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RespiratoryHealthinWomen:FromMenarcheto
Menopause
FerencMacsali,MDCecilieSvanes,MD,PhDLineBjrge,MD,PhDErnstR.Omenaas,MD,PhD
FranciscoGmezReal,MD,PhD
Posted:3/28/2012
ExpertRevRespMed.20126(2):187202.
AbstractandIntroduction
Abstract
Genderdifferencesinrespiratoryhealthhave,inrecentyears,beenthefocusofconsiderablescientificeffort.Thispaper
reviewsrecentliteratureonrespiratoryhealthinwomeninrelationtoageatmenarche,menstrualcycle,irregularmenstruation,
polycysticovariansyndrome,menopauseandexogenoussexhormones.Thisliteratureprovidessubstantialevidencethat
hormonalstatusplaysanimportantroleforrespiratoryhealthinwomen.Effectsofhormonalstatusontheairwaysoften
appeartobeheterogeneousandrecentliteratureinparticularsuggeststhattheinterplaybetweenhormonalandmetabolic
factorsisimportant.Aviewtodevelopmentalfactorsmayalsoberelevantfortheunderstandingofrespiratoryhealthaccording
tohormonalstatusinwomen.Furtherknowledgeofrespiratoryhealthinwomenholdsinterestingpotentialforinterventionand
personalizedtreatment.
Introduction
Asearlyasthe19thcentury,thesurgeonJohnHutchinsonpointedtothedifferencesinrespiratoryhealthbetweenmenand
women.Hecarriedoutextensiveobservationsof2104menand26women,andshoweddifferencesinbreathingmovements
betweenthegenders. [1]
Genderdifferencesarerelatedtothereproductivefunctionsofmenandwomen.Thedifferencesinvolvesexhormonesand
metabolicfactorsincloseinterplayinordertopromotereproduction.Hormonalandmetabolicfactorsinfluencealmostevery
processintheorganismandthelastfewdecadeshavebroughtincreasingknowledgeabouttheroleofreproductivefactorsin
chronicdisease,withmostfocusoncardiovasculardisease.Muchattentionhasbeenpaidtothromboembolismasasideeffect
oforalcontraceptivesandtocancerriskfollowinguseofhormonesubstitutionatmenopause.Atthesametime,the
importanceofpolycysticovariansyndrome(PCOS)asapredictorforchronicdiseasessuchascardiovasculardiseaseand
diabeteshasbeenrecognized.However,theunderstandingofhormonalandmetabolicfactorsinrelationtorespiratory
diseaseshasbeenlimited.
TheGlobalInitiativeforAsthma2010hasestimatedthat300millionpeoplesufferfromasthma, [2]andchronicobstructive
pulmonarydisease(COPD)isprojectedtobethefourthleadingcauseofdeathworldwideby2030. [3,4]Inspiteofits
importanceandtheextensiveresearchperformedduringthelastdecades,manyaspectsoffemalelunghealthstillremainin
thedark.
Agendershiftinasthmaincidencearoundpubertyhasbeenknownfordecades.Boyshavemoreasthmathangirlsbutwhen
reachingpubertythisrelationshipreversesandfrompubertyonwardswomenhavemoreasthmathanmen. [57]Ithasalso
beenshownthatwomenexperiencemoresevereasthmathanmenandaremoreoftenhospitalizedforasthmaexacerbations.
[7,8]Genderdifferencesinasthmaincidenceandpresentationsuggestbothgeneticandhormonalcomponentsinasthma.
Hormonalfactorsarecloselylinkedwithmetabolicfactorsandobesity.Thepopulationsofbothdevelopinganddeveloped
nationsareconvergingtowardsamoresedentarylifestyle.AccordingtotheWHO,1.5billionadultsover20yearsofageare
overweightand0.5billionareobese. [9]Bothincreasedweightandlessphysicalactivityfuelinsulinresistance,amajorrisk
contributortocommonchronicdiseases.Theimportanceoftheglobalobesityepidemicforrespiratoryhealthisnotfullyknown.
Duetothecloseinterplaywithhormonalfactors,metabolicfactorsarehighlyrelevantwheninvestigatingtherelationof
hormonalfactorstoairwaydiseases.
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Figure1.
ChangingHormonalStatusAlongWomensLifespan.PCS:olycysticovariansyndrome.Redrawnpermissionfrom[201].
Thepresentreviewdescribescurrentrespiratoryhealthinrelationtoaspectsofhormonalstatusinwomen.However,hormonal
statusininterplaywithmetabolicfactorsmightpossiblyhavewiderconsequences,witheffectsonhealthanddiseaseofthe
offspringgeneration.Barkerhypothesizedthatdevelopmentofchronicdiseasesstartsatconceptionandinintrauterinelife. [10]
Lowbirthweightandlowgestationalagehavebeenfoundtobeassociatedwithmanyaspectsofadulthealth,oneimportant
aspectbeinginsulinresistanceanddevelopmentofmetabolicsyndrome.Thereisalsoevidenceforeffectsonadultrespiratory
diseaseandlungfunction. [1012]
Theliteratureonlunghealthinwomenisconfusingandsometimescontradictory,notsurprisinggiventhatwomenare
hormonallyheterogeneousandlessinvestigatedthanmen(Figure1).ThegenderratiooftheHutchinsonstudyincluding2104
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menand26womenisnotentirelyuntypicaltwocenturieslater.However,althoughinvestigatingrespiratoryhealthinwomenis
particularlychallenging,considerableadvanceshavebeenmadeinrecentyears.
Menarche
Ageatmenarchesignalsthestartofawomensreproductivelifeandisdeterminedbyenvironmentalandgeneticfactors. [13,14]
Childrenclosertotheequator,atloweraltitudes,thoseinurbanareasandmildlyobesechildrenhaveearliermenarchethan
thoseatnorthernlatitudes,thosewholivehigherabovesealevels,thosewholiveincitiesandthosewithnormalweight. [13]
Recordsfromdifferentcountries,particularlyfromNordiccountries,haveshownthatduringthe100yearperioduntilthemiddle
ofthe20thCentury,ageofmenarchedecreasedfrom1617yearstoslightlylessthan13years. [13,15]Increasedbodyfatis
relatedtoearliermenarche,andleptinsecretedinadiposetissuehasbeenidentifiedasanimportantlinkbetweenbodyfatand
timingofmenarchehigherlevelsofleptinsignalearliermenarche. [16,17]Therearedifferencesinageatmenarchebetween
differentethnicgroups,implyingheritablecomponents.AfricanAmericansandMexicanAmericanshavemenarcheearlier
thanAmericansofEuropeandescent. [18]Menarche,inturn,signalsclosureoftheepiphysesandterminationoflengthgrowth.
[13]
Earlymenarcheisassociatedwithlatergeneralhealth.Increasedriskofbreastcancerandincreasedriskfordeveloping
metabolicsyndrome,includingobesity,Type2diabetesandcardiovasculardiseaselaterinlife,havebeenobserved. [19]A
Chinesestudydemonstratedearlymenarchetobeassociatedwithhigherriskofmetabolicsyndrome,raisedbloodpressure,
raisedfastingglucoseandhighertriglyceridelevels. [20]
Thereisevidenceofanassociationofmenarchewithasthmaandlungfunction.InastudyfromVarrasoetal.anassociation
betweenearlymenarche,increasedBMIandasthmaseveritywasfound.Clinicalasthmaseverityinthelast12monthswas
assessedbyascore(07)basedonthefrequencyofasthmaattacks,persistingsymptomsbetweenattacksandhospitalization.
Asthmaseverity,whichwasunrelatedtosex,increasedwithBMIinwomen(p=0.0001).Theassociationremainedafter
adjustmentforage,forcedexpiratoryvolumein1s(FEV 1),smokinghabitsandBMIadjusteddyspnea,andtakingintoaccount
familialdependence(p=0.0001).TheassociationbetweenBMIandseveritywasstrongerinwomenwithearlymenarchethan
inwomenwithoutearlymenarche(pinteraction=0.02). [21]IntheTucsonChildrensRespiratoryStudy,Guerraetal.followeda
birthcohortlongitudinally,inwhichanassociationbetweenincreasingBMIandasignificantincreaseinunremittingasthmaand
wheezingatages11and16yearswasshown. [22]Thisinvestigationalsodemonstratedthatchildrenwithunremittingwheezing
orasthmahadsignificantlyearlieronsetofpuberty. [22]AnotherstudyfromAlSahabetal.showedthatonsetofearly
menarche(<11.56yearsofage)predictedpostmenarchealincidenceofasthmagirlswhomaturedearlyhadmorethantwice
theriskofdevelopingasthmaduringearlyadulthoodthangirlswhomaturedatanaverageage(oddsratio[OR]:2.34CI:
1.194.59). [23]Onsetofpubertyingirlswasdefinedbasedonparentalreportsofthechildspubicand/orunderarmhair,breast
developmentormenstruation.Thisdefinitionhaslimitationsasthesethreeeventsnormallyoccuroveratimespanof
approximately2yearsfromameanof10.5yearsforbreastdevelopment,pubichairat11.0yearsandmenarcheat12.8years.
[13]AstudyofadultwomenbySalametal.showedanassociationofearlyageatmenarchewithincreasedriskofasthma,
womenwithmenarcheat12yearsofageorearlierhada2.08fold(95%CI:1.054.12)riskofasthmaafterpuberty. [24]Ina
Europeanpopulationstudyofadults,Macsalietal.foundthatwomenreportingmenarchebeforeage11years,comparedwith
womenwithmenarcheatage13years(referencecategory),hadlowerlungfunction(FEV 1:adjusteddifference113ml95%
CI:196to33ml)forcedvitalcapacity(FVC126ml95%CI:223to28ml)andFEV 1%predicted(3.28%95%CI6.25
to0.30%)FVCpercentpredicted(3.63%95%CI:6.64to0.62%).Womenwithearlymenarchealsohadmoreasthma
symptoms(OR1.8095%CI:1.092.97),asthmawithbronchialhyperreactivity(BHROR:2.7995%CI:1.067.34)and
higherasthmasymptomscore(meanratio1.5895%CI:1.122.21).ThefindingswereconsistentacrossEurope,suggestinga
biologicalratherthansocioculturalexplanation. [25]
Macsalietal.foundnorelationshipwithageofmenarchewithFEV 1/FVCratio,butthepopulationwasrelativelyyoungfor
investigatingCOPD(age2555years). [25]Salametal. [24]andGuerraetal. [22]didnotaddressCOPDintheiranalysesofvery
youngpopulations.InthecasecontrolstudyofasthmabyVarrasoetal., [21]investigationofCOPDwasnotfeasibleduetothe
studydesign.
Insummary,theliteratureconsistentlyshowsanassociationbetweenearlymenarcheandhigherriskofasthmaandasthma
symptoms.Onlyonestudyinvestigateslungfunction,andthefindingoflowerlungfunctioninwomenwithearlymenarchewas
consistentinamulticulturalpopulationandseemedratherconvincing.Thereisnoevidencetoconcludeapossibleassociation
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ofCOPDwithageofmenarche,mostlybecauseinvestigationofrespiratoryhealthandmenarcheismostlyperformedin
youngercohorts.
Thefindingthatwomenwithearlymenarchesubsequentlyhavemoreasthmaandlowerlungfunctionmaybeexplainedbytwo
differenttypesofmechanisms,andacombinationofthetwoseemsplausible.First,theremaybecommondevelopmental,
metabolicandhormonalfactorsdeterminingbothearlymenarcheandpoorerrespiratoryhealth.Thesecouldbefactorssuchas
unfavorablemetabolicprofile,insulinresistanceorpoorintrauterinedevelopment,sometimesreflectedinlowbirthweight.
Second,earlymenarcheitselfmightinducechangesinairwayfunction.Insulinresistanceandanunfavorablemetabolic
situationarefactorsthatcouldbepredictorsofearlymenarcheaswellasasthma.Forinstance,itseemsplausiblethatthe
terminationofgrowthsignaledbymenarchewouldalsoaffectlunggrowth.
MenstrualCycle
Thecourseandtimingofmenstruationissteeredthroughacomplexendocrineinterplaybetweenhormonesoriginatingfrom
thehypothalamus,thepituitaryglandandtheovaries.Extensivephysiologicalchangestakeplaceduringthemenstrualcycle.
Figure2showsanidealizedschemeofthevariationsinsexhormonesandbodytemperatureduringthemenstrualcycle. [26]
Figure2.
IdealizedSchemeoftheHormonalandBodyTemperatureChangesdDuringtheMenstrualCycle.FSH:Folliclestimulating
hormoneLH:Luteinizinghormone.Modifiedwithpermissionfrom[26].
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Manydiseasesareinfluencedbythemenstrualcycle.Diseasesasvariedasmigraine,epilepsy,bipolardisorder,inflammatory
boweldiseaseandrheumatoidarthritisareknowntoshowmenstrualcyclicity. [2729]
Amongasthmatics,fluctuationsinsymptomscanbecausedbyforinstanceinfections,pollenlevelsandworkrelated
exposures.However,foralargenumberofasthmaticwomenthecausesofvariationsindiseaseovertimearenotknown.It
seemsplausiblethathormonalandmetabolicvariationsduringthemenstrualcyclecouldinfluencetheairways.
Therehasbeenaconsiderablescientificefforttodescribevariationsinasthmaduringthemenstrualcycle.Respiratory
symptoms, [3032]peakexpiratoryflowrate, [3337]asthmaexacerbations, [31,38]hospitaladmissions, [39,40]BHR[41]and
fractionalexhalednitricoxide[32]haveallbeenfoundtovaryduringthemenstrualcycle.Gibbsetal.followed114asthmatic
womenattendinganoutpatientclinicand3040%reportedpremenstrualdeterioration. [34]Eliassonetal.conductedasurvey
amongasthmaticsandfoundthat33%ofwomenhadsignificantlyhighersymptomscoresduringthepremenstrualphase.In
thesewomen,worseningofrespiratorysymptomscorrelatedwithdysmenorrheaandpremenstrualsyndrome. [30]Mostofthese
studiesarebasedonsamplesofasthmaticwomenhowever,Dratvaetal. [41]investigatedbronchialhyperresponsivenessina
largepopulationbasedsampleofwomen.ThisstudyfoundthatwomenhadincreasedBHRintheperimenstrualphaseanda
tendencytoaperiovulatorypeak,withanORforbeinghyperresponsivetometacholinintheperimenstrualperiodof2.3(1.27
4.29). [41]ThisanalysisalsoshowedthatthecyclicalvariationsinBHRweresmalleramongwomentakingoralcontraceptives.
Anotheranalysisofalargegeneralpopulationsampleshowedgreatfluctuationsinrespiratorysymptomsduringthemenstrual
cycle.Symptomsweremoreprevalentduringthemidlutealtomidfollicularstages,oftenwithadipneartimeofovulation
however,peaksvariedbetweensubgroupswithdifferentcyclicalpatternsaccordingtoasthmastatus,smokingstatusandBMI.
[42]
Amajormethodologicalproblemwheninvestigatingmenstrualcyclicityistheuseofpredefinedcutoffpoints(i.e.,investigating
theperimenstrualortheprementrualperiod).Biologicalcyclicitydoesnotadvocatethis,andsuchcategorizationimpliesarisk
oflosingimportantinformationandbiastheidentificationofpeaks.Statisticalmethodologydesignedtoinvestigate
chronobiologicalrhythmicityisanimportantalternative.Mostoftheabovecitedanalysesrelatetopredefinedmenstrual
periods,withtheexceptionsofthestudybyDratvaetal.thatappliedtrigonometricfunctionsintheanalysisofbronchialhyper
responsiveness[41]andthestudybyMacsalietal. [42]thatusedmethodsforinvestigatingchronobiologicalrhythmicityas
developedbyMojonetal. [43]andfurtherdevelopedbyKoukkariandSothern. [26]Anotherimportantsourceoferroristhe
assessmentofselfreportedworseningofasthmainrelationtothemenstrualcycle,whichmayleadtodifferentialrecallbiasin
severalstudies.
Takingintoaccountthemethodologicalproblems,theliteratureisstillconvincingwithregardtothepresenceofmenstrualcycle
variationinasthma,asconsistentlydemonstratedinanumberofstudieswithdifferentdesignsandmethodology.However,the
literatureisinconsistentandpossiblybiasedwhenitcomestotheidentificationofspecificperiodsofthemenstrualcyclewhen
symptomsordiseasearemoreprevalentorsevere.Therehasbeenparticularfocusonpreorperimenstrualasthmaand
somefocusonperiovulatorychanges,butmoststudieshavenotusedmethodologyassignedtofreelyidentifypatterns.Onthe
otherhand,theidentificationofpeaksmaybeoflessimportanceforpracticalpurposesasthestudyofMacsalietal. [42]
indicatesdifferencesinpatternbetweensubgroups,eachasthmaticwomancouldidentifytheirowncyclicalpatternandadapt
treatmentthereafter.
Toourknowledge,possiblevariationsinCOPDexacerbationsduringthemenstrualcyclehavenotbeeninvestigated.Relatively
fewwomenwithCOPDareinthefertileagehowever,forthesefewwomenthequestionmightberelevant.
Thebiologicalmechanismsunderlyingthemenstrualcyclicityinasthmaandairwayhyperresponsivenessarenotwell
understood.Estrogensarelikelytobeofimportance, [44,45]aswellasprogesterone. [46]AstudybyMandhaneetal. [47]showed
thatincreasedfractionalexhalednitricoxideasamarkerofairwayinflammationwasinverselyrelatedtoestrogeninthe
menstrualcycle,whiletheoppositewastrueforprogesterone.ArecentstudybyJainetal. [48]showedprogesteronereceptors
ontheproximalregionoftheciliaofairwayepithelia.Ifexposedtoprogesterone,theciliabeatfrequencywasdecreased.
However,noconsistentresultshavebeenfoundwhenmeasuringsexhormonesagainstvariousclinicaloutcomes.Thisisnot
surprisinggiventhelargeindividualvariationsofsexhormoneswithinawomanandbetweenwomen,aswellasthecomplexity
ofhormonalandphysiologicalchangesduringthemenstrualcycle.Itseemsunlikelythatoneortwohormonesalonecan
explainthecyclicityofasthma.
IrregularMenstruation&PCOS
IrregularmenstruationisamainfeatureinPCOS,andwillusuallyreflectPCOSinwomenoffertileage.
[49]Theprevalenceof
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IrregularmenstruationisamainfeatureinPCOS,andwillusuallyreflectPCOSinwomenoffertileage. [49]Theprevalenceof
PCOSamongwomenoffertileagemightbeashighas15%dependingonhowitisdefined. [50]Itisthemostcommon
endocrinologicaldisturbanceamongwomenoffertileage,withbothhormonalandmetaboliccomponents.PCOSisan
importantcauseofsubfertility.PCOSisalsoassociatedwithanincreasedriskfordiabetesmellitusandcardiovascular
diseasesanditisstronglyrelatedtoobesity.ThemainpathologicalfeatureofPCOSisinsulinresistancewithsystemic
inflammation.PCOSissometimesconsideredavariationofmetabolicsyndromeexpressedinwomenoffertileage.
Hyperandrogenismisanothermainfeature,andwhetherthisisacauseorconsequenceofinsulinresistanceisnotfully
understood.Thereisadevelopmentallinkfromimpairmentinintrauterinedevelopmentthroughlowbirthweight,childhood
disadvantagesuchascatchupgrowth,prepubertalobesityandearlymenarche.PCOSisfurtherlinkedtosubfertility,andin
thecaseofpregnancy,topreeclampsiaandgestationaldiabetes(Figure1).
Despiteitsrelevanceforchronicinflammatorydiseases,theliteratureonirregularmenstruationandPCOSinrelationto
respiratoryhealthislimitedtotwoarticlesbasedoncrosssectionalanalyses.InanalysisofapostalsurveyofalargeNorthern
Europeangeneralpopulationincluding8588womenaged2642years,Svanesetal. [51]showedirregularmenstruationtobe
associatedwithhigherriskofasthma(OR:1.54CI:1.112.13),asthmasymptoms(OR:1.4795%CI:1.161.86),and
asthmawithhayfever(OR:1.95CI:1.302.96).Thiswasalsoobservedwhenexcludingwomentakingasthmamedication,
andthefindingswereadjustedforBMI.Inananalysisof1631womenaged2844yearsparticipatingintheEuropean
CommunityRespiratoryHealthSurvey,Realetal. [52]showedirregularmenstruationtobeassociatedwithlowerFVC(adjusted
difference:63ml95%CI:124to1),moreasthmasymptoms(OR:1.76CI:1.292.40),andmoreasthmawithatopic
sensitization(OR:2.46CI:1.434.23).Thelungfunctiondeficitdemonstratedamongwomenwithirregularmenstruationwas
relativelylarge.TherewasaninverseUshapedassociationoflungfunctionwithBMI,showingmaximallungfunctionatBMI
ofapproximately2425kg/m2.IrregularmenstruationandBMIshowedadditiveeffectsonasthmaandFVC.TheFEV 1/FVC
ratiowasnotsignificantlydifferentbetweenwomenwithregularandirregularmenstruation,andtherewasnoindicationofa
relationshipwithCOPDinthisyoungagegroup.
TheliteraturethusshowsalinkbetweenrespiratoryhealthandPCOS.Thisrelatestoasthmaandlungfunction,whileCOPD
inrelationtoirregularmenstruationhasnotbeeninvestigated.ThetimesequencebetweenPCOSandasthmahasalsonot
beeninvestigated.Anassociationisplausible,asoverweight,whichisanothermarkerofinsulinresistance,isawellknownrisk
factorforasthmaandlowerlungfunction.Furthermore,intrauterinedevelopmentasreflectedinlowbirthweightisrelatedboth
toPCOSandimpairedrespiratoryhealththus,commondevelopmentalfactorsmayalsobeofimportanceforanassociation.
ThefewpublishedstudiessuggestthatthepresenceofPCOSoranyofitsclinicalfeaturesshouldgiveawarningregarding
possibleimpairmentinrespiratoryhealthamongwomen.Giventhatrecommendationshavebeenputforthtoassesstheriskof
metabolicsyndromeinallpatientswithPCOS,itseemsplausiblealsotoconsiderrespiratoryhealthinthiscontext.
OralContraceptives
Gestagensandestrogenscombinedinoralcontraceptivepills(OCPs)havebeeninextensiveuseworldwideduringthelast50
years.Therehasbeengreatpublicityconcerningsideeffectsoforalcontraceptive,inparticularwithregardtocardiovascular
events,butthereislimitedknowledgeaboutpotentialinfluencesonrespiratoryhealth.
RespiratoryhealthhasnotbeeninvestigatedinlargecontrolledtrialsofOCPs,andsofartheredoesnotappeartobean
intentionofincludingthisuponintroductionofnewOCPs.PublicationsonrespiratoryhealthinrelationtoOCParethusbased
onobservationalstudies,andcurrentknowledgemustbesoughtfromcarefulanalysisandinterpretationoffindingsfrom
imperfectstudydesigns.IntheCopenhagenCityHeartStudy,Langeetal.didnotfindanysignificantincreaseinwheezing(p
=0.997),asthma(p=0.964),asthmamedication(p=0.448)orcoughingatexertion(p=0.866)amongwomenusingOCPs.
[53]Forbesetal.showedthathormonalcontraceptiveshadnoinfluenceonasthmaseverityinwomenwithrelativelymild
asthma. [54]Salametal. [55]showedthattheOCPwasassociatedwithmorewheezeamongnonasthmatics(OR:1.75CI:
1.152.65)andlesswheezeamongasthmatics(OR:0.18CI:0.060.56).AnelevatedasthmariskinpastOCPuserswas
observedintheNursesHealthStudy(OR:1.52CI:1.082.13). [56]IntheTasmanianAsthmaSurvey,a7%decreaseinadult
onsetasthmawasindicatedperyearofOCPuse. [57]Thisanalysisisbasedonlongitudinaldatafromawellcharacterized
populationcohort.AcrosssectionalanalysisoftheRespiratoryHealthinNorthernEuropepopulationbasedstudyfoundan
increasedriskforasthmaamongwomenusingoralcontraceptive(OR:1.43CI:1.091.86). [58]However,whenstratifyingfor
BMI,thisassociationwaspresentonlyamongnormal(OR:1.45CI:1.022.05)andoverweightwomen(OR:1.91CI:1.20
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3.02)andanonsignificantprotectiveeffectwasindicatedamongleanwomen(OR:0.41CI:0.121.40).Thisinterplaywith
BMIseemsbiologicallyplausible,andisdifficulttoexplainbyconfoundingorbias.AnanalysisofBHRinageneralpopulation
showedlessvariationduringthemenstrualcycleinBHRinwomenusingOCP,butthestudydoesnotdescribepossible
differencesinBHRmeanlevelaccordingtoOCPuse. [41]Itseemsreasonablethatsomewomenwithstrongcyclicalvariation
intheirasthmacouldexperiencemorestabilitywhenchangingthehormonalprofilewithOCP.Apossibleassociationoforal
contraceptivewithCOPDhastoourknowledgenotbeenexamined.
ConfoundingbyindicationisaproblemintheobservationalstudiesofOCPandrespiratoryhealth.Oralcontraceptiveisfor
exampleusedasatreatmentforPCOS,whichappearstoberelatedtoasthmaandlowerlungfunction,aswellasdiabetes
andcardiovasculardisease.Hence,PCOSmaypossiblybeanimportantconfoundingfactorintheassociationoforal
contraceptivewithairwaysdisease,afactorthathasnotbeenaccountedforintheabovementionedstudies.Theissueis
complicatedbythefactthatOCPssometimescausesirregularmenstruation.
Thus,theliteratureismethodologicallyproblematicandapparentlygivesinconsistentresults.ThecontentsofOPCshasvaried
overtimepresentlyusedOCPshaveahigherdoseofprogesteronerelativetotheestrogencontentcomparedwithOCPsthat
wereusedsomeyearsago.Thus,theremaybesomedifferencesintheexposurebetweenthestudies.Confoundingby
indicationmaydifferbetweenthestudypopulations,asprevalenceofOCPusevariedconsiderablyevenamongthenorthern
Europeancountries. [58]PCOSisnotadequatelyaccountedforinanyoftheabovestudies.Definitionofreferencecategory
maycontributetodiscrepanciesbetweenstudies,asmaydifferencesinBMIwerepresentbetweentheinvestigated
populations.
Inconclusion,itseemslikelyandbiologicallyplausiblethatOCPsmayaffecttheairwaysandthatsucheffectscouldbe
heterogeneous.ThereareindicationsthatasthmamaybeasideeffectofOCPinsomewomen,butasolidlongitudinalstudy
indicatesprotectiveeffectsforadultonsetasthma.DifferencesaccordingtoBMIhavebeendemonstrated,aswellas
differencesineffectonrespiratorysymptomsbetweenasthmaticsandnonasthmatics.Onelargestudyshowedreducedcyclical
variabilityinBHRamongOCPusers.Forclinicalpurposes,doctorsshouldbeawareofthepossibilitythatexogenous
hormonesmayaffectrespiratoryhealth,andlistentotheindividualpatientsfurtheradviceisnotfoundintheliterature.
Thepossibilityforairwayseffectsis,however,morethansufficienttostronglyadvocatethatrespiratorysymptomsanddisease
areinvestigatedwhenintroducingnewOCPs.
Menopause&HormonereplacementTherapy
Menopauseinwomenisdefinedasthecessationofmenstruationfor12months.Themedianageofmenopauseis51years.
[59]InalargepopulationstudyincludingthepanEuropeanCommunityRespiratoryHealthStudyandtheSwissSAPALDIA
databases,Dratvaetal.showedanincreaseinmedianageofmenopausetowards54years. [60]Thesinglefactorwiththe
largestinfluenceonageofmenopauseissmoking:menopauseamongsmokershappens1.5yearsearlier,dependentonboth
numbersofcigarettesaswellasdurationofsmoking. [59,60]
Therearechangesinhormonallevelsduetotheapproachofmenopause.Amongothers,folliclestimulatinghormoneand
luteinizinghormonerisesandestrogenactuallyincreasesbeforeendocrineproductionceases,whileparacrineproductionof
estrogeninfattytissueismaintainedandeventuallyincreases. [61,62]Menstruationincreasinglybecomesirregularbeforeit
eventuallydisappears.Alargeproportionofwomenexperiencevasomotorsymptoms.Theaverageageforonsetofthe
perimenopausaltransitionis46yearswithanaveragedurationof5years. [59]Asubstantialproportionofwomenusehormone
replacementtherapy(HRT)forshorterorlongerperiods,althoughtheuseofHRThasdiminishedduetoastudyfromthe
WomensHealthInitiative. [63]
Therelationshipbetweenmenopauseandthemenopausaltransitiontolunghealthisstillnotwellunderstood.Thereasonsfor
thisareseveral.TherehasbeenagreatfocusonHRTwhiletheunderlyingconditionthemenopausaltransitionhasbeen
scarcelystudied.Inaddition,studydesignsandpopulationshavebeenheterogeneous.Thereisalsotheproblemofwhich
subgroupsofwomenarereallybeingcompared.ThesinglefactthatHRTispossiblerepresentsaselectionbiasinpopulation
basedstudiesofthemenopause.
Concerningmenopause,longitudinalanalysisoftheNursesHealthStudyfromtheUSAbyTroisietal. [56]showedthat
postmenopausalwomenwhowereneverusersofreplacementhormoneshadasignificantlylowerageadjustedriskofasthma
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thanpremenopausalwomen(relativerisk:0.65CI:0.460.92).
IncrosssectionalanalysesofthemulticentricandmultinationalEuropeanCommunityRespiratoryHealthStudy,Realetal. [64]
foundthatwomennotmenstruatingforthelast6months(n=43234%)hadsignificantlylowerFEV 1values(120ml95%CI:
177to63),lowerFVCvalues(115ml95%CI:181to50)andmorerespiratorysymptoms(OR:1.8295%CI:1.272.61),
especiallyinrelationtoallergy(OR:1.9195%CI:1.033.53),thanwomenofsimilaragemenstruatingregularly.Resultswere
similarwhenrestrictinganalysestothosewhoneversmoked,suggestingthatresultscouldnotbeeasilyattributedtoconfusion
withCOPD,andnosignificantassociationwithCOPDwasfound(OR:1.51,95%CI:0.882.59).Associationswere
significantlystrongeramongwomenwithBMIoflessthan23kg/m2(respiratorysymptoms:OR:4.0795%CI:1.888.80
FEV 1adjusteddifferences:16695%CI:263to70)thanamongwomenwithBMIsof2328kg/m2(respiratorysymptoms:
OR:1.10CI:0.611.97p[interaction]:0.04FEV 1adjusteddifference:5495%CI:151to43p[interaction]=0.06).
Strengthsofthisstudyweretheuseofobjectivedatasuchashormonallevels(estradiol,folliclestimulatinghormoneand
luteinizinghormone),lungfunctionmeasurementsandmeasurementsofIgE.
JarvisandLeynaert, [65]incrosssectionalanalysesofdatafromtheHealthSurveyforEngland,foundthatmenstrualcessation
thatwasduetosurgerywasassociatedwiththereportingofwheeze(OR:1.55CI:1.092.20)evenifwomendeniedever
usingHRT.
ConcerningHRTandrespiratoryhealth,theliteratureshowspuzzlingresults:whilestudiesdealingwithasthmaandrespiratory
symptomsagreeinanincreasedriskrelatedtoHRT,especiallyamongnonsmokersandleanwomen,thosestudyinglung
functionindicateeitherabeneficialoratleastaneutralassociationwithHRT.
Concerningasthmaandrespiratorysymptoms,Troisietal.s[56]longitudinalanalysesofTheNursesHealthStudyfoundthat
amongnaturallymenopausalwomen,theageadjustedrelativeriskofasthmaforeveruseofpostmenopausalhormoneswas
1.49(95%CI:1.102.00)forcurrentuseofhormones(conjugatedestrogenswithorwithoutprogesterone),1.50(95%CI:
0.982.30)andforpastuse,1.52(95%CI:1.082.13),comparedwithneveruseofhormones.
IncrosssectionalanalysesoftheCopenhagenHeartStudy,Langeetal. [53]foundamongpostmenopausalwomenaweakbut
consistentassociationbetweenHRTandselfreportedasthma(OR:1.4295%CI:0.952.12),wheeze(OR:1.2995%CI:
1.021.64),coughatexertion(OR:1.3495%CI:1.011.77)),anduseofasthmamedication(OR:1.4595%CI:0.972.18).
AnalyzingTheNursesHealthStudy,Barretal. [66]foundthatHRTwasassociatedwithnewlydiagnosedasthma(multivariate
rateratio[MRR]:2.2995%CI:1.593.29)butnotwithCOPD.Inthesamestudy,aninteractionofHRTwithBMIon
respiratorysymptomswasalsoobserved.HRTwasmorestronglyassociatedwithasthmaamongwomenwithaBMI<25
kg/m2comparedwiththosewithaBMI>30kg/m2(MRR:3.09vs1.58).
GomezRealetal. [67]observedincrosssectionalanalysesofthemultinationalandmulticentricRespiratoryHealthinNorthern
EuropestudythatHRTwasassociatedwithanincreasedriskforasthma(OR:1.5795%CI:1.072.30),wheeze(OR:1.60
95%CI:1.222.10)andhayfever(OR:1.4895%CI:1.151.90).Furthermore,theassociationswithasthmaandwheeze
weresignificantlystrongeramongwomenwithBMIinthelowertertile(asthmaOR:2.4195%CI:1.214.77andwheezeOR:
2.0495%CI:1.233.36)thanamongheavierwomen(asthma:p(interaction)=0.030wheeze:p(interaction)=0.042).
IncreasingBMIwasassociatedwithmoreasthma(OR:1.0895%CI:1.051.12perkg/m2),butthiseffectwasonlyfound
amongwomennottakingHRT(OR:1.1095%CI1.051.14perkg/m2)andnosuchassociationwasdetectedamongHRT
users(OR:1.0095%CI:0.921.08)perkg/m2p[interaction]=0.046).Menopausewasnotsignificantlyassociatedwith
asthma,wheezeorhayfever.
Jarvisetal. [65]foundincrosssectionalanalysesofdatafromtheHealthSurveyforEnglandthatcurrentuseofHRTwas
associatedwithfrequentwheeze,particularlyamongleanwomen(BMI<25OR:1.9095%CI:1.173.05BMI>25OR:1.02
95%CI:0.691.51).
InlongitudinalanalysesofalargedatabasecomprisedmostlyofFrenchteachers,Romieuetal. [68]foundanassociationof
HRTwithnewcasesofasthma(hazardratio[HR]:1.2095%CI:0.981.46),especiallyofHRTconsistingofestrogensonly
(HR:1.5495%CI:1.132.09),andparticularlyamongneversmokers(HR:1.8095%CI:1.152.80)andthosereporting
allergicdiseasepriortoasthmaonset(HR:1.8695%CI:1.182.93).Theeffectofmenopausalstatusonasthmawasnot
assessed.
ConcerningHRTandlungfunction,Carlsonetal.
[69]foundamongpostmenopausalwomenolderthan65yearsand
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ConcerningHRTandlungfunction,Carlsonetal. [69]foundamongpostmenopausalwomenolderthan65yearsand
participatingintheCardiovascularHealthStudythatHRTusewassignificantlyassociatedwithhigherFEV 1(p=0.031)and
withlowerprevalenceofobstruction(OR:0.6795%CI:0.480.95).
Inaprospectivecrossoverstudyinvolving20asthmaticwomen,Hepburnetal. [70]foundthatneitherthediscontinuationnorre
initiationofHRTinasthmaticpostmenopausalwomenhadanyeffectonobjectivemeasuresofairwayobstruction.
Pata[71]foundinarandomizedprospectivestudyinvolving75womenwithnoknownpulmonarydiseaseriskasignificant
increaseinFVCandFEV 1(p=0.001andp=0.0001,respectively)after3monthsofHRTregardlessofHRTtype.
Muelleretal. [72]observedinaninterventionstudythat27HRTuserswerelesslikelytoshowBHRcomparedwith58nonusers
(OR:0.1295%CI:0.030.55).
Cervriogluetal. [73]foundastatisticallysignificantincreaseinFEV 1andFVClevelsamong23postmenopausalwomenusing
continuouscombinedHRTfor3months(p<0.05)whencomparedwithacontrolgroupof25postmenopausalwomennot
usingHRT,butnodifferencewith19womenusingestrogenonly.
Theliteratureshowsapparentlycontradictingresults.ThiscanberelatedtopopulationdifferencesinBMI,doctorspractice
concerningHRTuse,thetypeanddurationofHRT,selfselectioninHRTuse,aswellasinmethodologicaldifferencesinstudy
designorassessmentofmenopause.Themainreasonfordifferentresultsislikelytobeadifferenceindefinitionofreference
groups.Furthermore,disentanglingtheeffectsofmenopauseitselffromHRTisverycomplex,andwillneedlargelongitudinal
studiesaswellascarefulinterpretationoffindings,supportedwithbetterknowledgeofbiologicalmechanisms.
BiologicalMechanisms
Asshowninthisreview,epidemiologicaldataconcerningtheroleofhormonalfactorsinobstructiverespiratorydiseasesis
complicated.Theexperimentaldataisevenmorecomplicated[44]andthusfardonotexplainthewholepicture.
Muchattentionhasbeenattachedtoestrogens,butestrogensalonedonotfullyexplaintheroleofhormonalfactorsin
respiratoryhealth,ashormonalstatusamongwomenvariesgreatlyaccordingtofactorsrelatingtoreproduction,suchas
menarche,menstrualcycleanditsregularity,pregnancy,lactation,proximitytomenopauseanduseofexogenoushormones
suchasoralcontraceptivesorHRT(Figure1).Inaddition,sexhormonelevelsandtheireffectsmayalsovaryaccordingtothe
underlyingmetabolicconditionaswellasvaryinginsulinsensitivitysuchasthatseeninobesity,PCOSordegreeofphysical
activity.Moreover,sexhormonesandbodyfatmassareinterrelated,andthelevelsofestrogensarecloselyrelatedtobodyfat
mass[74]andthesubjectsmetabolicstatus. [75]
Hormonalfactorsinobstructiverespiratorydiseasesshouldthusbestudiedintheperspectivethatgenderdifferencesexistin
ordertoreproduce,reproductionrequiringinteractingcorrecthormonal,metabolicandimmunologicalstatus.These
componentsshouldnotbestudiedseparately.
Thecomplexitywithbothproandantiinflammatoryeffectsofsexhormonesinlunginflammationandasthmahasbeen
documentedinclinicalstudies.Estrogenreceptorsarefoundonbothvascularendothelialandsmoothmusclecellsbeing
influencedbyhormonalexposure, [61,76]andthusmaybeofimportanceinthepathogenesisofasthmaandallergy.Itappears
thatestrogenshavebothproandantiinflammatoryeffects,sometimesseeminglydependingonwhethertheyareendogenous
orexogenous,anddosage,timingorlengthofadministration. [7782]Murinestudieshaveshownadualroleofestrogeninthe
airways.Insomestudiesithasbeenfoundthatestrogenincreasesallergicinflammation. [8386]Ontheotherhand,estrogen
decreasesairwayshyperresponsiveness. [87,88]
Theoccurrenceofasthmasymptomsappearstobeleastfrequentwhenserumestradiollevelsareatasustainedhighlevelin
themenstrualcycle. [89]Whileasthmasymptomsarelow,levelsofexhalednitricoxidearehighduringmidcyclewhen
endogenousestrogenlevelsareattheirhighest. [79,90]
Estrogenandprogesteronereceptorsareobservedonmastcellsintheairways. [91]Eosinophilsstimulatedbyacombinationof
thesexhormonesestradiolandprogesteronehaveshownsignificantdegranulation,characteristicofanallergicreaction.
[92,93]ProgesteroneisalsofoundtoincreaseBHR. [93]
Ingeneral,estrogenssuppresscellularimmunitybutstimulatehumoralimmunity.
[94]Estrogendeficiency,however,promotes
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Ingeneral,estrogenssuppresscellularimmunitybutstimulatehumoralimmunity. [94]Estrogendeficiency,however,promotes
cellular(Th1type)immunity.ProgesteronestimulatesaswitchfromTh1toTh2typeimmuneresponses. [94]WomenusingHRT
hadmoreBcells,higherTcellproliferationandhigherlevelsofTNF. [95]Thisrepresentsareversalofimmunealterations
associatedwithnormalaging,suggestingthattheuseofHRTpreservesorimprovesimmunefunction. [96]Thus,bothhormonal
statusanduseofHRTcaninfluenceimmunityandmaybeofimportanceinthepathogenesisofasthmaandallergy.
Creactiveprotein(CRP)isaninflammatorymarkerknowntoberelatedtosmoking,obesityandcardiovasculardisease. [90]
IncreasedlevelsofCRParesignificantlyassociatedwithrespiratorysymptoms,suchaslowerFEV 1,increasedBHR[97]and
nonallergicasthma, [90]butnotwithallergicasthma. [90]Alongwithothermarkersofinflammation,CRPincreaseswithuseof
oralpreparationscontainingestrogenssuchasoralcontraceptivesandHRT. [80,82,98,99]
Endothelin1isastrongvasoconstrictor[100]andbronchoconstrictorwithproinflammatoryproperties. [101]Itisproducedin
endothelialcells,smoothmusclecells,airwayepithelialcellsandmacrophages,andisconsequentlyrelatedtoeosinophilic
airwayinflammation. [102]Estrogensareknowntodecreaseplasmalevelsofendothelin1. [103]Estrogensmaythusdecrease
inflammationinallergicasthmathroughthismechanism,anddeficitofestrogensatsomepointinawomenslifemayincrease
allergicasthma.
Adysfunctionalendotheliummaybeapathophysiologicalfactorrelatingsexhormonestotheairways.Inflammationdueto
dysfunctionalendotheliumisrelatedtobothasthma[104,105]andlungfunction. [104,106]Bothsexhormonesandinsulin
resistanceinfluencethisinflammation.Pulmonaryfunctionabnormalities,includingreductioningastransferandlungfunction,
mayberelatedtoimpairedpulmonarymicrovasculatureandinjuredalveolarepithelialbasallamina. [106]Inaddition,respiratory
impairmentisassociatedwithcardiovascularrisk. [107]Adysfunctionalendotheliumcouldcontributetocomorbiditybetween
obstructiveairwaysdiseases,cardiovasculardiseasesandobesity.
Thereisagrowingawarenessthatasthmaisasystemicdiseaseandthatsystemicinflammationseemstobeimportantin
phenotypesofasthma. [108]Inthisway,inflammationrelatedtometabolicdysfunctionmightbeimportantinthedevelopment
ofobstructivelungdiseases,althoughthisissueisfarfrombeenunderstood.Androgensandestrogenshaveeffectsonlipid
andcarbohydratemetabolisminbothmenandwomen,aswellasonvascularfunctions. [109]Womenbecomemoreinsulin
resistantduringthemenopausaltransition[110]withanincreasedriskforcardiovasculardiseases. [111,112]Healthymenopausal
womenalsohaveacertaindegreeofinsulinresistance. [113]Estrogenappearstoimproveinsulinsensitivity,whileadded
gestagensmayattenuatethisbeneficialeffect. [113,114]Estrogenssignificantlyreducefastingserumglucose, [115]butalackof
estrogensresultinthedevelopmentofinsulinresistanceandthemetabolicsyndrome. [75,112,116]Thereisevenevidenceof
varyinginsulinlevelsandinsulinsensitivityduringthemenstrualcycleduetoestradiolandprogesterone. [117]
Thereisexperimentalevidencethatsexsteroidsandinsulininteractintheireffectsontissues.Atphysiologicallevels
testosteroneandestradiolareconsideredtomaintainnormalinsulinsensitivity,whileoutsidethenormalrangetheymay
promoteinsulinresistance. [118]Inmenopausalwomenandinmen,estrogenisproducedinanumberofextragonadalsites,
includingthebreast,bone,thevascularsystemandthebrain.Withinthesesites,aromatasescanlocallygeneratehighlevels
ofestradiolwithoutsignificantlyaffectingcirculatinglevels. [119]CytokinessuchasIL6andTNFplayanimportantrolein
regulatingestrogensynthesisinperipheraltissues. [120]NovelfindingssuggestthattheIL6pathwaylinksinsulinresistance
withinflammationbycoordinatingtheinterfacebetweenadaptiveandnaturalimmunity. [121]
Obesityimpliesinsulinresistance. [122]IncreasedBMI,obesityandinsulinresistancearerelatedtoastateofinflammation, [123]
expressedasincreasedCRP [124]andadipokines,especiallyTNFandIL631. [125127]anddecreasedantiinflammatory
moleculessuchasadiponectin. [123,128]Thisstateofinflammationisalsoexpressedaschronicactivationoftheinnateimmune
system. [129]Inflammationrelatedtoinsulinresistance,themetabolicsyndrome,obesityandcardiovasculardiseasesmaybe
mediatedbyIL6andTNF, [130]andappearstoincreaseperipheralproductionofestrogens. [120]Thisisapossible
mechanismexplainingtherelationshipbetweenBMI,inflammationandasthma,andallergyandsexhormones.Theinteraction
ofestrogenswiththeimmunesystemandtheinflammatoryandimmuneresponsesmaybecentralinexplainingtheeffectsof
estrogensontheadipose/metabolicsystemandthecardiovascularsystem. [130]Itseemsplausiblethatthismaybethecasein
theairwaysaswell,butthishasthusfarnotbeenextensivelyinvestigated.
IncreasingBMIisrelatedtohigherriskofasthma[131133]andlowerlungfunction. [134]Furthermore,thereisevidencelinking
insulinresistancetoreducedlungfunction. [135140]Oligomenorrheaandmenstrualirregularity,anexpressionofinsulin
resistanceandsexhormonesdisturbance,arealsorelatedtolowerlungfunctionandasthma.Itisplausiblethattheairways
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canbeaffectedbyinflammationassociated,withinsulinresistancebeingseeminglyrelatedtobothnaturalandallergic
immunity,thusinitiatingasthma. [117]
AspointedoutbyLimetal., [44]thematterathandisnoteasilyexplainedbyonesinglehormoneorevenexperimentaldata
only.Forthisreason,wehavetriedtofocusonepidemiologicaldatainordertooutlinethemostrecentfindings.Findingsfrom
animalstudiesshouldbeextrapolatedwithcaution.
GeneralMethodologicalChallenges
Whyaretheresodiverseandoftenapparentlyinconsistentfindingsintheinvestigationofwomenslunghealth?Biasin
assessmentofhormonalstatusmaybeaproblem,thatis,menopausecannotbedetermineduntil1yearafteritactually
happens,andisoftenmadeimpossibletodeterminepreciselyduetotheuseofhormonesubstitution.Atleastitisreassuring
thattheliteraturesuggeststhatwomenrecallpastandpresenthormonalandmetaboliceventsfairlywell. [141,142]Themost
importantchallengeisrelatedtothefactthatwomendiffergreatlyinhormonalprofileduringtheirlifespanandmakeavery
heterogeneousstudypopulation(Figure1).Itisthereforeofutmostimportanceforresearchinthisfieldtoinvestigatesufficient
numbersofwomen,andwithsufficientcharacterizationofhormonalandmetabolicstatus,toobtainadequatepowerfor
analysisofwelldefinedgroups.Thechoiceofreferencecategorymustbewellfoundedandconsideredinordertointerpret
findings.Recently,severalstudieshavepointedtoanimportantinterplaybetweenhormonalandmetabolicfactors,alsointhe
fieldofrespiratoryhealthinwomen.Futureresearchneedstotakeintoconsiderationmetabolicstatus.Tobaccosmokinghas
antioestrogeneffects,andshouldalsobeconsideredinanyanalysisofrespiratoryhealthinwomen.Theissueofasthmain
relationtoHRTislikelytobestronglyinfluencedbysmokinghabits,BMI,doctorspracticeandselfselection,inaspecific
populationataspecifictime,anditisveryplausiblethatevenoppositeconclusionsmaybereachedinstudiesofdifferent
populations,definingthereferencegroupsdifferentlyamongothers.Thisareaisverycomplex,andcomparingdifferententities
islikelytoaccountformostofthediscrepanciesintheliterature.
ExpertCommentary
Hormonalfactorsinfluencerespiratoryhealthanddiseasethroughoutawomanslifetheliteratureisratherconvincingonthis
generalaspect.Therearesomeindicationsthatsuchhormonaleffectsontheairwaysmaybelarge.However,the
understandingofthespecifichormonalfactorsandpossiblebiologicalmechanismsislimited.Moststudiesinvestigateasthma
andasthmarelatedoutcomes,somestudiesinvestigatelungfunction,hardlyanystudiesaddressCOPD.Itseemsrelatively
convincingthatwomenwithearlymenarcheandirregularmenstruationhavemoreasthmaandlowerlungfunction.The
literatureconsistentlyshowsthatasthmaandrespiratorysymptomsvaryduringthemenstrualcyclethisimpliesatherapeutic
potential.Exogenoussexhormonesappeartoinfluencetheairways,buttheliteratureshowsinconsistentresultsregardingthe
directionoftheeffects,bothforOCPsandforHRT.Respiratoryhealthshouldbeincludedinclinicaltrialsofsuchdrugs.
Changesinrespiratoryhealtharoundmenopauseseemlikely,butarenotwellinvestigatedanddifficulttoassessdueto
selectionofHRTuse.
Theimportanceofunderstandingrespiratoryhealthinrelationtotheseveryfactorsisevident,asisthecomplexityin
investigatedhormonallyheterogeneouswomen.Particulareffortisneededtoelucidateairwaydiseaseamongwomentheera
forinvestigatingrespiratoryhealthin2000menand29womenhaspassed.
Atpresent,theroleofhormonalfactorsinrespiratoryhealthamongwomenissufficientlywelldocumentedfordoctorstobe
awareofpotentialclinicalmanifestationsinindividualpatients,butfarfromsufficienttofoundabasisfortreatmentstrategies.
Betterunderstandingofthisfieldhasarealisticpotentialtoenhancetheknowledgeofairwayspathophysiologyandto
contributetopersonalizedtreatmentforasthmaandCOPD.
FiveyearView
Amultidisciplinaryapproachisneededtobringforwardandintegratetheunderstandingofsexhormonesinrespiratoryhealth
anddisease.Clinicaltrialsofexogenoussexhormonesshouldincludeassessmentofrespiratoryhealth.Epidemiological
studiesneedlargeandwellcharacterizeddatabasestoteaseoutthecomplexinterrelationshipsbetweenhormonal,metabolic
anddevelopmentalinfluences.Experimentalstudiesareneededtoaddresstheroleofsexhormonesinthelungsandinterplay
withlocalandsystemicinflammation.
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ThereislittleknowledgeofwhetherhormonalstatusinfluencesCOPDandCOPDexacerbations.Itseemsplausiblethat
airwayeffectsofsexhormonesalsorelatetoCOPD.AlthoughCOPDisrelativelyrareamongwomenoffertileage,the
diseaseisbecomingmoreprevalentamongwomenandthecontinuousincreaseinprevalenceofoverweightindividualsmight
possiblycontributefurthertothistrend.Thus,thereisaneedforresearchthatshedslightonhowhormonalandmetabolic
factorsmayinfluenceCOPDandpossiblevariationsindiseaseintensity.
Theglobalincreaseinobesityislikelytobeofimportancefortheassociationofhormonalstatuswithrespiratoryhealth,and
mightevenchangetheoverallrelationshipsofhormonalfactorswithrespiratorydisease.Researchwithinthisareashouldbe
alerttothecloseinterplaybetweenhormonalandmetabolicfactors.
Wespeculatethatresearcheffortsinthisfieldduringthenextfewyearsmayleadtoindividualizedtreatmentofasthmain
relationtothemenstrualcycle,totheinclusionofrespiratoryhealthinriskassessmentforwomenwithPCOSandtothe
identificationofphenotypessuchaspolycysticasthmaormenopausalasthma.
Thepresentreviewfocusesonrespiratoryhealthinwomenfrommenarchetomenopausehowever,furtherunderstandingof
thisareamayalsobehighlyrelevantfortheunderstandingofhowhormonalfactorsinfluencerespiratoryhealthinmen.
KeyIssues
Earlymenarcheisassociatedwithmoreasthmaandlowerlungfunctioninadultwomen.
Thispointstoalinkbetweendevelopmental,metabolicandhormonalfactorsinrespiratoryhealth.
Menstrualcyclephaseaffectsbronchialhyperresponsiveness,respiratorysymptomsandasthma.
Womenshouldbeadvisedtomonitorsymptomsduringthemenstrualcycleanddiscussindividualizedtreatmentwith
theirdoctor.
Irregularmenstruationisassociatedwithrespiratorysymptoms,asthmaandlowerlungfunction.
Recommendedriskassessmentinpolycysticovariansyndromepatientsshouldincluderespiratoryhealth.
Theliteratureonoralcontraceptivesisnotclear,whileinfluenceontheairwaysinsomesubgroupsissuspected.
Clinicaltrialsfornewdrugsshouldincludeassessmentofasthmaandrespiratorydisease.
Menopauseappearstobeassociatedwithlowerlungfunctionfindingsonasthmaarecontradictory.Hormone
replacementtherapyappearstobeassociatedwithmoreasthmabutimprovedlungfunction.
Furtherstudiesareneededtodisentangletheeffectsofmenopauseandhormonereplacementtherapyonlunghealth.
Hormonalandmetabolicfactorsappeartointerplayinrelationtorespiratoryhealth.
Metabolicstatusneedstobetakenintoaccountinstudiesofhormonalfactors.
Theliteratureclearlyshowsthathormonalstatusisimportantforrespiratoryhealthinwomen,whileunderstandingof
specificfactorsandmechanismsisfragmentary.
Amultidisciplinaryapproachisneededtobringtheresearchfieldforward.
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