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REVIEWARTICLEOPENMedicallyinducedamenorrheainfemaleastronautsVarshaJain1,2,3,4andVirginiaEWotring4,5Medicallyinducedamenorrheacanbeachievedthroughalterationsinthenormalregulatoryhormonesviatheadoptionofatherapeuticagent,whichpreventsmenstrualow.
Spaceight-relatedadvantagesformedicallyinducedamenorrheadifferaccordingtothetimepointintheastronaut'strainingschedule.
Pregnancyiscontraindicatedformanypre-ighttrainingactivitiesaswellasspaceight,thereforeeffectivecontraceptionisessential.
Inaddition,thepracticalitiesofmenstruatingduringpre-ighttrainingorspaceightcanbechallenging.
Duringlong-durationmissions,femaleastronautshaveoftencontinuouslytakenthecombinedoralcontraceptivepilltoinduceamenorrhea.
Long-actingreversiblecontraceptives(LARCs)aresafeandreliablemethodsusedtomedicallyinduceamenorrheaterrestriallybutasofyet,notextensivelyusedbyfemaleastronauts.
IfLARCswereused,dailycompliancewithanoralpillisnotrequiredandnoupmassortrashwouldneeddisposal.
Militarystudieshaveshownthathighproportionsoffemalepersonneldesireamenorrheaduringdeployment;bettereducationhasbeenrecommendedatrecruitmenttoimproveuptakeandautonomousdecision-making.
Astronautsareexposedtosimilaraustereconditionsasmilitarypersonnelandparallelscanbedrawnwiththeseresults.
Offeringfemaleastronautsup-to-date,evidence-based,comprehensiveeducation,inviewoftheenvironmentinwhichtheywork,wouldempowerthemtomakeinformeddecisionsregardingmenstrualsuppressionwhilerespectingtheirautonomy.
npjMicrogravity(2016)2,16008;doi:10.
1038/npjmgrav.
2016.
8;publishedonline21April2016INTRODUCTIONPhysiologicalmechanismsduringthenaturalmenstrualcycleinvolveacoordinatedinterplayamongregulatoryhormones.
Hypothalamicreleaseofgonadotropin-releasinghormonestimu-latesthepituitaryglandtoproducefollicle-stimulatinghormoneandluteinizinghormone,whichpeaksmid-cycle.
Thispeakinvokesovulation.
Thedevelopingovumproducesestrogenanditsremaining'shell',i.
e.
,thecorpusluteumproducesprogester-one.
Endometrialthickeningcommencesinpreparationforapregnancy;however,whenfertilizationdoesnotoccur,estrogenandprogesteronelevelsdecreasecausingendometrialshedding.
Thisisreleasedcyclicallyasmenstrualow.
Medicallyinducedamenorrheaistheadoptionofatherapeuticdevice(e.
g.
,levonorgestrelintrauterinedevice(LNG-IUD))ortreatment(typicallyhormonalpreparations,e.
g.
,thecombinedoralcontraceptive(COC)pillordepotmedroxyprogesteroneacetate(DMPA))thatactonpartoralloftheabovemechanismsinordertopreventmenstrualow.
Routinely,21COCpillsaretakendaily;thesecontainactiveingredientsthatsuppressovulationandthintheendometrium.
Then,forthenext7days,eitherabreakistakenfromtheactiveingredientpillsorplacebopillsaretaken,andduringthistimeawithdrawalbleedoccurs.
Thisdiffersfromamenstrualbleed.
Medicallyinducedamenorrheawouldalsoincludethedelayorsuppressionofthiswithdrawalbleed.
Modernwomenlivinginanindustrializedcountryhavemoremenstrualcyclescomparedwithwomenofpre-historictimes.
Thereareanestimated450ovulationsperlifetimenow,comparedwith160ovulationspotentiallyduetolatermenarche,earlierrstbirths,frequentcloselyspacedpregnancies,longperiodsofbreastfeedingandlivingshorterlives.
1The21-daytreatment/7-dayplaceboCOCcyclewasdevelopedinthe1960stomimicanaturalcycleandincreaseadherencewithadailypill.
Thoughtsonwhetherwomenneedtomenstruateeverymonthvarywidelyandhaveculturaldeterminants2,3butmenstrualsuppressionisgainingfavorandbecomingmorecommon.
Physicians'attitudestomedicallyinducedamenorrheaalsovaryandmayaffectlong-termacceptance.
4Theside-effectprolesformenstrualsuppressionregimesaregrosslysimilartowhenthesameagentsareusedforcontraception(Table1)andreturntofertilityoccurswithtreatmentcessationwithmostagents.
5ADVANTAGESOFMENSTRUALSUPPRESSIONGeneralTherearenumerousreasonsformenstrualcyclecontrol.
Arrestingcyclescanalleviateorimprovemedicaldisorders,e.
g.
,gyneco-logicalproblemssuchasmenorrhagiaorendometriosis,hemato-logicconditionsincludinginheritedbleedingdisorders,andneurologicdiseasesuchasmenstrualheadaches.
6Menstrualcyclescanalsobesuppressedonashort-orlong-termbasisforconvenience,e.
g.
,duringexams,forspecialholidays,oraftertuballigationforsterilization.
Womencancontroltheircyclesaccordingtopersonalcircumstancesandconvenience.
SpaceightrelatedIndividualsinaustereconditions(deployedmilitarypersonnelorastronauts)maywelcomeamenorrhea,withadvantagesbeyondthosesoughtinthetraditionalclinicsetting.
Pregnancycandelayaspectsofastronautselectionandtraining.
Itiscontraindicatedforpre-ighttrainingactivities,including1NationalInstituteforHealthResearch,London,UK;2King'sCollegeLondon,London,UK;3QueenMary'sUniversity,London,UK;4CenterforSpaceMedicine,BaylorCollegeofMedicine,Houston,TX,USAand5DepartmentofPharmacology,BaylorCollegeofMedicine,Houston,TX,USA.
Correspondence:VEWotring(Virginia.
Wotring@bcm.
edu)Received18September2015;revised10January2016;accepted21January2016www.
nature.
com/npjmgravAllrightsreserved2373-8065/162016MacmillanPublishersLimitedTable1.
TherapeuticoptionsformedicallyinducedamenorrheaavailableforfemaleastronautsMedicationDosingFrequencyContraceptivefailurerateAmenorrhearateMechanismofactionforamenorrheaAdvantagesDisadvantagesContinuousCOCMultiplepreparations,tendtobe30–35μgethinylestradiolpillincontinuoususeDaily,withoutpill-freeweekContinuousandcyclicalusehavesimilarcontraceptiveefcacy34withtypicalusetheyhavea9%failurerate26Upto80%attheendof1yearofcontinuoususe26Estrogenandprogesteronesuppresshormoneproductionandfollicledevelopment,endometriumthinnerthannormalLonghistoryandexperiencewithcontinuoususeinspaceightProtectBMDcomparedwithDMPA/non-hormonalcontraceptivesCanbestoppedimmediatelyifrequiredDecreasedriskofovarian,endometrial,andcolorectalcancer,irondeciencyanemia,benignbreastdisease,functionalovariancysts,pre-menstrualsymptoms,anddysmenorrhea35NoimpactonbreastcancerrateDailycompliancerequired—potentialissuewithworldwidetravelandtrainingscheduleVariabledurationofmenstrualsuppressionBTBparticularlyininitialphaseHormonalsideeffects(estrogenicandprogestogenic):migraine,VTE,stroke,liverproblems,depression,glucoseimpairment,alteredlipidmetabolism,andvaginalinfectionsEstrogeniscontraindicatedinsomewomenMedicationstabilityproblematiconmulti-yearmissionsProgestin-containingintrauterinedeviceLNGrelease20μgperday,e.
g.
,Mirena(LNG-IUD)Every5years1-yearfailurerateis0.
2%8Upto80%at1yearofuse862%at2yearsinperi-menopausalwomenforendometrialprotectionduringHRTuse27LNGdownregulatesendometrialestrogenandprogesteronereceptorsmakingendometriuminsensitivetocirculatingestradiol,i.
e.
,stronganti-proliferativeeffect.
HighlocaldrugexposuretotheuterinecavityleadstolowLNGlevelsinserum(gradientofendometriumtoserum41,000-fold),leadingtominimalsystemicsideeffects36Longacting,i.
e.
,noneedtorememberdailymedicationNoeffectonBMDinfemurandlumbarspineat2years37ToptiercontraceptiveefcacyTreatmentofchoiceinmedicalconditionsincludingHMB,irondeciencyanemia,endometrialhyperplasia,endometriosis,adenomyosis,broids,anddysmenorrhea35ProliferativeendometriummuchlowerinLNG-IUDversusoralprogesterone,thereforerateofamenorrheaincreasedwithtime38FertilityregainedafterremovalCanbeusedinsuccessionforcontinualbenetsDiscontinuationratesmuchlowerthanCOCuse38NoupmassortrashtodisposeObviateslong-durationmedicationstabilityissuePerforation(rate1:1,000insertionsupto9:1,000insertions.
39–41Occurmainlyinrstyearofuse.
MayberelatedtoskilloftheoperatororundetecteduterineabnormalitiesExpulsionratebetween2and10%intherstyear41Infection(0.
51%intherstyear)42VariabledurationofinitialmenstrualsuppressionduetoBTBInitialexpenseInsertion-relatedpain/discomfortHormonalsideeffects—progesteronerelated(reducewithtime)Progestin-containingsubdermalimplantEtonorgestrel,e.
g.
,NexplanonLevonorgestrel,e.
g.
,Jadelle3years(Nexplanon)or5years(Jadelle)1-yearfailurerateis0.
05%41Variesbetween11%inrst90daysupto41.
25%at3years8,43–45Inhibitsovulationbysuppressinghormoneproductionandfollicledevelopmentrenderingtheendometriumthinnerthannormal(suchasCOC)46LongactingwithnoneedtorememberdailymedicationNoeffectonBMDat2yearscomparedwithnon-hormonalcontraceptives46FertilityregainedafterremovalCanbeusedinsuccessionforcontinualbenetsNoupmassortrashtodisposeObviateslong-durationmedicationstabilityissueSubdermalimplantmaybepalpableonarmPotentialscarringatthesiteofinsertionInsertiondiscomfortVariablelengthoftimeofmenstrualsuppressionwithinitialBTB(27–51.
25%irregularbleedingpattern)44,45InitialcostHormonalsideeffects(progesteronerelated)Abbreviations:BMD,bonemineraldensity;BTB,breakthroughbleeding;COC,combinedoralcontraceptivepill;DMPA,depotmedroxyprogesteroneacetateinjections;HMB,heavymenstrualbleeding;LNG,levonorgestrel;LNG-IUD,levonorgestrelintrauterinedevice;VTE,venousthromboembolism.
MenstrualsuppressioninastronautsVJainandVEWotring2npjMicrogravity(2016)160082016MacmillanPublishersLimitedvacuumchamberexercisesorhigh-performancejetying,andspaceight.
Witharigorouspre-ighttrainingphase,includingfrequentinternationaltravelfollowedbytimeinquarantinebeforemissions,lastingatleast6months,thisfurtherincreasesthetimeoverwhichreliableandeffectivecontraceptionisimportant(Figure1).
Duringtheshuttleera,therewereconcernsaboutpre-ightmissedpillsandthereforetheriskofpossiblepregnancy.
Thereare,however,nocaseswherepregnancypreventedanastronautyingherdesignatedmission.
7Theidealcontraceptivemethodwouldthereforehelpensureeffectiveamenorrheaaswellashigheradherenceratesinordertoreducepregnancyrisk.
Aswellascontraceptiveeffects,menstrualsuppressionisanaddedbenetofsomecontraceptivemethods.
ThewastedisposalsystemsonboardtheUSsideoftheInternationalSpaceStationthatreclaimwaterfromurinewerenotdesignedtohandlemenstrualblood,thusidealizingtheminimizationofbreakthroughbleedingduringmenstrualsuppression.
Thepracticalitiesofpersonalhygienewhilemenstruatingduringspaceightcouldbechallenging,e.
g.
,limitedwashwatersupplyorthetaskofchanginghygieneproductsinmicrogravity.
Nonetheless,fullamenitiesareavailableshouldastronautschoosetomenstruate.
Itismorecommonforastronautstocontinuallysuppresstheircyclesforlong-durationmissionscomparedwithshort-durationmissions(Jennings,R.
T.
,oralcommunication,12November2014).
Short-durationmissionsallowedtheexibilityformenstrualcyclestobetimedaccordingtomissiondates,thusavoidingmenstrua-tioninspaceaswellastheneedformenstrualsuppression(Baker,E.
S.
,oralcommunication,29October2014);femaleastronautscouldtimeshifttheircycleswithhormonaltherapyinadvanceofamission.
Thiscannotbedonewithlong-durationmissionsandthereforethequestionarisesastowhetherthefemaleastronautwishestosuppressornotsuppress.
MENSTRUALSUPPRESSIONMETHODSFORASTRONAUTSOptionsforfemaleastronautsTerrestrially,womenmaysuppressmensesviaextendedorcontinuoususeofthedailyCOCpill,dailyprogesterone-onlypills(POPs),thethreemonthlyprogestin-onlyinjectionDMPA,theprogestin-basedsubdermalimplantthatisviableforatleast3years,ortheLNG-IUDthatiscurrentlylicensedfor5years.
Aswellasavarianceintheirabilitytoinduceamenorrhea,thesemethodsarealsoliabletoindividualvariabilitywithintheirenduser.
Severalstudieshavefoundareductioninbonemineraldensity(BMD)withDMPA.
8Terrestrially,theselossesmayberecoveredoncethetherapyisceased,however,duetoirreversiblespaceight-relatedbonechanges,atreatmentoptionthatmayimpactBMDwouldnotbeacceptableforthissubpopulationofwomen.
Only50%ofwomenusingthePOPbecomeanovulatoryandtherestcontinuetomenstruateregularly.
Unlessawomanisunabletouseestrogen-containingproducts,thePOPwouldnotprovideanastronautwiththedesiredrateofmenstrualsuppressionorminimizedbreakthroughbleedingthatwouldbeneeded.
Theprogestin-basedsubdermalimplantprovidesvariableratesofamenorrhea,~11–42%.
TheseratesarelowerthancontinuousCOCuseortheLNG-IUD;however,thisdeviceprovidesanadditionallong-actingreversibleoptionforthosenotabletouseestrogenorforthoseaversetohavinganintrauterinedevice.
Therefore,continuoususeoftheCOC,thesubdermalimplant,andtheLNG-IUDappeartobethebestoptionsformenstrualsuppressioninthefemaleastronautpopulation.
AcceptabilityFortheastronautpopulation,theirmenstrualsuppressionregimehasofteninvolvedcontinuoususeofthedailyCOCfornumerousyears.
RegimesusedforCOCcanbetailoredaccordingtothewoman'sneeds.
ABraziliansurveyshowedthatcontinuoususeoftheCOCwasthemorefrequentprescribedmethodforinducingamenorrhea(79.
4%)withtheLNG-IUDfollowingcloselyat72.
7%.
Itisimportanttonotethatpatientsrequestedandgynecologistssuggestedtheseformsofcontraceptionin81%ofcases,with86.
2%specicallyprescribedtoinduceamenorrhea.
9Long-actingreversiblecontraceptives(LARCs)arenowavailableworldwideandprovideasafeandreliablealternatemethodtocontinuousCOCuseforinducingmenstrualsuppression.
LARCsencompasstheprogestin-containingsubdermalimplantandtheLNG-IUD.
Neithercontainestrogenandthereforearenotsusceptibletoestrogenicsideeffectsorrestrictions.
Theyprovidelong-actingcontraceptivebenetsandareusedmedicallytotreatmenorrhagia,broids,andendometriosis,whereasnotimpactingBMD.
LARCsofferlong-termtherapeuticadvantagesaswellasareductioninmissionupmassincomparisonwithdailyCOCs,nopackagingtodispose,andtheydispelconcernsregardingstabilityduringstorage.
DespitethenumerousadvantagesofusingLARCs(outlinedinTable1),aUSstudyevaluatingcontraceptiveuseterrestriallyupuntil2010discoveredthatofthe62%ofwomenusingcontra-ceptioninthestudy,only5.
6%usedLARCscomparedwith28%usingCOCand27%whoweresterilized.
10ThepercentageofwomenusingLARCsisfortunatelyincreasingandanotherstudythatevaluatedtheUSNationalSurveyofFamilyGrowthdatauntil2013highlightedarecentincreasefrom8.
5%(2009)to11.
6%(2012)inoverallLARCusage.
Thiswaspredominatelydrivenbyintrauterinedevice(IUD)use,whichrosefrom7.
7to10.
3%between2009and2012,ratherthanimplantusage,whichremainedlow.
11Whenno-costcontraceptionwasofferedtowomenaged14–45yearsinthecontraceptiveCHOICEproject,LARCswerethepreferredmethodofcontraception.
Inadditiontothis,satisfactionwithLARCsishigh,demonstratedby76.
7%ofLARCusersstillcontinuingwiththeircontraceptiveagentat24months,comparedwith40.
9%ofnon-LARCusers.
Thistrendwaspresentinboththeadolescent(14–19years)andadult(20–45years)groups.
12Anuptakerateof11.
6%in2012thereforerepresentsanunderutilizationofLARCs.
Bettereducationforbothphysiciansandpatientscouldimproveacceptabilityofthesetherapies.
RecentmilitarystudieshaveshowncontinuousCOCusageisonly15%inaviationpersonnel,despiteoperationallyrelevantbenetsassociatedwithitsuse.
13Militarywomendesiredtousemenstrualsuppressionasanalternativetoexperiencingmenstruationduringdeployment.
14Manywomendesiredsuppressionfordeployment(66%)butonly21%continuouslyusedCOCs.
Ofnote,desireformandatoryeducationaboutcontinuousCOCusageinthispopulationwashigh,with86%reportingthistypeofeducationshouldbeanentryrequirementforallfemalepersonnel.
15KnowledgegapsandcompliancedifcultieslimituseforcontinuousCOCsandthere-foremenstrualsuppressioninthemilitary.
15AsmallUKmilitarystudyhighlightedtheneedformilitaryhealthcareproviderstocounselpersonnelaboutcontraceptiveoptionsratherthanleavingthisresponsibilitywithnationalhealthcareprovidersdueFigure1.
Approximatetimeoverwhichmenstrualsuppression±contraceptionmayberequiredbyfemaleastronauts.
MenstrualsuppressioninastronautsVJainandVEWotring32016MacmillanPublishersLimitednpjMicrogravity(2016)16008tothehigherlevelsofexposuretofemalesoldiers.
LARCshadnotbeendiscussedwithlargenumbersofpersonnel,whereascontraceptiveusewasnotevendocumentedinoverhalfoftheconsultationrecordsintheyearleadinguptothestudy.
16ThemainbarrierstouptakeofLARCsincludewomen'sknowledgeofandattitudestowardsthemethods,practicepatternsamongproviders,andhighinitialupfrontcosts.
ThecontraceptiveCHOICEprojectremovedthesebarriers,andinturnfoundovertwo-thirdofparticipantschoseaLARC(56%choosinganIUDand11%selectingasubdermalimplant).
17BonehealthwithmedicallyinducedamenorrheaTheconstantinhibitionbyoralsyntheticestrogenandprogester-oneduringcontinuousCOCuseleadstosuppressionofhypothalamicandpituitaryreleaseoffollicle-stimulatinghormoneandluteinizinghormone.
18Thisinturnimpactsbioavailablelevelsofestrogenandprogesterone.
Estrogeninhibitsboneresorptionthroughitsactionsonosteoclasticactivityandhasanaboliceffectsonosteoblasts.
19ContinuousCOCcouldthereforepotentiallybenetastronautsbyreducingspaceight-relatedosteopenia.
Itishoweverunknownhowchroniclow-doseCOCtherapyanditslackofpeaksinestrogendeliveryalongsidetheimpactofmicrogravitytogethereffectbonemetabolismoverall.
EliteathleteswhoareamenorrheichavebeenshowntohavealowerBMDthanthosewithregularcycles.
20Exerciseisavitalcountermeasureforastronautsanditisunknownifamenorrheaaffectsastronautsatthesameratesaseliteathletes.
Mechanismsforosteopenicchangesinrelationtospaceightarelikelyduetogravitationalunloadingasopposedtochangesinthehypotha-lamic–pituitary–ovarianaxisasisthecasewitheliteathletes.
Itisunknownifthereisasynergisticmechanisticactioninsomefemaleastronautswhoareextremelyt.
PrescribingcontinuousCOCintheseathleticfemaleastronautstounderstandanypotentialadvantagesinrelationtodecreasedBMDinspaceisalsounknown.
Terrestrially,COCsdonotappeartonegativelyaffectBMD.
21However,low-dose(20μg)ethinylestradiolCOCshavebeenshowntocausethelossofBMDcomparedwithnon-hormonalcontraceptives(e.
g.
,thecopperIUD)at3yearsofuse.
22TheimpactonoverallBMDwasparticularlyevidentinadolescentsubjects;however,adecreasewasnotedspecicallyinthefemoralneckBMDinallpre-menopausalparticipants.
ThelossinBMDwassmall,evensmallerthantheeffectofmenopause;however,anyBMDdecreasewithintheastronautpopulationbecomesrelevantduetotheirreversiblebonechangesthatoccurasaresultofspaceight.
Littlesignicanceisgiventerrestriallytosuchsmalldecreasesduetoriskversusbenetratios,buttheconnotationofwhatmaybe'clinicallyrelevant',especiallyintermsofBMD,isdifferentinthespaceightrealm.
Thebalancebetweenestrogenandprogesteroneprovidedbyhormonalcontraceptionalsoneedsconsideration,asBMDwasnotlostin30–35μgofethinylestradiolCOCuserscomparedwith2yearscontinuoususeofDMPA,whichledto6%BMDloss.
23Subjectsinthisstudywerephysicallytandhealthyaseligibilityincludedbeingabletomeetminimumcriteriaforentryintothearmedforces.
Overthecourseofthestudy,therewasnorequirementforregularphysicalexercisebutthenumbersthatengagedinweight-bearingactivitydidnotdifferbetweenexperimentalorcontrolgroups.
Subjectswereaged18–33years,thereforetheirboneswerestillunderestrogenicinuence;however,intheastronautpopulation,wherebonepreservationisvital,thepotentialadvantagesoforalestrogencannotbeignored.
Thus,COCsof30–35μgofethinylestradiolhavebeenprescribedforcontinuoususeamongtheastronautpopulation.
7DecisionsregardingthedosageofestrogenwithintheCOCwerebasedonextrapolationfromterrestrialstudies,notfromactualspaceightevidence.
TherearecurrentlynostudiescomparingthedifferencesonbonelossinwomenwhodoordonotusetheCOCinspace,andthereforethishasnotbeenformallyevaluated.
Itisimportanttonotethattheprogestin-onlysubdermalimplantandtheLNG-IUDdonotnegativelyimpactBMDduringusageonEarthinpre-menopausalwomen.
21Thisfurtherincreasestheirpotentialviabilityforfemaleastronauts.
LIMITATIONSOFMENSTRUALSUPPRESSIONApotentiallimitationwithvirtuallyallmenstrualsuppressionregimesisdegreeofsuppressionfrominitialdosing.
Moststudiesquoteratesofunscheduled,unpredictableandirregularbleedingintheinitialmonthsofLARCusage.
Ithasbeenpostulatedthatthiscouldbeattributedtothetimingofinitiationandwhethertheendometriumisinproliferativeorsecretorystages.
Theremayalsobeanelementofwhetherthehypothalamic–pituitary–ovarianaxisissupportingovulatoryoranovulatorycycles.
6Weisbergetal.
24comparedlong-termbleedingpatternsinLNG-IUDversusprogestin-containingsubdermalimplantusers.
IrregularbleedingpatternsareevidentwithallLARCsbutamenorrhearatesappeartobesimilarinboththegroupsafter2yearsofuse.
Transexamicacidandmefanamicacidhavebothbeentrialedtoreducetheinitialbleedingorspotting'nuisances'withtheLNG-IUDbutneitherledtoasignicantreductioncomparedwithplaceboinadouble-blindrandomizedcontroltrial.
25EvidenceislimitedaroundmanagingirregularbleedingwithLNG-IUDsbutwithsubdermalimplants,non-steroidalanti-inammatorydrugs,orlow-doseCOCsmaybetrialedonashort-termbasisintheUnitedStates.
26Trialsinperi-menopausalwomen,wheretheLNG-IUDwasusedalongsideoralestrogentherapy,havefoundhighratesofamenorrhea,whicharealmostcomparablewithcontinuousCOCuse.
27Similarly,intheUnitedKingdom,upto3monthsofeithercontinuousorcyclical30–35μgofethinylestradiolCOCsarerecommendedtocombatirregularbleedingforbothLNG-IUDsandsubdermalimplants,althoughthisisunlicensed.
28LONG-TERMEFFECTSOFMENSTRUALSUPPRESSIONLong-termside-effectprolesformenstrualsuppressionbyafore-mentionedmethodsaregood.
Dataprovidereassuranceforthelong-termuseofCOCpillsandLARCs.
AdverseeventsassociatedwithextendedregimesofCOCsweresimilartothoseseenwith28-daycyclicalregimes.
29ReturntoanormalmenstrualpatternandfertilityispromisingwithbothcontinuousCOCuseandLARCs.
One-yearpregnancyrateaftertheremovaloftheLNG-IUDissimilartowomenofthesameagenotusinganyformofbirthcontrol.
30WomendiscontinuingextendeduseCOCregimeswithoutstartinganyotherhormonalcontraceptionhadamediantimetowithdrawalbleedingof32days,areturntoovulatorycapacitywithin32daysand99%ofwomenwerehavingspontaneousmenstruationorpregnancywithin3monthsofdiscontinuation.
29ThereisnoincreasedriskofbreastcancerinusersoftheCOCandithasbeenfoundthatovarian,endometrial,andcolorectalcancerrisksdecreaseasthelengthofCOCuseincreases,i.
e.
,makingCOCuseprotectiveagainstovarian,endometrial,andcolorectalcancer.
8,31TheLNG-IUDisrecommendedforthetreatmentofendometrialhyperplasiaandcanbeusedlongtermwithsurveillance.
8OPERATIONALCONSIDERATIONSFromanoperationalperspective,LARCswouldnotbeexpectedtointerferewiththeabilityoftheastronauttoperformhertasks.
TherearenoreportsintheliteraturesuggestinghighGloadingexperiencedduringlaunchorlandingwouldimpactsubdermalimplantorLNG-IUDplacementorbleedingpatterns;similargravitationalforcesmaybeexperiencedbyterrestrialwomen,e.
g.
,militaryjetpilotsbuttherearecurrentlynodataintheliteratureMenstrualsuppressioninastronautsVJainandVEWotring4npjMicrogravity(2016)160082016MacmillanPublishersLimitedregardingthispopulation.
PerforationoftheuterusorexpulsionoftheLNG-IUDisariskassociatedwithoperatorskillandmorefrequentintherstyearofuse.
ShouldaLARCbedesired(LNG-IUDorthesubdermalimplant),itwouldbeadvisabletoinsertitatleast1.
5–2yearsbeforeight,inordertojudgetheside-effectprolebutmoreimportantlythebleedingpattern.
Aftertheinitial6monthsofuse,bleedingpatternsorprobabilityofamenorrheacanbebetterjudgedwiththeLNG-IUD;however,bleedingpatternsmaydifferwiththesubdermalimplant.
OntherarechancetheLNG-IUDisexpulsedduringight,menstruationwouldoccurasnormalduringspaceightandthiswouldnotimpedeanastronaut'sabilitytoperformherjob.
UltrasoundcapabilitiesarealreadypresentonboardtheInternationalSpaceStationandatransvaginalultrasoundprobeaswellasgyneco-logicalexaminationkitcouldbeaddedtothehardwareifdesired.
Additionaltrainingaswellasskillretentionwouldneedtobeaddressedbeforetheimplementationofsuchequipment.
Immunedysfunctionmayoccurduringspaceight;however,thisshouldnothinderanastronaut'schoicewithregardstomenstrualsuppressionoptions.
Hormonalcontraceptionissafetouseinimmuno-compromisedpopulationsterrestrially,withCOCs,subdermalimplants,andLNG-IUDshavingallbeentrialed.
Apelvicinammatorydiseaseriskof0.
16per100womenyearshasbeendemonstratedwithinanimmuno-compromisedstudygroupwithIUDs,whichislow.
32Earth-basedanalogsdonotexisttopreciselyreplicatespaceightimmunedysfunctionbutextrapola-tionfromthesedatasuggestscontinuousCOCsandLARCswouldbesafeforfemaleastronauts.
ThedailyrequirementofthecontinuousCOCregimewouldmean~1,100pillswouldbeneededfora3-yearexplorationclassmission.
Drugstabilityhasnotbeentestedforhormonalmedicationsoversuchalongtimeinspaceorwiththeimpactofdeep-spaceradiation.
OptingforaLARCwouldremovethecost,upmass,packaging,wasteandstabilityissuesasadevicecouldbeinsertedbeforeamissionandreplacementwouldnotberequiredin-ight.
Considerationcouldbegivenastowhetherasmallnumberof30–35μgofethinylestradiolCOCpillsornon-steroidalanti-inammatorydrugscouldbeaddedtothemedicalkitsincasebreakthroughbleedingbecomesproblematic.
However,considerationmayneedtobegiventothesubdermalimplantandwhetheritcouldruborcatchonspecialistequipmentorattiresuchastheNeutralBuoyancyLaboratorydivingsuitortheextra-vehicularactivitysuit.
Theimplantdoesnotusuallyinterferewithnormalclothingwornbyterrestrialusers,andmostcommenttheyareunawareofitspositioningaftertheinitialinsertion.
Wesuspectsubdermalimplantpositioningwouldbenon-problematicforfemaleastronauts;however,thishasnotbeentrialed.
DISCUSSIONThereisalonghistoryofcontinuousCOCuseduringspaceightmissionsandtraining.
Itissafeandreliableforeffectivecontraceptionandmenstrualsuppression.
Othermethodscouldbeconsideredintheastronautpopulation,specicallyLARCs,whicharedependableandeffectivelong-actingcontraceptiveswithcomparableratesofamenorrhea.
TheimplantprovidesbetterratesofamenorrheacomparedwiththeLNG-IUDinthersttwoyearsofusehoweverthereafterratesofamenorrheadonotdiffersignicantly.
WiththeLNG-IUDcurrentlylicensedforveyearsversusthreeyearsfortheimplant,ourrecommendationswouldliewiththeLNG-IUDduetotimescalesoverwhichastronautsmayrequiremedicallyinducedamenorrhea.
TreatingbleedingirregularitiesinimplantusershasbeensuccessfulwithconcurrentCOCuse.
33UsageofCOChasnotbeeninvestigatedalongsidetheLNG-IUDandthiscouldbeaviableoptionforfemaleastronauts,potentiallyprovidingatop-tiercontraceptive,withtheadditionalbenetsofadd-backestrogen,whichmayreduceboneloss,animportantissueforastronauts.
Furtherresearchwouldbeneededtoseewhetherthisstrategydecreasesinitialirregularbleeding,breakthroughbleed-ing,orhasanyimpactonBMD.
RecommendationsforspaceightTheuniquenessofthespaceightenvironmentprovidesmanychallengesinconductingresearch.
Thenumberofsubjectsrequiredbyclinicalstudiescannotbematchedbythenumberofcurrentactivefemaleastronauts.
Combiningpharmacologicaldataonthebioavailabilityofhormonesduringspaceightwithanalogground-basedstudiesinvestigatingmenstrualsuppressionmayprovidetheevidencerequiredtotrialLARCsduringspace-ight.
Withlonger-durationmissions,theageatwhichfemaleastronautsareundertakingspaceightisincreasingandtheliteraturesupportstheLNG-IUDastheprogestincomponentforhormonereplacementtherapyinperi-menopausalandmenopausalwomen.
ResearchisneededintotheuseoftheLNG-IUDalongsideoralestrogenandwhetherthisinuencesBMDinthissubpopulationofastronauts.
Resourcelimitationsaswellasthecontinuousnumberofdaysworkedbymilitarypersonnelaresimilartoconditionsexperiencedbyastronauts.
Lessonslearnedfrommilitarystudiesdictatethateducationforallfemalepersonnelatrecruitmentwouldbeextremelybenecialinthesepopulationsofwomenautonomouslymakingdecisionsaboutmenstrualsuppression.
Itisultimatelythewoman'schoicetosuppressornot.
Respectingthisautonomyisimportant;however,optionsshouldbeavailabletohershouldshedecidetosuppressinconsiderationofherworkingenvironment.
ACKNOWLEDGMENTSWeacknowledgeDrsMichaelBarratt,SerenaAunon,RichardJennings,EllenBaker,andMichelleBlackwellforhelpfuldiscussions.
WewouldalsoliketothankandacknowledgeMsEliscaHicks,MsSherrieDillandMsJanineBoltonfortheircontinuedsupport.
VJwasfundedthroughtheRoyalCollegeofObstetriciansandGynaecologists/AmericanGynecologicalClubTravelFellowship2015,andtheNationalInstituteforHealthResearch,UK.
ShereceivedhonoraryacademicsupportfromKing'sCollegeLondonandBaylorCollegeofMedicine'sCenterforSpaceMedicine.
TheeffortsofVEWwerefundedbyNASA'sHumanResearchProgram.
CONTRIBUTIONSTheprojectwasconceivedbyV.
E.
W.
afterdiscussionswithJ.
D.
Polk,formerlyofNASAJohnsonSpaceCenter.
V.
J.
performedthemajorityoftheliteraturesearchandpersonalinterviewing.
V.
J.
andV.
E.
W.
collaboratedondraftingandamendingthismanuscript.
COMPETINGINTERESTSTheauthorsdeclarenoconictofinterest.
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