European Journal of Endocrinology 10.1530/EJE-16-1059 treatment aswellinfertilitytherapy( common, probablyduetoimprovementinacromegaly acromegaly, pregnancyisapparentlybecoming more Although fertilityisfrequentlyimpairedinwomenwith adenomas, mainly macroadenomas. secreting pituitary Acromegaly isusuallycausedbygrowthhormone(GH)- Introduction pregnancy orlactation. weight. Aggressivediseaseisuncommonandmayurgeindividualdecisionssuchassurgeryordrugtreatmentduring Drug exposure(somatostatinanalogs)duringearlyorwholepregnancymightincreasethechanceofalowerbirth pregnancy confirmationhasalsoproventobesafe,asdrugsarenotformallyallowedusedduringpregnancy. to ensurebetteroutcomes,andsurgicalcontrolshouldbeattemptedwhenfeasible.Treatment interruptionat pregnancy surveillance,controllingtumorsizeandhormonalactivitybeforeishighlyrecommended stability. Althoughthepaucityof datalimitsevidence-basedrecommendationsforpreconceptioncounselingand review, weshowthatpregnancyinwomenwithacromegalyisgenerally safe,usuallywithtumoralandhormonal the variousGHgeneshaveallowedabetterunderstandingofsomatotrophicaxisfunctionduringpregnancy. Inthis to thepreexistingliterature.Also,newGHassayswithselectivespecificitiesandknowledgeofexpression of pregnancy inpatientswithacromegalyhavebeenpublishedrecentyearsaddingnewandrelevantinformation common duetoimprovementinacromegalytreatmentaswellfertilitytherapy. Asaresult,severalstudieson Although fertilityisfrequentlyimpairedinwomenwithacromegaly, pregnancyisapparentlybecomingmore Abstract São Paulo,Brazil,and São Paulo, Brazil, 1 Julio Abucham review Acromegaly andpregnancy: acontemporary MANAGEMENT OFENDOCRINEDISEASE Neuroendocrinology Unit,EscolaPaulistadeMedicinadaUniversidadeFederalSãoPaulo, DOI: 10.1530/EJE-16-1059 www.eje-www.eje-online.org peptides to hypothalamic–pituitary disordersatboththeclinicalandmolecular levels. peptides tohypothalamic–pituitary University-New EnglandMedical Center, Boston,USA(1985–1988). Hisresearch focusmovedfromgut–brain at thatUniversity(1976–1984) followedbyapostdoctoralfellowshipwithSeymourReichlin atTufts Paulista deMedicina,Universidade FederaldeSãoPaulo,Brazil.HeobtainedhisMD,MSc and PhDdegrees Julio Abucham Invited Author’s profile Review online.org 2 Division ofEndocrinologyandMetabolism,NeuroendocrinologyUnit,University

1 , Marcello D Bronstein , MD, PhD, is Professor of Endocrinology and Chief of the Neuroendocrine Unit at Escola 3 Endocrinology Unit,UniversidadeFederaldeGoiás,Goiânia,Brazil © 2017EuropeanSociety ofEndocrinology © 2017EuropeanSociety ofEndocrinology J Abuchamandothers 2 and Printed inGreatBritain 1 ). Asaresult, Monike L Dias of GHimmunoassayswithselectivespecificities( preexisting literature( years haveaddednewandrelevantinformationtothe with acromegalythathavebeenpublishedinrecent ( single-center caseseries( 3 Acromegaly andpregnancy 3 Published byBioscientifica Ltd. , 4 ) andprospectivestudies( 6 , Downloaded fromBioscientifica.com at09/30/202107:17:21AM 2 7 ) andmulticenterretrospective ). Moreover, thedevelopment 5 ) onpregnancyinpatients (2017) Endocrinology European Journal of [email protected] Email to JAbucham should beaddressed Correspondence 177 177 : 1 177

:1 , R1–R12

8 R , 1–R12 9 ) and via freeaccess European Journal of Endocrinology to havearisenbygeneduplication( composed offiveexonsandfourintronsarethought to GHbutfunctionallycloserprolactin.Thesegenesare placental lactogen(PL),whichisstructurallyhomologous chorionic somatomammotropin(CS),alsoknownas and GH, GH-Vhasaconsensus sequence forN-glycosylation dispersed throughout the peptide chain ( 22K. Itssequencediffersfrom 22K-GHin13aminoacids acids, twodisulfidebridges andamolecularweightof product isGH-V, asingle-chainproteinwith191amino GH-V Placental GH ( across allagesandinvariousphysiologicalconditions 10% ofcirculating GHinnormalsubjectsofbothsexes, Average 20K-GH concentrations correspond to less than is generated by alternative mRNA splicing at exon 3 ( 176 amino acids that lacks residues 32–46 of 22K-GH and disulfide bridges.The20K-GHisashorterisoformwith a singlepolypeptidechainwith191aminoacidsandtwo GH availableforreplacementtherapies.The22K-GHhas with acromegaly( GH innormalmen,nonpregnantwomenandpatients GH,isthemaincirculatingprototype pituitary isoformof weights: 22K-GHand20K-GH.Theisoform,the its transcript,twomainisoformswithdifferentmolecular andyields,throughalternativemRNAsplicingof pituitary GH-N Pituitary GH 17q24.2 andcontainsthetwoGHgenes( genes. ThegeneticlocusencodingGHisonchromosome hormone consistingofseveralisoformsderivedfromtwo Human growthhormone(GH)isaheterogeneousprotein Growth hormoneisoforms assessment andtreatment. with specialemphasisonpracticalaspectsofdiagnosis, complex interactionbetweenacromegalyandpregnancy axis thattakeplaceduringpregnancy. our understandingofthechangesinsomatotrophic genes ( the increasingknowledgeofexpressionvarious www.eje-online.org 13 Review ), butareslightlyincreasedinacromegaly( We willreviewourcurrentunderstandingofthe GH-V isonlyexpressedintheplacentaanditsmain isexpressedinsomatotrophiccellsofthe anterior 10 , or 11 ) have allowed substantial improvement in GH2 13 ) andanotherthreegenesencoding ). 22K-GHisalsotherecombinant J Abuchamandothers 12 ). 16 GH-N ). Unlike 22K- 15 ). or GH1 14 ).

progressively replaces pituitary GHthroughanegative progressively replacespituitary rising bloodglucoselevels( ( nonpulsatile andisnotcontrolledbythehypothalamus fashion under hypothalamic control, GH-V secretion is In contrast to GH-N, which is secreted in a pulsatile values of 13–25 peak concentrationsinthethirdtrimester(mean weeksofpregnancyandrisesprogressivelytoreach 8 circulates inmaternalblood.GH-Visdetectableafter GH ( activities, buthasaweakerlactogenicactionthan22K- protein (GHBP)andalsoinitssomatogenicmetabolic half-life, bindingaffinitytogrowthhormone-binding remains unknown( of GH-Vhavebeenidentified,buttheirphysiologicalrole and glycosylated(25K-GH-V)isoforms( at position 140 and can be foundin both nonglycosylated (stimulatory) and somatostatin (inhibitory) on pituitary onpituitary andsomatostatin(inhibitory) (stimulatory) predominantly throughthe opposingeffectsofGHRH secretion ispulsatileandcontrolled bythehypothalamus, GH In normalmenandnonpregnant women,pituitary The somatotrophic axis developed ( for 22K-GH,20K-GH,both,andGH-Vhavebeen cross-react in most immunoassays, but specific assays and designoftheassaysystem( crossreactivities of the antibodies with GH-V and the type lead tospuriouslyhighorlowresultsdependingonthe 26 of the marked disparity among immunoassay results ( reference preparationsusedinGHassaysexplainmost of theassayantibodiesforeach isoform anddifferent ( to theheterogeneousmixtureofGHisoformsinblood presence oftwoGHBPsthatcomplexwithGHgivesrise disulfide-linked oligomerizationofGHmoleculesandthe generated byperipheralmetabolism,non-covalentand of monomericGHisoforms),circulating GHfragments molecules (N-acylation,deamidationandglycosylation Several posttranslationalmodificationsintheGH GH measurements feedback ( Acromegaly andpregnancy 24 21 , ). Thatheterogeneityandthedifferentcrossreactivities ). Like GH-N, GH-V secretion is acutely blunted by 27 GH-V isthemaincirculating placentalGHandonly During pregnancy, measurementofserum GHcan 18 ). ). 21 8 , , 23 19 ). , µg/L, depending on assay) ( 28 10 ). ). GH-Vissimilarto22K-GHinits Downloaded fromBioscientifica.com at09/30/202107:17:21AM 22 ). Aftermidgestation,GH-V 6 , 9 177 , 17 27 :1 ). Otherisoforms ). GHisoforms 19 , R2 20 25 via freeaccess ). ). , European Journal of Endocrinology phase ( up toseveralhundredtimes thosefoundinthefollicular rise progressively. Estradiolcanreachpeakconcentrations During pregnancy, circulating estradiol and estronelevels normal pregnancy The somatotrophic axis during oral estrogensarebeingusedconcomitantly( women withGHdeficiencyrequireshigherdosageswhen increased serumIGF-1,andGHreplacementinadult usually present increased serum GH levels without women onoralcontraceptivescontainingestrogens GH-blocking effectsofestrogenintheliver. Likewise, responseofGH-Ntocounteractthe as acompensatory havebeeninterpreted different. Thoseobservations is higherthanthatinmen,butIGF-1levelsarenot In pubertalandadultwomen,the24-hGHsecretion nonpregnant women The somatotrophic axisin generated intheliverthroughGHstimulation( fashion inseveraltissues,butcirculating IGF-1ismostly produced IGF-1canalsoactinaparacrine/autocrine the consequentstabilityofIGF-1levelsinplasma.Locally for thelonghalf-lifeofplasmaIGF-1(nearly18 complex formedbyIGF-1,IGFBP-3andALSisresponsible thus requirefunctionalintegrityoftheliver. Theternary andundernutrition GH andinhibitedbystarvation secretion ofIGF-1,IGFBP-3andALSareallstimulatedby complex withanacid-labilesubunit(ALS).Synthesisand proteins (IGFBP),mostlytoIGFBP-3,formingaternary Nearly 95% of circulating IGF-1 is bound to binding in numeroustissuesincludingbone,cartilageandmuscle. (IGF-1), whichisresponsiblefortheanabolicactionsofGH synthesis andsecretionofinsulin-likegrowthfactor1 GH toGHRin liver andseveralothertissuesactivates the by the enzymatic cleavage of GHR. Binding of circulating bound toGH-bindingprotein(GHBP),whichisgenerated release ( predominantly at the pituitary, also controls GH predominantly at the hypothalamus and of IGF-1, and lipolysisrespectively).AnegativefeedbackofGH, which areinfluenceddirectlybyGH(insulinantagonism metabolic signals like glucose and free fatty acids, both of sleep, fasting,exercise andstressisinhibitedby somatotrophic cells.GH-Nsecretionisenhancedby Review At physiologicallevels,nearly50%ofcirculating GHis 33 29 ). Suchhighestrogenenvironment isthought ). J Abuchamandothers 31 29 , 32 , h) and 30 ). ).

acromegaly ( normal pregnancyaswellinwomenwith understand the changes of thesomatotrophic axis during to induceastateofrelativeGHresistance,whichiskey feedback ofrisingGH-VandIGF-1concentrations( start todeclineprobablyinresponsethenegative by increasingIGF-1levels.Atmidgestation,GH-Nlevels progressively overcome theresistancetoGHasreflected duringthisperiod( observed riseinGH-Nlevelshasnotbeenuniformly compensatory by asignificantdeclineincirculating IGF-1,althougha levels wouldinduceastateofGHresistanceasreflected patients ( inGH-deficientpregnant development asobserved barrier andisnotessentialtonormalgestation form ofGHinmaternalblood,doesnotcrossplacental of GH-N found in active acromegaly, and the relative in latepregnancy, comparabletotheconcentrations effect ofthehighandsustainedconcentrationsGH-V levels resultsfromtheinteractionbetweenstimulatory individual variability( than pre-pregnancylevelsandalsoshowlargeinter- ( depending onassay, withawiderangefrom the end of pregnancy, average GH-V levels are 13–25 concentrations, whereasGH-Nismarkedlysuppressed.By weeks ofpregnancy, bothGH-VandIGF-1reach peak to rise,whereasGH-Nisfurthersuppressed.Inthelast maternal bloodduringpregnancy. estrogens, pituitaryGH(GH),placental GH(PGH)andIGF-1in Schematic representationofserum concentrationsof Figure 1 Acromegaly andpregnancy 19 , In thethirdtrimester, GH-VandIGF-1levelscontinue Thereafter, placentalGH-Vlevelsstarttoriseand In thefirsttrimester, GH-Nisstillthepredominant 20 ). IGF-1 levelsare, in average, nearly two-fold higher 35 , 33 36 , 34 ). During thisperiod, rising estrogen ). 39 Downloaded fromBioscientifica.com at09/30/202107:17:21AM , 40 37 ). SuchincrementinIGF-1 , 38 ). 177 www.eje-online.org :1 < 10 to60 20 µg/L, µg/L R3 ). via freeaccess European Journal of Endocrinology www.eje-online.org However, unlike normal pregnancy, both elevated whereas GH-Vlevelshavenotincreasedappreciably. levels havealreadyinducedastateofGHresistance, least duringthefirsthalfofpregnancy, whenestrogen acromegaly wouldbeexpectedtoimproveclinically, at GH/IGF-1 ( and insensitivetothenegativefeedbackofcirculating decline as tumoralGH-N secretion is largely autonomous which isexclusivelyderivedfromtheadenoma,donot with acromegaly. However, GH-N levels in acromegaly, GH arepredictabletooccurduringpregnancy in women and GH-V concentrations as well as increased resistance to place innormalpregnancysuchasincreasingestrogen Most ofthespecificchangesinhormonelevelsthattake in acromegaly The somatotrophic axisduringpregnancy stimulation mightoccur( limiting effectonthemaximalresponseofIGF-1toGH In addition,undersuchhighestrogenconcentrations,a betweenGHandIGF-1. right’ ofthedose–responsecurve That interactioncanalsobeunderstoodasa‘shifttothe to GHinducedbyhighestrogenconcentrations( peripheral resistance (mostly or exclusively at the liver) Review As aresultoftheaforementionedmechanisms, 5 , 6 ). Fig. 1 ) ( J Abuchamandothers 34 ). 31 , 32 ). high serum IGF-1before midgestation is suggestive of applied to pregnant women, as pituitary GHlevelsdecline applied topregnant women, aspituitary and post-glucose GH as well as for IGF-1 levels cannot be GH assays( to eitherfalselyelevated( GH canoften lead hormones withhomology to pituitary is challenging.Interferenceofcirculating placental Hormonal assessment of acromegaly during pregnancy during pregnancy Hormonal assessmentofacromegaly among patients( resistance, all of which are expected to be highly variable GH-N andGH-Vthedegreeofestrogen-inducedGH interaction oftheindividualconcentrationsboth IGF-1 concentrations, will conceivably depend on the hormonal activityofacromegaly, asreflectedbycirculating after midgestation in patients with acromegaly. Thus, GH-N andrisingGH-Vconcentrationswillcoexist pregnancy usuallyriseonlyaftermidgestation( gestation. However, asIGF-1concentrationsinnormal of normativedataforbothGHandIGF-1levelsduring should be postponed until puerperium due to the lack 40 and IGF-1levelsincreaseduringnormalpregnancy( Acromegaly andpregnancy ). Ifpossible,thedefinitediagnosisofacromegaly 9 ). Also,usualreferencerangesforbothbasal Fig. 2 Modified from Ref.( estrogen blockade(rightpanel). IGF-1 secretioninoppositionto the high GH-NandincreasingGH-V willdrive autonomous andsustained, both GH-N secretionbythetumoris In pregnantwomanwithacromegaly, blockade andIGF-1levelseventuallyrise. midgestation usuallyovercomethat increasing levelsofGH-Vafter IGF-1 generationinliver, butthe during pregnancyinhibitGH-induced midgestation. Thehighestrogenlevels of GHinmaternalbloodafter replaces GH-Nasthepredominantform through anegativefeedbackaction.GH-V IGF-1 inhibitpituitaryGH(GH-N)secretion of maternalIGF-1,andbothGH-V responsible forstimulatingtheproduction placental GH(GH-V)isthemajorhormone In normalpregnancy(mid-panel), Figure 2 ). Downloaded fromBioscientifica.com at09/30/202107:17:21AM 27 ) orsuppressedGHvaluesin 177 39 ). :1 41 R4 ), a 20 via freeaccess , European Journal of Endocrinology cross-react withplacentalGH ( pregnancy usingspecific immunoassaysthatdonot as shownbymeasurements of GHconcentrationsduring secretion ofGHfromtheusual somatotrophicadenoma, Pregnancy seemstohave nomajoreffectsonthe hormonal activityofacromegaly Effect ofpregnancy onclinicaland by theadenoma( inthelimitedintrasellarspace alreadyoccupied pituitary represent tumorexpansion,buttheeffectofanenlarging tumors, visual impairment during pregnancy may not in normalpregnancy. However, inwomenwithpituitary enlargement not expectedtoappearduethepituitary hormone levelsalongnormalpregnancy. growth increasing prolactin and decreasing pituitary hormonelevelsaspreviouslydiscussedforthe pituitary composition areassociatedwithchangesincirculating types remainsrelativelyconstant.Thosechangesincellular gonadotrophs decrease,whereasthenumberofothercell 44 and reach60%bythethirdtrimesterofpregnancy( cellsinthenonpregnantstate the anteriorpituitary (hyperplasia). Lactotrophiccellscorrespondto20%of both lactotrophic cell size (hypertrophy) and number glandreflectsaconspicuousincreasein the pituitary next sixmonths( decrease andreturnstopre-pregnancystatuswithinthe volume showsafurtherincrease,butthereafter, itstartsto the first three days of the puerperal period, pituitary dome-shaped and closer to the optic chiasm ( The superiorpartoftheglandbecomesmoreconvexand but usuallydoesnotexceed10 is morepronouncedthanthatinotherlineardimensions doubles bythethirdtrimester( increase significantlyandtheglandvolumenearly During pregnancy, all dimensions of the anterior pituitary and function Effect ofpregnancy onpituitarystructure suggestive ofacromegaly. highly specific assays during that period would also be third trimesterinnormalpregnancy, higherGHlevelsby are expectedtodeclinelessthan1 acromegaly. GHlevels Ontheotherhand,aspituitary Review ). Incontrast,thepopulationsofsomatotrophsand It isimportanttonotethatcompressivesymptomsare Histologically, thegestationalenlargementof 45 42 ). ). 42 mm inthethirdtrimester. 5 , J Abuchamandothers ). Theincreaseinheight 6 ). Ontheotherhand, µg/L ( 20 ) duringthe 42 ). During 43 , pharmacological treatment withorwithoutaprevious occurs inpatientssurgicallycuredorcurrentlyunder in thelastdecades.Atpresent,pregnancyusually both diagnosisandtreatmentofpatientswithacromegaly outcome is likely to reflect the overall improvement in in mostpatients( stable clinicalcourseofdiseaseactivityduringpregnancy 48 46 acromegaly hasbeenvariablyreportedtoimprove( among patients. Not surprisingly, clinical activity of induced resistancetoGH,allofwhicharehighlyvariable and increasing estrogen levels and consequent estrogen- concentrations, progressivelyrisingaftermidgestation concentrations, usually stable; placenta-derived GH interplay betweenseveralfactors:tumor-derivedGH pregnancy reflectsatemporallydynamicandcomplex clinical andhormonalactivitiesofacromegalyduring of increasingplacentalGH concentrationsonIGF-1 Interestingly, unlike normal pregnancy, theeffect relation to IGF-1 concentrations as pregnancy advances. eventually be considered hormonally controlled in patients withrelatively high butstableIGF-1 levels will concentrations overcoming estrogenblockade,even midgestation, reflectingincreasingplacental GH during normalpregnancyraiseprogressivelyafter IGF-1 generationinducedbyGH. and (III)blockingeffectsofincreasingestrogenlevelson medications for weeks/months after their interruption GH-secreting adenomas;(II)persistingeffectsofprevious activity ofmost duration inchangingthesecretory of influencepregnancyand/oritsrelativelyshort among severalfactorsaspregnancyadvances:(I)lack during pregnancyseemstoreflectthedynamicinterplay ( clinical symptomsafterdelivery by thesharpreboundofbothIGF-1concentrationsand pharmacological treatmentbeforepregnancyaswell pregnancy beingsimilartothoseobtainedwith acromegaly iswellillustratedbyIGF-1levelsthroughout ( minor signsofpossiblediseaseactivity(mostlyheadache) been welltoleratedorfollowedbyonlytransientand or cabergolineoncepregnancyisdiagnosedhasusually interruption oftreatmentwithsomatostatinanalogsand/ ( disease activity has already been significantly improved surgery.pituitary Inmostcases,clinicalandhormonal Acromegaly andpregnancy 5 2 ). Theusual‘therapeutic’effectofpregnancyon , , ), remainstable( 3 49 Contemporary experiencehasusuallyshownarather Contemporary In addition,astheupperreferencelimitsofIGF-1 The relativestabilityofIGF-1levelsoften observed , ). 4 , 5 ) beforeconception.Insuchpatients,prompt 2 , 2 3 , , 5 4 ) orworsenduringpregnancy( , Downloaded fromBioscientifica.com at09/30/202107:17:21AM 5 , 38 , 46 5 , , 50 52 177 , ). 51 www.eje-online.org :1 ). Such favorable R5 45 45 via freeaccess , , European Journal of Endocrinology multiple comparisons)(fromRef.( (repeated measured ANOVA, Bonferroni’s posttestfor mean valuesfrompatients.* obtained inourpregnantcontrols.Horizontallinesrepresent the BrazilianpopulationorrangesofIGF-1values puerperium) representtherangesofnormalIGF-1valuesin acromegaly. Bars(aftersurgery, beforepregnancyand IGF-1 levels(ULN)intenpregnanciespatientswith Figure 3 www.eje-online.org previously, it may aswelldeterioratelateronthe the protectiveeffectsofestrogens. However, asdiscussed hormonal activity of acromegaly may also improve due to has beeneffective( 58 acromegaly duringpregnancy( blockade aftermidgestation. some patientsmayeventuallyovercome theestrogen tumoral GH-NaswellinGH-Vconcentrations,and considerably amongpatientsduetothevariations in serum frompregnantwomenwithacromegalydiffer ( of IGF-1toGHstimulationinahighestrogenmilieu andadecreaseinthemaximalresponse response curve IGF-1 levels,ashifttotherightinGHvsdose– the well-knownnonlinearrelationshipbetweenGHand include plausible explanationsforthoseobservations from earlyandmidgestationlevels( as theirIGF-1levelsinlategestationwerenotdifferent in asubstantialdegreemostpatientswithacromegaly, concentrations after midgestation does not seem to occur 42 Review , ). Nevertheless,theoverallsomatogenicactivityin Less commonly, patientsarediagnosed with 59 , 60 ) ortheybecomepregnantbeforetreatment 6 , 61 ). Insuchcases,clinicaland P

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0.05 vsaftersurgery 5 )). J Abuchamandothers 3 , 53 i. 3 Fig. , 54 , ). Themost 55 , 56 , 57 , small tumorsorevenlarge distantfromtheoptic at ahigherriskforvisual impairment thanthosewith patients with larger tumors close to the optic chiasm are of aclinicallyrelevantgrowth isevensmaller. Obviously, pregnancy is relatively low, around 10% ( acromegaly Effect ofpregnancy ontumorgrowth in control beforepregnancy( complications have been correlated with hormonal shown tobeonlyslightlyincreased( Surprisingly, theprevalenceofbothconditionshasbeen pregnancy oninsulinresistanceandsodiumretention. acromegaly duetotheknowneffectsofexcessGHand pregnancy wouldbeexpectedtoincreasemarkedlyin The developmentofdiabetesandhypertensionduring associated comorbidities Effect ofpregnancy onacromegaly- peripheral GHresistance. placental GHmayeventuallyovercome estrogen-induced combined effects ofanexcessivelyhigh GH andincreasing or glucocorticoid( were medically managed with bromocriptine, octreotide other caseswithmasseffectsymptomsduringpregnancy ( wereincreasedintracranial pressure reasons forsurgery had acromegalydiagnosedduringgestation,andthe duringpregnancy.required surgery Ofnote,fourofthem properly analyzed)( a historicalreviewwith34casesscarce datatobe tumor growth. In nearly 180 cases reported (excluding in acromegalyisevenlesscommonthanasymptomatic secreting adenomas( the tumorsinthosetwocasesweremixedGH/PRL- ofpregnancy. Interestingly,MRI performedat6 months retrospective study( by postpartumMRIin3of27pregnanciesthelargest other hand,asymptomatictumorgrowthwasdetected and oneretrospectivewith13pregnancies( and pregnancy, one prospective with 10 pregnancies imaging (MRI) in two multicentric studies on acromegaly in tumorvolumeweredetectedbymagneticresonance GH-secreting adenoma to grow. In effect, no changes Pregnancy isnotconsideredtostimulatetheusual Acromegaly andpregnancy 48 ), apoplexy( Accordingly, theoverall risk of tumor growthduring Symptomatic tumorenlargementduringpregnancy 53 3 ) andvisualloss( , 62 3 54 38 ) andintwoofsixcasesbyroutine ), onlysixpatientswithacromegaly , ). Downloaded fromBioscientifica.com at09/30/202107:17:21AM 55 3 , ). 56 , 64 ). 3 177 , 58 :1 3 , , 3 60 ), and the risk 5 4 ) andthose , , 5 63 ). Onthe ). Afew R6 via freeaccess European Journal of Endocrinology therapeutic effectinclinical activityofacromegalythat with largeexperience. much as possible ( shouldbeavoidedorpostponedas Therefore, surgery in thefirsttrimesterandfetallosslasttrimester. pregnancy increases the risks for hypopituitarism, abortion throughout pregnancy. during Ontheotherhand, surgery sufficiently knowntorecommendtheirliberal use acromegaly treatmentonfetaldevelopmentarenot for bothmotherandfetus.Theeffectsofdrugsused in the risksandbenefitsoftreatmentagainstno primum nonnocere during pregnancyshouldstrictlyfollowtheprinciple The generalapproachforthetreatmentofacromegaly Treatment ofacromegaly duringpregnancy severe casesthatfailedtoresponddrugintervention. should beindividuallyevaluated,restrictedtothemost octreotide shouldbeattempted.Surgicalintervention improvement soonafterinitiatingdopamineagonists, by decreasing tumor size. In the absence of any significant either byrevertinglactotrophichyperplasiaor, lesslikely, dopaminergic agonistscanalleviatechiasmcompression, of coma( to theextensionofvisualimpairmentand/ordegree withglucocorticoid,orsurgical,according conservative, apoplexy,Thus, in pituitary management can be either imagingforpropertherapeuticmanagement. pituitary should bewellestablishedthroughpatient’s and history infarction enlargement andpregnancy-induced pituitary growth ofthetumor, tumorenlargementduetobleeding/ pregnancy ( glandduring physiological enlargementofthepituitary of somatostatinanalogs( after shrinkage’ofthetumorwithdrawal due tobleeding/infarction (apoplexy)( symptoms mayalsobecausedbytumorenlargement may notreflectproliferativegrowthofthetumor. Those within the cavernous sinus during pregnancy nerves denoting compression of the optic chiasm and/or cranial during pregnancyhasbeenrecentlyreported( case of a GH-secreting adenoma aggressively growing further evaluatedbyanMRIofthesellarregion.Therare and suprasellarextension,visualchangesshouldbe throughout pregnancy in patients with macroadenomas chiasm ( Review It should be noted that visual and/or ocular symptoms It shouldbenotedthatvisualand/orocularsymptoms As previouslydiscussed,pregnancy hasatransient 45 66 ). Visual fieldassessments arerecommended 56 ). Intheothertwosituations,atrialof ). Thedistinctionamongtrueproliferative (first,donoharm),takingintoaccount 67 ) and preferably performed in centers 2 , 38 J Abuchamandothers ) andevenbythe 53 ), ‘expansion 65 ). complications, mainly if the disease is not under control. should becounseledabouttherisksofmaternalandfetal with somatostatinanalogs( treatment in patients with recent shrinkage of the tumor afterinterruptionof asymptomatic, hasbeenobserved closer totheopticchiasm( pregnancy ( control ofdisease( are highestamongpatientswithpoorpre-pregnancy and/or visualdeteriorationareusuallyacceptable,they Althoughtheoverallrisksofmetabolic intervention. to bereconsideredand,morerarely, evensurgical or visualimpairmentthatwillrequiremedicaltherapy of diseaseactivity(mostlypersistentheadache)and/ 4 treatment canbesafelyinterruptedinmostpatients( to stimulatetumorgrowth.Accordingly, pharmacological can lastuntildelivery, andpregnancy frequent andmoreseverethan thatafterwithdrawalof after withdrawalofshort-acting octreotideismore fetalexposuretooctreotideasheadache unnecessary headache control, asstated, mightleadtomoreand recommendation to reintroduce the medication for in clinicalpractice.Ontheotherhand,following conception planningthatisoftendifficulttoimplement with thelong-actinganalog,itrequiresmoremeticulous exposure todruginrelationtheresidual first recommendation was proposed to reduce embryo for tumorand/orheadachecontrol( acromegaly shouldbewithheldandadministeredonly pregnancy, it also recommended that medical therapy of untilconception. During acting octreotideisnecessary before attemptstoconceive,withtheuseofshort- somatostatin analogsorpegvisomanttwomonths Society ( surgery.pituitary that willrequiremedicaltreatmentand,lessfrequently, metabolic complicationsand/orvisualimpairment be discussedalongwiththeprobabilityofdeveloping of discontinuingtreatmentduringpregnancyshould before pregnancy, theadvantagesandrelativesafety requiring medicaltherapyfortumorand/ordiseasecontrol risk ofvisualimpairmentduringpregnancy. Inpatients conception canbeconsideredinordertodecreasethe before surgery proximity totheopticchiasm,pituitary pregnancy occurs.Incaseswithlargeadenomasinclose control bothdiseaseactivityandtumorgrowthbefore That shouldencouragebothpatientandphysicianto Acromegaly andpregnancy , 5 ). Occasionalpatients,however, mayshowworsening Women withacromegaly who wishpregnancy Accordingly, a recent guideline from The Endocrine 69 ) suggests that discontinuation of long-acting 59 , 68 ), and in those with pituitary adenomas ), andinthosewithpituitary 3 ), withacromegalydiagnosedduring Downloaded fromBioscientifica.com at09/30/202107:17:21AM 45 2 , ). Tumor expansion,usually 50 ). 177 per se 69 www.eje-online.org :1 ). Althoughthe doesnotseem R7 2 , via freeaccess 3 ,

European Journal of Endocrinology www.eje-online.org associated tofetalexposure toSAeitheraloneor, as 87 and/or dopaminergicagonists ( of continuous exposure to somatostatin analogs (SA) (mostly infirsttrimester)noramuchsmallernumber 63 in nearly50( ( placenta hassomatostatinreceptorsthatbindoctreotide microsomia ( also beconsidered at ahigherriskformacrosomiaand hypertension duringpregnancy, theirnewborns should develop impaired glucose tolerance/diabetes mellitus and However, assomepatientswithacromegalymayhaveor normal womenorfromwithprolactinoma( 74 normal generalhealthstatusat2,3and6 years ofage( treatment duringpregnancyhavebeenshownto born from women with acromegaly who discontinued been typicallynormal( treatment beforeoratthebeginningofpregnancy have Newborns fromwomenwhointerruptedmedical per se Data regardingfetaloutcomesarescarce, butacromegaly fetal development Effect ofacromegaly anditstreatment on pregnancy shouldbeperformedwithoutcontrast( decisions havetobemade( and/or visual complications appear and management when metabolic in uneventfulcases,but are mandatory arenotrecommended IGF-1 levelsandMRIofpituitary field disturbances.RoutinemeasurementsofGHand as diabetes,hypertension,hypopituitarismandvisual for the control or development of complications such Thereafter, allpatientsshouldberegularlymonitored daysafterconception( pregnancy assoon7–10 measurement beforeeachinjection,whichshoulddetect patients at risk for pregnancy through a serum beta-hCG octreotide couldbefurtherminimizedbyscreening confirmed. Inthisscenario, fetal exposureto long-acting should bepromptlydiscontinuedoncepregnancyis or cabergolineand/orpegvisomant,andtreatment treatment withlong-actingsomatostatinanalogsand/ safer analgesics( long-acting octreotide( 78 Review , , ). Notwithstanding,concerns aboutlowbirthweight ), no serious adverse fetal outcomes have been detected 75 Although octreotidecrossesplacentalbarrierand In themoreusualcases,patientsconceiveduring 79 doesnotseemtoaffectfetal development. ), aswellIQscoressimilartothosebornfrom , 80 , 81 77 2 , , ) respectively. 5 3 82 ). , , 4 , 83 5 , , 70 7 84 2 , ), whichisusuallyresponsiveto , 36 ) casesoftransientexposure 3 , , 38 4 4 , 69 J Abuchamandothers , , 5 64 47 ). Also,MRIduring , , , 38 73 48 ). Also,children , , 75 50 , , 78 51 , , 85 55 72 , , ). 71 76 86 57 73 ). ). , , ,

as octreotide.Also,FDAriskclassificationfortheiruse degree ofmaternal–fetal transfer andplacentalbinding it isnotknownwhetherlanreotidewouldhavethesame both octreotideandlanreotidearetherapeuticallysimilar, not be used in women at risk for pregnancy. Although in PubMeduptoDecember2016andthatdrugshould 84 limited withlanreotidethanoctreotide( of fetal exposure to SA during pregnancy is even more octreotide injectioninasinglecasereport( been demonstratedtooccurtransientlyaftershort-acting SA isdecreasedbloodflowinuterineartery, whichhas A suggestedmechanismforthatlowbirthweightwith has notbeenassociatedwithalteredbirthweight( fetal exposuretoDAinpatientswithprolactinomas study andbyfewcase reports ( agonists (DA)havebeenraisedbyalargeretrospective more oftenreported,incombinationwithdopaminergic neonates and doesnotseem toinducefurther rebound Breastfeeding duringactive acromegalyseemssafeto Breastfeeding to beproperlyanalyzedforconfoundingfactors. pegvisomant. However, manycaseshadincompletedata associated withbothmaternalandpaternalexposure to were reported,ahigherrateofprematurebirth( throughout pregnancy. Althoughnofetalmalformations pregnancy wasconfirmedandonlythreemaintained it were reported. Most patients stopped pegvisomant when of paternalexposuretopegvisomantduringconception Twenty-seven casesofmaternalexposureandeight in acompilationofPfizer’s GlobalSafetyDatabase( data onpegvisomantuseduringpregnancywasreported and wasundetectableinbreastmilk.Morerecently, safety blood. Also,pegvisomantdidnotsuppressplacentalGH in cordbloodspiteofitstherapeuticlevelsmaternal lowconcentrations case, pegvisomantwasfoundinvery delivered ahealthyandnormal-sizedbaby( patient who usedpegvisomantthroughout pregnancy pegvisomant during pregnancy has been reported. One ( http://www.fda.gov not withoctreotide(ClassB)(Drugsleaflet,availableat: with lanreotide(andpasireotide)exposure(ClassC),but studies have shown serious adverse effects to the fetus during pregnancyisnotthesame.Animalreproduction Acromegaly andpregnancy Table 1 , 90 Finally, itshouldbenotedthatthereportedexperience Transient ( ). No reports of pasireotide in pregnancy were found ). 4 , , accessedinDecember12th,2016) 91 ) andtotal( Downloaded fromBioscientifica.com at09/30/202107:17:21AM 3 , 4 177 , 92 85 :1 ) exposureto , 88 75 92 ). However, 3 ). , ). Inthat 4 , 94 38 ) was R8 , 93 89 80 via freeaccess ). ). , European Journal of Endocrinology but controllingtumorsizeand hormonalactivitybefore preconception counseling and pregnancysurveillance, of datalimitsevidence-based recommendationsfor usually withtumoralandhormonal stability. Thepaucity Pregnancy inwomenwith acromegaly isgenerallysafe, Conclusion a negligibletransfertobreastmilk( is probablysaferinthebreastfeedingperiodasithasonly might notberelevantthroughtheoralroute.Pegvisomant their biologicalactivityandgastrointestinalabsorption Somatostatin analogsareexcretedinbreastmilk( octreotide orlanreotidetreatmentareextremelylimited. controversial. Dataonchildrenbreastfedbywomen breastfeeding under acromegaly treatment is still of acromegalyactivityortumorgrowth( + d (cabergoline, lanreotideandoctreotideLAR)weresuspendedatthetimeofpregnancydiagnosis. a Bromocriptine Cabergoline Pasireotide Octreotide Lanreotide Pegvisomant Drug outcomes associatedtotheiruseduringpregnancy(PubMed,from19902016). Table 1 Leaflet recommendation.B,noprovenriskinhumans;C,cannotberuledout. And afewmorecasesthatdonotspecifywhichSSAorDAwasusedRef.( Usually incombinationwithdopamineagonists. Review Short acting Long acting(LAR) Prolonged release(LA) Autogel (Depot) Pharmacological treatmentofacromegalyduringpregnancy:drugcharacteristicsandcompilationmaternal/fetal

1.7 h 3–7 days 4.8 h 63–109 h 12 h 35–42 days 23–30 days 6 days half-life Mean

J Abuchamandothers 92 Yes Yes Unknown Yes Unknown Unknown Minimal cord blood Presence in ). e c Cabergoline usethroughoutpregnancywasobservedinpatientswithprolactinoma. 5 ). However, Impaired Impaired Yes (rats) Yes Unknown Unknown Minimal breast milk Presence in (humans) lactation lactation 75 ), but 3 ). B C C B pregnancy for FDA class B B C

to declare. for Pfizer, NovartisandIpsen.MonikeLourençoDias(MLD)has nothing speaker forNovartisandIpsena principalinvestigatoronclinicaltrials of the Steering Committees for Chiasma, Novartis and Ipsen. M D B is a Ipsen. MarcelloDelanoBronstein(M DB)isaconsultantandmember and Ipsen and a speaker and advisory board member for Novartis and Julio Abucham(JA)isaprincipalinvestigatoronclinicaltrialsforNovartis Declaration ofinterest during pregnancyorlactation. or drugtreatment individual decisionssuchassurgery weight. Aggressivediseaseinsomepatientsmayurge pregnancy mightincreasethechanceofalowerbirth exposure (somatostatinanalogs)duringearlyorwhole not formallyallowedtobeusedduringpregnancy. Drug confirmation has also proven to besafe, asdrugs are when feasible.Treatment interruptionatpregnancy outcomes, andsurgicalcontrolshouldbeattempted pregnancy ishighlyrecommendedtoensurebetter Acromegaly andpregnancy b Partial exposureincludespatientsinwhichlong-actingdrugs a Not Not Not Not lactation Drug useduring Impaired Impaired Not recommended recommended recommended recommended lactation lactation recommended c Also presentinamnioticfluidandchildserum. Downloaded fromBioscientifica.com at09/30/202107:17:21AM Partial Cases exposed pregnancy 50 25 22 19 0 7 0 during + +

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e 177 Reduced newborn Not applicable No in7cases;small Spontaneous outcomes Maternal/fetal Usually uneventful Usually uneventful Not applicable www.eje-online.org :1 Ref. ( usually withDA Ref. ( specified in 0–4 cases(not size newbornsin ( pregnancy (one) (three), ectopic premature births abortions (two), gestational age size, smallfor 92 ) 3 3 )) ) R9 via freeaccess d ,

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