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Treatmentofmenopausalsymptomswithhormonetherapy

OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Treatmentofmenopausalsymptomswithhormonetherapy
Authors
KathrynAMartin,MD
RobertLBarbieri,MD

SectionEditor
WilliamFCrowley,Jr,MD

DeputyEditor
KathrynAMartin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Dec2015.|Thistopiclastupdated:Dec15,2015.
INTRODUCTIONNormalwomenhavemenopauseatameanageof51years,with95percentbecoming
menopausalbetweentheagesof45to55years.Estrogenisthemosteffectivetreatmentavailableforreliefof
menopausalsymptoms,mostimportantlyhotflashes.Menopausalhormonetherapy(MHTestrogenaloneor
combinedwithaprogestin)iscurrentlyindicatedformanagementofmenopausalsymptoms.Longtermusefor
preventionofdiseaseisnolongerrecommended.ThetreatmentofmenopausalsymptomswithMHT(estrogen
aloneorcombinedwithprogestin)willbereviewedhere.Anoverviewoftherisksandbenefitsofestrogen,
availablehormonepreparations,andanoverviewofmenopausaltherapiesforwomenwhochoosenottoorcannot
takeestrogenarediscussedseparately.(See"Menopausalhormonetherapy:Benefitsandrisks"and
"Preparationsformenopausalhormonetherapy"and"Menopausalhotflashes".)
OVERVIEWOFAPPROACHMenopausalhormonetherapy(MHT)isthebroadtermusedtodescribe
unopposedestrogenuse(forwomenwhohaveundergonehysterectomy)orcombinedestrogenprogestintherapy
(EPTforwomenwithanintactuteruswhoneedaprogestintopreventestrogenassociatedendometrial
hyperplasia).Byconvention,unopposedestrogentherapyisknownasET,combinedestrogenprogestintherapy
asEPT,andmenopausalhormonetherapyasMHT[1].
GoalsThegoalofMHTistorelievemenopausalsymptoms,mostimportantlyhotflashes(vasomotor
symptoms).Othersymptomsassociatedwithperimenopauseandmenopausethatrespondtoestrogentherapy
includemoodlability/depression,vaginalatrophy,andsleepdisturbances(whenrelatedtohotflashes).Detailson
managementofvasomotorsymptomsandtheuseofvaginalestrogenforvaginalatrophyarereviewedindetail
separately.(See"Menopausalhotflashes"and"Treatmentofvaginalatrophy".)
Inthepast,hormonetherapy(HT)wasalsousedlongtermforpreventionofchronicdisease(coronaryheart
disease[CHD]andosteoporosis).However,wedonotrecommendHTforpreventionofdisease,giventheresults
oftheWomensHealthInitiative(WHI),asetoftwolargerandomizedtrialsthatdemonstratedanunfavorablerisk
benefitprofileofHT.(See"Menopausalhormonetherapy:Benefitsandrisks",sectionon'Overview'.)
ImportanceofpatientageWhiletheWHIclearlydemonstratedadverseeffectsofHTinolderpostmenopausal
women(overage60years),thisisnottheagegroupthatpresentswithnewonsetofmenopausalsymptoms.
Almostallwomenwhoseekmedicaltherapyformenopausalsymptomsdosointheirlate40sor50s.Womenin
thisagegroupshouldbereassuredthattheabsoluteriskofcomplicationsforhealthy,youngpostmenopausal
womentakingHTforfiveyearsisverylow(figure1).(See"Menopausalhormonetherapy:Benefitsandrisks",
sectionon'Estimatesofriskinwomen50to59years'.)
Candidates/indicationsWeconsiderET(orEPTforwomenwithanintactuterus)tobeareasonableoption
formostwomenintheirlate40sor50swithmoderatetoseverevasomotorsymptoms,withtheexceptionofthose
withahistoryofbreastcancer,CHD,apreviousvenousthromboemboliceventorstroke,activeliverdisease,or
thoseathighriskforthesecomplications[13].OurapproachislargelyconsistentwiththeEndocrineSociety
ClinicalPracticeGuideline,whichpresentsanindividualizedapproachtotreatmentbaseduponcalculatinga
womansbaselinecardiovascularandbreastcancerriskspriortoinitiatingtherapy[4](See"Overviewof
cardiovascularriskfactorsinwomen"and"Riskpredictionmodelsforbreastcancerscreening".)
Vasomotorsymptomsoccurmostofteninthelatemenopausaltransitionandtheearlypostmenopause(figure2).
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Althoughtherearealternativetherapiesforvasomotorsymptoms,noneareaseffectiveasestrogen.The
physiology,clinicalmanifestations(includinginsomnia),andtreatmentofhotflashes(includingintractablehot
flashes)arediscussedindetailelsewhere(see"Menopausalhotflashes").Inaddition,anoverviewoftheclinical
manifestationsofthemenopausaltransitionandmenopausearefoundseparately.(See"Clinicalmanifestations
anddiagnosisofmenopause".)
VaginalatrophyTheepithelialliningsofthevaginaandurethraareverysensitivetoestrogen,andestrogen
deficiencyleadstothinningofthevaginalepithelium.Thisresultsinvaginalatrophy(atrophicvaginitis),
causingsymptomsofvaginaldryness,itching,andoftendyspareunia.Bothsystemicandvaginalestrogen
areeffectiveforgenitourinaryatrophysymptoms,butvaginalestrogenmayhavemorelocaleffectwithout
highsystemiclevels.(See"Treatmentofvaginalatrophy",sectionon'Vaginalestrogentherapy'.)
DepressionHT,aloneorincombinationwithanantidepressantsuchasaselectiveserotoninreuptake
inhibitor(SSRI),iseffectiveforwomenwhoexperiencemoodlabilityordepressionduringthemenopausal
transition.(See'Depression'below.)
JointachesandpainsItisunclearifthepainisrelatedtoestrogendeficiencyorarheumatologicdisorder,
butintheWomen'sHealthInitiative,womenwithjointpainorstiffnessatbaselineweremorelikelytoget
reliefwitheithercombinedestrogenprogestintherapy(EPT)orunopposedestrogentherapy(ET)thanwith
placebo.(See"Clinicalmanifestationsanddiagnosisofmenopause",sectionon'Jointpain'.)
CognitivefunctionanddementiaWecurrentlydonotsuggesttheroutineuseofHTforperiand
postmenopausalwomenwhoareexperiencingcognitivesymptoms(memorylossanddifficulty
concentrating).Althoughsubstantialbiologicevidencesupportstheimportanceofestrogentocognitive
function,clinicaltrialevidencehasgenerallyruledoutanyglobal(butnotdomainspecific)cognitivebenefits.
(See"Estrogenandcognitivefunction",sectionon'Clinicaltrialevidence'.)
Inaddition,wecurrentlydonotsuggesttheuseofHTtopreventdementia.Althoughsomeepidemiologicdata
suggestthatestrogenmaybebeneficial,clinicaltrialsofHTadministeredtowomenoverage65yearsshowed
harm.StrongevidenceofcognitivebenefitsforwomentakingMHTatyoungerages(eg,nearmenopause)isalso
lacking,andthusHTshouldnotbeprescribedforpreservationofcognitivefunctioninyoungerwomen.(See
"Estrogenandcognitivefunction",sectionon'Clinicaltrialdata'.)
LongtermuseforpreventionofdiseaseMHTisnolongerrecommendedforpreventionofchronicdisease.
WesuggestnotusingMHTforthepreventionofCHD,eveninyoungpostmenopausalwomen.
Althoughtheriskprofileappearstobemorefavorableinyoungwomentakingunopposedestrogen,use
forpreventionisstillnotwarranted[1,2,5,6].ThehormoneregimenstudiedintheWHIwasconjugated
estrogens(CE)andmedroxyprogesteroneacetate(MPA).Whileitispossiblethatotherestrogenor
progestinformulationsordosesmightnothavethesamenegativecardiovasculareffectsasCEand
MPA,datatosupporttheiruseforpreventionarenotavailable.(See"Menopausalhormonetherapyand
cardiovascularrisk",sectionon'Timingofexposure'.)
Althoughwepreviouslyrecommendedestrogenasafirstlinechoiceforpreventionandtreatmentof
osteoporosis,wenowrecommendbisphosphonates.However,intheoccasionalpatientwithpersistent
menopausalsymptomswhocannottoleratefirstandsecondlinetherapiesforosteoporosis,estrogen
maybeareasonableoption.(See"Overviewofthemanagementofosteoporosisinpostmenopausal
women",sectionon'Estrogen/progestintherapy'.)
PRACTICALASPECTSOnceadecisionhasbeenmadetotreatapostmenopausalwomanwithestrogen,
considerationshouldbegiventothetypeofestrogenandtheroutebywhichitistobegiven,aswellastheneed
forprogestinandthemostappropriateprogestinregimen.Estrogenisavailableinmanyforms:oral,transdermal,
topicalgelsandlotions,intravaginalcreamsandtablets,andvaginalrings.Insomecountries,estrogencanalso
begivenasasubcutaneousimplant(table1).
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Thepotencyandthereforethedosesoftheseestrogenpreparationsdiffer,buttheydifferlittleinefficacy[7].
Vaginalestrogenismostcommonlyusedinverylowdosesforthemanagementofvaginalatrophy.However,high
dosesofvaginalestrogencanalsobeusedtotreatvasomotorsymptoms,muchlikeatransdermalpreparation[8].
Wedonotrecommendthesehighdoses,ie,systemicestrogendoses,inwomenwhoneedtherapyfor
genitourinarysymptomsonly.(See"Treatmentofvaginalatrophy",sectionon'Vaginalestrogentherapy'.)
EfficacyforhotflashesTheeffectsofestrogenonhotflashesaredoserelated.Inasystematicdose
responsestudy,transdermalpatchesdelivering25,50,100,and200microgramsof17betaestradiolperday
causedaprogressivereductioninhotflashes[9].The200microgramdoseresultedinserumestradiolplasma
levelsof100pg/mL,anditwasestimatedthatwithaserumestradiolconcentrationof120pg/mL,womenwould
havea100percentreductionintheirhotflashes.
Inametaanalysisof24trialsofmenopausalhormonetherapy(MHT)in3329women(estrogenaloneorcombined
withprogestindurationofthreemonthstothreeyears),thefollowingresultswereseen[10]:
Therewasadecreaseinthemeannumberofhotflashesperweekforwomenreceivinghormonetherapy
(HT)comparedwithplacebo(weightedmeandifference18hotflashesperweekcomparedwiththose
receivingplacebo,95%CI22.86to12.99).Thiswasequivalenttoa75percentreductioninhotflash
frequencyforHTrelativetoplacebo.
TheseverityofhotflasheswasalsodecreasedwithHTcomparedwithplacebo,andwithdrawalforlackof
improvementinsymptomsoccurredmoreofteninwomenonplacebo(oddsratio[OR]10.51,95%CI5.00
22.09).
AlthoughadverseeventssuchasbreasttendernessandmoodsymptomsoccurredmoreoftenwithHTthan
placebo(OR1.41),withdrawalfromthetrialforadverseeventswassimilarinbothgroups.
Inasecondmetaanalysis,conjugatedestrogen(CE)0.625mg/dayand17betaestradiol(oral1mg/dayor
transdermal0.05mg/day)appearedtobeequallyeffectiveforthetreatmentofhotflashes[11].Thesedoses
eliminatehotflashescompletelyinabout80percentofwomen,andreducethefrequencyandseverityofthe
remainder[10].
StartingestrogenEstrogentherapyremainsthegoldstandardforreliefofmenopausalsymptoms,inparticular,
hotflashes.Allroutesofadministrationappeartobeequallyeffectiveforsymptomrelief(andbonedensity),but
theirmetaboliceffectsdiffer.Oralestrogenhasmorefavorableeffectsonlipidprofiles,butthereisnoevidence
thatthisresultsinlongtermclinicalbenefit.Ontheotherhand,oralestrogensareassociatedwithincreasesin
serumtriglyceridesandCreactiveprotein.Inaddition,oralestrogensincreasesexhormonebindingglobulin
(SHBG)morethantransdermalpreparations,whichresultsinlowerfreetestosteroneconcentrations.Intheory,
thiscouldresultinanegativeimpactonlibidoandsexualfunction,butthishasnotbeenproven.Similareffectson
thyroidbindingglobulin(TBG)andbioavailablethyroxine(T4)occurwithoralestrogen(increasedTBGandlower
bioavailableT4).Lastly,therisksofvenousthromboembolism(VTE)andstrokeappeartobehigherwithoralwhen
comparedwithtransdermalestrogen.Theseissuesarediscussedingreaterdetailseparately.(See"Menopausal
hormonetherapyandcardiovascularrisk"and'Factorsaffectingoralestrogenmetabolism'below.)
Wesuggesttransdermal17betaestradiolformostwomenbecauseofthepotentialadvantagesoutlinedabove.In
addition,theycontain17betaestradiol,themainestrogentheovarysecretespriortomenopause.However,the
baselineriskofbothVTEandstrokeisverylowinotherwisehealthy,youngpostmenopausalwomen.Therefore,if
apatientprefersanoralpreparationoveratransdermalone(costorpersonalpreference),weconsideroral
estrogentobesafe.Wetypicallychooseoral17betaestradiolpreparationsalthoughsomeclinicianspreferCE,a
preparationthathasbeenpopularhistorically(andthepreparationstudiedintheWomensHealthInitiative[WHI]).
Detailsonthetypesofestrogenpreparationsarereviewedseparately.(See"Preparationsformenopausal
hormonetherapy",sectionon'Estrogenpreparations'.)
Inadditiontooralandtransdermalestrogenpreparations,estrogenisavailableasavaginalringandasatopical
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spray,cream,orgel.Thetopicalspray(Evamist)hasbeenlinkedtoadverseeffectsinchildrenandpetsexposed
tothedrugviaskincontact.(See"Preparationsformenopausalhormonetherapy",sectionon'Topicalestradiol'.)
TheUSFoodandDrugAdministration(FDA)nowrequirestheaddingoflabelstoallestrogenandestrogen
progestinproductswarningofthepossibleriskofheartdisease,stroke,andcancer[12].
DoseWetypicallybeginwithatransdermalestradiol0.025mgpatch(orifusingoralestradiol,0.5mg/day).
Ifhotflashesarestillpresentafteronemonth,weincreasetransdermalestradiolto0.0375mgandreassessone
monthlater.Ifsymptomsarestillnotrelieved,weincreasefurtherto0.05mg.Anexceptiontothisapproachisthe
patientwithseveresymptomswestartwithatransdermaldoseof0.05mgtoachievemorerapidreliefof
symptoms.
Standarddosesofestrogengivendaily(CE0.625mgoritsequivalent)aresufficienttoreducehotflash
frequencyandseveritybyapproximately75percentrelativetoplacebo[11].Inasystematicreviewandmeta
analysisoftrialsofestrogenforhotflashes,CEand17betaestradiol(oralortransdermal)wereequallyeffective
[10].
Inthepast,aonesizefitsallapproachtodosingwasused,withCE0.625mgoritsequivalent(oralestradiol1
mg,transdermal17betaestradiol0.05mg[50mcg])prescribedtomostwomen.Ifsymptomswererelieved,the
samedosewascontinuedindefinitely.However,thecurrentapproachistostartwithlowerdoses,suchas
transdermalestradiol0.025mgororalestradiol0.5mg,andtitrateuptorelievesymptoms.Lowerdosesare
associatedwithlessvaginalbleedingandbreasttenderness[13].Itisnotknowniftheywillbeassociatedwitha
betterriskprofileforthebreastandcardiovascularsystem.(See"Preparationsformenopausalhormonetherapy",
sectionon'Lowdoseestrogen'.)
Thelowestavailabletransdermalestradioldoseis0.014mgitisapprovedforpreventionofboneloss.However,
about50percentofwomenderivesomebenefitforhotflashes.[14].Progestindosesmaybeloweredwithlow
doseestrogen,butthereisnoconsensusonoptimalregimens.(See'Addingaprogestin'below.)
Estrogenshouldbeadministeredcontinuouslypastregimenswhereestrogenwasadministereddays1to25of
thecalendarmonthareconsideredtobeobsolete.Womenwilloftengethotflashesduringthedaysoff,andthere
isnoknownadvantagetostoppingforseveraldayseachmonth.
Thesedosesofestrogen(transdermalestradiol0.025to0.050mgortheirequivalent)areadequateforsymptom
reliefinthemajorityofwomen.Anexceptionisyoungerwomenafterbilateraloophorectomy.Theyoftenrequire
higherdoses(eg,upto0.1mgtransdermalestradiol)forthefirsttwotothreeyearsaftersurgerythedosecan
subsequentlybetapereddown.
FactorsaffectingoralestrogenmetabolismThereareseveralsituationsinwhichthemetabolismof
exogenousestrogenisalteredandthereforeachangeinthedosemaybeneeded.Increasedmetabolismmay
resultinlowerserumestrogenconcentrations,whiledecreasedmetabolismcanresultinhigherserum
concentrations.
Theabovedosingsuggestionsmayneedtobeincreasedinwomentakinganticonvulsantdrugs(phenytoin,
carbamazepine),whichincreasethehepaticclearanceofestrogensandothersteroidhormones.However,
thereisnowaytopredicthowmuchmoreestrogenisneeded[15].Inthissituation,atransdermalestrogen
maybebetterthanoralestrogensinceitavoidsthefirstpasshepaticmetabolism.
InwomenreceivingT4replacementtherapy,theadditionoforalestrogentherapymayincreaseT4
requirements.(See"Treatmentofhypothyroidism".)
Concurrentacutealcoholingestionwithoralestradiolhasbeenfoundtocauseathreefoldriseinserum
estradiolconcentrations,apparentlybyslowingthemetabolismofestradiol[16].Whileitwouldbedifficultto
alterthemedicationdosebaseduponthesefindings,womentakingexogenousestrogenshouldbe
encouragedtolimitalcoholintake.
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Womenwithendstagerenaldiseasehavehigherserumestradiolconcentrationsafteranoraldoseof
estrogenthandonormalwomen[17].
AddingaprogestinAllwomenwithanintactuterusneedaprogestininadditiontoestrogentoprevent
endometrialhyperplasia,whichcanoccurafteraslittleassixmonthsofunopposedestrogentherapy(ET).
Womenwhohaveundergonehysterectomyshouldnotreceiveaprogestin,astherearenootherhealthbenefits
otherthanpreventionofendometrialhyperplasiaandcarcinoma.(See"Menopausalhormonetherapy:Benefitsand
risks",sectionon'Endometrialhyperplasiaandcarcinoma'.)
ThemostextensivelystudiedformulationforendometrialprotectionisthesyntheticprogestinusedintheWHI,
medroxyprogesteroneacetate(MPA2.5mgdaily).WhileMPAisendometrialprotective,itwasassociatedwithan
excessriskofcoronaryheartdisease(CHD)andbreastcancerwhenadministeredwithCEintheWHI.In
addition,regimensusingcontinuousversuscyclicMPAmaybeassociatedwithahigherriskofbreastcancer.
(See"Menopausalhormonetherapyandtheriskofbreastcancer",sectionon'Effectofprogestins'.)
Analternativeprogestin,naturalmicronizedprogesterone,isalsoconsideredtobeendometrialprotective(200
mg/dayfor12days/monthor100mgdaily).Althoughtherearereasonstobelievethatnaturalprogesteronemight
besaferforthecardiovascularsystem(noadverselipideffects)andpossiblythebreast,thisremainsunproven.
(See"Menopausalhormonetherapyandcardiovascularrisk",sectionon'Effectsofprogestins'and"Menopausal
hormonetherapyandtheriskofbreastcancer",sectionon'Typeofprogestin'.)
Inourpractice,weprescribeoralmicronizedprogesteroneasourfirstlineprogestin.Forwomenwhoare
perimenopausalornewlymenopausal,westartwithcyclicadministration.Continuousadministrationinthis
populationisassociatedwithirregular,unscheduledbleedingduetotheexogenoushormonesandthecontinued
endogenousovarianfunction.Forwomenwhoare2to3yearspostmenopause,weuseacontinuousregimen
irregularandbreakthroughbleedingislessofaproblemonceovarianfunctionhasceased.Whilethereisoften
earlybreakthroughbleedingevenaftermenopause,mostwomendoeventuallydevelopamenorrhea,adesiredgoal
ofcontinuousadministration.(See"Preparationsformenopausalhormonetherapy",sectionon'Bleedingpatterns'.)
Moodsymptomsand/orwithdrawalbleedingSomewomenareunabletotoleratecyclicprogestin
administration(withanytypeoforalprogestin)becauseofmoodsideeffectsandbloating.Inaddition,cyclic
progestinsalmostalwaysresultinmonthlywithdrawalbleeding,whichcanbealifestyleconcernformanywomen.
Foranyoftheseconcerns,wesuggestswitchingtoacontinuousregimen.Thisoftenresolvestheissueofmood
symptomsandbloating.However,forwomenwhoarenewlymenopausal,breakthroughbleedingcanbe
anticipated.(See"Preparationsformenopausalhormonetherapy",sectionon'Bleedingpatterns'.)
WomenwhocannottolerateoralprogestinsSomewomenareunabletotolerateanyoralprogestin,
whethergiveninacyclicorcontinuousregimen.Inthiscase,weoftensuggestofflabeluseofthelowerdose
levonorgestrelreleasingintrauterinedevice(IUD)(table2).(See"Preparationsformenopausalhormonetherapy",
sectionon'Levonorgestrelreleasingintrauterinedevice'.)
Otherprogestinsthathavebeenusedincludequarterlyregimens(progestinadministeredonlyeverythirdmonth)
andoralnorethindrone.Quarterlyprogestinadministrationisnotconsideredtobestandardtherapy,asdataon
efficacyareconflicting.(See"Menopausalhormonetherapy:Benefitsandrisks",sectionon'Protectiveeffectof
progestins'and"Preparationsformenopausalhormonetherapy",sectionon'Progestinpreparations'.)
Anotheroptionisthecombinationofbazedoxifene,aselectiveestrogenreceptormodulator(SERM),withCE.This
productisavailableintheUnitedStatesforthetreatmentofmenopausalvasomotorsymptomsandosteoporosis
prevention.Inthiscombination,theSERMbazedoxifenepreventsestrogeninducedendometrialhyperplasiaso
thatadministeringaprogestinisnotnecessary.Potentialcandidatesincludewomenwithmoderatetoseverehot
flasheswhohavebreasttendernesswithstandardestrogenprogestintherapyorwomenwhocannottolerateany
typeofprogestintherapybecauseofsideeffects.LikeotherSERMs,theriskofVTEisincreasedwith
bazedoxifene.Todate,noadditiveeffectonVTEhasbeenobservedwiththecombinationbazedoxifene
conjugatedestrogen,butlongerstudiesareneededtofullyaddressthisrisk.(See"Menopausalhotflashes",
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sectionon'Bazedoxifene/Conjugatedestrogen'.)
DurationForpostmenopausalwomenwithmoderatetoseverevasomotorsymptoms(andnocontraindications
toestrogenuse),wesuggestestrogentherapyasthetreatmentofchoice.Thelowesteffectivedoseofestrogen
shouldbeused.Shorttermtherapyisconsideredtobetwotothreeyears,andgenerallynotmorethanfiveyears
[18].Onlytheminorityofwomenwhoareunabletosuccessfullydiscontinueestrogen(becauseofpersistent
symptoms)shouldconsiderextendeduseofestrogentherapy.
DataontheattributablerisksandbenefitsofHTforaperiodoffiveyearsinwomenages50to59yearsare
availableandcanbeusedforevidencebaseddecisionmaking[2].(See"Menopausalhormonetherapy:Benefits
andrisks",sectionon'Estimatesofriskinwomen50to59years'.)
MonitoringIntheWHI,theriskofbreastcancerwithcombinedestrogenprogestintherapy(EPT)didnot
increaseuntilthefourthyear.However,abnormalmammogramsweremorecommonwithbothETandEPT
(althoughmorecommonwithEPT).Whilethemajorityofabnormalmammogramsrepresentedrequestsfor
additionalviews,routinemammogramsandbreastexamsarerecommendedinwomentakingHT,evenifused
shortterm.Ofnote,stoppingtherapyshorttermdoesnotreducemammographyrecallrates.(See"Menopausal
hormonetherapyandtheriskofbreastcancer",sectionon'Abnormalmammography'.)
SideeffectsCommonsideeffectsofestrogenincludebreastsoreness,whichcanoftenbeminimizedbyusing
lowerdoses.Asnotedabove,somewomenexperiencemoodsymptomsandbloatingwithprogestintherapy.
Vaginalbleedingoccursinalmostallwomenreceivingcyclicestrogenprogestinregimensandiscommoninthe
earlymonthsofcontinuousestrogenprogestinregimen.(See'Addingaprogestin'above.)
Estrogen,especiallyincombinationwithaprogestin,isalsoassociatedwithincreasedbreastdensityandahigher
rateofabnormalmammogramsandbreastbiopsies.(See"Menopausalhormonetherapyandtheriskofbreast
cancer",sectionon'Abnormalmammography'.)
TheimpactofHTonmigraineheadachesisdiscussedbelow.(See'Migraines'below.)
UseoforalcontraceptivesduringthemenopausaltransitionAlowestrogenoralcontraceptive(OC)isan
optionforperimenopausalwomenwhoseekreliefofmenopausalsymptoms,whoalsodesirecontraception,and
whoinsomeinstancesneedbleedingcontrol(incasesofheavybleeding)[19].Mostofthesewomenarebetween
theagesof40and50yearsandarestillcandidatesfororalcontraception.Forthem,anOCpillcontaining20mcg
ofethinylestradiolprovidessymptomaticreliefwhileprovidingbetterbleedingcontrolthanconventionalestrogen
progestintherapybecausetheOCcontainshigherdosesofbothestrogenandprogestin(whichsuppressesthe
hypothalamicpituitaryovarianaxis).OCsshouldbeavoidedinobeseperimenopausalwomenbecausetheyareat
greaterriskforthromboemboliccomplications.ContraindicationstoOCuseinthispopulationincludesmoking,
hypertension,andmigraineheadaches.(See"Overviewoftheuseofestrogenprogestincontraceptives",section
on'Perimenopausalwomen'.)
Contraceptionremainsimportantduringperimenopause,aswomencannotbecertainofinfertilityuntiltheyreach
menopause(ie,12monthswithoutmenses).Thepossibilityofpregnancyinwomenage45to49yearsnotusing
contraceptionisestimatedtobe2to3percent,fallingtolessthan1percentafterage50years.
Inourpractice,whenwomentakingalowdoseOCduringperimenopausereachage50or51years,wediscuss
stoppingthepillaltogetherorchangingtoapostmenopausalestrogenregimenifnecessaryforsymptoms.If
estrogenisthengiven,thesamerecommendationsforusewouldapply.(See"Overviewofcontraception",section
on'Whenisitsafetostopusinghormonalcontraception?'.)
Becausewomenatthisageareapttohavehotflusheswhenestrogenisstoppedabruptly,wesuggesttapering
theOCbyonepillperweekasdescribedforestrogentherapyinthefollowingsection.
STOPPINGHORMONETHERAPYManywomenhavenotroublestoppingestrogen.Observationalstudies
reportthat40to50percentofwomenwhostartmenopausalhormonetherapy(MHT)stopwithinoneyear[20],
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and65to75percentstopwithintwoyears[21],oftenwithnoassistancefromtheirhealthcareprovider.
However,abruptwithdrawalofexogenousestrogenatanyagemayresultinthereturnofhotflashesandother
menopausalsymptoms.Thiswasillustratedinacrosssectionalsurveyof8405womenwhohadparticipatedin
theWomensHealthInitiative(WHI)combinedestrogenprogestintrial,allofwhomwereinstructedtoabruptly
discontinuetheirMHTwhenthetrialwasstopped[22].Comparedwithpatientsintheplacebogroup,thewomen
whoabruptlydiscontinuedhormoneweresignificantlymorelikelytodevelopmoderatetoseveresymptoms
whethertheyhadhotflashesatbaseline(56versus22percent)ordidnothavehotflashesatbaseline(21versus
5percent).
Womensubsequentlyusedavarietyofnonestrogenstrategiestomanagetheirsymptomswithvariabledegrees
ofsuccess.Only5percentofsubjectsresumedMHT,astheywerediscouragedbytheircliniciansfromdoingso.
TaperingDataregardingthestrategyofabruptcessationofhormonetherapy(HT)versustaperingare
conflicting.IthadbeenassumedthattaperingMHTwouldlowertheriskofrecurrentsymptoms,andasurveyof
377womenprovidedsupportforthisapproach[23].Asecondsurveyalsoreportedlowermenopausalsymptom
scoresafterstoppingHTinwomenwhohadfollowedthetaperapproachcomparedwiththosewhohadstopped
abruptly[24].However,womenwhotaperedwerealsomorelikelytorestartMHT.
However,inarandomizedtrial,91postmenopausalwomenwhowereonMHTforatleastthreeyears(primarilyfor
hotflashes)wererandomlyassignedtoeitheranabruptorgradualdiscontinuation(oversixmonths)oftheirMHT
[25].Vasomotorsymptomswereworseintheabruptgroupduringthefirstthreemonths,butworseinthetaper
groupatsixmonths,withnodifferencesbetweengroupsby9to12months.Afterstoppingtherapy,asimilar
percentageresumedtherapyinthetwogroups(42and36percentintheabruptandtapergroups,respectively).In
asecondtrial,arapidtaperovertwoweeksdidnotseemtobebetterthanstoppingabruptly[26].
Theclinicalrelevanceofthesefindingsisunclearthesecondtrialwasunblindedandthereforepatientswere
awarewhentheywerenolongeronestrogen,andthepercentageofpatientsresumingMHTwashigherthanwhat
hasbeenpreviouslyreported.Asanexample,inanobservationalstudy,26percentof377womenwhohadbeen
treatedforatleastoneyearresumedestrogentherapybecauseofbothersomesymptoms[23].Inaddition,as
notedabove,only5percentofwomenintheWHIresumedestrogen,presumablybecauseofthestrongmessage
theyreceivedfromhealthcareproviders[22].
Insummary,manywomenhavenodifficultywithrecurrentsymptomswhentheystopMHT,whileothershave
symptomssevereenoughtorequireresumptionoftherapy.BasedupontheWHIresults,onecananticipatethat
roughly55percentwillhavesomerecurrentvasomotorsymptomsifMHTisstoppedabruptly[22].
AlthoughtaperingHThasnotbeenproventobemoreeffectivethanstoppingabruptly,wetakethispragmatic
approach,particularlyinwomenwithahistoryofseverevasomotorsymptoms.
Whentapering,onesuggestedapproachistodecreasetheestrogenbyonepillperweek(ie,sixpillsperweek,
thenfivepillsperweek,etc)untilthetaperiscompleted.Theprogestinistaperedonthesameschedule.Inour
experience,womenwhoareunabletotolerateasixweektapertemporarilyresumetheirestrogen,andwethentry
amuchslowertaper,sometimesoveroneyear(sixpillsperweekfortwomonths,fivepillsperweekforone
month,etc).
Anothertypeoftaperonecantryiswithtransdermalestradiol,graduallydecreasingthedoseovertime(the
transdermalpreparationscomeinavarietyofdoses:0.1,0.075,0.05,0.0375,0.025,0.0114mgpatches).
ImplicationsofstoppingTheimplicationsofstoppingestrogenprogestintherapyinclude:
Returnofestrogendeficiencysymptoms(hotflashes,butnotgenitourinaryatrophysymptoms,mightbe
minimizedwithataper)(see"Menopausalhotflashes").TheNorthAmericanMenopauseSocietysuggests
thatafterafailedattemptatstoppingtherapy,extendeduseofMHTmaybereasonableinwomenwhofeel
thatthebenefitsofsymptomreliefoutweighrisks[27].Inthissetting,wemakeadditionalattemptsatalater
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datetostoptheMHT.
Resumptionofboneloss[2830].(See"Postmenopausalhormonetherapyinthepreventionandtreatmentof
osteoporosis".)
Decreaseinbreastcancerrisk[31,32].(See"Menopausalhormonetherapyandtheriskofbreastcancer",
sectionon'PostWHIrates'.)
Theeffectofestrogencessationoncoronarydisease,particularlyinyoungpostmenopausalwomen,is
unclear[32].
ManagingrecurrentsymptomsUnfortunately,inwomenwhohaverecurrentvasomotorsymptomsafter
stoppingtherapy,thereiscurrentlynowaytodeterminewhetherthesymptomswillresolvequicklyorpersistfora
prolongedtime.Inwomenwhodeveloprecurrenthotflashes,wefirstencouragethemtomonitortheirsymptoms
overthesubsequentfewmonthstoseeiftheyresolveorimprove.Ifthereisnoimprovement,oriftherecurrent
flushesduringorimmediatelyafterthetaperaredifficulttotolerate,wetryanonestrogenalternative,suchasa
selectiveserotoninreuptakeinhibitor(SSRI)orgabapentin.
Ifineffective,wethenrestartestrogenatthelowestdosepossible(ifthevalueofsymptomreliefoutweighsthe
potentialrisks)andmakeplansforafutureattempttostoptheestrogen.AScientificStatementoftheEndocrine
SocietyprovidestheattributablerisksandbenefitsofHTforaperiodoffiveyearsinwomenages50to59years.
Thesedatacanbeusedforevidencebaseddecisionmaking[2].(See"Menopausalhormonetherapy:Benefits
andrisks",sectionon'Estimatesofriskinwomen50to59years'.)
SPECIALISSUES
MigrainesMigraineheadaches(withorwithoutaura)arenotconsideredtobeacontraindicationtomenopausal
hormonetherapy(MHT).Forwomenwithhotflashesandestrogenassociatedmigraines(whichtypicallyworsen
duringperimenopause),estrogentherapyoftenimprovesbothsymptoms.Inthissettingwesuggestcontinuous
transdermalhormoneregimens(asopposedtocyclicregimens)toavoidtriggeringestrogenwithdrawalheadaches.
Theeffectofhormonetherapy(HT)onstrokeriskinpostmenopausalwomenwithmigrainesisnotwellstudied.
However,lowdosesoftransdermalestradiol(50mcgthedoserangeweroutinelyrecommend)havenotbeen
associatedwithanexcessriskofstrokeinnormalwomen(see'Dose'above).Thetopicofmenopause,HT,and
migraineisreviewedinmoredetailseparately.(See"Estrogenassociatedmigraine",sectionon'Migrainesand
menopause'.)
DepressionTheriskofdepressionduringperimenopauseishigherthanduringthepreorpostmenopausal
years.Perimenopausaldepressionincludesbothnewonset(firstepisode)depressionaswellasarelapsein
womenwithahistoryofdepression(see"Clinicalmanifestationsanddiagnosisofmenopause",sectionon
'Depression').
Inonetrialofestrogentherapyforperimenopausaldepression,50perimenopausalwomenwithmajordepression,
dysthymia,orminordepressivedisordersreceivedtransdermalestradiol(0.1mg)orplacebofor12weeks.
Remissionofdepressionoccurredin68percentofpatientscomparedwithonly20percentreceivingplacebo[33].
TheKEEPSstudy(KronosEarlyEstrogenPreventionStudy),atrialofMHTinyoungermenopausalwomenages
45to54yearswhounderwentextensivemoodevaluations,reportedthatfouryearsoforalestrogenappearedto
improvemood,aswomenreceivingoralconjugatedestrogencombinedwithmicronizedprogesteronehadlower
depressionandanxietyscoresthanthosereceivingeithertransdermalestradiolwithmicronizedprogesteroneor
placebo[34].
Selectiveserotoninreuptakeinhibitors(SSRIs)areeffectiveforperimenopausaldepression,andsomeprovide
modestbenefitforhotflashesaswell[35,36](see"Menopausalhotflashes",sectionon'Nonhormonal
pharmacotherapy').Dataalsosuggestthataddingestrogentoantidepressanttherapymayresultinadditional
benefitforperimenopausalwomenwithdepression[37].
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Ourapproachistochooseinitialtherapybaseduponthewomanspredominantsymptom.Ifhermainconcernis
depression,andhotflashesarenotsevere,westartwithanSSRI.Ontheotherhand,ifvasomotorsymptomsare
themajorsymptomanddepressionormoodsymptomsaremild,westartwithHT(see'Startingestrogen'above).
Forwomeninwhomdepressionandvasomotorsymptomsarebothsevere,westartbothestrogenandanSSRI
andrefertoapsychopharmacologistforfurtherconsultationandmonitoring.
PrimaryovarianinsufficiencyDatafromtheWomensHealthInitiative(WHI),asetofHTtrialsinolder
postmenopausalwomen,shouldnotbeextrapolatedtowomenwithprematureovarianfailure(nowtermedprimary
ovarianinsufficiency,definedasmenopausebeforeage40years).HTisstartedatayoungerageinthesewomen,
andcurrentguidelinessuggestthattherapyshouldbecontinueduntiltheaverageageofmenopause(age50to51
years)topreventprematureboneloss,coronaryheartdisease(CHD),andstroke.Atthatpoint,ifHTisstopped
andmenopausalsymptomsaremoderatetosevere,thesamediscussionofpotentialrisksandbenefitsofMHT
shouldtakeplace.
BreastcancerpatientsAlthoughwomenwithbreastcanceroftenexperienceearlymenopauseduetoadjuvant
chemotherapyandmayhavevasomotorsymptomsduetotamoxifentherapy,estrogentherapyshouldnotbe
prescribed.Theepidemiologicdataandclinicaltrialdatahavebeeninconsistent,buttheincreasedriskofbreast
cancerrecurrencewithestrogentherapyinonetrial(HormonalReplacementAfterBreastCancerIsItSafe?
[HABITS])isofgreatconcern.Wethereforedonotrecommendestrogenforwomenwithapersonalhistoryof
breastcancer.Wesuggestthatotherestablishedmeansofcontrollingsymptomsorpreventingosteoporosis
shouldbeutilizedbeforeconsideringestrogentherapyinthesewomen.(See"Menopausalhormonetherapyand
theriskofbreastcancer",sectionon'Personalhistoryofbreastcancer'.)
KnownthrombophiliaMHTincreasestheriskofvenousthrombosisbyapproximatelytwofold.Thisappears
tobetruefororalpreparations,butperhapsnotfortransdermalpreparations.However,availabledatacomesfrom
observationalstudies,notclinicaltrials.DatasuggestthatwomenwhohavefactorVLeidenanduseoralHThave
a15foldincreasedriskofvenousthromboembolism(VTE).Therefore,oralMHTshouldbeavoidedin
postmenopausalwomenwithprothromboticmutations.(See"Menopausalhormonetherapyandcardiovascular
risk",sectionon'Venousthromboembolism'.)
RoleofandrogentherapyTheknowndecreaseinovarianandrogenproductionratesandserumandrogen
concentrationshascausedconcernthatmenopausemightbeassociatedwithadeclineinlibido.Anage
associateddeclineinsexualdesirehasbeenobservedinbothmenandwomen.However,itisunclearwhether
thedeclineinlibidoinwomenisageormenopauserelated,sincestudiesinwomenhavenotshownasignificant
correlationbetweenlibidoandtheserumestradiolortestosteroneconcentration[38].
Clinicaltrialsofexogenoustestosteronereplacementsuggestbenefitsoftestosteronetherapyinsome
postmenopausalwomen.However,therearepotentialrisksassociatedwithandrogenreplacement.Untilthe
beneficialeffectsofandrogenreplacementarebetterestablished,itcannotberoutinelyrecommendedto
postmenopausalwomen.(See"Overviewofandrogendeficiencyandtherapyinwomen"and"Sexualdysfunction
inwomen:Management",sectionon'Androgens'.)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
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Basicstopics(see"Patientinformation:Menopause(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Menopause(BeyondtheBasics)"and"Patient
information:Menopausalhormonetherapy(BeyondtheBasics)"and"Patientinformation:Nonhormonal
treatmentsformenopausalsymptoms(BeyondtheBasics)"and"Patientinformation:Vaginaldryness
(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Thegoalofmenopausalhormonetherapy(MHT)istorelievemenopausalsymptoms,mostimportantlyhot
flashes(vasomotorsymptoms).Othersymptomsassociatedwithperimenopauseandmenopausethat
respondtoestrogentherapyincludemoodlability/depression,vaginalatrophy,andsleepdisturbances(when
relatedtohotflashes).(See'Goals'above.)
Healthysymptomaticwomenintheir50sshouldbereassuredthattheabsoluteriskofcomplicationsfor
healthy,postmenopausalwomentakinghormonetherapy(HT)forfiveyearsisverylow(figure1).(See
'Importanceofpatientage'above.)
Forperi/postmenopausalwomenintheir50s(orlate40s)withmoderatetoseverevasomotorsymptoms,we
suggestshorttermHTasthetreatmentofchoice(Grade2B).Exceptionsincludewomenwithahistoryof
breastcancer,coronaryheartdisease(CHD),apreviousvenousthromboemboliceventorstroke,activeliver
disease,orthoseathighriskforthesecomplications.(See'Candidates/indications'above.)
Wesuggesttransdermal17betaestradiolformostwomenstartingMHT(Grade2C).Alltypesandroutesof
estrogenareequallyeffectiveforhotflashes,buttransdermalpreparationsareassociatedwithalowerriskof
venousthromboembolism(VTE)andstroke.(See'Startingestrogen'above.)
Forwomenwithanintactuteruswhochooseestrogentherapy,progestintherapymustbeaddedtoprevent
endometrialhyperplasiaandcarcinoma.(See'Addingaprogestin'above.)
Wesuggestmicronizedprogesteroneasourfirstlineprogestinbecauseitiseffectiveforendometrial
hyperplasia,ismetabolicallyneutral,anddoesnotappeartoincreasetheriskofeitherbreastcanceror
CHD,althoughdataarelimited(Grade2C).
Recommendationsforwomenwhochoosenottotakesystemicestrogen,havecontraindicationsto
estrogen,orhavestoppedtheirMHTandarehavingrecurrentsymptomsarefoundelsewhere.(See
'Managingrecurrentsymptoms'aboveand"Menopausalhotflashes",sectionon'Nonhormonal
pharmacotherapy'.)
Theuseofvaginalestrogenisreviewedindetailelsewhere.(See"Clinicalmanifestationsanddiagnosisof
vaginalatrophy"and"Treatmentofvaginalatrophy",sectionon'Vaginalestrogentherapy'.)
WecurrentlysuggestnotusingHTforthepreventionofchronicdisease(osteoporosis,CHD,ordementia)
(Grade2B).However,womenwhocannottolerateotheroptionsforosteoporosismaybereasonable
candidates.(See'Candidates/indications'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
Topic7450Version16.0

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GRAPHICS
Risksandbenefitsofmenopausalhormonetherapy(MHT)

UpdatedsummaryoftheeffectsoforallyadministeredCEEaloneorcombinedwith
MPAinwomenages50to59yearsduringinterventionphaseofWHI.Onesetof
analysesexaminedtherisksandbenefitsoftheseagentsinwomenages50to59
years.Thisfigureplotsthesedata,whichareexpressedhereasexcessrisksand
benefitsper1000womenusingMHTforfiveyears.Becausewomendecidingtouse
MHTaremorelikelytocontinuethisforaperiodofyearsratherthanoneyear,this
figureisconstructedaccordingtothatassumption.WHIstudieswerenotpoweredfor
agerelatedsubsetanalyses,andnoneofthedatapresentedinthefigureare
statisticallysignificant.Nonetheless,thisfigurerepresentsthebestestimatesthatare
availableatthepresenttimeandarelikelymorereliablethansimilarestimatesbased
onobservationalstudiesasreportedpreviouslyinTheEndocrineSocietyScientific
Statement.
TheHR(95%CI)valuesforthebarsinthefigurearelistedherewithreferencetothe
alphabeticaldesignationsshownnexttothebars:(a)HR0.60(0.351.04)(b)HR
1.34(0.822.19)(c)HR0.82(0.501.34)(d)HR1.21(0.811.80)(e)HR0.99
(0.531.85)(f)HR1.51(0.812.82)(g)HR1.53(0.633.75)(h)HR2.05(0.89
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4.71)(i)HR1.66(0.763.67)(j)HR3.01(1.366.66)(k)HR0.71(0.301.67)(l)
HR0.79(0.292.18)(m)HR1.00(nsns)(n)HR1.12(0.452.75)(o)HR0.62
(0.301.29)(p)HR0.90(0.721.11)(q)HR0.82(0.681.00)(r)HR5.01(0.59
42.9)(s)HR0.17(0.021.45)(t)HR0.70(0.461.09)(u)HR0.67(0.431.04)(v)
HR0.83(0.671.04)and(w)HR0.85(0.661.09).(RJSanten,etal.Competencyin
menopausemanagement:whithergoesttheinternist?JWomen'sHealth(Larchmt)
201423:281,courtesyofMaryAnnLiebert,Inc).
CEE:conjugatedequineestrogenE:estrogenE+P:estrogenprogestinHR:hazardratio
MHT:menopausalhormonetherapyMPA:medroxyprogesteroneacetateWHI:Women's
HealthInitiative.
RepublishedwithpermissionofTheEndocrineSociety,from:StuenkelCA,DavisSR,GompelA,
etal.TreatmentofSymptomsoftheMenopause:AnEndocrineSocietyClinicalPractice
Guideline.JClinEndocrinolMetab2015.Copyright2015permissionconveyedthrough
CopyrightClearanceCenter,Inc.
Graphic87938Version5.0

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TheStagesofReproductiveAgingWorkshop+10stagingsystemfor
reproductiveaginginwomen

Arrow:elevatedFMP:finalmenstrualperiodFSH:folliclestimulatinghormoneAMH:antimllerian
hormone.
*Blooddrawoncycledays2to5.
Approximateexpectedlevelbasedonassaysusingcurrentinternationalpituitarystandard.
Reproducedwithpermissionfrom:HarlowSD,GassM,HallJE,etal.ExecutiveSummaryoftheStagesof
ReproductiveAgingWorkshop+10:AddressingtheUnfinishedAgendaofStagingReproductiveAging.JClin
EndocrinolMetab2012.Copyright2012TheEndocrineSociety.
Graphic82933Version3.0

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Someestrogenproducts
Drugand
USbrand
name

Availablestrengths

Estrogenpreparationsanddosesforthe
managementofvasomotorsymptoms

Minivelle
(twice
weekly)

0.0375,0.05,0.075,0.1mg
perday

Vivelle
Dot
(twice
weekly)

0.025,0.0375,0.05,0.075,
0.1mgperday

Climara
(weekly)

0.025,0.0375,0.05,0.06,
0.075,0.1mgperday

0.3,0.45,0.625,0.9,1.25

Menostar

0.014mgperday

mg

(weekly)

0.5,1,2mg

0.3,0.625,1.25,2.5mg

Oralestropipate

Ortho
Est

0.75,1.5,3mgestropipate
(equivalentto0.625,1.25,
2.5mgconjugatedequine
estrogen)

Oralconjugatedequineestrogen(CEE)*

Premarin

Oralconjugatedsyntheticestrogens(Aand
B)*

A:
Cenestin

0.3,0.45,0.625,0.9mg

B:
Enjuvia

0.3,0.45,0.9,1.25mg

Oralestrogenprogestincombinations

Prempro

Prefest
Activella,
Mimvey
FemHRT

0.3mgCEE/1.5mg
medroxyprogesterone,
0.45/1.5mg,0.625/2.5mg,
0.625/5mg
1mgestradiol/0.09mg
norgestimate(cyclic)
0.5mgestradiol/0.1mg
norethindroneacetate,1
mg/0.5mg
2.5mcgethinylestradiol/0.5
mgnorethindroneacetate

Jinteli
Angeliq

Estradiolpatches*

0.025,0.05,0.075,0.1mg
perday

Oralesterifiedestrogen*

Menest

Availablestrengths

Alora
(twice
weekly)

Oralestradiol*

Estrace

Drugand
USbrand
name

Estrogenprogestinpatches

Combi
Patch
(twice
weekly)

0.05mgestradiol/0.14mg
norethindrone,0.05
mg/0.25mgperday

Climara
Pro
(weekly)

0.045mgestradiol/0.015
mglevonorgestrelperday

Gel*

EstroGel
0.06

0.75mgestradiolperpump

percent
Elestrin
0.06
percent

0.52mgestradiolperpump

Divigel
0.1
percent

0.25,0.5,1mgestradiolper
pouch

5mcgethinylestradiol/1mg
norethindroneacetate

Emulsion*

0.5mgestradiol/0.25mg
drospirenone,1mg/0.5mg

Topicalspray*

Estrasorb

EvaMist

0.025mgestradiolperpouch

1.53mgestradiolperspray

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Oralconjugatedequineestrogensand
bazedoxifene

Duavee

Intravaginalrings*

Femring
0.45mgCEE/20mg
bazedoxifene

0.05mgestradiolperday
overthreemonths,0.1mg
estradiolperdayoverthree
months

Vaginalestrogenpreparationsfor
treatmentofgenitourinaryatrophy
(inadequatedosetorelievevasomotor
symptoms)
Vaginalring

Estring

7.5mcgestradiolperday,
releasedoverthreemonths

Vaginaltablet

Vagifem

10mcgestradiolpertablet

Vaginalcream

Estrace
0.01
percent

0.1mgestradiolpergram
cream

Premarin

0.625mgCEEpergram
cream

Someesterifiedestrogenmethyltestosterone(EEMT)combinationsremainavailableinUS.
TheseareconsideredunapprovedproductsbyUSFoodandDrugAdministration(FDA)andare
notrecommendedrefertosectiononandrogensinUpToDatetopicreviewoftreatmentof
menopausalsymptomswithhormonetherapy.
CEE:conjugatedequineestrogens.
*Forwomenwithanintactuterus,aprogestinmustbeaddedtoestrogentherapy.
AlsoavailableasagenericproductinUnitedStates(US)andsomeothercountries.
AlsoavailableasPremphasewhichcontainsbothcombinationtabletsandestrogenalone.
Graphic78136Version5.0

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Longactingreversiblecontraception
UStradename
(manufacturer)

Estrogen
(micrograms)

Progestin(mg)*

DepoProveraintramuscular
(Pfizer)

Medroxyprogesteroneacetate
(150mg/mL)

None

DepoSubQProvera104

Medroxyprogesteroneacetate

None

subcutaneous(Pfizer)

(104mg/0.65mL)

Liletta52mgintrauterine
device(Actavis)

Levonorgestrel(releases
0.0186mg/day,decreasingto
approximately0.0163mg/day

None

at1year,thendecreasingto
approximately0.0143mg/day
at2years,and0.0126mg/day
at3years)
Mirena52mgintrauterine
device(Bayer)

Levonorgestrel(releases
approximately0.02mg/day,
decreasingprogressivelyto
0.01mg/dayby5years)

None

Skyla13.5mgintrauterine
device(Bayer)

Levonorgestrel(releases0.014
mg/day,decreasingto
approximately0.01mg/day
after60days,thendecreasing
toapproximately0.005

None

mg/dayafter3years)
Nexplanon68mgsubdermal
implant(Organon)

Etonogestrel(releases0.06to
0.07mg/dayinweeks5to6,
decreasingtoapproximately

None

0.035to0.045mg/dayby1
year,thendecreasingto
approximately0.03to0.04
mg/daybyyear2,andthento
0.025to0.03mg/daybyend
ofyear3)
*Differentprogestinsarenotequivalentonamilligrambasis.
Ethinylestradiolandmestranolarenotequivalentonamilligrambasistheresultsofsomestudies
indicatethat30to35mcgofethinylestradiolisequivalentto50mcgofmestranol.
Decreasesto0.01mg/dayby5years.Donotleavesamesysteminplacefor>5years.
Alsocontainsradiopaque(bariumsulfate15mg).
AdaptedwithspecialpermissionfromTheMedicalLetteronDrugsandTherapeutics,September14,
2015Vol.57(1477):e133e134.www.medicalletter.org.
Additionaldatafrom:
1. USFood&DrugAdministrationOrangeBook:ApprovedDrugswithTherapeuticEquivalence
Equations.Availableat:http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm(Accessedon
September30,2015).
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2. Lexicomponline.Copyright19782016byLexicomp,Inc.Allrightsreserved.
Graphic104648Version2.0

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