyroiddisorders.CurrentOpinioninObstetricsandGynecology18(4):446,2006

136 ChahalJ,SchlechteJ:Hyperprolactinemia.Pituitary11:141,2008

137 AfarahBM,NasrallahMP:Pituitarytumors:pathophysiology,clinicalmanifestationsandmanagement.EndocrinerelatedCancer8:287,2001

138 AzzizR,CarminaE,DewaillyD,DiamantiKandarakisE,EscobarMorrealeHF,FutterweitW,JanssenOE,LegroRS,NormanRJ,TaylorAE,WitchelSF:TheandrogenexcessandPCOSSocietycriteriaforthepolycysticovarysyndrome:thecomplextaskforcereport.FertilityandSterility91(2):456,2009

139 WolthersOD,CameronFJ,ScheimbergI,HonourJW,HindmarshPC,SavageMO,StanhopeRG,BrookCGD:Androgensecretingadrenocorticaltumours.ArchDisChild80:46,1999

140BhattacharyaSM:Polycysticovarysyndromeandabnormalitiesinglucosetolerance.InternationalJournalofGynecologyandObstetrics105:29,2009

141 RossiB,SukalichS,DrozJ,GriffinA,CookS,BlumkinA,GuzickDS,HoegerKM:Prevalenceofmetabolicsyndromeandrelatedcharacteristicsinobeseadolescentswithandwithoutpolycysticsyndrome.JournalofClinicalEndocrinologyandMetabolism93(12):4780,2008

142 PeriN,LevineD:Sonographicevaluationoftheendometriuminpatientswithahistoryoranappearanceofpolycysticovariansyndrome.JUltrasoundMed26:55,2007

143 CrissmanJD,AzouryRS,BarnesAE,SchellhasHF:Endometrialcarcinomainwomen40yearsofageoryounger.JournalofObstetricsandGynecology57(6):699,1981

144 NalaboffKM,PelleritoJS,BenLeviE:Imagingtheendometrium:diseaseandnormalvariants.Radiographics21(6):1409,2001

145 BansciLFJMM,BroekmansFJM,EijkemansMJC,deJongFH,HabbernaJDF,teVeldeER:Predictorsofpoorovarianresponseininvitrofertilization:aprospectivestudycomparingbasalmarkersofovarianreserve.FertilityandSterility77(2):328,2002

146 HartR,HickeyM,FranksS:Definitions,prevalenceandsymptomsofpolycysticovariesandpolycysticovarysyndrome.Best



PracticeandResearchClinicalObstetricsandGynecology18(5):671,2004

147 SunW,StegmannBJ,HenneM,CatherinoWH,SegarsJH:Anewapproachtoovarianreservetesting.FertilityandSterility90(6):2196,2008

148MillerK,KlibanskiA:Amenorrheicboneloss.JClinEndocrinolMetab84(6):1775,1999

149 EftekhariN,MohammadalizadehS:Pregnancyratefollowingbromocriptinetreatmentininfertilewomenwithgalactorrhea.GynecolEndocrinol25(2):122,2009

150 ThePracticeCommitteeoftheAmericanSocietyforReproductiveMedicine:Useofexogenousgonadotropinsinanovulatorywomen:atechnicalbulletin.FertilSteril90(3):S7,2008

151 KettelLM,RoseffSJ,BergaSL,MortolaJF,YenSS:Hypothalamicpituitaryovarianresponsetoclomiphenecitrateinwomenwithpolycysticovarysyndrome.FertilSteril59:532,1993

152 ZainMM,JamaluddinR,IbrahimA,NormanRJ:Comparisonofclomiphenecitrate,metformin,orthecombinationofbothforfirstlineovulationinduction,achievementofpregnancy,andlivebirthinAsianwomenwithpolycysticovarysyndrome:arandomizedcontrolledtrial.FertilSteril91(2):514,2009

153 ShohamZ,BalenA,PatelA,JacobsHS:Resultsofovulationinductionusinghumanmenopausalgonadotropinorpurifiedfolliclestimulatinghormoneinhypogonadotropichypogonadismpatients.FertilSteril56:1048,1991

154 CostelloMF,EdenJA:Asystematicreviewofthereproductivesystemeffectsofmetformininpatientwithpolycysticovarysyndrome.FertilSteril79(1):1,2003

BacktoTop

Menstruation and Menstrual Disorders_ Anovulation

Documents

Truth and fallacies about menstruation

Menstruation and Education in Nepal

Chinese Herbal Medicine for Infertility with Anovulation ... · Review Articles Chinese Herbal Medicine for Infertility with Anovulation: A Systematic Review Li Tan, MMed,1,2 Yao

PHYSIOLOGY OF MENSTRUATION

Menstruation cycle by Haliunaa Battulga

TRHCUEMEE Physiology of Menstruation€¦ · Physiology of Menstruation TRHCUEMEE. Learning objectives: By the end of this lecture the students should be able to: Define menstruation

Menstruation disorders and treatment

Menstruation 101

Chronic Anovulation and the Polycystic Ovary Syndrome

Anovulation- the most frequent cause of female infertility. It can be connected with: Irregular menstruation Irregular menstruation Oligomenorrhea Oligomenorrhea

Early Knowledge Regarding Basic Subjects on Menstruation ...hrmars.com/hrmars_papers/Early_Knowledge_Regarding_Basic_Subjects_on_Menstruation...Menstruation is a nature of creation

Menstruation and menstrual disorders

Rationelle Diagnostik der Anovulation

Physiology of menstruation

Cycling a guide to menstruation

Prevalence and Risk Factors for Postpartum Anovulation in Dairy Cows

Prevalence polycystic ovaries in with anovulation and

Menstruation among Nepalese Adolescent girls - Theseus

HE MODULE : MENSTRUATION

Amenorrhea & Anovulation Andrea Chymiy, MD Swedish Family Medicine