Copyright© ABE&M todos os direitos reservados. review 144 during the study. The most common identifiable fac and15%becamepregnant have unexplainedinfertility ofcouples –for35%.Fivepercent and femaleinfertility for 8%andboth–male couples,maleinfertility fertile accountsfor37%ofcausesin that femaleinfertility tries, theWorld Health Organization (WHO)estimates ). theywanted(secondary ber ofchildren I INTRODUCTION Accepted onNov/25/2013 Received onSept/30/2013 [email protected] 22440-901 –RiodeJaneiro, RJ, Brazil Av. Ataulfo dePaiva, 135, sala1014 VasconcellosRita Weiss Correspondence to: 2 1 Health, RiodeJaneiro, RJ, Brazil Endocrinology Sector, of Ministry FederalHospital daLagoa, do RiodeJaneiro (UERJ);and Center, Universidade doEstado Biology (BioVasc), Biomedical ResearchExperimental on Vascular RJ), RiodeJaneiro, RJ, Brazil Católica doRiodeJaneiro (PUC- (IEDE); Pontifícia Universidade e EndocrinologiaLuizCapriglione conceive (primary infertility) ortoconceivethenum infertility) conceive (primary to 10% to15%ofallcoupleswillexperiencedifficulties > 35years(1).Epidemiologicaldatasuggestthatabout not usingcontraceptionandaftersixmonthsinwomen Laboratory for Clinicaland Laboratory Instituto deDiabetes Estadual Based on a survey performed in developedcoun performed Based on a survey one year of regular intercourse inwomen<35years intercourse one yearofregular toconceiveafter isdefinedasthefailure nfertility http://dx.doi.org/10.1590/0004-2730000003021 Infertility; infertilitycauses;propaedeutics;;ovarianfactor Keywords Infertilidade; causasdeinfertilidade;propedêuticadaanovulação;fatorovariano Descritores Female origin infertility ofendocrine proteger suafertilidade. disfunções ovulatórias. As mulheresdevemseraconselhadasaevitarfatoreslimitadoresdeforma senvolvidas. Fornecemos aquiinformaçõessobrecomoidentificarpacientes endocrinológicoscom podem afetarafertilidade. A infertilidade éumfenômenocadavezmaiscomumnassociedadesde lidade. Diferentestranstornoshipotalâmicos,pituitários,tireoideanos,adrenaiseovarianos também de infertilidade feminina. A idade avançada, a obesidade e as drogas têm um efeito negativo na ferti dos casaissãoinférteis. Os problemasdeanovulação sãoresponsáveispor25%a50%dascausas causadoras deinfertilidade feminina.Osdadosepidemiológicossugeremquecercade10% a15% com maisde35anos.Foi feitaumarevisãodascausas,manejoetratamentocausasendócrinas relações sexuaisregularesemmulherescommenosde35anoseapósseismeses A infertilidade é definida como uma falha na concepção, sem anticoncepcionais, após um ano de RESUMO tobeavoided, inordertoprotecttheirfertility.limiting factors about howtoidentifyendocrinepatientswithovulatory dysfunction. Women mustbeadvisedabout ity aswell.Infertility isagrowingphenomenonindevelopedsocieties. We hereprovide information on . Different hypothalamic, pituitary, , mayaffect adrenal,andovarian disorders fertil 25% to50%ofcausesfemaleinfertility. Advanced age,, anddrugs,haveanegativeeffect suggest thataround10% to15% ofcouplesareinfertile. Anovulatory problemsareresponsiblefrom ment andtreatmentofendocrinecausesfemaleinfertility was performed.Epidemiologicaldata andafter inwomen<35years 6monthsinwomen>35years. course A reviewoncauses,manage Infertility withno contraception, after is defined as thefailure toconceive, oneyearof regularinter ABSTRACT Rita VasconcellosWeiss Infertilidade feminina endócrina deorigem Arq BrasEndocrinolMetab. 2014;58(2):144-52 1 , RuthClapauch - - - - these two are common causes offemaleinfertility.these twoare Male as tus (bytransvaginalultrassound ouhysteroscopy), and endometrial cavitysta of hysterossalpingography) tochecktubalpatency(usuallybymeans is important cycles,it is highlysuspected,likethose with irregular (2,3),eveninwomenwhomit of femaleinfertility Albeit anovulationaccountsfor25%to50%ofthecauses INVESTIGATION (2). half ofthecausesfemaleinfertility than formore as responsible disorders scribe ovulatory de (7%).Otherreports (11 %),andhyperprolactinemia (11%), tubalblockageotherabnormalities (25%),(15%),pelvic adhesions disorders tors thataccountedforfemaleinfertility, ovulatory were 2 Arq BrasEndocrinolMetab. 2014;58(2):144-52 Arq Bras Metab. Endocrinol 2014;58/2 ------ and outcomes, hirsutism, acne, galactor pregnancies contraceptive use, previous two yearsaftermenarche, sincethefirst pattern age,menstrual prising menarchal have lutealinsufficiency. Complete anamnesis,com (5),orto outtobeanovulatory turn these features gest .However, upto10%ofwomenwith the cycleforafewhoursandabundantmucus,allsug Regular cycles,lowabdominalpaininthemiddleof andphysicalexam History OVULATION PROPAEDEUTICS Arq Bras Metab. Endocrinol 2014;58/2 fator; (B) Tubo-peritoneal fator. fator;(C)Uterine D) Cervical Figura 1.Infertilitycausesandevaluation. Femalecauses: ( A) Ovarian dysfunctions. toasovulatory referred modalitieswillbehere three however, tothetubes.Allthese nooocyteisreleased consistentwithovulation.Effectively, levelsare terone cur inthemucus,andvaginalcytology;proges changesoc Inthissituation,secretory . itundergoes luteinization, beingabletoproduce there and turity, withoutrupture, intheovary butremains (LUF),whenthefollicledevelopstoitsma drome folliculesyn (4); and(iii)luteinizednon-ruptured issettled endometrial stabilityuntilHCGproduction tion by the corpus luteum is not enough to maintain tion withlutealinsufficiency, secre whenprogesterone 1. infigure presented coupleare the infertile in Themainfactorstobeaddressed to delaytreatment. not inorder in whichinvestigationshouldbeshortened advancedage, inwomenofmore especially important Assessment ofmultiplecausesis least onespermogram. investigatedbymeansofat ­factors shouldbepromptly Ovarian fatorscomprise(i)anovulation,(ii)ovula Evaluation oftheinfertilewoman Evaluation Male factor ------rhea, weightchangesandhotflashesshouldbecon act likemonitorsoftheovulationperiod.Women seek mucus,may usingsalivainsteadofcervical microscopes, mucusallovertheircycle. ofestrogenic same pattern PCOSpatients,onthecontrary, showthe Anovulatory during thegenitalexam,togetherwithapalemucosa. mucus. inestrogenic can beobserved leaves resembling fern magnification: atypicalpattern, atlow onaslidetobeexaminedinmicroscope dry is possibletocollectasampleofthemucusandletit tacky (gestagenic mucus). During the genital exam, it andmucusbecomessticky,cosity increases grainy, and peak. After ovulation, vis rise and the ovulatory trogen mucus),inparalleltoes to themid-cycle(oestrogenic volumewhen gettingcloser mucusofincreasing pery Women cyclesshowclear, smooth,slip withovulatory mucus Cervical detect ovulation(6): status. estimation ofestrogenic an sexualdevelopment,andmayprovide normal sure andgenitalexaminationen Breast features. syndrome (PCOS)stigmata,aswellgoiterorTurnersyndrome Physical examshouldincludepolycysticovary sidered. for ovulation confirmation nowadays. for ovulationconfirmation methodalsolimited aswell, makingthisindirect ture ever, can alter bodytempera infectionsandevenstress Celsius.How in0.3a0.5degrees body temperature during luteal phaseincreases secretion Progesterone temperature body Basal method. other andbasophilic.LUFisalsoalimitationforthis When ovulationoccurs,cellsbecomeclosertoeach andeosinophiliccellsinthefollicularphase. tered, A vaginalPapanicolaustainedsmearshowflat,scat cytology Hormonal genitalinfecctionsandLUF,lation are amongothers. to detecttheirpossibleperiodofovulation. high,allowingwomen levelsare mucus whenestrogen incervical present pattern showing thesameferning magnifiedbythelens, andare their cycle.Samplesdry putsalivasamplesonthe deviceacross ing Nowadays, personal devices, which are infactmini Nowadays, personaldevices,whichare womenshowlittleor nomucus Hypoestrogenic employed to of themethodsbeloware One or more Limiting factorsformucusanalysisindetectingovu 145 ------

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 146 to identifyanovulation intheLUFsyndrome. notable luteallevelsare tection kitsandprogesterone momentsofthecycle: assess ovulation,intwoormore to inorder dosagesmaybeperformed Blood andurinary dosages Hormonal Female infertility Like the other methods described before, LHde Like theothermethodsdescribed before, – – – than originally presumed, ifthecycleisnotbe than originallypresumed, day also becausedbyovulationinadifferent butcan ng/mL suggestlutealinsufficiency ovulation.Valuesin proper between3and10 imply inanovulation,and>10ng/mL period, or8daysafterovulation)<3ng/mL thenextmenstrual luteal phase(7daysbefore levelsinthemid- :progesterone 20% ofthewomenanalyzed(10). LHpeakin80% andby48hoursin the urinary within24hours of Follicular collapseoccurred 25.5mIU/mLto 48.7 mIU/mL. ranged from thelowestleveldetectedaspositive compared, LHkitswere (9).Whendifferent respectively firstdescribedas73and92%, LH testwere within 24or48hoursafterapositiveurine values for follicular collapse Positive predictive tests. ges itscolour, urinary justlikepregnancy a day, thestickchan­ andwhenLHincreases, the patientplacesstickintourineflowonce sticks sensibletoLHsurge detection.Typically, testkits, which come with five to seven urinary patient withthehelpofovulationprediction plexity. LHsurge canalsobeidentifiedbythe cycles of low com vels in assisted reproduction le­ intheblood,togetherwithestrogen sured For monitoring purposes, LH peak can be mea peak. anovulatory follicular phaseandreach the risesteadlyfrom FSH andprogesterone, levels,aswellthose of LH peak. ginning ofLHrise,and8-20hoursafterthe lation usually occurs 28-36 hours after the be above baseline levels. Ovu ing two to fourfold ovulation,achiev Mid cycle:LHpeaksbefore pening withinhibinBlevels<45pg/mL(8). (7),thesamehap innolivebirths as resulting reported nancy outcome,and>18IU/Lwere of poor preg predictive considered IU/L are for lation, especially in older women candidates hibin Blevelsmayshowthelikelihoodofovu ing monitored. Early follicularphase(2 fertilization (IVF).FSHlevels>10 in vitrofertilization nd -5 th day):FSHandin ------be employed in association, are shownin table1. be employedinassociation,are patter ovulatory and athree-fold 10mm, (12), aswellaendometrialthicknessaround ovulation predict visualizationmayfurther oophorus whenmeasuring18-24mm.Cumulus torupture prone mature, 1-2mmperdayandare general, folliclesgrow toobserver. In observer from canvary cule measures toring, andideallybythesameperson,becausefolli byadoctorexperiencedinovulationmoni performed functional ovulationparameters.SerialUSshouldbe accuracyinanalyzinganatomicaland fers evenmore dosagesandUSmonitoringcon between hormonal elicits corpuslu­ Theadditionofdopplerfluxometry LUF syndrome. Itisalsotheonlymethodabletodetect lar rupture. the9-10 from performed tion offolliculardevelopmentispossible.Itusually dir the evaluationofovulation,where (US) methodfor mostprecise This isthegoldstandard, ultrassound transvaginal Serial proportion of women who are intentionally delaying ofwomenwho are proportion issues. The oftheseimportant vented withawareness conceive (14,15). cycle,awomanismostlikelyto during themenstrual aninadequateknowledgeofwhen, clearly presented fertility. thatobesityandsmokingaffect aware They age45.Mostwomenwere todeclinebefore ity starts age 35, and male fertil to decline before tility starts todecline.Femalefer starts male andfemalefertility byabout10years,theage at which underestimated, Themajorityoftherespondents now orinthefuture. to 45yearswhowishedhaveachildoranother was questioned among women aged 18 of intercourse fertility,affect suchas age,obesity, , andtime ofmodifiablefactors that Knowledge about the effects Modifiable factors age atmenopause(13). and ageat , endometriosis, uterinefibroids, andfertility, reproduction including affecting Genetic factorscontributetoriskofmanycommon Genetic factors CAUSES OFOVULATORY DYSFUNCTION The methodsformonitoringovulation,whichcan Factors that modify the risk of infertility canbepre Factors thatmodifytherisk of infertility teum evaluation(11).Theassociation Arq Bras Metab. Endocrinol 2014;58/2 th dayofthecycleuptoovu n. ect visualiza ------Arq Bras Metab. Endocrinol 2014;58/2 (17). maternity andfuture fertility out against nicotine on behalf of their should be carried age,anactivecampaign Among womeninreproductive quality. ofpoorer in thedevelopmentofembryos used.Passive smokingresults ver stimulationprotocol inIVFcycles,whate­ vels, andleadstopoorprognosis (AMH)le­ anti-Müllerianhormone (AFC) andserum antralfolliclecount bydecreased asreflected reserve, tobeclarified(16). trial, remain those adverseoutcomes,whetherovarianorendome technologies.Themechanismsunderlying productive inobesewomenundergoing assistedre been observed oocyteshave follicles, andlowernumberofretrieved consumption,fewerselected increased Unfavorable ovarianstimulation characteristics, suchas status havealsobeenblamedfortheseadverseeffects. Coexistingfactors,suchasageandPCOS miscarriage. rateof ratesandincreased andlivebirth pregnancy bodymass index,lower sociation betweenincreased as seemstobeastrong orobese.There rently, womenare nearlyhalfofthereproductive-age (15). declineinfemalefertility yet toage-related technologyhasnoanswer nation, assistedreproductive andeggdo the exceptionofoocytecryopreservation with that,atpresent, unaware choice, andwomenare ing acareer. aconscious Delayedchildbearingisrarely withobtainingadditionaleducation andbuild dren the optimalbiologicalperiodforwomentohavechil inthepastdecadesbecauseof clashbetween greatly beyondtheageof35years hasincreased pregnancy Table 1. Methodsofassessingovulation Early follicularphase(2 Phase ofthecycle anddays* (9 –ovulation Mid-luteal phase(8daysafterovulation) Ovulatory phase(12 Ovulatory th day–uptoexpectedresult) Active smoking is associated with reduced ovarian Active smokingisassociatedwithreduced Cur toepidemicproportions. Obesity hasgrown th -15­ nd th -5 day) th day) FSH andinhibinBlevels Analysis of cervical mucusorsaliva Analysis ofcervical Urinary testkitsforLHpeakdetection Urinary Progesterone levels Serial transvaginalultrassound(US) Basal bodytemperature Hormonal cytology Method ------Prolactinomas tion andinfertility: dysfunc Many endocrineconditionsleadtoovulatory Endocrine disorders torrhea, or regular cycleswith infertility. orregular torrhea, Thesecretion galac abnormalities, menstrual varies from cal picture Theclini but notthesolecauseofhyperprolactinemia. tumors, themostcommonpituitary are Prolactinomas adenomas pituitary Functional thatcharacterizesHA(2). secretion tibility ofwomentothefunctionalchangesinGnRH RHR, andKAL1)maycontributetothevariedsuscep geneticmutations(FGFR1,PROKR2,GN tion. Rare been shown to induce GnRH pulsatility andmenstrua ing hypothalamicfunction,asleptinadministrationhas agnosis (18-20). fordi isnotaprerequisite and exercise. weightloss, stress, main typeshavebeenrecognized: thusbeingadiagnosisofexclusion.Three normalities, 6 months without evidence of anatomic or organic ab than cyclesformore (HA) istheabsenceofmenstrual cal definitionoffunctionalhypothalamicamenorrhea hypothalamic lesions,oritmaybefunctional.Apracti rhea. ItcanbeduetocongenitalGnRHdeficiency, pulse generator, andamenor withovulationfailure oftheGnRH ofepisodicsecretion pattern the normal achangein from results Hypothalamic amenorrhea Hypothalamic appears to play an important role inregulat role Leptin appearstoplayanimportant FSH <10IU/LandinhibinBlevels>45pg/mL pattern closertoovulation Clear, smooth, mucusofincreasingvolumewithferning andslippery Ovulation usuallyoccurs8-20hoursafterLHpeak Progesterone levels>10ng/mLimplyproperovulation 18-24 mm. Visualization offolliculardisappearanceismandatory Follicles grow1-2mmperdayandarematurewhenmeasuring secretion uponovulation Increases in0.3a0.5ºCbodytemperatureafterprogesterone closer toeachotherandbasophilicnearovulation Flat, scatteredandeosinophiliccellsinthefollicularphasebecome Results suggestingovulation Female infertility 147 ------

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. Hiperthyroidism 148 tothoseineuthy SHBG andestradiol (E2)compared of hyperthyroidism. scribed (50%),duetoearlier detectionandtreatment de withwhathadbeenpreviously 21.5% compared cyclesis ce ofirregular (24). Nowadays,theprevalen was described to be 5.8% sociated withhyperthyroidim as infertility orsecondary ofprimary The prevalence disorders Thyroid Several explanationshavebeenputforward: and hirsutism. , (SHBG), increased Protein in PCOS,suchasobesity, Binding lowSexHormone comparabletothoseobserved are Cushing syndrome of Many features common findingsinthissyndrome. are fertility dysfunctionanddecreased Menstrual Cushing’s in 50%ofwomenwithacromegaly. maybe: Thereason present are fertility dysfunction and decreased Menstrual Acromegaly levels(<50ng/mL)(21). women withborderline in particularly sellarimagingisrequested, twice before has beendescribed. cycles ofovulatory restoration GnRH isadministered, inthese patients. Whenpulsatilie of GnRH is abnormal Female infertility – – – Thyrotoxicosis results in increased serum levels of serum in increased results Thyrotoxicosis – – ismeasured thatserum It isrecommended ovulation (23). an LH, assuggestedbyhypothalamicchronic of GnRH and secretion hypothalamic-pituitary the High levelsofCRHandACTHmayaffect levels. sulting inlowestrogen re canblockGnRHrelease Hypercortisolemia axis. hypothalamic-pituitary acyclicfeedback tothe lead toinappropriate infatcellstogetherwithobesity would trogen (2,22). toGHinducedinsulinresistance or secondary on the excessive GH/IGF-I secretion of effect – direct syndrome Polycystic axisdysfunction. pothalamic-pituitary-ovarian inhy resulting stalkcompression and pituitary adenoma; tinemia duetomixedGH-Prolactin cells;hyperprolac ofgonadotroph pression Acyclic conversion of adrenal toes androgen Acyclic conversionofadrenal orcom suchasdestruction effects, Pituitary ------normalized after using antithyroid drugs. afterusingantithyroid normalized andthatthisfeature wasalsoincreased, LH secretion unknown. Early miscarriages rates are increased, to increased, ratesare unknown. Earlymiscarriages is inhypothyroidism ofinfertility prevalence The real outcome(2,25). pregnancy developedafter¹³¹I,sincethelatermayimpair roidism nohypothy tobesure after administration,inorder It isadvisedthatconceptionavoideduntil6months ongonadsisexpected. that nosignificantdamageeffect topointout active iodine(370MBq),itisimportant by: women.ThehighlevelsofE2maybeexplained roid long-term impact of postpartum thyroiditis. impact ofpostpartum long-term and (Tg)antibodies,andtheprevalence thyroglobulin (TPO)and/oranti- positive for anti-thyroperoxidase women ineuthyroid delivery andpreterm miscarriage andfetalhealth,theassociationbetween on maternal andsubclinical hyperthyroidism cal hypothyroidism now focusingonthepotentialimpactofsubclini to theEndocrineSociety(27),studiesare According hypothyroidism Subclinical (26): are inpatientswithhypothyroidism plaining infertility Themainchangesex difficulties. gether withfertility – – – withtheaveragedoseofradio If apatientistreated In patientswithGraves’sdisease,itwasshownthat – – – or delayed response toGnRH. or delayedresponse ofLH,andablunted pulsatilerelease abnormal in thatresult Disturbances in GnRH secretion in polymenor Defects in hemostasis, resulting duetoTRHhypothalam Hyperprolactinemia, dione, aswellitsraisedconversionratetoE2. levels offactorsVII,VIII,IX,andXI. explainedbydecreased rhea andmenorrhagia, ic secretion. stateisachieved. when euthyroid normalizes Thisfeature increased. fractions are andE2,althoughtheirunbound in total plasma concentrations ofboth decrease is a theresult ing activityofSHBGisdecreased, and . As plasma-bind to testosterone in peripheral aromatization and increase trone, and es clearance of androstenedione creased Increased levels of testosterone and androstene levels of testosterone Increased levels ofSHBG. Increased Altered peripheral estrogen metabolism:de peripheralestrogen Altered Arq Bras Metab. Endocrinol 2014;58/2 ------Congenital adrenal hyperplasia adrenal Congenital Arq Bras Metab. Endocrinol 2014;58/2 patientswithAddison’s dis alo- andglucocorticoids, therapywith miner replacement with state-of-the-art Even cortex. theadrenal towards autoimmune reaction usuallycausedbyan precursors, hormonal androgen and aldosterone characterized bydeficiency ofcortisol, (Addison’sdisease) is insufficiency adrenal Primary disease Addison’s implantation(2,29). bryo em inadequate endometrial maturation and impaired in cycle may result (follicular) phase of the menstrual duringthepreovulary 17-OHP and/orprogesterone penetration.Inaddition,elevatedlevelsof ing sperm mucus,prevent withthequalityofcervical interfere during thefollicularphaseinwomenwithNCAHmay Likewise, persistently elevated levels of progesterone cyclicityandfecundity. menstrual inpreventing role concentrationsplayanimportant evated progesterone inwomenwithclassicalCAHsuggestthatel Reports inanovulation. cycleresulting hormonal the normal whichinhibit PCOSandhyperandrogenism, secondary dueto fertility reduced perplasia (NCAH)oftenpresent totheseverityof . with CAHisrelated amongwomen Thenumberofpregnancies (SV) forms. tients withSaltWasting (SW)andSimpleVirilizing inpa frequent beingmore CAH, withamenorrhea commoninfemaleswith mensesare . Irregular duetomutations intheCYP21A2 disorder recessive deficiency isa common autosomal (21-hydroxylase) hyperplasia(CAH)due toP450c21 Congenital adrenal disorders Adrenal 0.3–3.0 mIU/L. trimester: second trimester:0.2–3.0mIU/L;third (28):firsttrimester:0.1–2.5mIU/L; ing pregnancy ranges dur the following TSH reference recommends Association(ATA) TheAmericanThyroid thyroiditis. tibodies inthefirsttrimesterwilldeveloppostpartum positiveforTPOorTgan to 50%ofwomenwhoare trimester,that exceeds4.0mIU/Lbythethird andup Tg antibodies in the first trimester will develop a TSH andpositiveforTPOor euthyroid women whoare ofthe Sixteenpercent euthyroid. tibodies, andare positiveforTPOorTgan are mester ofpregnancy Ten womeninthefirsttri to20%ofallpregnant Women Hy withNon-ClassicalCongenitalAdrenal ------Polycystic ovary syndrome (PCOS) syndrome ovary Polycystic of those at reproductive age,characterizedbyovula of thoseatreproductive upto10% quent endocrinopathyinwomen,affecting (PCOS)isthemostfre syndrome Polycystic ovary disorders Ovarian (30). children andtorear pregnancy forwantingandplanninga ergy andvitalityrequired ofdisease,withlossen andtheburden insufficiency ofadrenal treatment patients, aswellinappropriate inthese fertility possiblecausesofreduced (POI) are ovarianinsufficiency diseaseandpremature thyroid good.Concomitantdiseases,suchasautoimmune ered with knownAddison’sdiseasehasusuallybeenconsid gnancy,pre inpatients ofpregnancies buttheprognosis in has beenassociatedwithAddison’sdiseasepresent and inspontaneousabortions andincrease ence fertility couldpossiblyinflu androgens life. Thelossofadrenal qualityof health-related ease consistentlyshowreduced sity iscommon inPCOS,itisnotsurprising thatthese risk. Because obe sential component of cardiovascular whichisanes process, and modulatetheinflammatory visfatin) determine cesses. Otheradipokines(resistin, pro inthedevelopmentofatherogenic role permissive omentin may have an important tension, while reduced systemoveractivityandhyper for sympatheticnervous mayberesponsible leptinsecretion Increased particles. tering ofelevatedtriglyceridesandsmall,denseLDL theclus butalsoindetermining ing insulinresistance, notonlyininduc role tion ofadiponectinhasacrucial secre ofPCOS.Inparticular,reduced and progression indevelopment duction ofadipokinesplaysamain role selection ofthedominantfollicule. FSH,thuspreventing from ness offolliculesrecruited responsive andreducing folliculerecruitment, mordial AMHlevels inhibitingpri PCOS (32),withincreased fordisturbedfolliculogenesis detectedin be responsible ofAMH would thatthe increase hypothesisare rent activity. GnRH secretory indicative of disrupted Cur likely contributetotheovarianphenotype,mightbe LH-FSHratios,which LH pulsatilityandperturbed withhigher secretion gonadotropin Dysregulated cancer (31). disease,andendometrial type 2diabetes,cardiovascular alifetimeriskof PCOSpresents changes. Furthermore, andmetabolic dysfunction,, tory Experimental studies have shown that altered pro Experimental studieshaveshownthataltered The physiophatologyofanovulationiscomplex. Female infertility 149 ------

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 150 folliclesinthe solelybysmall, growing tor produced fac (AMH),agrowth ling. Anti-Müllerianhormone counsel aidinearlydiagnosisandfertility therefore, atriskofPOIwould, whetherwomenare that predicts women develop POI. A marker more cancer treatments, ofmany malignancies. Giventhegonadotoxiceffect ratesforbothpediatricandadult survival to increasing cell autoimmunity(2). orsteroidogenic receptor follicle-stimulating hormone dysfunction, forexample,owingtomutationsinthe of thefollicularpool,orcanbeattributedto exhaustion ofpremature 40 years.POIistheresult levels in women aged < gonadotropin and increased lowestrogen characterizedbyamenorrhoea, disorder (POI),isa orinsufficiency ovarianfailure Premature failure ovarian Premature levels ofLHandLH/FSHratio(36). tivity, index,butshowedincreased androgen andfree bodymassindex,insulinsensi patients hadanormal uncommon. These phenotypewasrelatively drogenic found. The normoan classic PCOSphenotypeswere to milder clinical and endocrine alterations compared common (28.8% of patients), and PCOS was relatively (LH/FSH)ratio.OvulationintypeII ulating hormone ovaries hadahigherluteinizinghormone/follicle-stim mal ovaries(typeIIPCOS),thepatientswithpolycystic anovulation but nor and chronic hyperandrogenism ovaries: typeIclassicPCOS)withpatientspresenting anovulation,andpolycystic chronic perandrogenism, nosis (35). and one other criterion for diag cal hyperandrogenism of clinical/biochemi thepresence which recommends types ofPCOSascriticizedbytheAE-PCOSSociety, pheno different created size). Thesecriteriaeffectively ian volume10mland/or12follicleslessthan9mmin appearanceatanultrasound(ovar (iii) polycysticovary or (ii) clinical and/or biochemical hyperandrogenism, exclusion ofotheretiologies:(i)oligo-oranovulation, after present, were features two ofthefollowingthree ommended thatPCOSshouldbedefinedwhenatleast itwasrec (34),where meetinginRotterdam an expert (33). severe particularly excess,inPCOS,adipokinedysfunctionis of androgen However, ofmetabolicsyndrome. prevalence because adipokinelevelsandincreased altered patients present Female infertility Moreover, advancesincancertherapeuticshaveled PCOSphenotype(hy When comparingthesevere from and diagnostic criteria arose Useful research ------pituitary-gonadal axis function, and decrease tounde axisfunction,anddecrease pituitary-gonadal independentofhypothalamic- AMHlevelsare serum ofovariansenescence,as help toassesstheprogression follicles.Inaddition,AMHcouldpotentially growing withthenumber of strongly correlate of this hormone ovary, mightconstitutesuchamarker, levels asserum needed, specific treatments are cited below. are needed, specific treatments Depend if anovulationpersistsandovulationstimulationisstill andsoon.Upon correction, placed withL-tyroxine, re withdopamineagonists, hypothyroidism treated shouldbe So,hyperprolactinemia weight normalized. andbody shouldbeaddressed Endocrine disorders PRINCIPLES OFTREATMENT poor, andexpectations(37,38). thustailoringprotocols willbe identifyingwomenwhoseresponse treatments, IVF isinwomenabouttostart for AMHmeasurement tectable levelsatmenopause.Themostestablishedrole do not conceive after six months should be offered go do notconceiveaftersixmonths shouldbeoffered (41).Resistantwomen,orthosewho the pregnancies inupto7%10% of reported multiple pregnancies (40),with 73%, 36%and29%perwoman, respectively rates reach andlivebirth cycles. Ovulation,pregnancy butclomipheneuseshouldbelimitedto6 no response, upto150mg/dayincaseof The dosecanbeincreased 50 mg/dayduring5daysinthebeginningofcycle. withclomiphenecitrate shouldbeperformed treatment ofpatients.Initial thelargest group PCOS, represents ally supplementedwithprogesterone. LH surge and cause ovulation. The luteal phase is usu tosimulatethe 18 mmanHCGinjectionisprovided during 10-14 days. When the dominant follicle reaches 37.5to150IU/day withdosisrangingfrom protocols, days2or3ofthecycle,instep-up orstep-down from ofFSHandLH),starting (purified FSHoramixture withinjectable can bealsoperformed orhypothalamicdisorders tion stimulationinpituitary months respectively, mostlysingle(39).Ovula andare 80%to93%after6and12 ratesrangefrom Pregnancy administrationbymeansofapump. hormone releasing withpulsatilegonadotrophin- origin canbetreated oral agentsinlowdoses. canoccur evenwith and hyperstimulationsyndrome byserialtransvaginalUS,because ovariancysts tored ployed. Ovulationstimulationshouldalwaysbemoni em are drugs ing onthetypeofanovulation,different Normogonadotropic anovulation,comprising Normogonadotropic anovulationof hypothalamic Hypogonadotrophic Arq Bras Metab. Endocrinol 2014;58/2 ------Arq Bras Metab. Endocrinol 2014;58/2 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: attempts. pregnancy available thatcanhelptheirfuture an optionnow orovariantissuecryopreservation, about hypogonadism should be informed pergonadotropic Women procedure. donation isthestandard atriskforhy ovariandrillingisthenextoption(5). laparoscopic (44). lation ormultiplepregnancies isusuallynotassociatedwithovarian hyperstimu drug this aftermetformin, tripletpregnancy arare reported rates(43).Althoughwe livebirth scribed toimprove associationwasde toclomiphene, resistant citrate alone.However, inobesewomenand those withclomiphene ratecompared rates, butnotlivebirth ovulationandclinical pregnancy miphene improved andclo withmetformin described thatco-treatment (42) Cochranereview patients.Arecent lin-resistant oflessthan1%and6%,respectively.tiple pregnancy and mul rates of ovarian hyperstimulation syndrome rateof55%to70%,with and acumulativepregnancy show monofollicular ovulation in 70% of the patients, but low-dose FSH regimens stimulation syndrome, ovarianhyper andsevere risk ofmultiplepregnancies havehigher regimens conventional dosegonadotropin InPCOSpatients, orothertreatments. nadotropins

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