ABC of subfertility Extent of the problem AlisonTaylor Oneinsixcoupleshaveanunwanteddelayinconception. Definitionsofsubfertility Roughlyhalfofthesecoupleswillconceiveeither spontaneouslyorwithrelativelysimpleadviceortreatment.The Subfertilityisafailuretoconceiveafteroneyearofunprotected regularsexualintercourse.Subfertilitycanbeprimaryorsecondary otherhalfremainsubfertileandneedmorecomplextreatment, Primarysubfertility—adelayforacouplewhohavehadnoprevious suchasinvitrofertilisationandotherassistedconception pregnancies techniques;abouthalfofthesewillhaveprimarysubfertility. Secondarysubfertility—adelayforacouplewhohaveconceived Mostcouplespresentingwithafertilityproblemdonothave previously,althoughthepregancymaynothavebeensuccessful(for absoluteinfertility(thatis,nochanceofconception),butrather example,miscarriage,ectopicpregnancy) relativesubfertilitywithareducedchanceofconception becauseofoneormorefactorsineitherorbothpartners.Most coupleswithsubfertilitywillconceivespontaneouslyorwillbe amenabletotreatment,sothatonly4%remaininvoluntarily cwhitihldoleustst.rAeastemaechntc,oreulpatlienhgatshaespuobtestnatniatilablecnheafnitcoefotfrecaotnmceeinvtintog n rate 1.0 o trheaeliirstcihcaanpcpersaoisfacloonfctehieviandgdneadtubreanlelyfiitsoimffeproedrtabnyttrtoeagtmiveenat oncepti 0.8 options. ulative c 0.6 m u C Chance of spontaneous conception 0.4 Conceptionismostlikelytooccurinthefirstmonthoftrying 0.2 (abouta30%conceptionrate).Thechancethenfallssteadilyto about5%bytheendofthefirstyear.Cumulativeconception 0 ratesarearound75%aftersixmonths,90%afterayear,and 0 2 4 6 8 10 12 14 95%attwoyears.Subfertilityisdefinedasafailuretoconceive Months afteroneyearofunprotectedregularsexualintercourse.Itis usuallyinvestigatedafterayear,althoughforsomecouplesit Cumulativeconceptionrateinthefirstyearoftrying maybeappropriatetostartinvestigationssooner.The likelihoodofspontaneousconceptionisaffectedbyage, previouspregnancy,durationofsubfertility,timingof Prior pregnancy (x1.8) Cumulative average rate intercourseduringthenaturalcycle,extremesofbodymass, <36 months infertility (x1.7) Male/tubal defect (x0.5) andpathologypresent.Areasonablyhighspontaneous pregnancyratestilloccursevenafterthefirstyearoftrying. Female <30 years (x1.5) Endometriosis (x0.4) Age birth rate 50 Aftehmestirarolleantagega3es0.sTsohacineadtrieoednaureclyxtii4os0tnssi.bnFeoftewrrewteiolnitmysueisnbgfaergreteaidltiet3yst5ai-nn3d9wiyonemcarreesnatshiinneg mulative live 3400 chanceofconceivingspontaneouslyisabouthalfthatofwomen Cu aged19-26years.Thenaturalcumulativeconceptionrateinthe 20 35-39agegroupisaround60%atoneyearand85%attwo years. 10 Thismarked,agerelateddeclineinspontaneousconception isalsomirroredintheoutcomeofassistedconception treatment.Recentevidenceshowsthatmalefertilityalso 0 0 6 12 18 24 30 36 declineswithage.Geneticdefectsinspermandoocytesthatare Months likelytocontributetoimpairedgametefunctionandembryonic developmentincreasewithage.Theagerelateddeclinein Cumulativelivebirthrateandprognosticinfluenceofhistoryandfindings femalefecundityiscausedbyasteadilyreducingpoolof incouplesnotconceivinginthefirstyearoftrying.Thepresenceof competentoocytesintheovaries. endometriosis,tubalfactor,orsuboptimalspermqualitymayhalvethe likelihoodofspontaneousconception.DatafromCollinsetal(seeFurther readingbox) Durationofsubfertility Thelongeracouplehastotrytoconceive,thesmallerthe chanceofspontaneousconception.Ifthedurationof Socialchangesmeanthatmorecouples subfertilityislessthanthreeyears,acoupleis1.7timesmore aredelayingthestartoftheirfamilyuntil likelytoconceivethancoupleswhohavebeentryingforlonger. womenareintheirlate30sandthisbrings asubstantialreductionintheirlikelihood Withunexplainedsubfertilityofmorethanthreeyears,the ofconception chancesofconceptionoccurringareabout1-3%eachcycle. Previouspregnancy Whenadelayinconceptionhasnoobviouscausethe likelihoodofconceptionisincreased1.8-foldifthecouplehas Factorsaffectingfertility secondaryratherthanprimarysubfertility. Increasedchanceofconception x Womanagedunder30years Timingofintercourseduringovulatorycycle x Previouspregnancy Thechanceofconceptioninanovulatorycycleisrelatedtothe x Lessthanthreeyearstryingtoconceive dayinthecycleonwhichintercoursetakesplace.Thewindow x Intercourseoccurringduringsixdaysbeforeovulation,particularly twodaysbeforeovulation ofopportunitylastssixdays,endingonthedayofovulation.A x Woman’sbodymassindex(BMI)20-30 studybyDunsonetal(2002)showedthattheprobabilityof x Bothpartnersnon-smokers conceptionrosefromsixdaysbeforeovulation,peakedtwo x Caffeineintakelessthantwocupsofcoffeedaily daysbeforeovulation,thenfellmarkedlybythedayof x Nouseofrecreationaldrugs ovulation.Thisshowsthatspermneedtobedepositedinthe Reducedchanceofconception femalegenitaltractbeforeovulationtomaximisechancesof x Womenagedover35years conception.Thisisconsistentwiththeprogesteroneinduced x Nopreviouspregnancy changesincervicalmucusthatoccurimmediatelyafter x Morethanthreeyearstryingtoconceive ovulationandimpedethepenetrationofsperm. x Intercourseincorrectlytimed,notoccurringwithinsixdaysbefore ovulation x Woman’sBMI <20or >30 Weight x Oneorbothpartnerssmoke Pregnancyislesslikelyifthewoman’sbodymassindex(BMI) x Caffeineintakemorethantwocupsofcoffeedaily (weight(kg)/(height(m)2))is >30or <20.WomenwithaBMI x Regularuseofrecreationaldrugs >30needadviceaboutmodifyingtheirdietanddoingmore exercisetoloseweightandtheyshouldaimforaBMI <30. WomenwithaBMI <20shouldbeadvisedtogainweight andreduceexerciseiftheyareexercisingexcessively.Being considerablyunderweightisassociatedwithanincreasedriskof miscarriageandintrauterinegrowthretardation. Obesityisalsoassociatedwithan Otherfactorsaffectingfertility increasedriskofmiscarriageandobstetric Thechanceofconceptionmaybereducedbysmoking,caffeine, complicationssuchashypertension, anduseofrecreationaldrugs.Theeffectofsomeofthese gestationaldiabetes,thromboembolism, factorsmaybeattributedinparttoanassociationwithother andcomplicateddelivery factorsthataffectfertility,suchasanincreasedriskofsexually transmittedinfection. Theeffectofalcoholonfertilityisnotclearastheresultsof studiesareconflicting.Somestudieshavefoundimpaired fertilityinwomendrinkingmorethanfiveunitsofalcohola Ithasbeenestimatedthatsmokersare3.4 week,whereasothershavefoundthatlowtomoderatealcohol timesmorelikelytotakemorethanayear consumptionmaybeassociatedwithahigherconceptionrate toconceivethannon-smokers,andineach thaninnon-drinkers.Excessalcoholconsumptioninmencan cyclesmokershavetwothirdsthechance contributetoimpotenceanddifficultieswithejaculationand ofconceivingcomparedwithnon-smokers mayimpairspermatogenesis. Is subfertility getting more common? Fecundityratesmaybedeclining.However,itisdifficultto separatechangesinsocialbehaviourandtrendsindelaying startingafamilyfromotherfactorsthatmightreducethe chanceofconception,suchasenvironmentalfactors.Several studieshavereportedasteadydeclineinmeanspermcounts overthepastfewdecadesinEuropeandtheUnitedStates. Theyalsoreportedthattheincidenceoftesticulartumours, cryptorchidism,andhypospadiasisincreasing.Skakkebaeketal (1994)havesuggestedthatariseinenvironmentaloestrogenic pollutantsmaybecausingthesechanges. Major causes of subfertility Themajorcausesofsubfertilitycanbegroupedbroadlyas ovulationdisorders,malefactors(whichincludedisordersof Beingunderweightand exercisingexcessivelycan spermatogenesisorobstruction),tubaldamage,unexplained, increasetheriskofanovulation, andothercauses,suchasendometriosisandfibroids.The subfertility,andintrauterine proportionofeachtypeofsubfertilityvariesindifferentstudies growthretardationin andindifferentpopulations.Tubalinfertilityismorecommon pregnancy inthosewithsecondarysubfertilityandinpopulationswitha higherprevalenceofsexuallyacquiredinfections. The impact of subfertility Preconceptionadvice Pre-existingmedicalproblems* Theimpactofexperiencingdifficultyconceivingshouldnotbe x Stabilisemedicalconditionsandensurethatmedicalcontrolis underestimatedforcouplespresentingwiththeproblem.Many optimal finditstressfultoseekprofessionalhelpforsuchanintimate x Checkthatdrugsneededaresafeforuseinpregnancyanddonot problemandfeelasenseoffailureathavingtodoso.Itisnot affectspermfunction uncommonfortheproblemtoputastrainontherelationship x Whereappropriate,referwomantoanobstetricphysicianfor andmanycouplesexperienceadeteriorationintheirsexual adviceonimplicationsoftheconditioninpregnancy relationshipwhichexacerbatestheproblem.General Weight practitionerscanprovideinvaluablesupporttocouples x CheckBMI x AdviseonweightgainorlosswhereBMIis <20or >30 undergoinginvestigationandtreatmentandforthosefaced withintractableinfertility. Smoking x Advisebothpartnerstostopsmoking Recreationaldrugs Preconception advice x Advisebothpartnerstostopusingrecreationaldrugs Folicacid Ifacoupleareconsideringstartingafamilytheymayapproach x Womenwhoaretryingtoconceiveshouldtakefolicacid theirgeneralpractitionerforadviceonconceiving.Areasfor supplements(0.4mg)dailytoreducetheriskofneuraltubedefects. discussionshouldincludethingsthatmayimprovethechances Womenwithahistoryofneuraltubedefectorepilepsyshouldtake ofconceptionorincreasethechanceofasuccessfuloutcometo 5mgdaily thepregnancy(byminimisingtheriskofabnormalityorof Virologyscreening pregnancyrelatedcomplicationsforbabyandmother). x Screenforrubellaimmunityandofferimmunisationtothosenot immune x ConsiderscreeningforHIVandhepatitisBandCingroupsatrisk Managing subfertility Prenataldiagnosis x Tellolderwomenaboutoptionsforprenataldiagnosis Acouplepresentingwithadelayinconceptionshouldbedealt Timingofintercourse withsympatheticallyandsystematicallyaccordingtoalocally x Checkcouple’sunderstandingofovulatorycycleandrelatemost agreedprotocolofinvestigations.Manyoftheseinvestigations fertiledaystothelengthofwoman’scycle canbestartedbythecouple’sgeneralpractitionerand x Advisethatintercourseoccursregularly.Twotothreetimesaweek completedinsecondarycare.Acooperativeapproachallows shouldcoverthemostfertiletime promptdiagnosisoftheproblem,afterwhicharealistic Factorsaffectingfertility discussioncantakeplaceabouttheprognosis—thecouple’s x Discussanyfactorsineitherpartner’shistorythatmightwarrant chanceofconceivingspontaneouslyandofconceivingwith earlyreferralforspecialistinfertilityadvice differenttreatmentoptions.Formulatingaplanofactionwith *Forexample,hypertension,diabetes,epilepsy,thyroiddisorder,cardiac thecouplecanhelpeasesomeofthedistressassociatedwith problems,anddrughistory theproblem. The role of general practitioners Furtherreading Generalpractitionersareoftenthefirstcontactforcouples concernedabouttheirfertility.Theycanofferadviceand x Managementofinfertilityinprimarycare:Theinitialinvestigation andmanagementoftheinfertilecouple.Evidencebasedclinical supportthatcanalleviateanxiety.Theirroleincludesgiving guidelines,1998 generalpreconceptionadvice,takingahistory,andstarting www.rcog.org.uk/guidelines.asp?pageID=108&GuidelineID=25 appropriatetests.Theyshouldtrytoseebothpartnerstogether, x BalenAH,JacobsHSInfertilityinpractice.ChurchillLivingstone: althoughthismaybedifficultiftheyareregisteredwith London,1997 differentpractices.However,thecoupleshouldbeencouraged x BolumarF,OlsenJ,BoldsenJ.Smokingreducesfecundity:a toapproachtheproblemtogetherandmustunderstandthat Europeanmulticenterstudyoninfertilityandsubfecundity.The theywillbothneedinvestigation.Generalpractitionerscanalso EuropeanStudyGrouponInfertilityandSubfecundity.AmJ Epidemiol1996;143:578-7 ensurepromptandappropriatereferral,andadviseonlocal x BolumarF,OlsenJ,RebagliatoM,Saez-LloretI,BisantiL.Body servicesavailableinsecondaryandtertiarycareandlocal massindexanddelayedconception:aEuropeanmulticenterstudy fundingpoliciesforinvestigationandtreatment. oninfertilityandsubfecundity.AmJEpidemiol2000;151:1072-9 x CollinsJA,BurrowsEA,WillanAR.Theprognosisforlivebirth TheABCofsubfertilityiseditedbyPeterBraude,professorandhead amonguntreatedinfertilecouples.FertilSteril1995;64:22-8 ofdepartmentofwomen’shealth,Guy’s,King’s,andStThomas’s x FormanR,Gilmour-WhiteS,FormanN.Drug-inducedinfertilityand SchoolofMedicine,London,andAlisonTaylor,consultantin sexualdysfunction.Cambridge:CambridgeUniversityPress,1996 reproductivemedicineanddirectoroftheGuy’sandStThomas’s x SkakkebaekNE,GiwercmanA,deKretserD.Pathogenesisand assistedconceptionunit.Theserieswillbepublishedasabookinthe managementofmalefertility.Lancet1994;343:1473-9 winter. x DunsonDB,ColomboB,BairdDD.Changeswithageinthelevel Competinginterests:Nonedeclared. anddurationoffertilityinthemenstrualcycle.HumReprod 2002;17:1399-403 BMJ2003;327:434–6 ABC of subfertility Making a diagnosis AlisonTaylor Couplespresentatasurgeryorclinicbecausetheyhavenot conceivedasquicklyastheyhadexpected.Someareconcerned theremaybeseriousproblemthatwillstopthemhavinga family.Subfertilityinvestigationsdeterminewhetheraproblem existsandenablearationaldiscussionaboutoptionsfor treatment.Thetreatmentmayincludewaitingfora spontaneousconception.Someofthedistressassociatedwith subfertilitymaybereducedbyapromptandsystematic protocolofinvestigationsthatallowscouplestomovequicklyto themostappropriatetreatment. Investigations: who and when Subfertilityisdefinedasfailuretoconceiveafteroneyearof unprotectedregularsexualintercourse.Althoughusuallyit wouldbereasonabletostartinvestigationsafterthistime,earlier Coupleconsultingdoctor investigationsandreferralmaybejustifiedwherethereare importantfactorsineitherpartner’shistory. Factorsthatmaywarrantearlyreferralorinvestigation* Awoman’sageisoneofthemainfactorsaffectingher chanceofconception.Thechancesofmosttreatmentsbeing Female x Age >35years successfularereducedsubstantiallyafterawomanreaches35 x Previousectopicpregnancy yearsandbecomenegligiblebyhermid-40s.Hence,ifcouples x Knowntubaldiseaseorhistoryofpelvicinflammatorydiseaseor aretogainthemaximumbenefitfromthemostappropriate sexuallytransmitteddisease treatment,investigationsshouldbestartedpromptly(aftersix x Tubalorpelvicsurgery monthsoftryingifthewomanisover35)andcompleted x Amenorrhoeaoroligomenorrhoea accordingtoalocallyagreedprotocolbetweengeneral x Presenceofsubstantialfibroids practitionersandhospitalproviders.Couplescanthenbe Male counselledabouttheimplicationsoftestresults,anda x Testicularmaldescentororchidopexy x Chemotherapyorradiotherapy managementplanagreedthattakesintoaccountthetestresults x Previousurogenitalsurgery andthecouple’sbeliefsandwishes. x Historyofsexuallytransmitteddisease Atinitialpresentationbothpartnersshouldhaveahistory x Varicocele takenandbeexamined.Regularintercoursetwotothreetimes *Beforeayear aweekshouldbeadvised,butbasalbodytemperaturechartsare nothelpfulandshouldbeavoided. Thefemalepartnerofcouplespresenting A rational approach to investigation withsubfertilityshouldhavetheirrubella statuscheckedsothatifimmunisationis Initialinvestigationsshouldbecompletedwithinthreetofour requireditwillnotdelayanytreatment monthsandshouldestablishthefollowingpoints. x Doesthewomanovulate? x Ifnot,thenwhynot? x Isthesemenqualitynormal? Initialinvestigationsthatcanbedoneinprimarycare x Istheretubaldamageoruterineabnormality? Female x Luteinisinghormone,folliclestimulatinghormone(FSH),and Bothpartnersmustbeinvestigatedbecauseanappropriateplan estradiolconcentrations—shouldbemeasuredinearlyfollicular ofmanagementcannotbeformulatedwithoutconsideringboth phase(days2to6) maleandfemalefactorsthatmayoccurconcurrently.Initial x Progesteronetest—shouldbedonemid-lutealphase(day21or investigationscanbestartedinthecommunity,withthe sevendaysbeforeexpectedmenses) assessmentoftubalpatencytakingplaceinhospital x Thyroidstimulatinghormone,prolactin,testosteronetest—should bedoneifwoman’scycleisirregular,shortened,orprolongedorif progesteroneindicatesanovulation Starting investigations in primary care x Rubellaserologytest—shouldbecheckedevenifthewomanhas beenimmunisedinpast Doesthewomanovulateandifnotwhynot? x Cervicalsmear—shouldbecarriedoutasnormalscreening TheUKRoyalCollegeofObstetriciansandGynaecologists’ protocol x Transvaginalultrasoundscan—shouldbedoneifthereisthe guidelinesincludecheckingamid-lutealphaseprogesteroneto possibilityofpolycysticovariesorfibroids confirmovulationinaregularcycle.Timethesampleatthe Male correctphaseofthecycle(sevendaysbeforeexpectedmenses). x Semensampleforanalysis—sampleshouldbetakenaftertwoor Wherecyclesareirregularorthewomanhasoligomenorrhoea threedays’abstinenceandrepeatedaftersixweeksifabnormal (acyclelengthof >35days)orpolymenorrhoea(<25days), ovulationisunlikelyandsoaprogesteronetestisoflittlevalue. Thyroidstimulatinghormone,testosterone,andprolactin concentrationsneedbecheckedonlyifcyclesareirregularor absent,suggestinganovulation,galactorrhoea,orsymptomsof thyroiddisorder.Transvaginalultrasonographyisasimple investigationthatwilldetectpolycysticovariesanduterine fibroids.Luteinisinghormone,FSH,andestradiolshouldbe checkedearlyinthecycle(days2to6). Issemenqualitynormal? Themalepartnershouldhaveasemenanalysisandifsome parametersareabnormal,thenasecondtestshouldbedonesix weekslater.Ideallythesamplesshouldbeanalysedinthe laboratoryusedbythefertilityclinictowhichthecouplewillbe HyCoSyshowingpatencyandflowthroughonecornuof theuterus referred.Moredetailedspermfunctiontestsarenotneededasa routinepartoftheinitialinvestigations.Thepostcoitaltestis unreliableandisnolongerrecommendedasaroutine Completinginvestigationsinsecondarycare investigation. Female Investigationsstartedinprimarycareshouldbecompleted Assesstubalstatusanduterinecavity inadedicatedreproductivemedicineorfertilityclinic. x HSG x HyCoSy x Laparoscopyanddyetestwithhysteroscopy Male Investigations in secondary care Ifazoospermiaispresent x FSH,luteinisinghormone,andtestosterone(withorwithout Istheretubaldamageoruterineabnormality? prolactin,thyroidstimulatinghormone)tests Assessmentofawoman’stubalstatusanduterinecavitycanbe x Cysticfibrosisscreeningandkaryotypeif <5×106/ml performedby x Centrifugationofejaculateandexaminationofpelletfor x Hysterosalpingography(HSG) spermatozoa x Hysterosalpingo-contrastsonography(HyCoSy) x Testicularbiopsyorexploration x Laparoscopyanddyetestwithhysteroscopy. Ifoligozoospermiaandsignsofhypogonadotrophichypgonadism x FSH,luteinisinghormone,prolactinthyroidstimulatinghormone, Testsfortubalpatencyshouldtakeplaceinthefirst10daysofa andtestosteronetest cycletoavoidthepossibility,howeverunlikely,ofdisruptingan earlyspontaneouspregnancy.Unlesscervicalscreeningfor chlamydiahasbeenperformed,prophylacticantibioticssuchas doxycyclineandmetronidazoleshouldbegiventominimisethe riskofinfectiondevelopingaftertheprocedure. HSGandHyCoSy HSGandHyCoSyare“dynamic”outpatientinvestigationsdone byinsertingacatheterintothecervicalcanal,afterwhich contrastisinjectedintotheuterinecavity.HSGusesrealtime xrayimagingtofollowtheflowofcontrastintothetubesand spillintotheperitonealcavity,whereasHyCoSyuses ultrasonography.Bothgiveinformationabouttheshapeofthe uterinecavity.HyCoSygivesextrainformationbecausean ultrasoundscanofthepelvisisperformedatthesametime, allowingthedetectionoffibroidsorpolycysticovaries. Hysterosalpingogramshowinganormalpelvis Laparoscopyanddyetest Alaparoscopyanddyetestneedsgeneralanaesthesiaand carriesthehazardsoflaparoscopy.However,itgives informationaboutthedegreeofanytubaldamagepresentand enablesendometriosistobedetected.Additionally,laparoscopic treatmentsuchasdiathermyorlaserablationofendometriosis orsalpingolysisorsalpingostomymaybedoneatthesame time.HyCoSyandHSGcanbeusedasaninitialscreen, reservinglaparoscopyforpatientswithahistoryorsymptoms indicatingariskoftubaldamageorendometriosis,andfor thosewhohaveanabnormalHSG.Ifinvestigationofthemale partnershowssubstantiallyimpairedsemenquality,suchthat assistedconceptiontreatment(forexample,intracytoplasmic sperminjection)islikely,tubalassessmentmaynotbeneeded. However,informationabouttheuterinecavitymaybehelpfulif Laparoscopyshowinganormalpelviswithpassageofblue ultrasonographyshowsthepresenceofsubmucosalfibroids. dyethroughthefimbrialendofthelefttube Further investigation of azoospermia Investigatingazoospermia,bysiteofabnormality in secondary care Obstructive Non-obstructive Post-testicular Testicular Hypothalamic- Wheretheinitialsemenanalysisrevealsazoospermiaa pituitary centrifugedsampleshouldbeexaminedforsperminthepellet. Congenital Vasalaplasia, Geneticcauses, Kallman’ssyndrome, Evenifonlyafewspermcanbeidentified,intracytoplasmic causes cysticfibrosis, cryptorchidism, isolatedFSH sperminjectioncanbeofferedaseffectivetreatmentto mulleriancysts anorchia deficiency circumventtheinfertility. Acquired Gonorrhoea, Radiotherapy, Craniopharyngioma, Ifazoospermiaisconfirmeditisimportanttodistinguish causes chlamydia, chemotherapy, pituitarytumour, betweenobstructiveandnon-obstructiveazoospermia. tuberculosis, orchitis,trauma, pituitaryablation, prostatitis, torsion anabolicsteroids Inobstructiveazoospermia,spermatogenesisisnormalbut vasectomy thereisablockintheepididymisorvasdeferens.Ifcongenital Testicular Normal Small,atrophic Small,prepubertal absenceofvasdeferensissuspected,bothpartnersshould size undergocysticfibrosisscreeningbecausemanyofthesemen FSH Normal Raised Low willcarryoneofthecysticfibrosismutations.Innon-obstructive Testosterone Normal Low Low azoospermia,spermatogenesisisimpaired.Thisimpairment maybecausedbytesticularfailure(sotheman’skaryotype shouldbecheckedandmultipletesticularbiopsymayshow isolatedfociofspermatogenesis)orduetoafailuretostimulate spermatogenesisbythehypothalamicpituitaryaxis (hypogonadotrophichypogonadism).Althoughrare,this conditionshouldbedetectedasthesepatientsrespondto gonadotrophintreatment. Interpretingresultsofinvestigationsoffemalepartners Test Result Interpretation Interpreting results and discussing Progesterone <30nmol/l Anovulation: Checkcyclelengthandtimingin treatment options mid-lutealphase;completeother endocrinetests;scanforpolycystic Femalepartner ovaries;adviseonweightgainor Wheretheprogesteroneconcentrationislowtakethefollowing loss;mayneedovulationinduction; steps. clomifeneshouldnotbestarted x Checkthelengthofthecycleinwhichthesamplewastaken withouttubalpatencytest x Ensurethatsamplewastakeninthemid-lutealphase—that FSH >10IU/l Reducedovarianreserve: Mayrespondpoorlytoovulation is,sevendaysbeforeexpectedperiod x Ensurethatotherendocrinetestsarecompleted induction;mayneedeggdonation x Anultrasoundscanisvaluabletodiagnosepresenceof Luteinising >10IU/l Maybepolycysticovaries: hormone Ultrasonographytoconfirm polycysticovariesifanovulationisconfirmedortheluteinising Testosterone >2.5nmol/l Maybepolycysticovaries: hormoneortestosteroneconcentrations,orboth,areraised Ultrasonographytoconfirm x Adviseaboutweightgainorlosstoachieveabodymass >5nmol/l Congenitaladrenalhyperplasia: index(weight(kg)/(height(m)2))of20-30.Thisisthekeyto Check17-OHPandDHEAS successfultreatment. Prolactin >1000IU/l Maybepituitaryadenoma: Asingleraisedearlyfollicularphasefolliclestimulating Repeatprolactintoconfirmraised hormone(FSH)concentrationisapoorprognosticindicator concentration;exclude hypothyroidism;arrangemagnetic forwomentryingtoconceive.Itimpliesareducedovarian resonanceimageorcomputed reserveandthepossibilityofincipientprematureovarian tomogram;ifconfirmed failure.Thisisdifficulttotreatbecausetheresponsetoovarian hyperprolactinaemiastart stimulationislikelytobepoor.Refractorycasesmayneedegg dopamineagonist donation. Rubella Non-immune Offerimmunisationandonemonth AfteranabnormalhysterosalpinogramorHyCoSy,further contraception tubalassessmentbylaparoscopywillbeneeded.Themain HSGor Abnormal Maybetubalfactor: treatmentoptionsinclude: HyCoSy Arrangelaparoscopyanddyetestto x Surgery(openorlaparoscopic) evaluatefurther;maybe x Transcervicaltubalcannulation intrauterineabnormality—for x Invitrofertilisation. example,fibroidoradhesions; evaluatefurtherbyhysteroscopy Thechoiceofprocedurewilldependonfactorssuchasthe Laparoscopy Blockedtubes Tubalfactorconfirmed: degreeoftubaldamage,thesemenquality,andthepatient’s anddye Possiblysuitablefortranscervical age.Intrauterinelesionssuchassubmucousfibroidsor cannulation,surgeryorinvitro adhesionsneedfurtherevaluationbyhysteroscopy,atwhich fertilisation(alsodependsonsemen timetheymayberesected. quality) Endometriosis Endometriosis: Assessseverity;maybenefitfrom Malepartner diathermyorlaserablation;medical Semensamplescanvarygreatly.Ifthesemenvolumeislow, suppressionnothelpfulforfertility checkwhethercollectionoftheejaculatewascomplete.Ifthe Mayneedinvitrofertilisation firstpartoftheejaculate,whichcontainsmostofthesperm, DHEAS=dihydroepiandrosteronesulphate; missedthepot,theresultswillnotberepresentative. 17-OHP=17-hydroxyprogesterone Lubricantsformasturbation—forexample,soaporKYjelly Interpretingasemenanalysis maybespermicidalandtheiruseshouldbeavoided.Ifthemale partnerhasdifficultyproducingasamplebymasturbationthen Parameter Normal Commentsifabnormal anon-spermicidalcondomcanbeused. Volume 2-5ml Iflow,checkifcollectionwas Therapeuticdrugsthatmaybeassociatedwithimpaired incomplete(“missedthepot”) spermatogenesisincludechemotherapy,sulfasalazine,and Count >20×106/ml Repeatsample.Checkthatno acuteillnessoccurredintwo cimetidine. monthsbeforesample.Lifestyle Abnormalsemenqualitiesareanindicationforearly adviceonsmoking,alcohol,and referraltoafertilityclinic,preferablyoneofferingafullrange drugs.If <10×106/mlinvitro ofassistedconceptiontechniques. fertilisationorintracytoplasmic sperminjection.Referearly Conclusion Motility >50% Repeatsample;referearly progressively motile Coupleswhopresentwithsubfertilityrarelyhaveabsolute >25%rapidly infertility(thatis,nochanceofconceptionspontaneously). progressive Factorsthatarecontributingtotheproblemusuallycause Morphology >15%normal Repeatsample;referearly relativesubfertility(thatis,areducedchanceofconceiving shape spontaneously)toagreaterorlesserdegree,andtheremaybe relevantfactorsinbothpartners. Investigationsshouldfollowasystematicprotocoldesigned toidentify: x Tubaloruterineabnormalities Furtherreading x Anovulation x Impairedspermatogenesis. x RoyalCollegeofObstetriciansandGynaecologistsevidencebased clinicalguidelines.Initialinvestigationandmanagementofthe Promptinvestigationandappropriatereferralallowa subfertilecouple.London:RCOGPress,1998 x TempletonA,AshokP,BhattacharyaS,GazvaniR,HamiltonM, coupletoreceiveadviceandtreatmenttohelpthemreachtheir MacMillanS,etal.EvidencebasedfertilitytreatmentLondon:RCOG goalofapregnancymorequickly,andmayalleviatesomeofthe Press,London,2000 distressassociatedwithsubfertility.Doctorsinprimarycarecan x BalenA,JacobsH.Infertilityinpractice.2nded.London:Churchill haveaninvaluableroleinstartingthisprocessandproviding Livingstone,2003 supportduringfurtherinvestigationandtreatment. x TempletonA,AshokP,BhattacharyaS,GazuaniR,HamiltonM, MacMillanS,etal.ManagementofinfertilityfortheMRCOGand TheABCofsubfertilityiseditedbyPeterBraude,professorandhead beyond.London:RCOGPress,2000 ofdepartmentofwomen’shealth,Guy’s,King’s,andStThomas’s SchoolofMedicine,London,andAlisonTaylor,consultantin reproductivemedicineanddirectoroftheGuy’sandStThomas’s Competinginterests:Nonedeclared. assistedconceptionunit..Theserieswillbepublishedasabookinthe winter. BMJ2003;327:494–7 Amemorablepatient Bella and the blood sample Shedidn’tspeakanyEnglishandhadaterribletemperaftera smallbloodsampleforresearchpurposes.Chimpanzeesare recentprobablestroke,sotakingabloodsamplewasgoingtobe resistanttotheeffectsofinfectionwiththehuman particularlyproblematic.Alongstandingneedlephobiawasone immunodeficiencyvirus,asimilarsituationobservedinavery oftheleastseriousissues.Itwasfeltthatthebestpolicywouldbe smallminorityofthepatientsinfectedwithHIV-1whomwesee. tosedateherfirst,andwediscussedthiswhileshesatthere Unravellingthehostfactorsinvolved,whysomeindividuals grumbling.HerfavouritedrinkwasCoca-cola,althoughshe becomeinfectedanddonotdevelopdisease,mayleadto rarelyhadit,soweplacedasmallamountofabenzodiazepinein promisingnewtreatments. amugful.Shespatoutthefirstmouthfuldisdainfully,andthe Thecollaborationworksbothways:wegetourbloodsamples, second.Theneedlephobiawasnowveryapparent. andthestaffatLondonZoo,whoarealwaysinneedofmedical Weweretoldthateverytwomonthsshehadanentiretubof equipment,getsomeofourredundantanaestheticmachines. BenandJerry’sChocolateChipCookieDoughicecream—her absolutefavourite,whichsurelywouldn’tfail.Wedutifullyplaced JustinStebbing registrar thesedativeinatuboftheicecream.Shegrabbeditandtook FrancesGotch headofdepartment whatseemedlikeanenormousmouthful,shovellingitinwithher lefthand,asherrightwasweak.Shespatitoutagainandlooked BrianGazzard professorofmedicine,departmentofimmunology, absolutelyfurious.Westoodwellawaybeforeshecouldshowher ChelseaandWestminsterHospital,London displeasureinmorepracticalways,butshecalmlyproceededto Wewelcomearticlesupto600wordsontopicssuchas scoopupsomeofherexcrementthatwasonthefloor,placeitin Amemorablepatient,Apaperthatchangedmypractice,Mymost thetub,andhandthisbacktous.Theonlyoptionleftwasto shootherwithatranquilliserdart. unfortunatemistake,oranyotherpiececonveyinginstruction, Bellaisa42yearoldchimpanzeeatLondonZoo,and,justlike pathos,orhumour.Pleasesubmitthearticleonhttp:// anyotherpatient,shehadherownparticularwayoftellingusto submit.bmj.comPermissionisneededfromthepatientora “getlost.” relativeifanidentifiablepatientisreferredto.Wealsowelcome WehaveacollaborationwiththeZoologicalSocietyofLondon contributionsfor“Endpieces,”consistingofquotationsofupto80 sothat,whentheyanaesthetisetheirnon-humanprimatesfor words(butmostareconsiderablyshorter)fromanysource, reasonsconcernedonlywiththehealthofthatanimal,wetakea ancientormodern,whichhaveappealedtothereader. ABC of subfertility Anovulation DianaHamilton-Fairley,AlisonTaylor Disordersofovulationaccountforabout30%ofinfertilityand oftenpresentwithirregularperiods(oligomenorrhoea)oran GnRH Hypothalamus absenceofperiods(amenorrhoea).Manyofthetreatmentsare Positive feedback/stimulation simpleandeffective,socouplesmayneedonlylimitedcontact Negative feedback withdoctors.Thismakesiteasierforacoupletomaintaina privatelovingrelationshipthaninthestressful,more LH FSH Apintuteitraioryr technologicalenvironmentofassistedconception.However,not allcausesofanovulationareamenabletotreatmentby ovulationinduction.Anovulationcansometimesbetreatedwith medicalorsurgicalinduction,butitisthecauseofthe anovulationthatwilldeterminewhetherovulationinductionis possible.Thevariousoptionsarediscussedlaterinthisarticle. Estradiol and Corpus Follicles progesterone luteum Ovary Causes suitable for ovulation Dominant induction follicle Hypothalamic-pituitarycauses Hypogonadotrophichypogonadismischaracterisedbya Estradiol selectivefailureofthepituitaryglandtoproduceluteinising Ovulation hormoneandfolliclestimulatinghormone.Thecommonest causeisexcessiveexercise,beingunderweight,orboth.Women Hypothalmic-pituitary-ovarianaxis(FSH=folliclestimulatinghormone; whohavealowbodymassindex(weight(kg)/(height(m)2))(for GnRH=gonadotrophinreleasinghormone;LH=luteinisinghormone) example, <20)orwhoexerciseexcessively—forexample, gymnasts,marathonrunners,ballerinas—maydevelop amenorrhoeabecauseofaphysiologicalreductioninthe hypothalamicproductionofgonadotrophinreleasinghormone. Womenwhoareunderweightfortheirheightwhentheyget Causesofanovulationsuitableforovulationinduction pregnantaremorelikelytohave“smallfordates”babies;and treatment childrenofwomenwhohaveeatingdisordersaremorelikelyto Hypothalamic beadmittedtohospitalwithfailuretothrive. x Lowconcentrationofgonadotrophinrealeasinghormone Sheehan’ssyndrome(panhypopituitarism),causedby (hypogonadotrophichypogonadism) infarctionoftheanteriorpituitaryvenouscomplex(usually x Weightorexerciserelatedamenorrhoea aftermassivepostpartumhaemorrhageortrauma),and x Kallman’ssyndrome Kallman’ssyndrome(amenorrhoeawithanosmiacausedby x Stress x Idiopathic congenitallackofhypothalamicproductionofgonadotrophin Pituitary releasinghormone)arerare.Childrentreatedfora x Hyperprolactinaemia craniopharyngiomaorsomeformsofleukaemiamayhave x Pituitaryfailure(hypogonadotrophichypogonadism) hypogonadotrophichypogonadismsecondarytocerebral x Sheehan’ssyndrome irradiation,whichmayaffectthehypothalamusorthepituitary. x Craniopharyngiomaorhypophysectomy Hyperprolactinaemiaisusuallycausedbyapituitary x Cerebralradiotherapy microadenoma.Thisleadstoareductionintheproductionof Ovarian pituitaryluteinisinghormoneandfolliclestimulatinghormone. x Polycysticovaries Althoughthecommonestpresentationissecondary Otherendocrine amenorrhoea,somewomenmaypresentwithgalactorrhoea.A x Hypothyroidism smallernumbermayhaveheadachesordisturbedvisionthat x Congenitaladrenalhyperplasia mayindicateamacroadenoma,whichneedsurgent investigationandtreatment.Amicroadenomaiseasilytreated withdrugswithasubsequentresumptionofmensesand fertility. Ovariancauses Polycysticovarysyndromeisthecommonestcause(70%)of anovulatorysubfertility.Theprimaryabnormalityseemstobe Transvaginalscanofa anexcessofandrogenproductionwithintheovarythatleadsto polycysticovary.Typically10or therecruitmentoflargenumbersofsmallpreovulatoryfollicles, morefolliclesof<10mmin whichfailtorespondtonormalconcentrationsoffollicle diameter(“stringofpearls”) areinasingletransverseor stimulatinghormone.Thus,adominantfollicleisrarely longitudinalsectionthrough produced.Womenwithpolycysticovarysyndromecommonly theovary.Stromaldensityand presentintheirlateteensorearly20swithhirsutism,acne,or ovarianvolumeincrease

Alison Taylor, ABC of Subfertility

Similar Alison Taylor, ABC of Subfertility