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through negative feedbackmechanisms. Several other through secretion pituitary consequently regulate levels and prolactin these cellstosensecirculating istoallow The functionofPRLRsin TIDA neurons byaPRLRs-independent mechanism(3). brain barrier theblood- crosses prolactin membrane (1,2).Serum receptors locatedtarget on the plasma cells via specific systemandactson bythecirculatory is transported (1).Prolactin secretion andprolactin expression ofprolactin causingsuppression lactotrophs, in pituitary which leads to the activationofdopamineD2receptors system, dopamineintothehypophysealportal secrete nucleus ofthehypothalamus(ARH).Theseneurons locatedinthearcuate (TIDA)neurons especiallythetuberoinfundibular endocrine neurons, byhypothalamic iscontrolled secretion (1). Prolactin isunknown ofthisproduction physiological importance butthe insomebrain areas, also belocallyproduced may suggeststhat prolactin evidence, atleastinrodents, Prolactin ;pSTAT5; ;Kiss1; Keywords Arch Metab. Endocrinol 2016;60/6 P INTRODUCTION neurons thatexpressthe axisbyacting onspecificpopulationsof that prolactinmaymodulatethereproductive hypothalamic dysfunction andmayleadtoinfertility inmalesandfemales.Recently, severalstudieshaveindicated interact withthedopaminesystem.Notably, hyperprolactinemia isafrequentcauseofreproductive is mainlyduetothepresenceofaprolactinomaorpharmacologicaleffects inducedbydrugsthat of transcription5causesmosttheknowneffects ofprolactin.Pathological hyperprolactinemia through several signaling pathways, although the recruitment of thesignal transducer and activator tract organs. PRLRs may exertbrain regions and reproductive Upon activation, prolactin’s functions including fertility. Prolactin (PRLRs)arewidelyexpressedinseveraltissues,including receptors However, prolactinisapleiotropichormonethatabletoaffect severalphysiological functions, Prolactin is bestknownfor its effects of stimulating developmentand lactogenesis. ABSTRACT Jose Jr. Donato tocontrol reproduction Interactions betweenprolactin and aspects, wewilldiscusswhethertheinteractionbetweenprolactinand we willsummarize thecurrent knowledgeaboutprolactin’s actionsonreproduction. Among other which ofgonadotropin-releasing hormoneneurons.Inthepresentreview, arepowerfulactivators prolactin-induced infertility. can affect reproductionand howkisspeptinsmaybecomeanovel therapeuticapproach totreat secreted by the anterior . Sparse by the secreted and produced isaprotein rolactin 1 , Frazão Renata Kiss1 Kiss1 Arch EndocrinolMetab. 2016;60(6):587-95 gene. The 2 Kiss1 geneencodesneuropeptidesknownaskisspeptins, targets to treat prolactin-induced infertility. prolactin-induced targets totreat ofkisspeptinsasnovelpotential therole regarding especially of reproduction, signaling and the control ofpossiblemechanismslinkingprolactin the discovery advancesin istosummarizeanddiscussrecent review (11).Theobjectiveofthepresent hyperprolactinemia causeof gene thatencodesthePRLRscanalsobearare dopamine system. Loss-of-functionmutationsinthe thatinteractwiththe inducedbydrugs effects orisduetopharmacological ofaprolactinoma presence ismainlycausedbythe Pathological hyperprolactinemia inmalesandfemales(10-13). may leadtoinfertility dysfunctionand causeofreproductive is afrequent tract(2,4-9). skin, immunesystemandreproductive aswellthebone,,gut, brain regions, PRLRs,including different cell populationsalsoexpress of their cytoplasmic tail. In rats, for example, the of theircytoplasmic tail.Inrats,for example, the inthelengthandcomposition been identified,differing ofmembrane-boundPRLRshave Multiple isoforms PROLACTIN SIGNALING Clinical evidence indicates that hyperprolactinemia Clinical evidenceindicatesthathyperprolactinemia Kiss1- expressing neurons USP, SãoPaulo, SP, Brasil Instituto deCiênciasBiomédicas, Accepted onSep/26/2016 Received onJuly/11/2016 [email protected] –SãoPaulo, SP,05508-000 Brasil Av. Prof. LineuPrestes, 2415 Renata Frazão Correspondence to: 2 1 DOI: 10.1590/2359-3997000000230 Paulo (USP),SãoPaulo, SP, Brasil Biomédicas, Universidade deSão Biofísica, Instituto deCiências Departamento deFisiologiae Departamento Departamento de Anatomia, Departamento review 587

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. voltage-independent Ca ofintracellularmessengersthatopen the production 588 pathway, kinase-dependentK tyrosine fast-acting signalingmechanisms,suchasthePI3K occurbecausePRLRs activationcanactivate effects (14-18).Such the membraneexcitabilityofneurons on acutely induces rapideffects For example, prolactin thatleadtochanges inmembraneexcitability.effects that PRLRsactivationisalsoinvolvedinrapidacute cascade (1,2).Inaddition,ithasbeendemonstrated cascade orthe phosphatidylinositol 3-kinase (PI3K) kinase (MAPK) such asthemitogen-activatedprotein signalingpathways, lead totheactivationofdifferent whichcan docking siteforothersadapterproteins as a of the activated PRLRmay also serve residues ontarget genescanoccur.effects Thephosphotyrosine genomic dimers thentranslocatetothenucleus,where STATwith anotherphosphorylated molecule.STAT residues itsphosphotyrosine homodimers through or hetero- by thePRLR/JAK2complexandform the PRLRs.STAT becomephosphorylated transducerof asthemostimportant is recognized STAT5, glandfactor, earlierknownasmammary of PRLRs,includingSTAT1, STAT3 andSTAT5a/b. astransducermolecules recognized of thisfamilyare of transcription(STAT) family. members Three molecules, suchasthesignaltransducerandactivator asbindingsites fortransducer serve Phosphotyrosines residues. oftyrosine JAK2 leadstothephosphorylation with theintracellulardomainofPRLRs.Activation kinase 2 (JAK2), which is constitutively associated ofJanus inarapidphosphorylation activation results Thereceptor biologicaleffects. induce prolactin to intracellular signalingpathwayscanberecruited been described(2).AfterPRLRsactivation,different ofthePRLRshave isoforms short long andthree acids), andlong(591aminoacids).Inmice,one (393amino (291aminoacids),intermediate short identified: were majorPRLRsisoforms following three Prolactin, kisspeptinandreproduction containing protein (CIS) (1). (CIS)(1). containing protein include SOCS1,SOCS3and -inducibleSH2- STAT fordockingsitesonPRLRs.Theseproteins which inhibitJAKkinasesandcompetewith proteins, ofcytokinesignaling(SOCS) inhibited bysuppressors itself.TheJAK/STATthe receptor complexcanbe desensitize synthesis that caninturn activation isprotein (1,15). OneofthefinalmechanismsinducedbyPRLRs thecellmembrane allows forionicchanges across 2+ channels, which in turn channels,whichinturn + channels or channelsor PRLRs activation.InPRL ofSTAT5modulated bytherecruitment upon proteins isdirectly consistent evidencethatsuchprogression amplified.Severalstudieshaveprovided gland isgreatly thealveolardevelopmentofmammary production, toprolactin andinresponse mice. Followingpregnancy and lateral lobules in wild-type virgin adult with terminal ofa branched ductalsystemthatisdecorated formation glanddevelopmentincludesthe lactogenesis. Mammary inmammopoiesisand isbestknownforitsrole Prolactin FUNCTIONS INPERIPHERALORGANS PROLACTIN-MEDIATED REPRODUCTIVE in PRLR couldnot be observed development uponpregnancy gland signaling(22).Ofnote,mammary upon prolactin mice, indicatingthatsuchdevelopmentisdependent PRLRsknockout female non-lactating heterozygous in evenobserved glanddevelopmentwere mammary to wild-type mice (20,21). Deficiencies in as compared budsoccurstoalesserextent development ofterminal and doubleknockoutSTAT5a/b femalemice;however, elements alsooccursintheglobalSTAT5a, STAT5b ofductal lateral lobulations(19).Thedifferentiation and branching network that is devoid of both terminal into anextended glandductalsystemgrows mammary Both short and long isoforms of PRLRs have been and long isoforms Both short atleastinrodents. the signalingofthishormone, is clearly dependent upon indicating that reproduction well-characterized usingknockout mousemodels, (23). differentiation epithelium andmaintenanceof ofmammary survival butalsoforthe cell proliferation/differentiation isessentialnotonlyforpregnancy-mediated protein thatthis determined loxp-mediated recombination, epithelium,usingCre- themammary locus onlyfrom (20,21). Inaddition,thespecificdeletionofStat5 mannerinSTAT5b normal relatively knockoutmice Conversely, glanddevelopmentoccursina mammary inducedbysuckling. secretion stimulation ofprolactin gland development, even after maximal mammary STAT5a knockoutmicefailtolactatedueincomplete mediating mammopoiesisandlactogenesis.Global that STAT5 istheprincipaltranscriptionfactor hasledtothedetermination The totalbodyofresearch STAT5a/b knockoutfemalesduetotheirinfertility. tree grows normally. grows tree However, inadultPRL andtheductal duringpuberty endbudsform terminal The effects of prolactin on fertility havebeen onfertility ofprolactin The effects -/- female mice, as well as in global double female mice,aswellinglobaldouble -/- orPRLR Arch Metab. Endocrinol 2016;60/6 -/- female mice, femalemice, -/- mice, the mice, the

to be the main cause of their infertility (21). to bethemain causeoftheirinfertility either fewornocorporalutea, whichwasdetermined well (20,21).STAT5a/b knockoutmiceovariesexhibit solely STAT5a orSTAT5b as infertile knockouts,are Double STAT5a/b knockoutfemalemice,but not function onlyinratsandmice,butnotallmammals. hasthisparticular mentioningthatprolactin worth (19,22). However, it is luteinizing effects prolactin’s inknockoutfemalesiscausedbythelackof infertility to develop correctly inPRLR to developcorrectly eggsfailed demonstrated thatmostofthefertilized development ofembryos study ofpreimplantation 12 days. The wild-type animals that mated every 3-4days,incomparisonto matingevery regularly are infertile (19,22).AdultPRL infertile are Similarly, PRLR despite noobviousdefectsinovarianhistology(19). Thesemutantsfailtobecomepregnant, or estrus. cycles,withmultipledaysofproestrus estrous irregular Arch Metab. Endocrinol 2016;60/6 females, PRL defectsexhibitedbymutant Despite thereproductive to implantation (22). refractory made the type blastocysts,indicatingthatthelackofPRLRs female wasnotabletoaccepttheimplantationofwild- mice. Forexample,PRL deficitsin leadstoreproductive signaling disruption andtheinhibitionofovulation (2).Prolactin ovum,maintenanceof implantation ofthefertilized bytheovariesisessentialfor produced intheuterus. expression receptor in progesterone bylutealcellsandtoinducetheincrease production tostimulateprogesterone withgonadotropins concert actsin and (24,25).Intheovaries,prolactin cycleorduringpregnancy change alongtheestrous and hypothalamus) may tissues (e.g., the , uterus in several milieu, PRLRs expression on the hormonal (1,9).Depending responsive known tobeprolactin hypothalamus tomodulatetheactivityofneurons andatthe geneexpression to modulateprolactin level Estradiolactsatthepituitary secretion. prolactin thatstimulates isthemainovarianhormone (24-26). anddeciduaintheuterus and lutealcellsoftheovaries,, inthegranulosa,interstitial described tobeexpressed In addition, it was found that the uterus ofaPRLR In addition,itwasfoundthattheuterus mothers.wild-type to transferred development when capableofnormal thatfailedtodevelopwere embryos PRLR -/- males are fertile, whichdemonstratesthatthe fertile, males are -/- male mice are fully fertile, andmost fullyfertile, malemiceare -/- female mice are infertile, despite infertile, female mice are -/- or PRLR -/- mothers, althoughthe -/- female micehave -/- female mice -/- addition, prolactin is also known as an important factor factor isalsoknownasanimportant addition, prolactin duringthisperiod (17).In of dopaminesecretion forthesuppression mechanism sofarthatisresponsible isthebest-known hydroxylase intyrosine during lactation,thesignificantdecrease to prolactin electrically responsive remain neurons BecauseTIDA for physiologicalhyperprolactinemia. to allow issuppressed lactation, dopaminesecretion (15-17).However,dopamine secretion during depolarization ofcellmembranes,whichstimulates postsynaptic stimulusandadirect an acuteprolactin induction of STAT5 (pSTAT5) phosphorylation after asdemonstrated by the to prolactin responsive directly are (1,15-17).TIDAneurons secretion prolactin dopamineandcontrol networktorelease synchronous thatactasa iscomposedofTIDAneurons effects involvingprolactin best knownhypothalamiccircuitry The 1). axis (Figure energy balance and the reproductive behaviorsandthemodulationof ofmaternal expression negativefeedback,the through secretion prolactin of populations,includingtheregulation neuronal itsactionondefinedhypothalamic through prolactin by regulated (9,27,28). Severalbiologicalfunctionsare system,especiallyinthehypothalamus central nervous denselydistributedinthe cellsare Prolactin-responsive BIOLOGICAL FUNCTIONS PROLACTIN TOMODULATE SEVERAL THE HYPOTHALAMUS ASATARGET OF populations. by prolactinthroughitsactionon definedhypothalamicneuronal Figure 1. Schemethatsummarizesdifferentbiological functionsregulated Prolactin, kisspeptinandreproduction 589

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 590 MPO (31). Interestingly, while PRLR bilateral infusionsofaPRLRsantagonistintothe inanimalsgiven wasimpaired response full maternal (30).Incontrast,overall controls faster thanrespective behavior significantly them anddisplayedfullmaternal over thepups,crouched (MPO)retrieved area preoptic into the medial directly Animals infused with prolactin behavior (30). stimulation of maternal a pronounced in whichresulted region, intothepreoptic of prolactin bilateral infusions studies performed of time. Previous overthemforasetamount themandcrouching grouping pups to thenest, exhibit behaviors,suchasretrieving analyzed byevaluatingthelatencyofanimalto can be care maternal (29).Inrodents, area preoptic distributedinthe dependonneurons care maternal on ofprolactin behaviors. Inthiscase,theeffects tomaternal related that mediatesadaptiveresponses Prolactin, kisspeptinandreproduction and diabetesmellitus(33).Accordingly, PRLR associated withmetabolicimbalances,suchasobesity isfrequently metabolic aspects.Hyperprolactinemia locatedintheMPO(14). neurons tomodulatethemembraneexcitabilityof by prolactin acutelyrecruited independent signalingpathwaysare demonstratedthat fastSTAT5-we havepreviously behavior. tomodulatematernal Infact, be necessary byPRLRsactivationmay signaling pathwaysrecruited Consequently, care. of maternal the expression other demonstrating thatSTAT5 for signalingisnotrequired behavior deficits, maternal showed no postpartum (22,32), brain-specificSTAT5a/b knockoutmice behavior ofmaternal showed acompletedisruption adaptations commonly observed in pregnant animals. inpregnant adaptations commonlyobserved manymetabolic fororchestrating is responsible turn, which, in leadtoleptinresistance, during pregnancy levels these findingssuggestthat changesinprolactin gestational metabolicadaptions (38).Altogether, miceandmitigatesmajor sensitivityinpregnant gene in -expressing cells improves inactivationoftheSocs3 (37).Furthermore, prolactin to responsive directly inmice are neurons expressing (35,36). Indeed,severalpopulationsofleptinreceptor- apositiveenergy balance the metabolismtowards statethatchanges infusions inducealeptinresistance adiposity. Thesestudiesshowedthat centralprolactin pregnancy, infoodintake and suchastheincrease during to themetabolicchangestypicallyobserved or placental lactogens contribute indicate that prolactin mice showaleanphenotype(34).Severalstudiesalso Prolactin may also regulate foodintakeandother mayalsoregulate Prolactin -/- female mice femalemice -/-

modulate energy balanceinspecificsituations. maycentrally Thus, thesestudiesindicatethatprolactin both humansandanimalmodels(44-46).Conversely, a in andinfertility ofpuberty leads tothedisruption (KISS1R,alsoknownasGPR54) kisspeptin receptor inthe encodingkisspeptins Loss-of-function critically involvedinreproduction. knownaskisspeptins,thatare encodes , theKiss1gene(4-8,43).The that express acting onaspecificpopulationofhypothalamicneurons axisby maymodulatethereproductive that prolactin Recently,secretion. new evidence studies provided ongonadotropin effects for theprolactin-mediated responsible probably populations are other neuronal (16,42),suggesting that modulated byprolactin isnotacutely membrane excitabilityofGnRHneurons pSTAT5.the PRLRsorprolactin-induced Inaddition, express ofGnRHneurons smallpercentage only avery ithasbeendemonstratedthat byprolactin, regulated thought tobepotentialcandidatesdirectly were axis.AlthoughGnRHneurons the reproductive thatmaymodulate neurons possible prolactin-target severalstudiesinvestigated reproduction, affects (12,40). To betterunderstandhowhyperprolactinemia qualityandinfertility dysfunction, changesinsperm lossoflibido,erectile symptoms suchgalactorrhea, with ofmalepatients present A smallpercentage enlargement (40,41). field defects due to the pituitary such as headaches and visual to a sellar mass effect, typicallysecondary symptomsare the mostfrequent andinfertility. , are Inmen, in women common symptoms of hyperprolactinemia in humansandanimalmodels(12,39-41).Themost andmayleadtohypogonadisminfertility secretion, (FSH) (LH)andfolliclestimulating hormone hormone (GnRH), -releasing of causesdisruption frequently Hyperprolactinemia KISSPEPTIN SYSTEM INTERACTION BETWEENPROLACTINANDTHE and PeN neurons together as the rostral periventricular periventricular together astherostral and PeNneurons denominateAVPV groups (48). Ofnote,someresearch (PeN) andtheARHof hypothalamusinrodents nucleus (AVPV), periventricularnucleus the rostral periventricular mainlylocated intheanteroventral are defineddistributioninthebrain.Theseneurons very exhibit a neurons in humans(47).Kiss1-expressing KISSR-activating mutationleadstoprecocious Arch Metab. Endocrinol 2016;60/6 or the or the

Arch Metab. Endocrinol 2016;60/6 ARH express pSTAT5ARH express after acute intraperitoneal (i.p.) inthe neurons 80%ofKiss1-expressing Approximately of a transgenicmousemodelthatallowsthevisualization using obtainedbyourgroup were (4,5,8). Similarresults canbefoundonTable (detailed information neurons 1) stimulus caninducepSTAT5 inKiss1-expressing functionalbecauseanacuteprolactin are these receptors thePRLRs(6,7).Additionally, co-express neurons by thedemonstrationthatmostofKiss1-expressing levelswasprovided modulatedbyprolactin directly are neurons thatKiss1-expressing The confirmation (4,42). ventricle(RP3V)inrodents ofthethird area Table ofthestudiesthatinvestigatedinteractionbetweenprolactin andkisspeptin 1.Summary Jayasena andcols., 2014 2009 Ramaswamy andcols., Kadokawa andcols., 2008 Hashizume andcols., 2010 Szawka andcols., 2010 Effects ofkisspeptinonprolactinsecretion Li andcols., 2011 Araujo-Lopes andcols., 2014 Effects ofprolactinon Li andcols., 2011 Sjoeholm andcols., 2011 2014 Araujo-Lopes andcols., Brown andcols., 2014 Evidence ofresponsivenesstoprolactin Li andcols., 2011 Kokay andcols., 2011 Brown andcols., 2014 Sonigo andcols., 2012 Presence ofprolactinreceptorsin Reference -expressing neurons through a reporter protein. protein. areporter through neurons Kiss1-expressing Kiss1 Human Monkey culture cell Bovine/ Goat culture Rat/cell Human Sheep Rat Human Sheep Rat Rat Mouse Human Sheep Rat Mouse Mouse Species expression Kiss1 in healthywomen Acute ortwice-dailyfor1weekscadministration ofkisspeptin-54(6.4 nmol/kg)inducednoeffectonserumprolactinlevels mulatta Intravenous infusionofkisspeptin-10(10 or 30μg)inducesnochangeinprolactinserumconcentrationmale 8-month-old castratedmalecalves cells,Kisspeptin-10 (1µMor10µM)increasesmediaprolactinconcentrationofanterior pituitary extractedfrom Intravenous administrationofkisspeptin-10(5mg/kg)doesnotalterbasalserumprolactin levels cellculture Kisspeptin-10 doesnotalterprolactinsecretioninanteriorpituitary in OVXfemales, diestrusfemales ormales Kisspeptin-10 icvinfusion(3nmol)increasesserumprolactinreleaseinOVX+E2and proestrusfemales, buthadno effect Not described females Icv prolactininfusion(20µg/hr/1week)doesnotsignificantlychange Icv (4µg/µL)orsc(0.5mg/0.2mL)prolactininjectioncausesasignificantreduction of Not described 60% of ARH kisspeptinimmunoreactiveneuronsco-expressPRLRsinOVXfemales 79% and45%ofKiss1-expressingneuronsinthe ARH ofOVXorOVX+Etreatedanimals, respectively, co-expressPRLRsmRNA 86% ofKiss1-expressingneuronsinthe AVPV co-expressPRLRsmRNAinOVX+E2treatedfemales 3 scdosesofprolactin(100µg/200µg)causeasuppression immunoreactivity inthe AVPV and ARH Chronic infusionofprolactin(7μg/24hr/28days)significantlydecreaseshypothalamic Comments Not described females No co-expressionbetweenKiss1mRNAandprolactin-inducedpSTAT5 (icv, 20µg/hr/1week)inthe ARH ofOVX+E2 65-75% of ARH kisspeptinneuronsofprimiparousratsco-expresspSTAT5 aftericvprolactininfusion(2.5or100ng/rat) or lactatinganimals 70-80% of ARH kisspeptinimmunoreactiveneuronsexpresspSTAT5 afterprolactinicvinfusion(0.5µg/2µL)invirginOVX induced pSTAT5 inmicediestrus 65% ofkisspeptinimmunoreactiveneuronsinthe AVPV and35%ofkisspeptinneuronsinthePeNexpressprolactin- -expressing neurons reduction in plasma LH levels (4,5,43). inplasmaLHlevels(4,5,43). reduction leadingtoa hypothalamicKiss1expression suppresses infusion (icv)prolactin or intracerebroventricular inanimalmodels(Tableexpression 1).Systemic infusiononKiss1 consequences ofprolactin bystudiesthatevaluatedthe gonad axiswasprovided causes significantimpacttothehypothalamic-pituitary- andkisspeptin system interaction between prolactin evidencethatthe More and kisspeptinsecretion. neurons theactivityofKiss1-expressing may regulate of pSTAT5 togetherindicatethatprolactin byprolactin ofPRLRsandtheinduction 2).Theexpression (Figure administrationinfemalemicediestrus prolactin Kiss1 mRNAinthe ARH ofOVXmice Kiss1 mRNAexpressioninthe ARH ofOVX+E2 Prolactin, kisspeptinandreproduction Kiss1mRNAandkisspeptin Kiss1 mRNAinthe ARH ofOVXrats Macaca mRNA mRNA 591

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. administration may induce prolactin secretion through through secretion administration mayinduceprolactin thatkisspeptin demonstration, atleastin rodents, manner, not onlyin female rats but also in males.The inanestrogen-dependent inhibition ofTIDAneurons through secretion prolactin that kisspeptins increase Additionally, andcols.(54)demonstrated Ribeiro femalesormalerats(52). (OVX) females,diestrus inovariectomized rats,but had noeffect or proestrus levels only in ovariectomized E2-primed (OVX+E2) prolactin serum Icv infusionofkisspeptin-10increases levels, asdemonstratedinrodents. circulating to related seems tobedirectly secretion prolactin women (53).Infact,theabilityofkisspeptintoinduce levelsinhealthy prolactin onserum induced noeffect secretion, a doseknowntostimulategonadotropin subcutaneous (sc) administrations of kisspeptin-54, at In humans,forexample,acuteoraweekoftwice-daily (Tableunable todemonstratesucheffect 1)(50-53). (49).However,secretion severalotherstudieswere prolactin 8-month-old castratedmalecalvesincreased cellsextractedfrom withanteriorpituitary prepared media Administration of kisspeptin-10 to culture aswell. secretion prolactin possibly control activity of 592 third ventricle. Scalebar: inset=23µm. photomicrograph=100µm; higher magnificationofdual-labeledneuronsinthe ARH. Abbreviations: 3V, prolactin-responsive of ovineprolactin(10µg/g)beforeperfusion. Arrows illustrateexamplesof publications (Cravoandcols., 2013). Micereceivedasinglei.p. injection in diestrus. Details about this mouse model can be found in previous gene and prolactin-induced pSTAT5 immunoreactivity of a female mouse (hrGFP) whichisexpressedunderthetranscriptionalcontrolofKiss1 showing the expression of humanized Renilla green fluorescent protein . Fluorescentphotomicrographsofhypothalamicsections Figure 2. Prolactin-responsive Prolactin, kisspeptinandreproduction Interestingly, the affect notonlymayprolactin -expressing neurons, but kisspeptins neurons, Kiss1-expressing -expressing neurons.Kiss1-expressing The Kiss1-expressing neuronsinthemouse inset represents a represents a responsible for modulating prolactin secretion. secretion. formodulatingprolactin responsible ofthefeedbackcircuitry mayalsobepart neurons s inhibitionsuggests that TIDA neuron whether the suppression of GnRH release induced by ofGnRHrelease whether thesuppression mice (43).Additionally, Sonigoandcols.,(43) tested cyclicity andovulationrate even inhyperprolactinemic estrous daily i.p.injectionsofkisspeptin-10 recovered oftheircycles.Remarkably,mice showeddisruption female cycles, hyperprolactinemic estrous regular animals displayed While control infusion of prolactin. sc wasinducedbyachronic Hyperprolactinemia modelinmice(43). infertility prolactin-induced andovariancyclicityina secretion gonadotropin by conventionaltherapy(60). wassimilartothatobtained rate of kisspeptin treatment in women with subfertility. birth Of note, the efficacy implantation,andsuccessfullive embryo fertilization, result in to able to trigger egg maturation sufficiently been tested.Asinglescinjectionofkisspeptin-54was therapyhavealso fertilization undergoing invitro kisspeptins administrationoneggmaturationinwomen (59). Additionally,8 weeks of treatment of the effects evenafter elevated thelevelsofreproductive period. Thisprotocol twice-weekly overaprolonged sc whenkisspeptin-54 wasadministered effective wasmore of womenwithhypothalamicamenorrhea (58).Infact,thetreatment wasobserved secretion ongonadotropins significanteffect and nofurther desensitization ledtoreceptor kisspeptin-54 treatment However,comparison tothevehiclegroup. 2weeksof and estradiol levels, in in plasma increase showed a rapid and marked hypothalamic amenorrhea first kisspeptin-54 injection, womenwithfunctional kisspeptin-54 administration for 2 weeks. After the oftwice-daily sc subjectedtoaprotocol were women withfunctionalhypothalamicamenorrhea bya clinical trial in which wasprovided of this effect infertility. totreat therapeutic effects Thefirstevidence 58), kisspeptinadministrationmayhavepotential in bothhumansandanimalmodels(48,56- secretion stimulationinLHandFSH to causeapowerful able (55)andtheyare activators ofGnRHneurons knownasthemostimportant Because kisspeptinsare PROLACTIN-INDUCED INFERTILITY? THERAPEUTIC APPROACH TOTREAT MAY KISSPEPTINBEUSEDASANOVEL Kisspeptin administration can also restore Kisspeptin administration can also restore Arch Metab. Endocrinol 2016;60/6 expressing Kiss1-expressing Arch Metab. Endocrinol 2016;60/6 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: cial support. tion (Fapesp-Brazil,13/07908-8,2015/10992-6)for the finan Founda Acknowledgements: wethanktheSãoPauloResearch kisspeptin system. and the interaction between prolactin bidirectional which highlights a putative secretion, prolactin of kisspeptins seem to contribute to the control Furthermore, withkisspeptinreplacement. be treated canpossibly infertility hyperprolactinemia-induced Therefore, secretion. of GnRH andgonadotropins leadingtoalower activation kisspeptin secretion, of induces suppression on acts directly Prolactin onreproduction. effects of prolactin’s mediators important are neurons Kiss1-expressing investigation. further humans stillrequires in infertility prolactin-induced totreat approach whether kisspeptinmaybeusedasanoveltherapeutic Nevertheless, during hyperprolactinemia. secretion of gonadotropin cause of the suppression the primary ofKiss1 reduction the (43).Therefore, by changesinkisspeptinsecretion ismediated secretion actionongonadotropin inhibitory demonstrating that prolactin GnRHsecretion, restore Notably, withkisspeptin-10wasableto co-treatment toprolactin. was significantlyinhibitedafterexposure intothemedium medium. Asexpected,GnRHrelease inaculture treated femalemicewere obtained from medialbasalhypothalamus explants GnRH secretion, Totreatment. ofkisspeptins on demonstratetheeffects by kisspeptin could be reversed hyperprolactinemia In conclusion, recent evidenceindicates that In conclusion,recent Neuroendocrinol. 2014;26(12):898-908. lactation-induced suppressionof kisspeptinexpression.J of kisspeptinneuronesinthemouse brainanditsroleinthe Brown RSE,Herbison AE, Grattan DR.Prolactin regulation of prolactinreceptor. FASEB J. 2016;30(2):1002-10. Binart N,etal.Prolactin transport intomousebrainisindependent Brown RSE, Wyatt AK, HerbisonRE, KnowlesPJ, LadymanSR, 1998;19(3):225-68. phenotypes observedinPRLreceptorknockout mice.EndocrRev. (PRL) anditsreceptor:actions,signaltransductionpathways and Bole-Feysot C,Goffin V, EderyM,Binart N, Kelly P. Prolactin 2000;80(4):1523-631. structure, function,andregulationofsecretion.Physiol Rev. Freeman ME,Kanyicska B,Lerant A, NagyG. 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