Menstruation and Menstrual Disorders_ Anovulation

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 2/ 9/2015 Menstruat i on and Menstrual Disorders: Anovul ati on ht tp: // www.g lo wm. co m/ se ct io n vie w/ heading/Menst ru at ion%2 0and%2 0Me nst rual%2 0Disord ers: %2 0Anovu la ti on/i te m/ 295 1/2 5 Print This Page This chapter should be cited as follows: This chapter was l ast updated: Davis, J, Segars, J, Glob. libr. women's med ., (ISSN: 1756-2228)  2009; DOI 10.3843/GLOWM.10296  May 2009 Menstruation and Menstrual Disorders: Anovulation Joseph B. Davis, DO  Akron General Medical Center, A kron, Ohio, U SA James H Segars, MD  Reproductive Biology and Med ical Branch, Eunice Kennedy Shriver, National Inst itute of Child Healt h and Huma n Development , National In stit utes of  Health, Bethesda, Maryland, USA INTRODUCTION ETIOLOGY DIAGNOSIS AND TREATMENT REFERENCES INTRODUCTION  Anovulation is the failure of the ovary to release ova over a period of time generally exceeding 3 months. The normal functioning ovary releases one ovum every 25–28 days. This average time between ovulation events is variable, especially during puberty and the perimenopause period. 1  For nonpregnant women aged 16–40 anovulation is considered abnormal and a cause of inf ertility in 30% of fertility patients. 2 One of the cardinal signs of anovulation is irregular or absent menstrual periods. Oligomenorrhea is defined as more than 36 days between menstrual cycles or fewer than eight cycles per year. 3  In the absence of pregnancy, menstruation follows ovulation by approximately 14 days. Because menstruation is linked to ovulation, the clinical finding of oligomenorrhea correlates with oligoovulation. This predictable pattern of ovulation and menstruation is regulated by a cyclic change in hormones. Consequently, the diagnosis of ovulation dysfunction includes the assessment of the hormones and systems involved in ovulation and not just the symptom of amenorrhea. This chapter includes a basic review of the process of ovulation and the primary mechanisms of anovulation. Anovulation is covered using a systems approach. This approach includes hypothalamic and brain, pituitary, ovarian, and systemic based anovulation . Each system review includes diagnosis and treatment options. The process of ovulation To understand anovulation, one must first understand ovulation. Ovulation involves a progression of cellular changes in follicles that occur from fetal life until menopause. 4  At any given time in the ovary follicles are at different stages of maturity. Primordial follicles progress to immature follicles and acquired hormone responsiveness by a process that remains unclear. 5, 6 These small immature follicles, called resting follicles or antral follicles, are acted upon by several hormones to either progress to a growth phase or regress by atresia. 4  Granulosa and theca cells of the follicle make up the two-cell system that is responsible for follicular growth. 5  Gonadotropin hormones from the pituitary effect a structural change in these cells that causes the follicles to enlarge. The number of granulosa cells and theca cells within each follicle increases and a follicular fluid containing hormone products is accumulated in the follicle as it progresses through the growth phase. Follicle stimulating hormone (FSH) is the primary gonadotropin responsible for this progression. 4  As the follicles enlarge, FSH stimulates the production of more FSH receptors on the granulosa cells. This allows the follicle to become more sensitive to

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Transcript of Menstruation and Menstrual Disorders_ Anovulation

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    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

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    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.

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    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

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    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.

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    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

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    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

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    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

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    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

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    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.

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    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

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    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

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    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

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    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

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    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

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    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.

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