DynaMed Plus - Hormonal Replacement Therapy (HRT)

20/12/2015
DynaMedPlus:Hormonalreplacementtherapy(HRT)
Hormonalreplacementtherapy(HRT)
RelatedSummaries
Hormonalreplacementtherapy(HRT)andcardiovasculardisease
Hormonalreplacementtherapy(HRT)andosteoporosis
Hormonalreplacementtherapy(HRT)andvenousthromboembolism
Hormonalreplacementtherapy(HRT)andbreastcancer
Menopause
Overview
alsocalledestrogenreplacementtherapy(ERT),sometimesHRTusedtoimplyadditionof
progestins
seeMenopauseforestrogentreatmentofmenopausalsymptoms
longtermuseofcombinedestrogen/progestin(HRT)hasmorerisksthanbenefitsinhealthy
postmenopausalwomen,including
breastcancer
venousthromboembolism
cardiovasculardisease
deathduetolungcancer
otherrisks
benefitsincludepreventionofosteoporoticfracturesandcolorectalcancer
nodifferencesinoverallmortalityorqualityoflife
longtermuseofestrogenalonehasbenefitsthatdonotoutweighrisksoverall
risksincludestrokeandpossiblydeepveinthrombosis
benefitsincludepreventionofosteoporoticfracturesandpossiblylowerriskofinvasive
breastcancer
nodifferencesinoverallmortality,cardiovasculardisease,colorectalcancerorqualityoflife
discontinuationofHRTassociatedwithrecurrenceoronsetofmenopausalsymptoms
Recommendations
UnitedStatesPreventiveServicesTaskForce(USPSTF)recommendations
routineuseofcombinedestrogenandprogestinnotrecommendedforpreventionofchronic
conditionsinpostmenopausalwomen(USPSTFGradeD)
routineuseofestrogenalonenotrecommendedforpreventionofchronicconditionsin
postmenopausalwomenwhohavehadahysterectomy(USPSTFGradeD)
ReferenceUSPSTFrecommendationstatementonmenopausalhormonetherapyfor
primarypreventionofchronicconditions(AnnInternMed2013Jan1158(1):47,editorial
canbefoundinAnnInternMed2013Jan1158(1):69,oratUSPSTF2012Oct23fulltext)
supportingsystematicreviewforupdatedrecommendationscanbefoundinAnnInternMed
1/43
20/12/2015
2012Jul17157(2):104fulltext
CanadianTaskForceonPreventiveHealthCare(CTFPHC)recommendations
HRTforprimarypreventionofchronicdiseases
useofcombinedestrogenprogestintherapyandestrogenonlytherapynot
recommendedforprimarypreventionofchronicdiseasesinmenopausalwomen
(CTFPHCGradeD)
discussrisksandbenefitsofHRTforalleviatingmenopausalsymptomswith
individualpatients
ReferenceCMAJ2004May11170(10):1535fulltext
postmenopausalHRTforprimarypreventionofcardiovascularandcerebrovasculardisease
useofHRTnotrecommendedforprimarypreventionofmyocardialinfarctionand
cardiovasculardeathinperimenopausalwomenwithoutcoronaryarterydisease
(CTFPHCGradeD)
insufficientevidencetomakerecommendationonuseofHRTforprimaryprevention
ofstrokeanddeathfromcerebrovasculardisease
ReferenceCMAJ2004Apr27170(9):1388fulltext
EvidenceforOverallRisksvs.Benefit
Cochranereview
longtermhormonereplacementtherapyincreasesriskofcoronaryevents,venous
thromboembolism,stroke,breastcancer,anddeathduetolungcancerinpostmenopausal
women(level1[likelyreliable]evidence)
basedonCochranereview
systematicreviewof23randomizedtrialslasting1yearcomparingHRTvs.placeboin
42,830postmenopausalwomen
allresultsincludeddatafromWHIandWISDOMtrialssummarizedbelow
comparedtoplacebo,inrelativelyhealthywomencombinedcontinuousHRTassociated
withincreasedriskof
coronaryevents(myocardialinfarction[MI]orcardiacdeath)after1year(absolute
risk[AR]4per1,000,95%CI37)
venousthromboembolismafter1year(AR7per1,000,95%CI411)
strokeafter3years(AR18per1,000,95%CI1423)
breastcancerafter5.6years(AR23per1,000,95%CI1929)
gallbladderdiseaserequiringsurgeryafter5.6years(AR27per1,000,95%CI2134)
deathfromlungcancer(nonsmallorsmallcell)after5.6yearsuseplus2.4years
followup(AR9per1,000,95%CI613)
dementiaamongwomen>65yearsoldafter4years(AR18per1,000,95%CI1130)
comparedtoplacebo,inrelativelyhealthywomenestrogenonlytherapyassociatedwith
increasedriskof
venousthromboembolismafter12years(AR5per1,000,95%CI210)
strokeafter7years(AR32per1,000,95%CI2540)
gallbladderdiseaseafter7years(AR45,95%CI3657)
inwomenwithcardiovasculardisease,combinedcontinuousHRTincreasedriskofvenous
thromboembolismafter1year(AR9per1,000,95%CI329)
comparedtoplacebo,inallwomen
combinedHRTassociatedwithdecreasedriskoffracturesafter5.6years(AR86per
1,000,95%CI7984)
2/43
20/12/2015
estrogenonlytherapyassociatedwithdecreasedriskoffracturesafter7.1years(AR
102per1,000,95%CI91112)
ReferenceCochraneDatabaseSystRev2012Jul11(7):CD004143,commentaryonearlier
versioncanbefoundinEvidenceBasedMedicine2006JanFeb11(1):22,Cochranefor
ClinicianssummaryofearlierversioncanbefoundinAmFamPhysician2006Nov
174(9):1501fulltext
Women'sHealthInitiative(WHI)trial
longtermuseofHRTassociatedwithmorerisksthanbenefitsinhealthypostmenopausal
women(level2[midlevel]evidence)
basedonrandomizedtrialwithearlytermination
Women'sHealthInitiative(WHI)islargestrandomizedtrialofHRT,stoppedearlydueto
risksexceedingbenefits
16,608postmenopausalwomenaged5079yearswithintactuteruswererandomizedto
HRT(equineestrogens0.625mg/medroxyprogesteroneacetate2.5mg[Prempro])vs.
placeboorallyoncedailyformean5.2years(range3.58.5years)
fewwomenhadcardiovasculardiseaseatbaseline(1.61.9%hadhistoryofmyocardial
infarction,2.82.9%hadhistoryofangina,1.11.5%hadhistoryofCABGorpercutaneous
coronaryintervention,0.71%hadhistoryofstroke)
discontinuationofstudydrugoccurredin42%HRTand38%placebopatients,while
additionofHRTthroughpersonalclinicianwasstartedin6.2%HRTand10.7%placebo
patientsintentiontotreatanalysiswasperformed,soresultslikelyunderestimate"per
protocol"results
nodifferencesinoverallmortalityorendometrialcancer
resultsreportedasannualizedpercentages(eventratesperyearoftherapy)
numberneededtoharm(NNH)ortreatforbenefit(NNT)reportedasnumbertreated
withHRTfor1year
comparingHRTvs.placebo(foradverseoutcomesmorecommonwithHRT)
coronaryheartdiseaseevents0.37%vs.0.3%(P<0.05,NNH1,428),
differencesrelatedtononfatalmyocardialinfarctions
stroke0.29%vs.0.21%(p<0.05,NNH1,250)
invasivebreastcancer0.38%vs.0.3%(p<0.05,NNH1,250)
venousthromboembolicevent0.34%vs.0.16%(p<0.05,NNH555)
pulmonaryembolism0.16%vs.0.08%(p<0.05,NNH1,250)
absoluteexcessinrisk1.7%vs.1.51%(p<0.05,NNH526)basedonglobal
indexofdeath,coronaryheartdiseaseevent,stroke,pulmonaryembolism,
breastcancer,endometrialcancer,colorectalcancer,orhipfracture
comparingHRTvs.placebo(foradverseoutcomeslesscommonwithHRTthan
placebo)
colorectalcancer0.1%vs.0.16%(p<0.05,NNT1,667)
hipfracture0.1%vs.0.15%(p<0.05,NNT2,000)
vertebralfracture0.09%vs.0.15%(p<0.05,NNT1,429)
anyosteoporoticfracture1.47%vs.1.91%(p<0.05,NNT228)
ReferenceJAMA2002Jul17288(3):321
editorialcanbefoundinJAMA2002Jul17288(3):366,commentarycanbefoundinBMJ
2008May10336(7652):1033(commentarycanbefoundinBMJ2008May
24336(7654):1148)
considerablecommentarycanbefoundinJAMA2002Dec11288(22):2819,CMAJ2002
Aug20167(4):377fulltext,ACPJClub2002SepOct137(2):41,JFamPract2002
3/43
20/12/2015
Oct51(10):821,EvidBasedNurs2003Jan6(1):20,CanFamPhysician2003Feb49:157,
CurrRheumatolRep2003Feb5(1):43,JAMA2003Dec24290(24):3193,JAMA2003Jun
25289(24):3241,JAMA2004Aug11292(6):683,JAMA2005Mar16293(11):1322,
JAMA2006Jul19296(3):280,SAfrMedJ2003Aug93(8):554,EvidBasedMed2008
Oct13(5):142
editorialcommentarycanbefoundinBMJ2002Jul20325(7356):113fulltext(correction
canbefoundinBMJ2002Aug24325(7361):435),BMJ2002Nov2325(7371):1036full
text,BMJ2002Nov23325(7374):1243fulltext
HRTdidnothaveclinicallymeaningfuleffectonhealthrelatedqualityoflifeinWHI
trial(NEnglJMed2003May8348(19):1839),editorialcanbefoundinNEnglJMed
2003May8348(19):1835,commentarycanbefoundinACPJClub2003Nov
Dec139(3):60,AmFamPhysician2004Jan1569(2):423,NEnglJMed2004Feb
5350(6):622
HRTassociatedwithmodestreductioninfrequencyofjointpainbutincreased
swellingat1year(level2[midlevel]evidence)
basedonposthocanalysisofWHItrial
ReferenceMenopause2013Jun20(6):600
HRTmayincreaseriskofovariancancer(level2[midlevel]evidence)
basedonfollowupstudyofWHI
meanfollowup5.6years
annualizedriskofinvasiveovariancancerwas0.04%withHRTvs.0.03%with
placebo(notsignificant)
HRTdidnotincreaseriskofendometrialcancer(0.06%vs.0.07%annualizedrisk)
but,duetovaginalbleeding,morewomenrequiredendometrialbiopsies(33%vs.6%,
P<0.05,NNH3.7)
ReferenceJAMA2003Oct1290(13):1739,commentarycanbefoundinJAMA
2004Jan7291(1):42
3yearsafterhaltofWHItrial,HRTassociatedwithhigherratesofcancerbutnot
cardiovasculardisease(level2[midlevel]evidence)
basedonpostinterventionphaseofrandomizedtrial
15,730womenfromWHItrialwerefollowedformean2.4yearsafterhaltoftrial
8,052womenfromHRTgroup
7,678womenfromplacebogroup
comparingHRTvs.placeboduringpostinterventionphase
allcausemortality2.9%vs.2.6%(notsignificant)
malignancies(includinginvasivebreastcancer,endometrialorcolorectal
cancer)in3.5%vs.2.8%(p<0.05,NNH142)
invasivebreastcancerin0.09%vs.0.08%(notsignificant)
totalcardiovasculardiseaseeventsin4.3%vs.4.2%(notsignificant)
anyfracturein4.2%vs.4.5%(notsignificant)
ReferenceJAMA2008Mar5299(9):1036,commentarycanbefoundinJAMA
2008Jun18299(23):2744,ACPJClub2008Aug19149(2):11
HRTmaynotbeassociatedwithincreasedriskforlungcancerbutmayincreaserisk
ofmortalityfromlungcancer(level2[midlevel]evidence)
basedonpostinterventionphaseofWHIrandomizedtrial
16,608womenfromWHItrialwerefollowedformean2.4yearsafterhaltoftrial
comparingHRTvs.placeboduringpostinterventionphase
lungcancerin0.16%vs.0.13%peryear(notsignificant)
nonsmallcelllungcancerin0.14%vs.0.11%peryear(notsignificant)
smallcelllungcancerin0.02%vs.0.02%peryear(notsignificant)
4/43
20/12/2015
deathfromlungcancerin0.11%vs.0.06%peryear(p=0.01)
deathfromnonsmallcelllungcancerin0.09%vs.0.05%peryear(p=0.004,
deathfromsmallcelllungcancerin0.02%vs.0.01%peryear(notsignificant)
poorlydifferentiatednonsmallcellcancerin0.04%vs.0.02%(p=0.03)
nonsmallcelllungcancerdistantmetastasesin0.06%vs.0.03%(p=0.04)
nosignificantdifferencesinlocalorregionalnonsmallcelllungcancerorinany
othercancergradeofnonsmallcelllungcancer
ReferenceLancet2009Oct10374(9697):1243fulltext,editorialcanbefoundin
Lancet2009Oct10374(9697):1217,commentarycanbefoundinLancet2010Jan
9375(9709):117
vasomotorsymptomsmayworsenafterstoppingestrogentherapy
basedonpostinterventionphaseofWHIrandomizedtrial
3,496womenfromWHItrialcontinuedassignedinterventiontotrialclosureand
completedsymptomsurveys7yearsafterstudyinitiationandafterstopping
intervention(306daysaftertrialclosure)
afterstoppinginterventionvasomotorsymptomsreportedby9.8%estrogengroupvs.
3.2%placebogroup(p<0.05)
amongwomenwithnomoderateorseveresymptomsatbaseline,hotflashesreported
afterstoppinginterventionin7.2%estrogengroupvs.1.5%placebogroup
ReferenceMenopause2010SepOct17(5):946fulltext
HRTassociatedwithincreasedriskofbreastcancerat11years
basedonadditionalfollowupofWHItrial
12,788womenwithnopriorhysterectomyfollowedformean11years
comparingHRTvs.placebo
invasivebreastcancerincidence0.42%peryearvs.0.34%peryear(hazardratio
[HR]1.25,95%CI1.071.46)
breastcancermortality0.03%peryearvs.0.01%peryear(HR1.9,95%CI1
4.04)
allcausemortalityafterbreastcancerdiagnosis0.05%peryearvs.0.03%per
year(HR1.57,95%CI1.012.48)
HRTassociatedwithincreasedriskofnodepositivebreastcancer(HR1.78,95%CI
1.232.58)
ReferenceJAMA2010Oct20304(15):1684,editorialcanbefoundinJAMA2010
Oct20304(15):1719
estrogenalonedoesnothavebenefitsthatoutweighrisksoverallinpostmenopausalwomen
withpriorhysterectomy(level2[midlevel]evidence)
basedonrandomizedtrialwithearlytermination
10,739postmenopausalwomenaged5079yearswithpriorhysterectomyinWomen's
HealthInitiative(WHI)trialrandomizedtoconjugatedequineestrogen0.625mg(Premarin)
vs.placeboorallydailyformeanofalmost7years
trialstoppedearlybyNIHsincetherewasnobenefitinprimaryoutcomeofreducing
cardiovasculardisease
comparingestrogenvs.placebogroups
coronaryheartdiseasedeathormyocardialinfarctionin3.33%vs.3.67%(not
significant)
strokein2.98%vs.2.17%(p<0.05,NNH123)
venousthromboembolismin1.9%vs.1.44%(notsignificant)
invasivebreastcancerin1.77%vs.2.28%(hazardratio1.2695%CI11.59)
colorectalcancer1.15%vs.1.07%(notsignificant)
hipfracture0.72%vs.1.18%(p<0.05,NNT217)
5/43
20/12/2015
anyfracture7%vs.7.52%(p<0.05,NNT192)
overallmortality5.48%vs.5.32%(notsignificant)
ReferenceJAMA2004Apr14291(14):1701,editorialcanbefoundinJAMA2004Apr
14291(14):1769,NephrolNewsIssues2004Aug18(9):54,61,commentarycanbefoundin
JAMA2004Aug11292(6):683,summarycanbefoundinAmFamPhysician2005Jan
1571(2):371
nosignificantdifferencesinmostoutcomesafter10years
basedon10.7yearfollowupof7,645womenfromWomen'sHealthInitiative
EstrogenAloneTrial
postinterventionannualizedriskforoutcomecomparingestrogenvs.placebo
coronaryheartdisease0.64%vs.0.67%(notsignificant)
stroke0.36%vs.0.41%(notsignificant)
deepveinthrombosis0.17%vs.0.27%(hazardratio0.63,95%CI0.410.98)
invasivebreastcancer0.26%vs.0.34%(notsignificant)
hipfracture0.36%vs.0.28%(notsignificant)
nosignificantdifferencesinmortality,coronaryheartdiseasemortality,myocardial
infarction,pulmonaryembolismorcolorectalcancer
ReferenceJAMA2011Apr6305(13):1305fulltext,editorialcanbefoundin
JAMA2011Apr6305(13):1354(correctioncanbefoundinJAMA2011Jun
15305(22):2418)
estrogenalonedidnothaveclinicallymeaningfuleffectonhealthrelatedqualityoflifein
WHItrial(ArchInternMed2005Sep26165(17):1976),commentarycanbefoundinBMJ
2005Oct22331(7522),commentarycanbefoundinAmFamPhysician2006Apr
1573(8):1453,commentarycanbefoundinEvidenceBasedMedicine2006May
Jun11(3):76
estrogenwithorwithoutprogesteronemaynothaveoverallbenefitsat13years(level2
[midlevel]evidence)
basedonfollowupofWHItrialsabove
27,347postmenopausalwomenaged5079yearswereevaluated
75%participatedinextensionphasesoftrials
medianoverallfollowup13years
coronaryheartdiseasein0.55%vs.0.53%(notsignificant)
invasivebreastcancerin0.43%vs.0.33%(p=0.007,NNH1,000)
endometrialcancerin0.08%vs.0.13%(p=0.007,NNT2,000)
nosignificantdifferencesinstroke,pulmonaryembolism,colorectalcancer,hipfracture,or
allcausedeath
comparingestrogenalonevs.placebo
coronaryheartdiseasein0.68%vs.0.72%(notsignificant)
invasivebreastcancerin0.27%vs.0.34%(notsignificant)
nosignificantdifferencesinstroke,pulmonaryembolism,colorectalcancer,endometrial
cancer,hipfracture,orallcausedeath
ReferenceJAMA2013Oct2310(13):1353,editorialcanbefoundinJAMA2013Oct
2310(13):1349
WISDOMtrial
HRTincreasesriskofcardiovasculardiseaseandvenousthromboembolisminolder
postmenopausalwomen(level1[likelyreliable]evidence)
6/43
20/12/2015
basedonrandomizedtrial
5,692postmenopausalwomenaged5069years(meanage63years)whohad80%
complianceduring12weekruninperiodwererandomizedtohormonereplacementtherapy
vs.placebo
womenwithuteruswererandomizedtocombinationHRT(Prempro)vs.placebodaily
womenwithoututerusandunwillingtotakeplacebowererandomizedtoPremprovs.
estrogenalone(Premarin)0.625mgorallydaily
womenwithoututerusandwillingtotakeplacebowererandomizedtoPremprovs.
Premarinvs.placebodaily
medroxyprogesteroneacetate5mg(Premique)orallydailygiventowomenwithuterusand
within3yearsoflastperiod,womenaged5053years,andolderwomenwithunacceptable
breakthroughbleeding
medianfollowup11.9monthsduetoearlyclosureoftrial
majorcardiovasculardiseasedefinedasunstableanginarequiringhospitalization,
myocardialinfarction(fatalornonfatal),orsuddencoronarydeath
comparingcombinationtherapyvs.placeboinanalysisof4,385women
majorcardiovasculardiseasein0.32%vs.0(p<0.05,NNH312)
rateofmajorcardiovasculardisease26.9vs.0per10,000personyears(p=0.016,
NNH371personyears)
venousthromboembolismin1%vs.0.14%(NNH116)
rateofvenousthromboembolism85.1vs.11.5per10,000personyears(p<0.001,
NNH136personyears)
osteoporoticfractures1.8%vs.2.6%(p<0.05,NNT125)
rateofosteoporoticfractures155.3vs.226.2per10,000personyears(p=0.07)
nosignificantdifferencesinratesofcerebrovasculardisease,cancer,ordeath
comparingcombinationHRTvs.estrogenalonein1,641women
nosignificantdifferencesinmajorcardiovasculardisease,venousthromboembolism,
cancer,osteoporoticfractureordeath
somecombinationHRTwomencountedinthisanalysisandinanalysiscomparedto
placebo
of11womenwhohadmajorcardiovascularevents,9were>64yearsoldandhadother
cardiovascularriskfactors
ReferenceWISDOMtrial(BMJ2007Aug4335(7613):239fulltext),editorialcanbe
foundinBMJ2007Aug4335(7613):219fulltext,commentarycanbefoundinEvidBased
Med2008Apr13(2):52
HeartandEstrogen/ProgestinReplacementStudy(HERS)trial
HRTdoesnotreduceoverallrateofcoronaryeventsinpostmenopausalwomenwith
establishedcoronarydisease(level1[likelyreliable]evidence)
basedonrandomizedtrial(HeartandEstrogen/progestinReplacementStudy[HERS])
2,763postmenopausalwomen<80(meanage66.7)withcoronarydisease(stableforatleast
6months)andintactuterusrandomizedtoconjugatedequineestrogens0.625mgplus
medroxyprogesteroneacetate2.5mgin1tablet(Prempro)vs.placeboorallyoncedaily
multipleexclusioncriteriaincludingpoorcomplianceinplaceboruninperiod
82%thoseassignedtohormonetreatmentweretakingitat1year,75%at3years
nosignificantdifferencescomparingPremprovs.placeboin
primaryoutcomeofnonfatalmyocardialinfarctionorcoronaryheartdiseasemortality
(12.5%vs.12.7%),coronarymortality(5.1%vs.4.2%)
7/43
20/12/2015
nonfatalmyocardialinfarction(8.4%vs.9.3%)
coronaryrevascularization
unstableangina
heartfailure
resuscitatedcardiacarrest
strokeortransientischemicattack
peripheralarterialdisease
allcausemortality
nooveralleffectdespite11%lowerLDLcholesteroland10%higherHDLcholesterollevels
inhormonegroup
statisticallysignificanttimetrend,withmorecoronaryeventsinhormonegroupinyear1
andfewerinyears4and5
increasedriskscomparingPremprovs.placebo
venousthromboembolicevents(2.5%vs.0.9%,NNH[numberneededtoharm]60)
gallbladderdisease(6.1%vs.4.5%,NNH62.5,borderlinestatisticalsignificance)
noincreasedriskoffracture,cancerortotalmortality
interpretation
basedonpatternofearlyincreaseinriskofcoronaryevents,startingHRTnot
recommendforsecondaryprevention
givenfavorablepatternofcoronaryeventsafterseveralyearsoftherapy,itcouldbe
appropriateforwomenalreadyreceivingHRTtocontinue
ReferenceJAMA1998Aug19280(7):605,editorialcanbefoundinJAMA1998Aug
19280(7):650,commentarycanbefoundinACPJClub1999JanFeb130(1):8,JAMA
1999Mar3281(9):794,JAmGeriatrSoc2000Dec48(12):1717,JAMA2001Nov
28286(20):2544,JAMA2003Jun25289(24):3241
HRTonlyimprovesqualityoflifeinwomenwithpostmenopausalsymptoms,
otherwiseworsensqualityoflife(level1[likelyreliable]evidence)
basedonHERStrial
amongwomenwithflushingatbaseline,hormonesassociatedwithimprovedmental
healthandfewerdepressivesymptomscomparedtoplacebo
amongwomenwithoutflushingatbaseline,hormonesassociatedwithdeclinesin
physicalfunctionandenergy/fatiguecomparedtoplacebo
ageandclinicalillnesshadgreateraffectonqualityoflifemeasuresthanhormoneuse
ReferenceJAMA2002Feb6287(5):591,editorialcanbefoundinJAMA2002Feb
6287(5):641,commentarycanbefoundinJAMA2002May1287(17):2210,Evid
BasedNurs2002Jul5(3):83fulltext,ACPJClub2002NovDec137(3):105,Evid
BasedMentHealth2002Nov5(4):112fulltext
BenefitsofHRT
Overviewofbenefits
estrogenproventoalleviatemenopausalsymptoms,seeMenopause
HRTmaypreventbonelossandosteoporoticfractures
HRTmayreducecolorectalcancerrisk
otherpotentialbenefits
possiblereductionintotalmortalityinwomen<60yearsold
mayreduceriskofdiabetes
mayreduceriskofosteoarthritis
8/43
20/12/2015
mayreduceriskofcataracts
HRTmaypreventbonelossandosteoporoticfractures
hormonereplacementtherapy(HRT)preventsboneloss(increasesbonemineraldensity)(level3
[lackingdirect]evidence)andfracturesinrandomizedtrials,butrisksoflongtermusemay
outweighbenefits
largestrandomizedtrialofestrogen/progestincombinationtherapy(Women'sHealthInitiative
[WHI]with16,608patients)showedreductioninhipfractures(NNT2,000peryear),vertebral
fractures(NNT1,429peryear)andosteoporoticfractures(NNT228peryear)
estrogenalonemayreducefractureratesbutincreasesriskforstrokeandpossiblyvenous
thromboembolism(level2[midlevel]evidence)
systematicreviewsofrandomizedtrialsbeforeWHItrialfoundHRTassociatedwithreducedrisk
for
nonvertebralfractures,butonlysignificantforwomen<60yearsold
vertebralfractures
observationalstudiesfindassociationbetweenlongtermHRTuseandreducedfractures
fractureriskreductionmayrequireuseofHRTforatleast5years
fractureriskreductionappearstodiminishrapidlyaftercessationofHRT
alendronate(Fosamax)10mgorallyoncedailypreventsbonedensitylossafterdiscontinuationof
HRT
seeHormonalreplacementtherapy(HRT)andosteoporosisfordetails
HRTmayreduceriskofcolorectalcancer
estrogenplusprogestintherapyassociatedwithreducedriskofcolorectalcancerbutnot
colorectalcancermortality(level2[midlevel]evidence)
basedonfollowupstudyofWomen'sHealthInitiativetrial
16,608postmenopausalwomenwererandomizedtoconjugatedequineestrogens0.625mg
plusmedroxyprogesteroneacetate2.5mg(hormonereplacementtherapy[HRT])vs.placebo
perday
meantreatmentdurationwas5.6yearsandmeanfollowupwas11.6years
frequencyofbowelscreeningexamsduringtrialandfollowupweresimilarforeachgroup
263colorectalcancersdiagnosed
invasivecolorectalcancerincidence0.12%peryearvs.0.16%peryear(p=0.014,
NNT2,500peryear)
colorectalcancermortality0.04%peryearvs.0.03%peryear(notsignificant)
lymphnodepositivecancerin50.5%vs.28.6%(p<0.001)insubgroupofwomen
whodevelopedcancer
comparingstageofcanceratdiagnosisforHRTvs.placeboinsubgroupofwomenwho
developedcancer
distantorregionalstagein68.8%vs.51.4%
localstagein31.2%vs.48.6%
HRTassociatedwithtrendtowarddiagnosisofcolorectalcanceratmoreadvanced
stage(pfortrend=0.003)
ReferenceJClinOncol2012Nov1030(32):3983fulltext,reportofeffectofHRTon
colorectalcancerat5.2yearsfollowupcanbefoundinNEnglJMed2004Mar
4350(10):991fulltext
9/43
20/12/2015
HRTmaynotalterriskofsmalladenomas
basedoncohortstudy
59,002postmenopausalwomenfromNurses'HealthStudywerefollowedupto14years
currenthormoneuserslesslikelythannonuserstodevelopcolorectalcancerandadenomas>
1cm
pastuseanddurationofhormonereplacementnotsignificantlyrelatedtocolorectalcancer
risk
ReferenceAnnInternMed1998May1128(9):705PDF
useofestrogenreplacementtherapy(ERT)orHRTassociatedwithdecreasedriskofcolon
cancerinobservationalstudies(level2[midlevel]evidence)
basedon1metaanalysis,1cohortstudy,and1casecontrolstudy
metaanalysisof18epidemiologicstudies
20%reductioninriskofcoloncancerand19%reductioninriskofrectalcancerfor
postmenopausalwomenwhohadevertakenhormonetherapycomparedwithwomen
whohadnevertakenhormones,mostofapparentreductionincolorectalcancer
limitedtocurrenthormoneusers
ReferenceAmJMed1999May106(5):574,commentarycanbefoundinJAm
GeriatrSoc2002Apr50(4):768
DynaMedcommentaryobservationalstudiesunabletocontrolforbiasof
unrecognizedhealthierlifestyles
cohortstudyof7,701womenaged4498yearsfollowed14years
ageadjustedcolorectalcancerincidencerateper1,000personyears
2.67forwomenwhohadeverusedestrogen
3.30forlifetimenonusers
RR0.81,95%CI0.631.04
recentusershadonethirdtheincidenceoflifetimenonusers(RR=0.66,95%CI0.44
0.98)
nosignificantdifferencesincolorectalcancermortality
ReferenceDisColonRectum1999Oct42(10):1300
DynaMedcommentaryassumingcurrentusershaveincidenceof1.1per1,000
personyearsandestrogenistrulyprotective,455womenneedtotakepostmenopausal
estrogencontinuouslytoprevent1caseofcolorectalcancer
riskreductionwithtransdermalestrogenmaybegreaterthanwithoralestrogen,basedon
casecontrolstudy(BrJCancer2004Jan2690(1):76fulltext)
Mortalityreductioninyoungerwomen
HRTmightreducetotalmortalityinpostmenopausalwomen<60yearsold(level2[mid
level]evidence)
basedonsubgroupanalysisofWHItrialswithinadequatestatisticalpowerinindividual
trials
secondaryanalysisof2largeWHItrials
16,608postmenopausalwomenwithouthysterectomyrandomizedtoconjugated
equineestrogensplusmedroxyprogesteroneacetate(combinedHRT)vs.placebo,
including5,522womenaged5059years
10,739postmenopausalwomenwithhysterectomyrandomizedtoconjugatedequine
estrogens(estrogenalone)vs.placebo,including3,310womenaged5059years
totalmortalitycomparingHRTvs.placeboinsubgroupsofwomenaged5059years
incombinedHRTtrial1.23%vs.1.75%(hazardratio0.69,95%CI0.441.07)
inestrogenalonetrial2.08%vs.2.87%(hazardratio0.71,95%CI0.461.11)
10/43
20/12/2015
incombinedsubgroupanalysis1.54%vs.2.18%(hazardratio0.7,95%CI0.510.96,
NNT157,95%CI941,147)
ReferenceJAMA2007Apr4297(13):1465,correctioncanbefoundinJAMA2008Mar
26299(12):1426,commentarycanbefoundinJAMA2007Aug8298(6):623,ACPJClub
2007SepOct147(2):29
HRTmightreducetotalmortalityinpostmenopausalwomen<60yearsold(level2[mid
level]evidence)
basedonmetaanalysiswithmethodologiclimitations
systematicreviewof19randomizedtrialsofhormonereplacementtherapyvs.placeboorno
treatmentwithmeanage<60years,treatmentduration6monthsandreportofatleast1
death
DynaMedcommentarytrialselectioncriteriamaybiasresultsbyexcludingdatafrom
sometrialswithyoungerwomenandincludingdatafromolderwomen,andbyexcluding
trialswithnodeaths
trialsinanalysisincludedsubgroupanalysesfromWHItrials(butnotsubgroupanalyses
fromanyothertrials)
DynaMedcommentaryspecificmetaanalysisresultsnotreportedherebecause
dataanalyzedcountedWHIestrogenalonesubgrouptwicebecauseoferroneously
usingcombinedsubgroupdatainplaceoftheotherWHItrial
statisticalmethoddidnotclearlyanalyzedataintraditionalmetaanalysis
ReferenceAmJMed2009Nov122(11):1016
thesesameauthorspreviouslyreportedmetaanalysessupportingHRTforwomen<60
yearsoldbutthesemetaanalyseswereflawedbynotincludingWHIsubgroupdataandby
weighingmetaanalysiscontributionbydeaths(numeratordata)insteadofsamplesize
(denominatordata)
systematicreviewandmetaanalysisof30randomizedtrialswith26,708women
HRTnotassociatedwithsignificanteffectonoverallmortality
ReferenceJGenInternMed2004Jul19(7):791fulltext,editorialcanbe
foundinJGenInternMed2004Jul19(7):810fulltext,commentarycanbe
foundinBMJ2005Jan1330(7481),ACPJClub2005JanFeb142(1):1,JGen
InternMed2005Feb20(2):212fulltext
DynaMedcommentaryconclusionoflowermortalityinwomenaged<60
yearsinthisreviewnotconsideredvalidbecause
analysiswasbasedon4,141womenintrialswithmeanage<60years
analysisdidnotinclude5,522womenaged5059yearsinWHItrial
(whichhadmeanage63years)
analysiswithWHItrialwouldfindnodifferenceinmortality
DynaMedcommentaryentiremetaanalysisfundamentallyflawedby
weightingstudiesbasedonnumberofdeathsinsteadofsamplesize
forexampleconsiderthemetaanalysisoftrialswithmeanage<60years
whichincluded17trialsand4,141women
1trialwithhighmortalityin130ovariancancerpatientsprovided3%of
theoverallsamplesizebutwascalculatedasproviding41%oftheweight
inthismetaanalysis
similarconclusionsforoutcomeofcoronaryheartdiseaseevents(reducedriskin
women<60yearsold)reportedinmetaanalysisof23trialswith39,049women
conductedbysameauthors(JGenInternMed2006Apr21(4):363fulltext)but
similarmethodologicflawslimitvalidityofconclusion(DynaMedcommentary)
HRTmayreduceriskofdiabetes
11/43
20/12/2015
HRTmayreduceriskofdiabetesinwomenwithcoronarydisease(level2[midlevel]
evidence)
basedonposthocanalysisofHERStrial
2,763postmenopausalwomenwithcoronaryheartdiseasewererandomizedtoHRTvs.
placebofor4years
2,029didnothavediabetesmellitusatbaseline
incidencediabeteswasdefinedasselfreportofdiabetesordiseasecomplication,fasting
glucoselevel6.9mmol/Lorgreater(>125mg/dL),orinitiationoftherapywithdiabetes
medication
diabetesdevelopedin6.2%withHRTvs.9.5%withplacebo(p<0.05,NNT30)
ReferenceAnnInternMed2003Jan7138(1):1fulltext),editorialcanbefoundinAnn
InternMed2003Jan7138(1):69,commentarycanbefoundinACPJClub2003Sep
Oct139(2):39,AnnInternMed2003Dec16139(12):1043PDF,AnnInternMed2003Jan
7138(1):69PDF
DynaMedcommentarypreventionofdiabetesasdefinedmaynotbeclinicallyrelevant,as
therewasnotanoverallreductioninheartdiseaseamongpatientswithdiabetes,glycemic
controlisnotasimportantasotherfactorsinpreventingheartdisease
HRTmayreduceriskofosteoarthritis
hormonereplacementtherapymaynotaffectriskofhiporkneereplacement,but
unopposedestrogenmightbeassociatedwithfewerhipreplacements(level2[midlevel]
evidence)
basedonrandomizedtrialwithborderlinesignificance
26,321communitydwellingwomenaged5079yearsinWHIwererandomizedto
conjugatedequineestrogen0.625mg(plusmedroxyprogesterone2.5mgifintactuterus)vs.
placebooncedaily
10,720withhysterectomieswererandomizedtoestrogenvs.placeboformean7.1
years
16,049withouthysterectomieswererandomizedtoestrogen/progestinvs.placebofor
mean5.6years
comparingestrogenalonevs.placebo
anyarthroplastyin4.4%vs.5.2%(p=0.05,NNT125),or62vs.74casesper10,000
personyears
totalkneereplacementin3.3%vs.3.8%(notsignificant)
totalhipreplacementin1.1%vs.1.6%(p=0.07)
comparingestrogenplusprogestinvs.placebo
2.7%vs.2.6%hadanyarthroplasty,or48vs.48casesper10,000personyears(not
significant)
1.7%vs.1.8%hadtotalkneereplacement,or30vs.32casesper10,000personyears
(notsignificant)
1.1%vs.0.9%hadtotalhipreplacement,or19vs.16casesper10,000personyears
(notsignificant)
ReferenceArthritisRheum2006Oct54(10):3194fulltext
observationalstudiessuggestdecreasedriskofradiographicosteoarthritiswithhormone
replacement
postmenopausalestrogenreplacementtherapyassociatedwithreducedrateof
radiographicosteoarthritisofhip(level3[lackingdirect]evidence)incrosssectional
studyof4,366whitewomen>64yearsold(ArchInternMed1996Oct14156(18):2073)
continuousHRT>1yearassociatedwithdecreasedriskofradiographicosteoarthritis
12/43
20/12/2015
ofknee(level3[lackingdirect]evidence)instudyof606postmenopausalwomen(Ann
RheumDis1997Jul56(7):432PDF)
AdditionalpotentialbenefitsofHRT
estrogenaloneorinadditiontoprogestogenmayreducesexualdysfunctionin
perimenopausalandpostmenopausalwomen(level2[midlevel]evidence)
basedonCochranereviewoftrialswithmethodologiclimitations
systematicreviewof27randomizedtrialscomparinghormonetherapyvs.placeboorno
interventionin16,393womenwithmenopausalsymptomswhohadtheirmenstrualperiod
withinthepast12months(symptomaticperimenopausal)orpostmenopausalwomen
alltrialshad1limitationincluding
unclearallocationconcealment
highdropoutrateorhighlosstofollowup
primaryoutcomewascompositeofarousalandsexualinterest,orgasm,and/orpain
improvedcompositescoreinsymptomaticperimenopausalorearlypostmenopausalwomen
with
estrogen(standardizedmeandifference[SMD]0.38,95%CI0.230.54)inanalysisof
3trialswith699women
estrogenplusprogestogen(SMD0.42,95%CI0.190.64)in1trialwith335women
nonsignificantimprovementincompositescorewithtibolone,bazedoxifene(selective
estrogenreceptormodulator),andbazedoxifeneplusestrogeninsingletrials
ReferenceCochraneDatabaseSystRev2013Jun5(6):CD009672
combinationHRTassociatedwithimprovementsinmostpostmenopausalsymptomsand
somequalityoflifemeasures(level2[midlevel]evidence)
basedonrandomizedtrialwithlowfollowuprate
3,721postmenopausalwomenaged5069yearswithauterusrandomizedtocombinedHRT
(conjugatedequineestrogen0.625mgplusmedroxyprogesteroneacetate2.5/5mg)vs.
placebofor1year
qualityoflifedataavailablefor57.2%
significantimprovementswithcombinedHRTvs.placebo(allp0.001)
vasomotorsymptoms
sexualfunctioning
sleepproblems
hotflushes
nightsweats
achingjointsandmuscles
insomnia
vaginaldryness
combinedHRTalsosignificantlyassociatedwithincreasedbreasttendernessandvaginal
discharge
nosignificantdifferencesinothermenopausalsymptoms,depression,oroverallqualityof
life
ReferenceBMJ2008Aug21337:a1190fulltext
limitedevidenceregardingeffectofhormonetherapyonskinappearance
lowdoseHRTfor48weeksmaynotaffectagerelatedfacialskinchanges(level2[mid
level]evidence)
basedonrandomizedtrialwithuncertainallocationconcealment
485postmenopausalwomenrandomizedtoplacebovs.norethindroneacetate1
13/43
20/12/2015
mg/ethinylestradiol5mcgvs.norethindroneacetate1mg/ethinylestradiol10mcgfor
48weeks
nosignificantdifferencesincoarseandfinefacialwrinkling,skinlaxity/sagging,skin
texture/dryness,orwrinkledepthat24and48weeks
ReferenceJAmAcadDermatol2008Sep59(3):397
estrogenreplacementtherapymightdecreaseprobabilityofdryskinandskin
wrinklinginpostmenopausalwomen(level2[midlevel]evidence)
retrospectivereviewof3,875postmenopausalwomen>39yearsoldfollowedatleast
10years
prevalenceofskinwrinkling,drynessandatrophylowerinAfricanAmericanwomen
postmenopausalestrogentherapyshowedimprovementsevenaftercorrectionforage,
bodymassindexandsunlightexposureinwhitewomenbutnotinAfricanAmerican
women
ReferenceArchDermatol1997Mar133(3):339inQuickScanReviewsinFamPract
1997Sep22(6):29,commentarycanbefoundinArchDermatol1997
Nov133(11):1460
postmenopausalestrogentherapymaybeassociatedwithreducedriskforcataracts
postmenopausalestrogentherapyassociatedwithreducedriskforlensopacitiesinstudyof
529women6693yearsold(ArchInternMed2001Jun11161(11):1448)
postmenopausalestrogenmaybeprotectiveofocularcrystallinelens(Ophthalmology1997
Jun104(6):970
RisksofHRT(includingContraindicationsandSideEffects)
Overviewofrisks
increasedriskofendometrialcancer(ifestrogensusedwithoutprogestins)
increasedriskofbreastcancerseeHormonalreplacementtherapy(HRT)andbreastcancer
possibleincreasedriskforcardiovasculardisease
increasedriskofvenousthromboembolism
increasedriskofgallstonesandgallbladderdisease
possibleincreasedriskinovariancancer
possibleworseningofurinaryincontinence
Contraindications
precautions(notclearlycontraindications)
personalhistoryorknownhighriskofthromboembolicdisease
breastcancer
uncontrolledhypertension
unexplainedabnormalvaginalbleeding
abnormalliverfunction
historyofendometrialorovariancancer
highriskgallbladderdisease
ReferenceBMJ2012Feb16344:e763
Sideeffects
vaginalbleeding,breasttenderness,breastswelling,mastodynia(BMJ2012Feb16344:e763)
14/43
20/12/2015
weightgainmaybetransient,butnosustainedadverseeffectonweight
evidenceshowsnoeffectofestrogenorestrogen/progestinonweightgain,weightgainafter
menopausesimilarwithorwithouthormonereplacementtherapy22trialsreviewed,24
trialsawaitingassessmentsystematicreviewlastupdated1999May13(CochraneDatabase
SystRev2000(2):CD001018)
hormonereplacementtherapyover15yearperiodnotassociatedwithexcessweightgainor
centralobesity(JAMA1996Jan3275:46inQuickScanReviewsinFamPract1996
Jul21(4):18)
olderwomenstartingHRTcommonlydiscontinueHRTduetoadverseeffects
485women>65yearsoldentered3monthopenlabeltrialofHRTduringruninphase
priortorandomizedtrialcomparingHRTtoalendronateforosteoporosisprevention
112(23%)discontinuedHRTwithin3months
73(15%)discontinuedforreasonsconsideredHRTrelatedincludingbreastswellingor
tenderness,bloating,bleedingorspotting
ReferenceJWomensHealthGendBasedMed2001May10(4):343inJAMA2001Aug
22/29286(8):902
estrogenbutnotestrogen/progesteroneusemaybeassociatedwithRaynaud'sphenomenon
497postmenopausalwomeninterviewed,76%notusinghormones,13%usedestrogen
alone,10%usedestrogenandprogesterone
8.4%womenusinghormonereplacementtherapyreportedunusualcoldsensitivityandcolor
changeoffingers,significantlymorecommonamongwomenusingestrogenalone
ReferenceAnnInternMed1998Aug1129(3):208fulltext
HRTandbreastcancer
combinedestrogenandprogestin(hormonereplacementtherapy[HRT])associatedwithincreased
riskforbreastcancer,butevidenceforongoingriskafterstoppingtreatmentisconflicting
hormonereplacementtherapyassociatedwithincreasedriskforinvasivebreastcancer(level
2[midlevel]evidence)
currentuseofHRTassociatedwithincreasedriskofbreastcancerincidenceandmortality
(level2[midlevel]evidence)
conflictingevidenceforongoingriskofbreastcancerafterstoppingHRT
longtermuseofestrogenalonemayincreaseriskforbreastcancer
estrogenalonedoesnotappeartoincreaseriskforinvasivebreastcancerbutmayincrease
riskforabnormalitiesonfollowupmammograms(level2[midlevel]evidence)
estradiolalonefor>5yearsassociatedwithincreasedriskforbreastcancer(level2[mid
level]evidence)
useofunopposedestrogenfor>20yearsmightbeassociatedwithincreasedriskofinvasive
breastcancer(level2[midlevel]evidence)
HRTmayincreaseriskforrecurrentbreastcancerinbreastcancersurvivors,butevidenceis
conflicting
HRTappearstoincreaseriskofrecurrentbreastcancer(level2[midlevel]evidence)in2
randomizedtrials
HRTdoesnotappeartoincreaseriskforrecurrentbreastcancerbasedonsystematicreview
ofobservationalstudies
HRTassociatedwithnonsignificantincreaseinriskofnewbreastcancereventand
contralateralbreastcancerafter10years(level2[midlevel]evidence)
amongwomenwithbreastcancer,prediagnosticuseofhormonetherapymaybeassociated
withdecreasedbreastcancermortality(level2[midlevel]evidence)
15/43
20/12/2015
seeHormonalreplacementtherapy(HRT)andbreastcancerfordetails
HRTandendometrialcancer
unopposedestrogenreplacementassociatedwithincreasedriskofendometrialcancer
unopposedestrogenandtiboloneuseeachassociatedwithincreasedriskofendometrial
cancerinpostmenopausalwomen
basedoncohortstudy
716,738postmenopausalwomeninUnitedKingdomwithoutpreviouscanceror
hysterectomyfollowedformean3.4years
1,320women(0.18%)developedendometrialcancer
comparedwithneverusersofHRT,riskofendometrialcancerwas
increasedwithunopposedestrogen(relativerisk[RR]1.45,p=0.04)
increasedwithtibolone(RR1.79,p<0.0001)
lowerwithuseofcontinuouscombinedestrogenplusprogestin(RR0.71,p=
0.005)
unchangedwithcyclicprogestinplusestrogen(RR1.05,p=0.5)
ReferenceLancet2005Apr30365(9470):1543,editorialcanbefoundinLancet
2005Apr30May6365(9470):1517,commentarycanbefoundinLancet2005Jul
1622366(9481):200
riskofendometrialcancerwithunopposedestrogenappearstoincreasewithduration
ofuse
basedonprospectivecohortstudy
68,419postmenopausalwomenwithintactuteriandwithouthistoryofcancerexcept
nonmelanomaskincancerenrolledinNIHAARPDietandHealthstudyin1996
1997,completedbaselineriskquestionnairetoestablishuseofhormonereplacement
therapy,andwerefolloweduntil2006
885womendiagnosedwithepithelialendometrialcancerduringstudy,ofwhich85%
wereendometrioid
useofunopposedestrogenassociatedwithincreasedriskofendometrialcancer
(relativerisk1.74,95%CI1.22.54)
greaterriskinwomenusingunopposedestrogenfor10years(RR3.93,95%CI
2.625.89)
ReferenceIntJCancer2013Jan15132(2):417fulltext
estradiolaloneappearstoincreaseriskforuterinebleeding,endometrialbiopsyand
endometrialhyperplasia(level2[midlevel]evidence)
basedonrandomizedtrialwithallocationconcealmentnotstated
218postmenopausalwomenwithintactuteriwererandomizedtomicronized17beta
estradiol1mgvs.placebodailyfor2or3yearsin1of2randomizedtrials
patientshadtransvaginalultrasoundannually
comparingestradiolvs.placebo
atleast1episodeofuterinebleedingin67%vs.11%(p<0.001,NNH2)
endometrialbiopsy48%vs.4%(p<0.001,NNH2)
endometrialhyperplasiain9.4%vs.0(mostlysimplehyperplasiawithoutatypia)
ReferenceObstetGynecol2007Mar109(3):581
sequentialestradiolprogestintherapyfor5yearsassociatedwithincreasedriskof
endometrialcancer
basedoncohortstudy
224,015postmenopausalFinnishwomen>50yearsoldusingestradiolprogestintherapyfor
6monthsfrom1994to2006wereincludedinanalysis
16/43
20/12/2015
0.6%developedendometrialcancer
sequentialestradiolprogestintherapyregimenfor5yearsassociatedwithincreasedriskof
endometrialcancercomparedtogeneralpopulation
69%riskincreaseifprogestinaddedmonthly
276%riskincreaseifprogestinaddedat3monthintervals
ReferenceObstetGynecol2009Dec114(6):1197
continuouscombinedhormonereplacementtherapymaypreventdevelopmentof
endometrialhyperplasiaassociatedwithunopposedestrogen
nocasesofendometrialhyperplasiaorcancerfoundinlongtermfollowupof534
postmenopausalwomentaking17betaestradiol2mgandnorethisteroneacetate1mgorally
dailyfor16years
dataonendometrialspecimensavailablein526womenafter9months,465womenafter24
36months,and345womenat5years
ReferenceBMJ2002Aug3325(7358):239fulltext),editorialcanbefoundinBMJ2002
Aug3325(7358):231fulltext
higherprogestindosesinoralcontraceptivesmightbeassociatedwithlowerriskof
endometrialcancerinwomenwithbodymassindex22.1kg/m2(level2[midlevel]
evidence)
basedoncasecontrolstudywith434endometrialcancercasesand2,557controls
ReferenceGynecolOncol2006Nov103(2):535
HRTandcardiovasculardisease
routineuseofcombinedestrogenandprogestinnotrecommendedforpreventionofchronic
conditionsinpostmenopausalwomen(USPSTFGradeD)
hormonereplacementtherapy(HRT)associatedwithincreasedriskforcardiovasculardisease,
venousthromboembolism,andstrokeinsystematicreviewsandrandomizedtrials
HRTdoesnotreduceriskofcardiovasculardiseasebutdoesincreaseriskofstrokeand
venousthromboemboliceventsinpostmenopausalwomen(level1[likelyreliable]evidence)
HRTincreasesriskofcardiovasculardiseaseandvenousthromboembolisminolder
postmenopausalwomen(level1[likelyreliable]evidence)
hormonetherapyassociatedwithincreasedriskofstrokeinpostmenopausalwomen(level2
[midlevel]evidence)
observationalstudieshaveinconsistentevidence
seeHormonalreplacementtherapy(HRT)andcardiovasculardiseasefordetails
HRTandvenousthromboembolism
HRTdoesnotreduceriskofcardiovasculardiseasebutdoesincreaseriskofstroke(level1[likely
reliable]evidence)andmayincreaseriskofvenousthromboembolism(level2[midlevel]
evidence)inpostmenopausalwomen
oralHRTincreasesriskofvenousthromboembolicdisease(level1[likelyreliable]evidence)
estrogenalonemayincreaseriskofthromboembolism(level2[midlevel]evidence)
transdermalHRTmaynotincreaseriskofvenousthromboembolism(level2[midlevel]evidence)
seeHormonalreplacementtherapy(HRT)andvenousthromboembolismfordetails
HRTandgallstonesandgallbladderdisease
17/43
20/12/2015
HRTincreasesriskofgallbladderdisease
estrogen(withorwithoutprogestin)increasesriskofgallbladderdisease(level1[likely
reliable]evidence)
8,376women(withoutcholecystectomy)withhysterectomyrandomizedtoconjugated
equineestrogens0.625mgvs.placebodailyformean7.1years
annualizedincidenceofanygallbladderevent0.78%vs.0.47%(NNH322per
year)
annualizedincidenceofcholecystectomy0.65%vs.0.34%(NNH322peryear)
annualizedincidenceofcholecystitis0.63%vs.0.35%(NNH357peryear)
annualizedincidenceofcholelithiasis0.67%vs.0.36%(NNH322peryear)
14,203women(withoutcholecystectomy)withouthysterectomyrandomizedto
conjugatedequineestrogens0.625mgplusmedroxyprogesteroneacetate2.5mgvs.
placebodailyformean5.6years
annualizedincidenceofanygallbladderevent0.55%vs.0.35%(NNH500per
year)
annualizedincidenceofcholecystectomy0.46%vs.0.28%(NNH555peryear)
annualizedincidenceofcholecystitis0.46%vs.0.3%(NNH625peryear)
annualizedincidenceofcholelithiasis0.5%vs.0.3%(NNH500peryear)
ReferenceWHItrial(JAMA2005Jan19293(3):330),commentarycanbefoundin
AmFamPhysician2005May171(9):1783
hormonereplacementtherapy(HRT)mayincreaseriskofhospitaladmissionfor
gallbladderdisease,oralHRTmayincreaseriskmorethantransdermalHRT(level2
[midlevel]evidence)
1,001,391postmenopausalwomen(meanage56years)werefollowedformean6.1
years
32%werecurrentusersofHRT(77%oral,18%transdermal,5%otheror
unknown)
18%werepastusersofHRT
1.9%womenhadfirsthospitaladmissionforgallbladderdiseaseduringfollowup,
1.7%hadcholecystectomy
hospitaladmissionsforgallbladderdiseasein
1.6%ofneveruserofHRT
2.1%forcurrentusersoftransdermalHRT(p<0.05vs.neveruse,NNH200)
2.6%forcurrentusersoforalHRT(p<0.05vs.neveruse,NNH100p<0.05
vs.transdermal,NNH200)
cholecystectomyin
1.4%ofneverusersofHRT
2.3%ofcurrentusersofHRT(p<0.05vs.neveruse,NNH112)
1.8%offormerusersofHRT(p<0.05vs.neveruse,NNH250)
ReferenceBMJ2008Jul10337:a386fulltext
HRTassociatedwithincreasedriskforgallstonesinHeartandEstrogen/progestin
ReplacementStudy(HERS)(level2[midlevel]evidence)
2,763postmenopausalwomen<80yearsoldwithcoronarydiseaseandintactuterus
randomizedtoconjugatedequineestrogens0.625mgplusmedroxyprogesterone
acetate2.5mgin1tablet(Prempro)vs.placeboorallyoncedaily,followupaveraged
4.1years
hormoneuseincreasedriskofgallbladderdisease(6.1%vs.4.5%,NNH62.5,
borderlinestatisticalsignificance)
ReferenceJAMA1998Aug19280(7):605inJFamPract1998Nov47(5):333,
18/43
20/12/2015
editorialcanbefoundinJAMA1998Aug19280(7):650,commentarycanbefound
inJAMA1999Mar3281(9):794,JAMA2001Nov28286(20):2544,JAMA2003
Jun25289(24):3241
increasedrisksforvenousthromboembolismandbiliarytractsurgeryreported
withlongerfollowupofHERStrial
after4.1yearsofrandomizedtreatment,openlabelHRTwasprescribedat
physician'sdiscretionand2,321(93%ofsurvivingcohort)continuedfollowup
for2.7years
proportionswith80%adherencetohormonesdecreasedfrom81%to45%in
HRTgroupandincreasedfrom0%to8%inplacebogroup
significantrisksover6.8yearswithHRTwerefoundforvenous
thromboembolism(NNH5065)andforbiliarytractsurgery(NNH3135)
ReferenceJAMA2002Jul3288(1):58,editorialcanbefoundinJAMA2002
Jul3288(1):99,summarycanbefoundinAmFamPhysician2002Dec
166(11):2147,commentarycanbefoundinACPJClub2003JanFeb138(1):7
HRTandovariancancer
majorityofevidencesuggestsanassociationbetweenhormonereplacementtherapy(HRT)and
ovariancancer
HRTusefor5yearsassociatedwithexcessincidenceofovariancancerofabout1case
in1,000inpostmenopausalwomen(level2[midlevel]evidence)
basedonpooledanalysisofindividualpatientdatafromobservationalstudies
85,334postmenopausalwomen(meanage64years)from52studieswithdataon
hormonetherapyuse,parity,oophorectomy,hysterectomy,andovariancancerwere
analyzed
17studieswith12,110womenwithovariancancerand40,717controlsincluded
prospectivedataonhormonetherapyuse
35studieswith9,378womenwithovariancancerand23,129controlsincluded
retrospectivedataonhormonetherapyuse
comparedtoneverusersofhormonetherapy,increasedriskofovariancancer
associatedwith
everuse(relativerisk[RR]1.14,95%CI1.11.19)
currentusefor<5yearsduration(RR1.27,95%CI1.181.37)
currentusefor5yearsduration(RR1.34,95%CI1.281.41)
pastusefor5yearsdurationwithlastuse<5yearsprior(RR1.25,95%CI
1.131.39)
pastusefor5yearsdurationwithlastuse5yearsprior(RR1.11,95%CI
1.031.2)
consistentresultsinanalyseslimitedtoprospectivestudies
comparedtoneverusersofhormonetherapy,currentorrecentuseassociatedwith
significantlyhigherriskofseroustumorsandendometrioidtumors,butsignificantly
lowerriskofclearcelltumors
estimated5yearexcessincidenceofovariancancer
1in1,000womenwith5yearsofhormonetherapy
1in600womenwith10yearshormonetherapy
ReferenceLancet2015May9385(9980):1835fulltext,editorialcanbefoundin
Lancet2015May9385(9980):1804
HRTassociatedwithincreasedriskofovariancancer(level2[midlevel]evidence)
basedon3cohortstudies
19/43
20/12/2015
cohortof909,946Danishwomenaged5079yearswithouthormonesensitivecancer
orbilateraloophorectomywerefollowedformean8years
3,068ovariancancersoccurred(ofwhich2,681wereepithelialcancers)
incidencerateratioswithcurrentuseofHRTvs.HRTneverusers
1.38(95%CI1.261.51)forallovariancancer
1.44(95%CI1.31.58)forepithelialovariancancer
incidencerates(per1,000years)were0.52withcurrentvs.0.4withneveruse
ofHRT(absoluteriskincrease0.12per1,000years,approximates1extra
ovariancancerforroughly8,300womentakingHRTyearly)
nosignificantdifferenceinriskofovariancancerwithcurrentHRTusewith
differenthormonetherapiesordurationofuse
riskdeclinedwithyearssincelastuse
1.22(95%CI1.021.46)with02years
0.98(95%CI0.751.28)with>24years
0.72(95%CI0.51.05)with>46years
0.63(95%CI0.410.96)with>6years
ReferenceJAMA2009Jul15302(3):298,commentarycanbefoundinJAMA
2009Nov25302(20):2203
cohortof948,576postmenopausalwomeninUnitedKingdomMillionWomenStudy
whodidnothavepreviouscancerorbilateraloophorectomywerefollowedmean5.3
yearsforovariancancerand6.9yearsfordeath
2,273(0.24%)developedovariancancerand1,591(0.17%)diedfromovarian
cancer
currentusersofHRThadincreasedriskofovariancancer(relativerisk1.2,95%
CI1.091.32)anddeathfromovariancancer(relativerisk1.23,95%CI1.09
1.38)comparedtoneverusers
pastusersofHRTnotatincreasedrisk
ReferenceLancet2007May19369(9574):1703,editorialcanbefoundin
Lancet2007May19369(9574):1667,commentarycanbefoundinLancet2007
Sep15370(9591):932
cohortof909,946womenaged5079yearswithoutpriorhormonesensitivecanceror
bilateraloophorectomywerefollowedformean8yearsandstratifiedbyuseof
hormonetherapy
womenwhousedestrogenwithorwithoutprogestinwerecomparedtononusers
ofhormonetherapy
0.3%developedepithelialovariancancer
comparedtonohormonetherapy
oralestrogenswithoutprogestinsassociatedwith
increasedriskforseroustumors(incidencerateratio[IRR]1.7,
95%CI1.42.2)
increasedriskforendometrioidtumors(IRR1.5,95%CI12.4)
decreasedriskformucinoustumors(IRR0.3,95%CI0.10.8)
estrogenplusprogestintherapyassociatedwithincreasedriskforserous
andendometrioidtumors
ReferenceAmJEpidemiol2012Jun15175(12):1234fulltext
estrogenuse>10yearsassociatedwithovariancancer(level2[midlevel]evidence)
postmenopausalestrogenuse>10yearsassociatedwithincreasedriskofovarian
cancermortalityinprospectivestudy
211,581postmenopausalwomenfollowedfor14years
20/43
20/12/2015
944ovariancancerdeathsoccurred
womenusingestrogenatbaselinehadincreasedriskofdeathduetoovarian
cancer(relativerisk1.51,95%CI1.161.96)
annualageadjustedovariancancermortalityratesper100,000womenwere
38.364.4forestrogenuse>10yearsand26.4forneverusers
ReferenceJAMA2001Mar21285(11):1460,commentarycanbefoundin
JAMA2001Jun27285(24):3089
DynaMedcommentaryifestrogeniscausal,NNHwas746foranyuseof
estrogenreplacementtherapy
unopposedestrogenuse>10yearsandcombinedestrogen/progestinuse>5
yearseachassociatedwithovariancancer
basedoncohortstudywith97,638womenaged5071yearsfollowedforupto
4.2years
214ovariancancersoccurred
useofunopposedestrogen10yearsassociatedwithincreasedriskofovarian
canceramongallwomencomparedtonohormonetherapy(relativerisk1.89,
95%CI1.222.95)
inwomenwithintactuteri,comparedtonohormonetherapy
sequentialprogestin(<15dayspercycle)associatedwithincreasedrisk
ofovariancancer(relativerisk3.09,95%CI1.685.86)
continuousprogestin(15dayspercycle)associatedwithincreasedrisk
ofovariancancer(relativerisk1.82,95%CI1.033.23)
ReferenceJNatlCancerInst2006Oct498(19):1397fulltext
unopposedestrogenuse>10yearsassociatedwithovariancancerincohortstudy
44,241postmenopausalwomenfollowedfor21years
329developedovariancancer
inanalysesadjustedforage,menopausetype,andoralcontraceptiveuse,
ovariancancerwassignificantlyassociatedwitheveruseof
estrogenonly(rateratio[RR]1.6,95%CI1.22)
estrogenonlyusefor1019years(RR1.8,95%CI1.13)
estrogenusefor>20years(RR3.2,95%CI1.75.7)
nostatisticallysignificantriskswithestrogenprogestinuse
ReferenceJAMA2002Jul17288(3):334,commentarycanbefoundinJAMA
2002Nov27288(20):2538,correctioncanbefoundinJAMA2002Nov
27288(20):2544,summarycanbefoundinAmFamPhysician2002Dec
1566(12):2298
increasingestrogendosewithHRTassociatedwithincreasingriskofovariancancer
basedoncasecontrolstudywith376casesand1,111controls
increasingdosesofestrogenassociatedwithincreasedriskofovariancancer(odds
ratio1.31,95%CI1.011.7per5gofestrogen)
ReferenceArchInternMed2004Nov8164(20):2253
HRTmaynotincreaseriskofovariancancer(level2[midlevel]evidence)
basedonrandomizedtrialwithnonsignificantfindings
16,608postmenopausalwomeninUnitedStates(WHItrial)randomizedtoHRT
(conjugatedequineestrogens0.625mgplusmedroxyprogesteroneacetate2.5mg)vs.
placebooncedaily
annualizedriskofinvasiveovariancancerwas0.04%withHRTvs.0.03%with
placebo(notstatisticallysignificant,hazardratio1.58,95%CI0.773.24)
21/43
20/12/2015
HRTdidnotincreaseriskofendometrialcancer(0.06%vs.0.07%annualizedrisk)
but,duetovaginalbleeding,morewomenrequiredendometrialbiopsies(33%vs.6%,
NNH4)
ReferenceJAMA2003Oct1290(13):1739,commentarycanbefoundinJAMA
2004Jan7291(1):42
HRTandurinaryincontinence
HRTmaybeassociatedwithincreasedriskofdevelopingorworseningurinaryincontinence
estrogen(withorwithoutprogestin)associatedwithdevelopingorworseningurinary
incontinenceinWHItrial
27,347postmenopausalwomenaged5079yearsrandomizedtoconjugatedequine
estrogen0.625mg/day(plusmedroxyprogesteroneacetate2.5mg/dayifno
hysterectomy)vs.placebo,23,296women(85%)hadurinaryincontinencesymptoms
recordedatbaselineandat1year
among5,183womenwithouturinaryincontinenceatbaselinerandomizedtoestrogen
plusprogestinvs.placebo
stressincontinenceat1yeardevelopedin16%vs.8.7%(p<0.001,NNH13)
urgeincontinenceat1yeardevelopedin11.4%vs.10.8%(p=0.06,NNH166)
mixedincontinenceat1yeardevelopedin3.7%vs.2.8%(p=0.01,NNH111)
among3,073womenwithouturinaryincontinenceatbaselinerandomizedtoestrogen
vs.placebo(posthysterectomy)
stressincontinenceat1yeardevelopedin17.4%vs.8.5%(p<0.001,NNH11)
urgeincontinenceat1yeardevelopedin13.8%vs.11.9%(p=0.003,NNH52)
mixedincontinenceat1yeardevelopedin5%vs.3.2%(p=0.001,NNH55)
amongwomenwithurinaryincontinenceatbaseline,estrogen(withorwithout
progestin)associatedwithworseningamount,worseningfrequency,andworsening
limitationsofdailyactivitiesrelatedtourinaryincontinenceat1yearbutresultsonly
presentedasrelativeriskssoNNHcannotbedetermined
ReferenceWomen'sHealthInitiative(WHI)trial(JAMA2005Feb23293(8):935),
editorialcanbefoundinJAMA2005Feb23293(8):998,commentarycanbefoundin
CMAJ2005Apr12172(8):1003fulltext,commentarycanbefoundinBMJ2005Jun
11330(7504),commentarycanbefoundinEvidenceBasedMedicine2005Jul
Aug10(4):121,commentarycanbefoundinJAMA2005Dec7294(21):2696
hormonereplacementtherapyassociatedwithdevelopmentofincontinence
2,763postmenopausalwomen<80yearsoldwererandomizedtoconjugated
estrogens0.625mg/medroxyprogesteroneacetate2.5mgvs.placeboorallyoncedaily
formean4.2years
inanalysisof1,208womenwhoreportednolossofurineinprevious7daysat
baseline,64%HRTusersvs.49%placebogroupreportedweeklyincontinence(p<
0.001,NNH6)
highestriskofincontinencewithinfirst4months
ReferenceObstetGynecol2005Nov106(5):940fulltext
hormonereplacementtherapyassociatedwithworseningofincontinence
2,763postmenopausalwomen<80yearsoldwererandomizedtoconjugated
estrogens0.625mg/medroxyprogesteroneacetate2.5mgvs.placeboorallyoncedaily
formean4years
22/43
20/12/2015
analysisof1,525womenwhohadincontinenceatleastonceweeklyatbaseline
comparinghormonereplacementtherapyvs.placebo
worseningofincontinencein39%vs.27%(p=0.001,NNH8)
improvementinincontinencein21%vs.26%
differenceobservedforbothurgeandstressincontinence
ReferenceObstetGynecol2001Jan97(1):116
postmenopausalhormonetherapyassociatedwithincreasedriskofdevelopingurinary
incontinenceinlongitudinalcohortstudyof39,436postmenopausalwomenfollowedfor4
yearsinNurses'HealthStudyrelativerisksrangedfrom1.34fororalestrogenandprogestin
to1.68fortransdermalestrogens(ObstetGynecol2004Feb103(2):254
ultralowdoseunopposedestrogen(transdermalestradiol0.014mg/day)maynotbe
associatedwithdevelopment,improvementorworseningofurinaryincontinencein2year
randomizedplacebocontrolledtrialof417postmenopausalwomen6080yearsold(Obstet
Gynecol2005Nov106(5):946fulltext)
estrogenmayimprovesymptomsofoveractivebladder(frequency,urgency,incontinence,first
sensationtovoid,bladdercapacity),basedonsystematicreviewof11randomizedplacebo
controlledtrialswith466women(ActaObstetGynecolScand2004Oct83(10):892inACPJClub
2005MarApr142(2):48)
HRTandotherconditions
systemiclupuserythematosus(SLE)
hormonereplacementtherapyassociatedwithincreasedriskofsystemiclupus
erythematosus(SLE)inwomen(level2[midlevel]evidence)
238,308womenfromNurses'HealthStudy(NHS)andNHSIIcohortswereevaluated
262incidentcasesofSLEdiagnosedbetween1976and2003andconfirmedby
medicalrecordreview
significantmenopauserelatedriskfactorsforSLEinolderwomenaged3055yearsat
startofNHS
surgicalmenopause(RR2.3,95%CI1.24.5)
useofpostmenopausalhormones(RR1.9,95%CI1.23.1)
durationofpostmenopausalhormoneuse
<5years(RR1.8,95%CI13)
5years(RR2,95%CI1.13.6)
timesincelastpostmenopausalhormoneuse
5years(RR2.3,95%CI1.15)
<5years(RR2.8,95%CI1.55.4)
currentuse(RR1.7,95%CI12.9)
ReferenceArthritisRheum2007Apr56(4):1251fulltext,editorialcanbefoundin
ArthritisRheum2007Apr56(4):1048fulltext
hormonereplacementtherapy(HRT)mayincreaseriskofdiseaseflaresinwomenwith
SLE(level2[midlevel]evidence)
basedonrandomizedtrialwithhighratesofnonadherencetointervention
351menopausalpatients(meanage50years)withinactive(81.5%)orstableactive
(18.5%)SLEwererandomizedtoHRT(conjugatedestrogen0.625mg/dayplus
medroxyprogesterone5mgfor12dayspermonth)vs.placebofor12months
trialdiscontinuedearly,afterWomen'sHealthInitiativereportofincreasedriskof
breastcancer,strokeandcardiovasculardiseaseinwomentakingHRT
23/43
20/12/2015
proportionofpatientsfollowedfor12months82%vs.87%(notsignificant)
12monthnonadherencerate(studyterminationforanyreasonotherthansevere
flare)35%vs.27%(p=0.08)
SLEdiseaseflareoccurredin64%vs.51%(p=0.01,NNH7)
severeSLEflareoccurredin7.5%vs.4.5%(notsignificant)
rateofmildtomoderateflaresperpersonyear1.14vs.0.86(p=0.01)
rateofsevereflaresperpersonyear0.081vs.0.049(notsignificant)
adverseeventswithHRTincludeddeath(1patient),stroke(1patient),andthrombosis
(3patients)comparedtothrombosisin1patienttakingplacebo
ReferenceAnnInternMed2005Jun21142(12):953PDF,editorialcanbefoundin
AnnInternMed2005Jun21142(12):1014PDF
HRTuseassociatedwithincreasedriskfordryeyesyndrome(JAMA2001Nov
7286(17):2114),commentarycanbefoundinJAMA2002Feb6287(5):585
estrogenorHRTuseassociatedwithincreasedriskofnewdiagnosisofasthma(level2[mid
level]evidence)
Nurses'HealthStudyevaluatednewdiagnosisofasthmaorchronicobstructivepulmonary
diseasebyquestionnaireduring546,259personyearsoffollowup
comparedtonohormoneuse
currentuseofestrogenaloneassociatedwithincreasedriskasthma(multivariaterate
ratio2.29,95%CI1.593.29
currentusersofestrogenplusprogestinhadsimilarlyincreasedrateofnewly
diagnosedasthma
ReferenceArchInternMed2004Feb23164(4):379,commentarycanbefoundinArch
InternMed2004Dec1327164(22):2501
hormonalreplacementtherapy(HRT)maynotaffectfrequencyofurinarytractinfections,
basedonrandomizedplacebocontrolledtrialof2,763postmenopausalwomenfollowedformean
4years(ObstetGynecol2001Dec98(6):1045
HRTmaybeassociatedwithdeclineinkidneyfunction(level3[lackingdirect]evidence)
basedonprospectivecohortstudywithoutclinicaloutcomes
5,845women>66yearsoldwith2serumcreatininemeasurementsover2years(1,459used
HRT(estrogenonly,progestinonlyorboth)and4,386didnotuseHRT)
HRTuseassociatedwithsignificantlossofmeanestimatedGFR(eGFR)(p=0.004)
estrogenonlyuseassociatedwithadditionaldeclineinmeaneGFR
ReferenceKidneyInt2008Aug74(3):370
postmenopausalHRTassociatedwithincreasedriskforgastroesophagealrefluxdisease
(GERD)(level2[midlevel]evidence)
prospectivecohortwith51,637postmenopausalwomen
12,018women(23%)hadGERDsymptoms
oddsratiosforGERDsymptomscomparedtoneverusersofpostmenopausal
hormones
forpastusers1.46(95%CI1.361.56)
forcurrentestrogenusers1.66(95%CI1.541.79)
forcurrentestrogen/progesteroneusers1.41(95%CI1.291.54)
riskofGERDsymptomsincreasedwithhigherdoseandlongerdurationofhormones
ReferenceArchInternMed2008Sep8168(16):1798fulltext
crosssectionalstudywith21,686twinsinSwedishTwinRegistry
4,365(20%)hadreflux
anyuseofpostmenopausalestrogenassociatedwithreflux(oddsratio1.32,95%CI
24/43
20/12/2015
1.181.47)
noassociationwithoralcontraceptives
ReferenceGastroenterology2008Apr134(4):921fulltext
postmenopausalestradiol,butnotcombinationestradiolplusprogestin,maybeassociated
withincreasedriskformeningioma(level2[midlevel]evidence)
basedonretrospectivecohortstudy
nationalcohortofallwomen50yearsoldwhousedhormonalreplacementtherapyfor6
monthsin19942009inFinland
131,480womenusedestradiolonly
131,248womenusedestradiolplusprogestin
meanfollowup9years
comparedtogeneralpopulation,riskofmeningioma
increasedwithanyestradiolonlytherapy(standardizedincidenceratio[SIR]1.29,
95%CI1.151.44)
increasedwithuseofestradiolonlyfor3years(SIR1.4,95%CI1.181.64)
notsignificantlyaffectedbyuseofestradiolplusprogestin(SIR0.93,95%CI0.8
1.06)
ReferenceAmJEpidemiol2012Feb15175(4):309fulltext
HRTandCognitiveFunction
Effectoncognitivefunction
HRTdoesnotappeartoimproveorpreventcognitivedeclineinpostmenopausalwomen
HRTmaybeassociatedwithincreasedriskofprobabledementia
4,532postmenopausalwomen>65yearsoldinWHItrialwhowerefreeofprobable
dementiawererandomizedtoHRT(conjugatedequineestrogen0.625mgplus
medroxyprogesterone2.5mg)vs.placeboorallyoncedailyandfollowedformean4
years
probabledementiadevelopedin40patients(1.8%)withHRTvs.21patients(0.9%)
withplacebo(p=0.01NNH111),rate45vs.22per10,000personyears(NNH435
for1year)
nodifferencesinmildcognitiveimpairment
ReferenceJAMA2003May28289(20):2651,editorialcanbefoundinJAMA2003
May28289(20):2717,commentarycanbefoundinCMAJ2003Jul
22169(2):133fulltext,JAMA2003Oct1290(13):1706,EvidBasedMentHealth
2003Nov6(4):111fulltext,ACPJClub2003NovDec139(3):62,CanFam
Physician2004Feb50:235PDF
HRTdidnotimprovecognitivefunctioncomparedtoplacebointhistrial,based
on4,381participantswhoprovidedatleast1validcognitivefunctionscore(JAMA
2003May28289(20):2663)
similartrendinestrogenalonearminWHItrial
2,947womenaged6579yearswererandomizedtoconjugatedequineestrogens
0.625mgvs.placebodailyformean5.2yearswithinWHItrial
incidenceofprobabledementia37vs.25per10,000personyears(p=0.18)
incidenceofprobabledementiaormildcognitiveimpairment126vs.91per
10,000personyears(p=0.04)
ReferenceJAMA2004Jun2330291(24):2947
25/43
20/12/2015
anotheranalysisfoundestrogenalonegrouphadModifiedMiniMentalState
Examscores0.26lowerthanplacebogrouponaverage(JAMA2004Jun23
30291(24):2959),editorialcanbefoundinJAMA2004Jun23
30291(24):3005,commentarycanbefoundinBMJ2004Sep4329(7465)
conjugatedequineestrogens(CEE)doesnotappeartoimprovecognitive
functionoraffectinpostmenopausalwomenwithpriorhysterectomy(level2
[midlevel]evidence)
basedonsubgroupanalysisofrandomizedtrial
866postmenopausalwomen(meanage74years)withpriorhysterectomy,
withoutdementiaandenrolledinWomen'sHealthInitiative(WHI)andWHI
MemoryStudy(WHIMS)ConjugatedEquineEstrogens(CEE)Alonetrial
randomizedto0.625mgCEEdailyvs.placebo
nosignificantdifferencebetweengroupsin
verbalknowledge/fluency
memory
attentionandworkingmemory
finemotorspeed
affect
ReferenceJClinEndocrinolMetab2009Nov94(11):4152fulltext
HRTdoesnotappeartobenefitoverallcognitivefunctioninpostmenopausalwomen
systematicreviewof24randomizedtrialsevaluatingeffectofestrogenreplacement
therapyorhormonereplacementtherapyoncognitivefunctioninpostmenopausal
women
only16trialswith10,114womenhadanalyzabledata
estrogenreplacementtherapyfor5yearsandhormonereplacementtherapyfor4years
notassociatedwithpreventionofcognitiveimpairmentcomparedtocontrol
ReferenceCochraneDatabaseSystRev2008Jan23(1):CD003122
estrogen(withprogestinifintactuterus)maynothaveeffectsoncognitivemeasuresin
postmenopausalwomenwithrecentstrokeortransientischemicattack(level2[mid
level]evidence)
basedonrandomizedtrialwithoutintentiontotreatanalysis
664postmenopausalwomenwithrecentstrokeortransientischemicattack
randomizedtoestradiol17betavs.placebo
among461women,estrogentherapydidnothaveasignificanteffectoverallon
cognitivemeasuresatmeanfollowupof3years
possiblebenefitreportedinsubgroupwithnormalminimentalstatusexam(MMSE)
atbaseline(AmJObstetGynecol2005Feb192(2):387inAmFamPhysician2005
Nov172(9):1881)
ultralowdosetransdermalestradiolnotassociatedwithdifferencesincognitionor
qualityoflifein2yearrandomizedplacebocontrolledtrialin417postmenopausalwomen
(only16%ofwhomhadhotflashesatbaseline)(ArchNeurol2006Jul63(7):945)
HRTnotassociatedwithcognitivebenefits(andpossiblyassociatedwithcognitive
decline)in2yearfollowupof13,807womenaged7081yearsinNurses'HealthStudy
(Neurology2004Jul1363(1):101)
estrogentherapydoesnotappeartoaffectcognitivefunctioninpostmenopausal
women(level2[midlevel]evidence)
basedonsmallrandomizedtrial
57healthypostmenopausalwomenwererandomizedtomicronized17betaestradiol
26/43
20/12/2015
0.25mgvs.placebodailyfor3years
allwomenwhohadnothadhysterectomyalsogivenmicronizedprogesterone100
mg/dayorallyfor2weeksevery6months
nodifferencesbetweengroupsonanyneurocognitivemeasuresordepression
instruments
ReferenceJAmGeriatrSoc2007Mar55(3):426
longtermuseofestrogenwithorwithoutprogestinmaynotreduceincidenceof
dementiainwomen(level2[midlevel]evidence)
2,906womenaged75yearsold(52%hormoneusers)withoutdementiaatbaseline
adjustedhazardratiofordementia1.34(95%CI0.951.9)forestrogenusersand1.23
(95%CI0.941.6)forestrogen/progestinusers
ReferenceAmJEpidemiol2008Mar15167(6):692fulltext
HRTinwomenwithmenopausalsymptomsappearstoimprovecognitivedecline(level2
[midlevel]evidence)
basedonsystematicreviewofsmalltrialswithoutmetaanalysis
systematicreviewof29studies(9smallrandomizedtrialsand20observationalstudies)
evaluatinghormonereplacementtherapyforcognitivedeclineanddementiainhealthy
postmenopausalwomen
norandomizedtrialswithoutcomeofdementia
trialsnotcombinedinmetaanalysisduetoheterogeneity
benefitfoundformeasuresofcognitivedeclineonlyintrialsofpatientswithmenopausal
symptoms,nobenefitinasymptomaticpatients
metaanalysisof2cohortstudiesand10casecontrolstudiessuggestthatHRTassociated
withdecreasedriskfordementia
ReferenceJAMA2001Mar21285(11):1489,commentarycanbefoundinJFamPract
2001Jun50(6):547,commentarycanbefoundinJAMA2001Jun20285(23):2974
HRTmaynotbeassociatedwithdifferencesincognitivefunctioninyoungerwomen(level2
[midlevel]evidence)
basedonsecondaryanalysisof2randomizedtrials
1,326postmenopausalwomenaged5055yearsrandomizedtoconjugatedequineestrogens
0.625mg/dayifpriorhysterectomyand0.625mg/dayplusmedroxyprogesteroneacetate2.5
mg/dayifintactuterusvs.matchedplacebo(meantrialduration7years),andtelephone
administeredcognitivebatterygivenatmean7.2yearsaftertrialsended,andrepeated1year
later
nosignificantdifferencesinglobalcognitivefunctionscoresorforanyindividualcognitive
domain
ReferenceWHIMSYtrial(JAMAInternMed2013Aug12173(15):1429,editorialcanbe
foundinJAMAInternMed2013Aug12173(15):1437)
HRTandAlzheimerdisease
postmenopausalhormoneusenotassociatedwithchangeinriskofAlzheimerdisease(level2
[midlevel]evidence)
basedonsystematicreviewwithoutreportingassessmentofstudyquality
systematicreviewof15studies(1randomizedtrial,9prospectivecohortstudies,and5
nestedcasecontrolstudies)evaluatingpostmenopausalhormonetherapyuseandriskof
Alzheimerdiseaseordementia
studyfollowupperiodrangedfrom1to16years
comparedtoneverusingahormone,anyhormoneusenotassociatedwithasignificant
27/43
20/12/2015
differenceinriskofAlzheimerdisease(relativerisk0.88,95%CI0.661.16)inanalysisof9
studieswith14,368womenwithmoderatestatisticalheterogeneity
ReferenceEpidemiolRev201436(1):83
HRTreportedtodecreaseriskofAlzheimerdiseaseinelderlywomenONLYifinitiated
within5yearsofmenopauseandcontinuedfor10years(level2[midlevel]evidence)
basedonprospectivecohortstudywithoutadjustmentsforanalysisofmultipleoutcomes
1,768elderlywomen(meanage75years)withknownageatmenopausewerefollowedfor
mean7years
62.5%hadhistoryofhormonereplacementtherapy(HRT)use
10%developedAlzheimerdisease
comparedtonoHRTuse,useofanytypeofHRTinitiatedwithin5yearsofmenopauseand
takenfor10yearswasassociatedwithdecreasedriskofAlzheimerdisease(hazardratio
0.63,95%CI0.410.98)
nosignificantdifferencesinriskofAlzheimerdiseasecomparing
noHRTusevs.HRTinitiatedwithin5yearsofmenopauseandtakenfor<10years
noHRTusevs.HRTinitiated>5yearsaftermenopause
useofopposedHRTstartingwithin3yearsofstudybaselineassociatedwithtrendtoward
increasedriskofAlzheimerdisease(hazardratio1.93,95%CI0.943.96)
ReferenceNeurology2012Oct3079(18):1846fulltext,earlierreportat3years'followup
canbefoundinJAMA2002Nov6288(17):2123
AlternativestoHRT
OverviewofHRTalternatives
dependingonreasonsforHRT,alternativestoHRTmayinclude
phytoestrogens
blackcohosh
tibolone
raloxifene
selectiveserotoninreuptakeinhibitors(SSRIs)
DHEAsupplementscannotyetberecommended
"bioidenticalhormones"(plantderivedhormonespreparedbypharmacist)
AmericanCollegeofObstetriciansandGynecologists(ACOG)committeeopinionon
compoundedbioidenticalmenopausalhormonetherapy
conventionalhormonetherapypreferredovercompoundedhormonetherapybasedon
availabledata
insufficientevidencetosupportsuperiorityclaimsofcompoundedbioidentical
hormonesoverconventionalmenopausalhormonetherapy
customizedcompoundedhormonesposeadditionalriskdueto
variablepurityandpotency
lackofefficacyandsafetydata
possibilityofunderdosageoroverdosage(variablebioavailabilityand
bioactivity)
insufficientevidencetosupportclaimsofincreasedefficacyorsafetyfor
individualizedhormonetherapyregimensbasedonsalivary,serum,orurinarytesting
ReferenceACOGCommitteeOpinion532oncompoundedbioidenticalmenopausal
hormonetherapy(ObstetGynecol2012Aug120(2Pt1):411fulltext),reaffirmed
2014Jul
28/43
20/12/2015
FDAwarnsclaimsof"bioidenticalhormonereplacementtherapy"safetyandeffectiveness
areunsupportedbymedicalevidenceandareconsideredfalseandmisleading(FDAPress
Release2008Jan9)
"bioidentical"hormonereplacementtherapyassociatedwithendometrialcancerin3
casereports
authorsspeculatecasesmaybeduetoinsufficientprogestincomponentproducedby
compoundingpharmacists
ReferenceMedJAust2007Aug20187(4):244
reviewof"bioidentical"hormonetherapycanbefoundinJAmBoardFamMed2011Mar
Apr24(2):202fulltext
tiboloneandconventionalhormonetreatmentappeartohavesimilarclimactericeffectand
mayimprovedifferentaspectsoffemalesexualfunction(level2[midlevel]evidence)
140postmenopausalwomenrandomizedto1of3groupsandfollowedfor6months
tibolone2.5mgplusoneCal+Dtablet(calcium500mgandvitaminD200units)
daily
conjugatedequineestrogen0.625mgplusmedroxyprogesterone2.5mg(CEE/MPA)
plusoneCal+Dtabletdaily
oneCal+Dtabletdaily(control)
nosignificantdifferencebetweentiboloneandCEE/MPAin
vasomotorsymptoms(bothgroupssignificantlyimprovedvs.control)
totalsexualfunctionscoresandsexualsatisfactionsubscores
tiboloneimprovedfemalesexualfunctionscoresindomainsofdesire,arousalandorgasm(p
<0.001vs.CEE/MPAforeachdomain)
CEE/MPAimprovedfemalesexualfunctionscoresindomainsoflubricationand
dyspareunia(p<0.001vs.tiboloneforeachdomain)
ReferenceClimacteric2010Apr13(2):147
reviewofalternativestoHRTformenopausalsymptomscanbefoundinLancet2005Jul
30366(9483):409
Phytoestrogens
soyproteinsupplementation(phytoestrogens)mayrelievevasomotorsymptoms,basedonlimited
evidencefromrandomizedtrials,seediscussioninmenopause
postmenopausalsupplementationwithsoyproteinmaynotimprovecognitivefunction,bone
mineraldensityorplasmalipidlevels(level2[midlevel]evidence)
basedonrandomizedtrialwithoutintentiontotreatanalysis
200healthywomenaged6075yearsrandomizedto25.6gofsoyprotein(isoflavones99
mg)dailyvs.placebofor12months
among175womencompleting1postinterventionassessment,nosignificantdifferencesin
cognitivefunction,bonemineraldensity,orplasmalipids
ReferenceJAMA2004Jul7292(1):65,commentarycanbefoundinAmFamPhysician
2004Nov1580(10):1978
continualsoyusefor5yearsassociatedwithriskofendometrialhyperplasia(level3[lacking
direct]evidence)
basedonnonclinicaloutcomeinrandomizedtrial
376postmenopausalwomenwithintactuteruswererandomizedtosoytablets150mg/day
vs.placebofor5years
among298womencompletingtrial
3.37%withsoyvs.0withplacebohadendometrialhyperplasia
29/43
20/12/2015
nocasesofmalignancydetectedbybiopsy
70%withsoyvs.81%withplacebohadendometriumclassifiedasatrophicor
nonassessable,
ReferenceFertilSteril2004Jul82(1):145inBMJ2004Sep11329(7466):632),
commentarycanbefoundinLancet2004Dec1117364(9451):2081
someplantproducts,especiallysoy,haveweakestrogeniceffectandsomeantiestrogenic
effects
doseandpurityofcommercialphytoestrogensunknown,possibleadverseeffectsunknown
3trialswith300womensuggestthatsoyproteinsupplementationorincreaseddietaryintake
ofsoybeanfoodsreducesymptomsofmenopause,butnotallresultsstatisticallysignificant
andresultsreportedinsuchawayastomakeclinicalsignificanceunclear
ReferenceTheMedicalLetter2000Feb2142(1072):17
TheNorthAmericanMenopauseSocietyconsensusopiniononroleofisoflavonesinmenopausal
healthcanbefoundinMenopause2000JulAug7(4):215
reviewofphytoestrogenscanbefoundinArchInternMed2001May13161(9):1161
highdietaryphytoestrogenintake(isoflavones)associatedwithhigherlumbarbonemineraldensity
amongpostmenopausalbutnotpremenopausalwomeninstudyof650Chinesewomen(JClin
EndocrinolMetab2001Nov86(11):5217fulltext
Blackcohosh
activeingredientunknown
blackcohoshnotaphytoestrogeninclassicsenseasitsconstituentsdonotbindtoestrogen
receptorsmayhaveselectiveestrogenicaction
moststudiedproductisisopropanolicextractofblackcohoshknownasRemifemin
widelyadvocatedfortreatmentofmenopausalsymptoms
usualdoseofblackcohosh20mg(1tablet)twicedailyusingRemifemin
70%80%responseratesreportedbutinsufficientevidencetodetermineefficacyrelativeto
placebo(level2[midlevel]evidence)
doseof130mg/dayappearsnomoreeffectivethan40mg/day(level2[midlevel]evidence)
concernofhepatotoxicitybasedonsmallnumberofcasereportswithclinicalhepatotoxicity
blackcohoshshouldnotbeconfusedwiththehepatotoxicherbbluecohosh
seeBlackcohoshformenopausalsymptomsfordetails
Raloxifene(Evista)
Prescribinginformation
raloxifene(Evista)isaselectiveestrogenreceptormodulator(SERM)withestrogenagonist
activityonboneandestrogenantagonistactivityonbreastanduterinetissue
dose60mgorallyoncedaily
raloxifeneusedinpostmenopausalwomenfor
preventionandtreatmentofosteoporosis
reductioninincidenceofinvasivebreastcancer
seeRaloxifenefordetails
Efficacyinpostmenopausalwomenwithoratriskforcoronaryarterydisease
raloxifenereducesriskofbreastcancerandclinicalvertebralfracture,butincreasesriskof
30/43
20/12/2015
fatalstrokeandvenousthromboembolism(level1[likelyreliable]evidence)
10,101postmenopausalwomen>55yearsoldwithcoronaryheartdiseaseormultiplerisk
factorsforcoronaryheartdiseasewererandomizedtoraloxifene(Evista)60mgvs.placebo
oncedailyformedian5.6years
913(9%)discontinuedthestudyand1,149(11%)diedduringthestudy
nosignificantdifferencescomparingraloxifenevs.placeboformanyoutcomes
primarycoronaryevents(533vs.553,or2.06%vs.2.16%peryear)
totalstroke(249eventsvs.224events,or0.95%vs.0.86%peryear)
totaldeath(554deathsvs.595deaths,or2.07%vs.2.25%peryear)
cardiovasculardeath(362deathsvs.355deaths,or1.35%vs.1.34%peryear)
clinicalnonvertebralfractures(428vs.438,or1.67%vs.1.73%peryear)
raloxifenereducedriskforsomeoutcomes
invasivebreastcancerin40casesvs.70cases,or0.15%vs.0.27%peryear(NNT833
peryear)
clinicalvertebralfracturesin64vs.97,or0.24%vs.0.37%peryear(NNT769per
year)
raloxifeneincreasedriskforsomeoutcomes
fatalstrokesin59vs.39(NNH1,428peryear)
venousthromboembolismeventsin103vs.71(NNH833peryear)
hotflashesin8%vs.4.8%(NNH31)
legcrampsin9.7%vs.6.7%(NNH33)
peripheraledemain14.4%vs.12.1%(NNH43)
gallbladderdiseasein5.6%vs.4.5%(NNH91)
ReferenceRUTHtrial(NEnglJMed2006Jul13355(2):125fulltext),editorialcanbe
foundinNEnglJMed2006Jul13355(2):190fulltext,commentarycanbefoundinCMAJ
2006Jul18175(2):147fulltext,AmFamPhysician2006Nov174(9):1598,ACPJClub
2006NovDec145(3):73
resultsofRUTHtrialdidnotdifferacrosssubgroups,exceptriskofstrokedifferedby
smokingstatus(Stroke2009Jan40(1):147fulltext)
Efficacyinpostmenopausalwomenwithosteoporosis
raloxifenemayreduceriskofvertebralfracture(level3[lackingdirect]evidence)butnot
nonvertebralfractures(level2[midlevel]evidence)inpostmenopausalwomenwith
osteoporosis
7,705womenaged3180yearsin25countrieswhohadbeenpostmenopausalfor2years
andmetWorldHealthOrganizationcriteriaforosteoporosiswererandomizedtoraloxifene
60mg/dayvs.120mg/dayvs.placeboandfollowedforupto3640months
allwomengivensupplementalcalcium500mg/dayandcholecalciferol400600units/day
6,828women(88.6%)hadevaluableradiographsat36months
RatesofNewVertebralFractureonXray:
Raloxifene60
Raloxifene120
Placebo
mg/day
mg/day
Overallcohort
6.6%(NNT29)
5.4%(NNT21)
10.1%
Subgroupof2,304
womenwithprevious 14.7%(NNT15)
10.7%(NNT10)
21.2%
vertebralfractures
31/43
20/12/2015
Subgroupof4,524
womenwith
2.3%(NNT45)
2.8%(NNT59)
4.5%
osteoporosisbutno
priorvertebral
fracture
Abbreviation:NNT,numberneededtotreatfor3yearstoprevent1newvertebralfracture
comparedtousingplacebo.
nosignificantdifferencesinratesofnonvertebralfracturebyinterviews
comparedwithplacebo,raloxifeneincreasedbonemineraldensityinfemoralneckby
2.1%2.4%andinspineby2.6%2.7%(p<0.001)
womenreceivingraloxifenehad3.1timesincreasedriskofvenousthromboembolism(1%
withraloxifene60mgvs.1%withraloxifene120mgvs.0.3%withplacebo,NNH143)
adverseeventssignificantlymorecommonwithraloxifeneincludedinfluenzasyndrome,hot
flashes,legcramps,peripheraledema,andendometrialcavityfluidadverseevents
significantlymorecommonwithplaceboincludedhypertension,hypercholesterolemia,
hematuria
raloxifenedidnotcausevaginalbleedingorbreastpainandwasassociatedwithlower
incidenceofbreastcancer(statisticallysignificantbutabsolutenumbersnotgiven)
ReferenceMOREtrial(JAMA1999Aug18282(7):637fulltext),correctioncanbefound
inJAMA1999Dec8282(22):2124,editorialcanbefoundinJAMA1999Aug
18282(7):687,commentarycanbefoundinJFamPract1999Nov48(11):911,JAMA2000
May3283(17):2236,ACPJClub2000MarApr132(2):58
raloxifenereducedincidenceofclinicalvertebralfractureinthistrial,withclinicalvertebral
fracturedefinedasnewvertebralfractureassociatedwithsignsandsymptomssuchasback
pain
among6,828women(88.6%)withbaselineandfollowupxraysover3years,new
clinicalvertebralfractureswerereportedin
3.5%placebogroup
2.1%withraloxifene60mg/day(NNT72)
1.7%withraloxifene120mg/day(NNT56)
ReferenceArchInternMed2002May27162(10):1140fulltext
reductioninnewvertebralfractureswithraloxifenestillsignificantat4years,nosignificant
differenceinnonvertebralfractures(JClinEndocrinolMetab2002Aug87(8):3609full
text)
raloxifenereducedvertebralfracturesandbreastcancerinbothwomenwithandwithout
priorhormonetherapyinMOREtrial(JFamPract2004Oct53(10):789)
vitaminDdeficiencydidnotaffectresponsetoraloxifeneinthistrial(JClinEndocrinol
Metab2005Aug90(8):4566fulltext)
raloxifeneassociatedwithdecreasedriskofbreastcancerinpostmenopausalwomenwith
osteoporosis(level2[midlevel]evidence)
basedonrandomizedtrial(MOREtrial)withallocationconcealmentnotstated
inMOREtrial7,705postmenopausalwomenaged3180yearswithosteoporosiswere
randomizedtoraloxifene60mg/dayvs.120mg/dayvs.placeboandfollowedforupto36
40monthsinCOREtrial5,133participantscontinuedrandomizedassignment(with60
mg/dayusedforbothraloxifenegroups)for8years
inMOREtrial78%raloxifenepatientsvs.75%placebopatientscompletedtrial
13casesofbreastcancerconfirmedamong5,129women(0.25%)assignedto
raloxifenevs.27among2,576women(1.05%)assignedtoplacebo(p<0.001,NNT
126)
raloxifeneincreasedriskofvenousthromboembolicdiseasebasedonchartreview
32/43
20/12/2015
(NNH143forthromboembolicdiseaseandNNH500forpulmonaryembolism)
raloxifenedidnotincreaseriskofendometrialcancerinsubgroupof1,781women
whounderwenttransvaginalultrasonography
raloxifeneassociatedwithmorehotflashes(NNH25)andlegcramps(NNH33),no
significantdifferencesinvaginalbleedingorbreastpain
nosignificantdifferencesinmortality
ReferenceJAMA1999Jun16281(23)2189inJFamPract1999Sep48(9):659,
correctioncanbefoundinJAMA1999Dec8282(22):2124,editorialcanbefoundin
JAMA1999Jun16281(23):2243,commentarycanbefoundinJAMA2000Jan
19283(3):338,JAMA2001Apr25285(16):2079
raloxifenereducedvertebralfracturesandbreastcancerinbothwomenwithandwithout
priorhormonetherapyinMOREtrial(JFamPract2004Oct53(10):789
inCOREtrial(anextensionoftheMOREtrial)
5,213MOREparticipantscontinuedraloxifene60mg/day(ifpreviouslyassigned60
mgor120mg)vs.placebo(ifpreviouslyassignedplacebo)foranother4years
comparingraloxifenevs.placebo
incidenceofinvasivebreastcancerduringtrialextensionwas2vs.5per1,000
womanyears(NNT334womanyears)
8yearriskofpulmonaryembolismwas0.62%vs.0.16%(NNH217)
nosignificantdifferenceinmortality
ReferenceCOREtrial(JNatlCancerInst2004Dec196(23):1751fulltext),
commentarycanbefoundinAmFamPhysician2005Apr171(7):1390fulltext
raloxifeneappearstoincreaseriskforvenousthromboemboliceventsinwomenwith
basedonMOREtrialwithallocationconcealmentnotstated
anotherreportofMOREtrialincludesdifferentnumbersthan1999report,partially
explainedbyaddingretinalveinthrombosistototalnumbers
comparingcombinedraloxifenegroupsvs.placebogroup
deepveinthrombosisin0.84%vs.0.27%(p=0.01,NNH175)
pulmonaryembolismin0.35%vs.0.08%(notsignificant)
retinalveinthrombosisin0.08%vs.0.19%(notsignificant)
anyvenousthrombosisin1.15%vs.0.54%(p=0.01,NNH164)
ReferenceObstetGynecol2004Oct104(4):837
raloxifenenotassociatedwithreductionincardiovasculareventsinwomenwith
basedonMOREtrial(withallocationconcealmentnotstated)andCOREtrial(extensionof
MOREtrial)
nooveralldifferencesincombinedoutcomeofcardiovascularevents(myocardialinfarction,
unstableangina,coronaryischemia,stroke,ortransientischemicattack)inMOREtrial
insubgroupof1,035womenwithincreasedcardiovascularriskatbaseline,raloxifene
usewasassociatedwithsignificantlylowerriskofcardiovascularevents
ReferenceJAMA2002Feb20287(7):847,commentarycanbefoundinJFamPract
2002May51(5):481,JAMA2002Jul3288(1):42
inCOREtrial(4yearfollowupofMOREtrial)
4,011postmenopausalwomenwithosteoporosisrandomizedtoraloxifene60mgvs.
placeboorallyoncedailyfor4yearsaspartofMOREtrial,then4moreyearsaspart
ofCOREtrial(range2.659.1monthsbetweenendofMOREtrialandbeginningof
COREtrial)
effectofraloxifeneonincidenceofcardiovasculareventsnotpredefinedobjectiveof
COREtrial,butadjudicationandanalysisforcardiovasculareventsspecifiedbefore
33/43
20/12/2015
trialend
nosignificantdifferencescomparingraloxifenevs.placeboinincidenceof
cardiovascularevents(5.5%vs.4.7%)
cardiacevents(3.1%vs.2.6%)
cerebrovascularevents(2.7%vs.2.3%)
ReferenceAmJCardiol2006Feb1597(4):520fulltext
alendronateplusraloxifenecombinationmayincreasebonemineraldensity(BMD)more
thaneithermonotherapyinwomenwithosteoporosis(level3[lackingdirect]evidence)
basedonrandomizedtrialwithoutclinicaloutcomes
135postmenopausalwomenwithosteoporosisrandomizedtoalendronate70mg/weekvs.
raloxifene60mg/dayvs.combinationfor12months
alendronateandraloxifenealoneandincombinationsignificantlyincreasedBMDinlumbar
spine,femoralneck,andtotalhip
combinationhadgreaterincreaseinBMDcomparedtoeithermonotherapy(p<0.0001)
ReferenceClimacteric2011Jun14(3):369
teriparatide,zoledronate,alendronate,andrisedronateeachreportedtobemoreeffective
thanraloxifeneorcalciumplusvitaminDforpreventingnonvertebralfracturesinpatients
withosteoporosis(level3[lackingdirect]evidence)
basedonsystematicreviewwithmostlyindirectcomparisons
systematicreviewof116randomizedtrialsevaluatingefficacyofpharmacologicalagents
forpreventionofhip,vertebral,andnonvertebralfracturesin139,647patientswithoratrisk
forosteoporosis
mosttrialswereinpostmenopausalwomen
drugtherapyincludedteriparatide,denosumab,raloxifene,zoledronate,risedronate,
ibandronate,alendronate,vitaminD,calcium,andvitaminDpluscalcium
smallnumberofdirectcomparisontrialsreducesprecisionandconfidenceinresultsof
networkmetaanalyses
innetworkmetaanalysesofplacebocontrolleddata(combiningdirectandindirect
comparisons),significantreductionin
newhipfractureswithalendronate,risedronate,zoledronate,denosumab,andvitamin
Dpluscalcium
newvertebralfractureswithteriparatide,denosumab,zoledronate,risedronate,
alendronate,raloxifene,andibandronate
newnonvertebralfractureswithteriparatide,risedronate,zoledronate,denosumab,and
alendronate
comparativeefficacyinnetworkmetaanalyses(combiningdirectandindirectcomparisons)
forpreventionofhipfractures
zoledronate,risedronate,andalendronateweremoreeffectivethanraloxifene
zoledronate,risedronate,andalendronateweremoreeffectivethancalcium
and/orvitaminD
denosumabwasmoreeffectivethancalciumaloneorvitaminDalone
forpreventionofnonvertebralfractures
teriparatide,zoledronate,andrisedronateweremoreeffectivethanraloxifene
andcalciumand/orvitaminD
teriparatidewasmoreeffectivethanalendronate
ibandronateandalendronateweremoreeffectivethancalciumplusvitaminD
ReferenceJClinEndocrinolMetab2012Jun97(6):1871fulltext
DynaMedcommentarystudyfundedinpartbyTheEndocrineSocietyinpreparationfor
evidencebasedguidelinedevelopment
34/43
20/12/2015
Additionalefficacydatainpostmenopausalwomen
raloxifeneassociatedwithdecreaseinallcausemortalityinolderpostmenopausalwomen
basedonmetaanalysiswithoutsystematicsearch
metaanalysisevaluatingmortalityfrom2clinicaltrialsof15,234postmenopausalwomen
takingraloxifene60mg/dayvs.placebo
raloxifeneassociatedwith
lowerallcausemortality(hazardratio[HR]0.9,95%CI0.81)inanalysisof2trials
fewernoncardiovasculardeaths(HR0.78,95%CI0.650.93)
fewernoncardiovascular,noncancerousdeaths(HR0.72,95%CI0.560.93)
ReferenceAmJMed2010May123(5):469.e1
raloxifenedoesnotaffectcognitivefunctioninpostmenopausalwomen
7,478postmenopausalwomenwithosteoporosiswererandomizedtoraloxifene(60mgor
120mg)vs.placebodailyfor3years
meancognitivescoresinallthreegroupsimprovedslightlywithnosignificantdifferences
ReferenceMOREtrial(NEnglJMed2001Apr19344(16):1207),editorialcanbefound
inNEnglJMed2001Apr19344(16):1242
nonclinicaloutcomesinpostmenopausalwomen
raloxifeneimprovesbonedensitycomparedtoplacebobutlessthanconjugatedequine
estrogen,andmayreduceLDLcholesterollevels(level3[lackingdirect]evidence)
619postmenopausalwomen(meanage53years)withpriorhysterectomywere
randomizedtoraloxifene(60mg/dayor150mg/day)vs.conjugatedequineestrogen
0.625mg/dayvs.placebofor3years
bonedensityinlumbarspinedeclinedby2%intheplacebogroup,wasstableinboth
raloxifenegroups,andincreasedby4.6%inestrogengroupconsistentresultsinbone
densityintotalhip
raloxifeneandestrogeneachreducedlowdensitylipoprotein(LDL)cholesterol
levels,butonlyestrogenincreasedhighdensitylipoprotein(HDL)cholesterollevels
estrogenbutnotraloxifenewasassociatedwithurinaryincontinence
ReferenceArchInternMed2004Apr26164(8):871fulltext
raloxifenemaintainsbonemineraldensityat3years(level3[lackingdirect]evidence)
basedon2randomizedtrialsofidenticaldesignwithoutclinicaloutcomes
1,145healthypostmenopausalwomenaged4560yearswererandomizedto
raloxifene30mg/dayvs.60mg/dayvs.150mg/dayvs.placebofor3years
allwomengivenelementalcalcium400600mg
lumbarspineBMDchangedfrombaselineto36monthsby0.71%inraloxifene30mg
groupvs.1.28%inraloxifene60mggroupvs.1.2%inraloxifene150mggroupvs.
1.32%inplacebogroup
comparableBMDchangesinhip
changeinserumlowdensitylipoproteincholesterolat36months
12.1%withraloxifene150mg(p<0.001vs.placebo)
2%withplacebo
nosignificantdifferencesinstudywithdrawalsduetoanyreason(37%)or
withdrawalsduetoadverseevents(14%),onlysignificantadverseeffectwashot
flashes(25%in60mggroupvs.18%inplacebogroup,NNH14)
35/43
20/12/2015
ReferenceArchInternMed2000Dec1125160(22):3444fulltext
raloxifenemaydecreaseinsulinsensitivityinpostmenopausalwomen(level3[lacking
direct]evidence)
basedonsmallrandomizedtrialwithoutclinicaloutcomes
44healthypostmenopausalwomenwithoutdiabetesonglucosetolerancetestingwere
randomizedtoraloxifenevs.estrogenvs.placebofor8weeks
raloxifenedecreasedinsulinsensitivity,estrogen,andplacebodidnot
ReferenceJAmGeriatrSoc2003May51(5):683
raloxifenemayreduceLDLcholesterollevels(level3[lackingdirect]evidence)
ultralowdosetransdermalestrogenmaybesimilartoraloxifeneforeffectonbonemineral
densityinpostmenopausalwomen(level3[lackingdirect]evidence)
500postmenopausalwomenwithosteopeniarandomizedtomicrodose17betaestradiol
(0.014mg/day)transdermallyvs.raloxifene60mg/dayorallyfor2years
66%70%completedtrial
nosignificantdifferencescomparingestrogenvs.raloxifene
lumbarspinebonemineraldensityincreasedby2.4%vs.3%
nobonelossinlumbarspinein77.3%vs.80.5%
nohistologicalevidenceofendometrialstimulationin99%vs.100%
meandenseareainbreastmammograms19.8%vs.19%
ReferenceMenopause2009MayJun16(3):559
DHEAsupplements
DHEAreferstodehydroepiandrosterone
DHEAmaynotimprovequalityoflifeormenopausalsymptomsinmenopausalwomen
systematicreviewof28randomizedtrialsevaluatingdehydroepiandrosterone(DHEA)for
1weekin1,273womeninperiorpostmenopausalphase
mosttrialshad1limitationincluding
unclearallocationconcealment
smallsamplesize
unclearornoblinding
comparingDHEAtoplaceboornotreatment
nosignificantdifferenceinqualityoflifeinanalysisof9trials,resultslimitedby
significantheterogeneity
foreffectonmenopausalsymptoms
nosignificantdifferenceinmeansymptomscoresin2trialswith83women
DHEAsignificantlyreducedriskofnightsweats,lossoflibido,andtirednessin
1trialwith50women
DHEAassociatedwithnonsignificantimprovementinsexualfunctioninanalysisof6
trials,butimprovementnotclinicallyrelevant
foradverseevents
9trialsreportednoadverseeffectsoverall
totalandrogenicadverseeffects(acne,greasyskin,hirsutism)in23.4%with
DHEAvs.4.4%withplacebo(p=0.019,NNH5)in1trialwith52women
nosignificantdifferencesinacneinanalysisof4trialswith158women
comparingDHEAtoestrogentherapy(aloneorwithprogesterone)
36/43
20/12/2015
foreffectonmenopausalsymptoms
DHEAsignificantlyimprovedmeansymptomscoresin1trialwith24women
nosignificantdifferencesinriskofnightsweats,hotflushesandpalpitations,
andtirednessin1trialwith50women
DHEAassociatedwithnonsignificantimprovementinmeansexualfunctionscoresin
analysisof2trialswith41women
comparingDHEAtotibolone
DHEAsignificantlyimprovedmeansexualfunctionandmenopausalsymptomscores
in1trialwith24women
nosignificantdifferencesinriskoftiredness,hotflushesandpalpitations,andnight
sweatsin1trialwith50women
ReferenceCochraneDatabaseSystRev2015Jan22(1):CD011066
DHEAappearssimilartoHRTforincreasedsexualfunctionandimprovedclimacteric
symptomsinpostmenopausalwomen(level2[midlevel]evidence)
basedonsmalltrialwithinadequaterandomization
48healthypostmenopausalwomenaged5060yearsrandomizedto3groupsandthose
refusingHRThadvitaminD400unitspluscalciumcarbonate1,250mg/day(toprevent
osteoporosis)for12months
DHEA10mgorally/day
estradiol1mgplusdihydrogesterone5mgorally/day
tibolone2.5mgorally/day
climactericsymptomsimprovedinalltreatmentgroups(DHEA,estradiol/dihydrogesterone,
andtibolone)comparedtobaselineat12months(nochangeinvitaminD/calciumgroup)
increasedtotalsexualfunctionscoreswith(comparedtobaselineat12months)
DHEA(p<0.001vs.vitaminD/calciumnotsignificantvs.
estradiol/dihydrogesterone)
estradiol/dihydrogesterone(p<0.001vs.vitaminD/calciumnotsignificantvs.
DHEA)
tibolone(notsignificant)
increasedsexualintercoursefrequency(inlast4weeks)with(comparedtobaselineat12
months)
DHEA(p<0.01)
estradiol/dihydrogesterone(p<0.05)
tibolone(p<0.01)
nosignificantdifferencesamonggroups
nochangeinsexualintercoursefrequencyinvitaminD/calciumgroupandreduced
frequencycomparedtohormonetreatments(p<0.05)
ReferenceClimacteric2011Dec14(6):661
DHEAsupplementationfor1yearnotassociatedwithadverseendometrialeffectsor
changesinbloodlipidsorinsulinsensitivity(level3[lackingdirect]evidence)
93postmenopausalwomenrandomizedtoDHEA50mg/dayvs.placebofor52weeks
nosignificantdifferencesin
bloodlipids
insulinresistance
breakthroughbleedingpattern
adverseendometrialeffects
ReferenceMaturitas2009Jul2063(3):240
DHEAappearstohavenoeffectonlipidlevelsorbodyfatinolderfrailwomen(level3
[lackingdirect]evidence)
37/43
20/12/2015
basedonsmallrandomizedtrialwithoutclinicaloutcomes
99women(meanage76years)withlowDHEASlevelandfrailtyrandomizedto1of4
treatmentsandfollowedfor6months
DHEA50mg/dayplusyoga
DHEA50mg/dayplusaerobics
placeboplusyoga
placeboplusaerobics
allwomenreceivedcalcium1,0001,200mg/daythroughdietandsupplementationand
cholecalciferol1,000units/day
DHEAassociatedwithincreasedDHEAS,oestradiol,oestroneandtestosteronelevelsand
reducedsexhormonebindingglobulinlevels
nosignificantdifferencesbetweentreatmentsorwithintreatmentgroupsfrombaselineto6
monthsintotalcholesterol,HDLcholesterol,LDLcholesterol,triglycerides,bodyor
abdominalfat,fastingglucoseorbloodpressure
ReferenceAgeAgeing2010Jul39(4):451fulltext
dehydroepiandrosterone(DHEA)appearstohavenoeffectonbonemineraldensity
(BMD),lowerextremitystrengthorfunctioninolderfrailwomen
basedonsecondaryanalysisofrandomizedtrialabove
ReferenceJAmGeriatrSoc2010Sep58(9):1707
DiscontinuationofHRT
EffectsofdiscontinuingHRT
discontinuationofHRTaftermyocardialinfarction(MI)doesnotappeartoincreaseor
decreaseriskofreinfarctionormortalityat1year(level2[midlevel]evidence)
basedonretrospectivecohortstudy
3,322women40yearsoldwithMIsurviving30daysafterhospitaldischargewere
followedfor1year
allpatientsprescribedHRTattimeofMI
6.6%cardiovascularrelatedmorality,10.7%allcausemortality,and8.5%reinfarction
duringfollowup
nosignificantdifferencesat1yearcomparingdiscontinuationofHRTafterMIvs.
continuationofHRTinoverallanalysis
reinfarction(hazardratio[HR]0.9,95%CI0.681.19)
cardiovascularrelatedmortality(HR1.21,95%CI0.91.62)
allcausemortality(HR1.22,95%CI0.971.53)
discontinuationofvaginalestrogenafterMIassociatedwithreducedriskofreinfarctionat1
yearcomparedtocontinuation(HR0.54,95%CI0.340.86)
ReferenceBMJ2012Mar27344:e1802fulltext
discontinuationofestrogenandprogestin(HRT)associatedwithrecurrenceoronsetof
menopausalsymptoms(level2[midlevel]evidence)
basedonobservationaldatafromrandomizedtrial
16,608womenwithintactuterusinWHItrialrandomizedtoHRTvs.placeboandwere
instructedtostoptakingstudypillsbyJuly8,2002,atwhichtime9,351(56%)werestill
takingstudypillsandeligibleforsurvey8,405eligiblewomen(90%)completedsurvey8
12monthsaftercessationofstudypills
comparingwomendiscontinuingHRTvs.discontinuingplacebo,hotflashesandnight
sweatsin
38/43
20/12/2015
21.2%vs.4.8%overall(p<0.05,NNH6)
55.5%vs.21.3%forwomenwithvasomotorsymptomsatbaseline(p<0.05,NNH3),
21.6%vs.3.7%forwomenwithsymptomspriortobaselineonly(p<0.05,NNH5)
6.4%vs.1.2%forwomenwithnopriorvasomotorsymptoms(p<0.05,NNH19)
painorstiffnessin36.8%womendiscontinuingHRTvs.22.2%womendiscontinuing
placebo(p<0.05,NNH7
ReferenceJAMA2005Jul13294(2):183,editorialcanbefoundinJAMA2005Jul
13294(2):245
changeinqualityoflifefollowingHRTdiscontinuationmayvarywithage(level2[mid
level]evidence)
basedonlongitudinalstudy
2,357womenusingHRTin2002whocompletedsurveysin2002and2003,43%
discontinuedHRTduringthestudyincluded
amongwomenaged6574years,HRTdiscontinuershaddecreasedhealthrelatedqualityof
lifeby4differentmeasures
amongwomenaged85yearsandolder,HRTdiscontinuershadbetterhealthrelatedquality
oflifethanHRTcontinuersin3differentmeasures
ReferenceBMCWomensHealth2005May165:7fulltext
Timingofdiscontinuation
mostwomenmaybeabletostopHRTabruptlywithoutilleffect(level2[midlevel]
evidence)
basedoncohortstudyof670womenaged5069yearssurveyed6monthsafterpublication
ofWHItrial
377(56%)triedtostopHRT,mainreasonsforcontinuingHRT(44%)werehotflashes
(26%)andosteoporosisprevention(19%)
74%of377womenattemptingtostopHRTsuccessfullystoppedHRT(71%abruptly,29%
tapered)
mostwomenwhoresumedHRTduetosymptomshadsymptomswithin1week
ReferenceObstetGynecol2003Dec102(6):1233,commentarycanbefoundinAmFam
Physician2004Aug1570(4):769
gradualandabruptdiscontinuationofHRTassociatedwithsimilarfrequencyandseverity
ofhotflashesandsimilarriskofresumptionoftherapy
81postmenopausalwomentreatedwithHRTforhotflasheswererandomizedtogradual
taperingvs.abruptdiscontinuationofHRTandfollowedupto12months
about50%resumedHRTwithin1year
nosignificantdifferencesin
numberorseverityofhotflashes
healthrelatedqualityoflife
frequencyofresumptionofHRT
ReferenceMenopause2010JanFeb17(1):72,editorialcanbefoundinMenopause2010
JanFeb17(1):10
gradualdiscontinuationofHRTmaypostponebutnotreducereappearanceofmenopausal
symptoms
basedonrandomizedtrialofabruptvs.gradualHRTdiscontinuationin91postmenopausal
womenusingHRTfor>3years
39/43
20/12/2015
about40%womenresumedHRTwithin9months
ReferenceMenopause2006MayJun13(3):370
GuidelinesandResources
Guidelines
UnitedStatesguidelines
InstituteforClinicalSystemsImprovement(ICSI)guidelineonmenopauseandhormonetherapy
(HT):collaborativedecisionmakingandmanagementcanbefoundatICSIPDF2008Oct
AmericanCollegeofObstetriciansandGynecologists/AmericanSocietyforReproductive
Medicine(ACOG/ASRM)CommitteeOpinion532oncompoundedbioidenticalmenopausal
hormonetherapycanbefoundinObstetGynecol2012Aug120(2Pt1):411fulltext,reaffirmed
2014Jul,oratACOG/ASRM2012AugPDF
AmericanCollegeofObstetriciansandGynecologists(ACOG)CommitteeOpinion556on
postmenopausalestrogentherapy:routeofadministrationandriskofvenousthromboembolism
canbefoundatACOG2013AprPDF
NorthAmericanMenopauseSociety(NAMS)positionstatementson
hormonetherapycanbefoundinMenopause2012Mar19(3):257PDF,commentarycanbe
foundinMenopause2013May20(5):587,additionalstatementcanbefoundatNAMS2015
PDF
estrogenandprogestogenuseinpostmenopausalwomencanbefoundinMenopause2010
Mar17(2):242
priorNAMSpositionstatementforestrogenandprogestogenuseinperiand
postmenopausalwomencanbefoundinMenopause2007MarApr14(2):168,
summarycanbefoundinAmFamPhysician2007Jul1576(2):295,commentarycan
befoundinBMJ2007Apr28334(7599):860fulltext
roleofprogestogeninpostmenopausalhormonereplacementtherapycanbefoundin
Menopause2003MarApr10(2):113
consensusstatementonmenopausalhormonetherapycanbefoundinClimacteric2013
Apr16(2):203PDF,endorsedbyTheAmericanSocietyforReproductiveMedicine,AsiaPacific
MenopauseFederation,TheEndocrineSociety,EuropeanMenopauseandAndropauseSociety,
TheInternationalMenopauseSociety,TheInternationalOsteoporosisFoundationandTheNorth
AmericanMenopauseSociety
UnitedStatesPreventiveServicesTaskForce(USPSTF)recommendationonmenopausalhormone
therapyforprimarypreventionofchronicconditionscanbefoundatUSPSTF2012Oct23full
text,orinAnnInternMed2013Jan1158(1):47fulltext,editorialcanbefoundinAnnInternMed
2013Jan1158(1):69,oratNationalGuidelineClearinghouse2013Jan21:38537
AmericanCollegeofPreventiveMedicine(ACPM)guidelineonperimenopausaland
postmenopausalhormonereplacementtherapycanbefoundinAmJPrevMed1999Oct17(3):250
AmericanSocietyforReproductiveMedicine(ASRM)guidelineonestrogenandprogestogen
therapyinpostmenopausalwomencanbefoundinFertilSteril2004Jan81(1):231
Canadianguidelines
40/43
20/12/2015
CanadianTaskForceonPreventiveHealthCare(CTFPHC)recommendationstatementson
hormonereplacementtherapyforprimarypreventionofchronicdiseasescanbefoundin
CMAJ2004May11170(10):1535fulltext
postmenopausalhormonereplacementtherapyforprimarypreventionofcardiovascularand
cerebrovasculardiseasecanbefoundinCMAJ2004Apr27170(9):1388fulltext
Europeanguidelines
ItalianConsensusConferenceWorkingGroupstatementoninformingwomenabouthormone
replacementtherapycanbefoundinBMCWomensHealth2009May299:14fulltext
expertrecommendationsoncollectionandanalysisofendometrialbiopsiesforhormonetherapies
canbefoundinClimacteric2012Feb15(1):52fulltext
AssociationoftheScientificMedicalSocietiesinGermany(AWMF)interdisciplinaryguidelineon
hormonetherapyinperimenopauseandpostmenopausecanbefoundinArchGynecolObstet2011
Aug284(2):343fulltext
ZurichDiscussionGroup(ZurcherGesprachskreises)consensusstatementoncomplicationsof
hormonalcontraceptioninclimactericandpostmenopausalwomencanbefoundinGynakol
GeburtshilflicheRundsch200949(1):45[German]
Asianguidelines
AsiaPacificTiboloneConsensusGroupupdatedclinicalrecommendationsonuseoftibolonein
AsianwomencanbefoundinClimacteric2010Aug13(4):317fulltext
AustralianandNewZealandguidelines
RoyalAustralianandNewZealandCollegeofObstetriciansandGynaecologists(RANZCOG)
evidencebasedconsensusstatementonuseofpostmenopausalhormonetherapycanbefoundat
NationalHealthandMedicalResearchCouncil2004Aug12
Reviewarticles
reviewcanbefoundinBMJ2012Feb16344:e763
ACOG'sHormoneTherapyreportinObstetGynecol2004Octsupplementcontains
comprehensiveinformation(ObstetGynecol2004Oct104(4Suppl):1S)
reviewcanbefoundinObstetGynecol2010Apr115(4):839
reviewcanbefoundinJFamPract2005May54(5):428
reviewcanbefoundinArchInternMed2004Nov22164(21):2308
reviewcanbefoundinMedJAust2003Jun16178(12):630fulltext
reviewcanbefoundinAdvStudMed2003Apr3(4):205PDF
reviewcanbefoundinBMJ2003Feb8326(7384):322fulltext,commentarycanbefoundin
BMJ2003Jun21326(7403):1398fulltext,BMJ2003Jun21326(7403):1398fulltextandreply
reviewcanbefoundinNEnglJMed2001Jul5345(1):34,commentarycanbefoundinNEnglJ
Med2002Jan3346(1):63
reviewcanbefoundinWestJMed1999Jul17127(AmFamPhysician2000Jan161(1):203)
evidencebasedreviewcanbefoundinCMAJ2003Apr15168(8):1001fulltext
briefreviewcanbefoundinJFamPract2003Feb52(2):149
41/43
20/12/2015
systematicreviewofpostmenopausalHRTcanbefoundinJAMA2002Aug21288(7):872,
discussionofclinicalapplicationscanbefoundinJAMA2002Aug21288(7):882,commentary
canbefoundinJAMA2003Jan1289(1):44,commentarycanbefoundinACPJClub2003Mar
Apr138(2):41
reviewofrisksandbenefitscanbefoundinMedJAust2007Jun18186(12):643
reviewoflowdosehormonetherapyinmanagementofmenopausalsymptomscanbefoundinJ
AmBoardFamMed2009SepOct22(5):563fulltext
reviewoflongtermeffectsofHRTcanbefoundinLancet2002Sep21360(9337):942,
commentarycanbefoundinLancet2003Jan18361(9353):253
reviewofhormonalreplacementtherapycanbefoundinBMJ1998Aug15317(7156):457
reviewoforalcontraceptiveuseandchangingtopostmenopausalhormonereplacementtherapyin
perimenopausalwomencanbefoundinAmFamPhysician1998Oct1558(6):1373
reviewofperimenopausecanbefoundinAnnInternMed2015Feb3162(3):ITC1
PatientInformation
FDAwebsiteonhormonetherapyincludesinformationinEnglishandSpanish(AmFam
Physician2003Dec168(11):2280)
References
Recommendationgradingsystemsused
UnitedStatesPreventiveServicesTaskForce(USPSTF)gradesofrecommendation(afterJuly
2012)
GradeAUSPSTFrecommendstheservicewithhighcertaintyofsubstantialnetbenefit
GradeBUSPSTFrecommendstheservicewithhighcertaintyofmoderatenetbenefitor
moderatecertaintyofmoderatetosubstantialnetbenefit
GradeCUSPSTFrecommendsselectivelyofferingorprovidingtheservice(basedon
professionaljudgmentandpatientpreference)withatleastmoderatecertaintyofsmallnet
benefit
GradeDUSPSTFrecommendsagainstprovidingtheservicewithmoderatetohigh
certaintyofnonetbenefitorharmsoutweighingbenefits
GradeIinsufficientevidencetoassessbalanceofbenefitsandharms
ReferenceUSPSTFGradeDefinitions
UnitedStatesPreventiveServicesTaskForce(USPSTF)gradesofrecommendation(June2007
June2012)
GradeAUSPSTFrecommendstheservicewithhighcertaintyofsubstantialnetbenefit
GradeBUSPSTFrecommendstheservicewithhighcertaintyofmoderatenetbenefitor
moderatecertaintyofmoderatetosubstantialnetbenefit
GradeCcliniciansmayprovidetheservicetoselectpatientsdependingonindividual
circumstances,however,onlysmallbenefitislikelyformostindividualswithoutsignsor
symptoms
GradeDUSPSTFrecommendsagainstprovidingtheservicewithmoderatetohigh
certaintyofnonetbenefitorharmsoutweighingbenefits
GradeIinsufficientevidencetoassessbalanceofbenefitsandharms
ReferenceUSPSTFGradeDefinitions
42/43
20/12/2015
CanadianTaskForceonPreventiveHealthCare(CTFPHC)gradesofrecommendation
GradeAgoodevidencetorecommendclinicalpreventiveaction
GradeBfairevidencetorecommendclinicalpreventiveaction
GradeC
conflictingevidencedoesnotallowrecommendationfororagainstuseofclinical
preventiveaction
otherfactorsmayinfluencedecisionmaking
GradeDfairevidencetorecommendagainstclinicalpreventiveaction
GradeFgoodevidencetorecommendagainstclinicalpreventiveaction
GradeI
insufficientevidence(inquantityorquality)tomakerecommendation
otherfactorsmayinfluencedecisionmaking
References
CTFPHCnewgradesforrecommendations(CMAJ2003Aug5169(3):207fulltext)
CTFPHCrecommendationstatementonhormonereplacementtherapyforprimary
preventionofchronicdiseases(CMAJ2004May11170(10):1535fulltext)
CTFPHCrecommendationstatementonpostmenopausalhormonereplacement
therapyforprimarypreventionofcardiovascularandcerebrovasculardisease(CMAJ
2004Apr27170(9):1388fulltext)
DynaMededitorialprocess
DynaMedtopicsarecreatedandmaintainedbytheDynaMedEditorialTeam.
Over500journalsandevidencebasedsources(DynaMedContentSources)aremonitoreddirectly
orindirectlyusinga7Stepevidencebasedmethodforsystematicliteraturesurveillance.
DynaMedtopicsareupdateddailyasnewlydiscoveredbestavailableevidenceisidentified.
TheparticipatingmembersoftheDynaMedEditorialTeamhavedeclaredthattheyhaveno
financialorothercompetinginterestsrelatedtothistopic.
Theparticipatingreviewershavedeclaredthattheyhavenofinancialorothercompetinginterests
relatedtothistopic,unlessotherwiseindicated.
McMasterUniversityisapartnerthatprovidessupportinidentifyingPracticeChangingDynaMed
Updates.Over1,000practicingphysiciansfrom61disciplinesin77countriesratethesearticlesto
helpyoufindthemostusefulnewevidenceaffectingyourpractice.
F1000isapartnerthatprovidessupportinidentifyingPracticeChangingDynaMedUpdates.Over
2,000practicingcliniciansfrom20disciplinesin60countriesratethesearticlestohelpyoufind
themostusefulnewevidenceaffectingyourpractice.
Howtocite
NationalLibraryofMedicine,or"Vancouverstyle"(InternationalCommitteeofMedicalJournal
Editors):
DynaMedPlus[Internet].Ipswich(MA):EBSCOInformationServices.1995.RecordNo.
113927,Hormonalreplacementtherapy(HRT)[updated2015Mar15,citedplacecited
datehere][about29screens].Availablefromhttp://www.dynamed.com/login.aspx?
direct=true&site=DynaMed&id=113927.Registrationandloginrequired.
43/43

DynaMed Plus - Hormonal Replacement Therapy (HRT)

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

DynaMed Plus - Hormonal Replacement Therapy (HRT)

Uploaded by

Copyright:

Available Formats

20/12/2015

You might also like