Practice PRACTICE - Epocrates

1 THERAPEUTICSH ormonereplacementtherapyMarthaHickeyprof essorof obstetricsand gynaecology1, Jane Elliottseniorlecturer2, Sonia LouiseDavisonseniorpostdoctoralresearchf ellow31 Universityof Melbourne,The Royal Women sHospitaland the Universityof Melbourne,Melbourne,VIC3052,Australia;2 Universityof Adelaide,DisciplineofObstetrics&Gynaecol ogy,SchoolofPaediatricsandReproductiveHe alth,Adelaide,SA5005,Australia;3 MonashUniversity,Women sHealthResearchProgram,Departmentof Epidemiologyand PreventiveMedicine,Schoolof PublicHealthand PreventiveMedicine,The AlfredCentre,99 CommercialRoad,Melbourne,VIC3004,Austral iaThis is one of a series of occasionalarticleson therapeuticsfor commonor seriousconditions,coveringnew drugs and old drugs with importantnew indicationsor seriesadvisersare RobinFerner,honoraryprofessorof clinicalpharmacology,Universityof BirminghamandBirminghamCityHospital,andP hilipRoutledge,professorofclinicalpharma cology, suggesta topic for this series.

2 Pleaseemail us at 51 year old womanpresentsto her generalpractitionerwithtroublesomehot flushesand night sweatsfor the past is sexuallyactive and her last period was about 5monthsago. She has taken a numberof over-the-counterpreparations, wants advice about managingher hormonereplacementtherapy?Menopauseisano rmalphysiologicaleventinwomen,occurringa t a medianage of 51 years. Hormonereplacementtherapy(HRT)containsoe strogenforrelievingmenopausalsymptoms;fo r womenwho still have their uterus it is combinedwith aprogestogenfor oestrogen(oestradiol,oestradiol17 , oestrone,or conjugatedequineoestrogen)can be oral, intravaginal,or be oral, transdermal,or deliveredvia anintrauterinedevice(Mirena,BayerScherin g).InHRTregimensthe oestrogenis taken daily, with progestogenadded eithersequentially(cyclicregimen)or daily (continuouscombinedregimen)if it is an oral syntheticsteroidpreparationwith oestrogenic,androgenic,and HRT, but the role of supplementaltestosteronewill not becoveredin this key indicationfor HRT or tiboloneis the presenceoftroublesomevasomotorsymptoms(h otflushesandnightsweats,with or withoutawakening).

3 Vasomotorsymptomsare normalandaffectabout80%ofwomenduringthem enopausetransitionand are severe in about 20% of these durationofthese symptomsvaries, with a medianof four years, but maycontinueforasmanyas12yearsinabout10% be indicatedwhen menopausalsymptomsare adverselyaffectingqualityof is currentlythe most effectivetreatmentfor reductionin the frequencyof hot flushesby around18 aweek and in the severityof hot flushesby 87% randomisedcontrolledtrials have confirmedthat HRT also significantlyreducesfracturerisk, improvesvaginaldrynessand sexual function,and may also improvesleep,muscleachesandpains, 5 Thefigure providestheestimatedabsolutebenefitsfrom HRT use in postmenopausalwomenaged 50-59 years or<10 years after menopause,based on backgroundrisk inAmericanwomen,6using data from the largestrandomisedcontrolledtrial of HRT versus placeboto date (the Women sHealthInitiativestudy)4and the prospectiveobservationalNurses 7 HRT (oestrogenalone and combined)showssignificantabsolutebenefit forthetreatmentofvasomotorsymptoms,vagin aldryness,and fracturereductionand for thepreventionof relativeefficacyof tibolonecomparedwith ,multicentrerandomiseddoubleblind controlledtrial found that tibolonereducedhotflushesas much as low dose (1 mg)

4 Oral the first three monthsof treatmentand less breasttenderness8and may also improvesexual to: M Hickey personal use only: See rights and reprints : ;344:e763doi: (Published16 February2012)Page 1 of 6 PracticePRACTICEC linicalindicationsforHRTC urrentevidencebased guidelines6 10-12advise considerationofHRT for troublesomevasomotorsymptomsin perimenopausaland early postmenopausalwomenwithoutcontraindicati onsand after individualiseddiscussionof likely risks and in womenover age 60 years is womenwith premature(age <40 years) orearly (<45 years) menopause,currentguidelinesrecommendHRT until aged 50 for the treatmentof ,butincreasedrisk of osteoporosisalone is not an indicationfor ,althoughHRT may also improvemood and libido,these are not primaryindicationsfor do not requiresystemicHRT and can bemanagedwith local HRT?

5 For most symptomaticwomen,use of HRT for 5 years is of the benefitsand harms of HRTin womenaroundthe normalage of menopause(50-59years), shows the estimatedrisks associatedwith HRT use inpostmenopausalwomenaged 50-59 years or <10 years ,these data are derivedlargelyfrom thesubgroupaged 50-59 years in the Women sHealthInitiativeStudy4and the Nurses backgroundrisk ofmost adverseevents linked with HRT increaseswith age, andrisks will differ accordingto age and currenthealth ,the Women sHealthInitiativestudy used aregimenof oral conjugatedoestrogen(Premarin)(with orwithoutmedroxyprogesteroneacetate)vers usplacebo, principalrisks of HRT to considerarethromboembolicdisease(venoust hromboembolismandpulmonaryembolism);stro ke;cardiovasculardisease;breastand endometrialcancer.

6 And (combinedoestrogenandprogestogen,andoest rogenonly)increasestheriskofvenousthromb oembolism,pulmonaryembolism,and risks increasewith age and withother risk factors,such as obesity,previousthromboembolicdisease,sm oking,and younger(<60 years)healthywomenthe absoluterisk of type, dose, and deliverysystemof both oestrogenandprogestogenmay influencethe risk of thromboembolicdisease forexample,a recent systematicreviewfound thatoral but not transdermalHRT increasedthe risk of ,low dose ( mg oral, or 50 g transdermal)oestradioldidnot increasethe incidenceof venousthromboembolismin lowrisk clinicalpractice,previousvenousthromboem bolismand high risk of venousthromboembolismare contraindicationsfor HRT. If HRT is used by womenatincreasedrisk of thromboembolicdisease,a transdermalpreparationand reducedoestrogendose are theabsenceof personalor family history,screeningfor inheritedthrombophiliasis not indicatedbefore , gorless,17but this has not been shown in randomisedcontrolledtrials.

7 Inolderwomen(>65years) clinicalpracticeavoid HRT or tibolonein womenat highrisk of relationbetweenHRT and cardiovasculardiseaseiscontroversial,but the timing and durationof HRT, as well aspre-existingcardiovasculardisease, the estimatedrisks for youngerwomen(aged 50-59 years)(figure ), there was no (>60), who are more likely to have larger trials suggeststhatstartingHRT in youngerpostmenopausalwomenmay have afavourableeffect on cardiovascularhealth,19but the validityofthis timinghypothesis those who start HRT at about age 50 yearsandcontinuebeyondage60yearsthecardi ovascularrisksfromHRT are (oestrogenplusprogestogen)increasestheri skof a breast cancer diagnosisor breast cancer of breast cancer with tiboloneis not established,but sHealthInitiativestudy reportedan excess breast cancer riskattributableto combinedHRT of 8 per 10 000 womena yearafter four to five years of use.

8 This equatesto about a the risk of havingan are conflictingover the risk of breast cancer withoestrogen-onlyHRT. In the Women sHealthInitiativestudy,conjugatedequineo estrogen(Premarin)did not increasetheriskofbreastcancerforuptoseve nyearsofuseinwomenwhohad had a 18 Most observationalstudiesreportno increasedrisk for up to five years of use,6but the large,observationalMillionWomenStudy showedan with combinedHRT than with ,unopposedoestrogenmaylead to endometrialhyperplasiaand increasesthe risk this reason womenwho retain theiruterus and use oestrogenshouldalso take does not increasethe risk ofendometrialcancer providedthat adequatedurationand doseofprogestogenareused, not increasethe risk of endometrialhyperplasiaor randomisedcontrolledtrials have shown that HRTincreasesthe risk of (theFor personal use only.)

9 See rights and reprints : ;344:e763doi: (Published16 February2012)Page 2 of 6 PRACTICEM illionWomenStudy)show that this risk may be reducedbyusing transdermalrather than oral HRT, avoidingonecholecystectomyin every 140 consensushas been reachedon absolutecontraindicationsto HRT. However,on the basis of the above data, we adviseavoidingor discontinuingHRT in patientswith the following: A historyof breast cancer,as HRT may increasethe riskof breast cancer recurrenceand of new breast increasesthe risk of breast diseaseand investigateanyabnormalitiesbefore startingHRT. CounselwomenconsideringHRT that it may increasetheir risk of anabnormalmammogramand that combinedHRT mayincreasetheir risk of breast cancer after four to five yearsof use Apersonalhistoryorknownhighriskofvenouso rarterialthromboembolicdisease,including stroke andcardiovasculardisease,as HRT may risk in older HRTis prescribed,a transdermalpreparationwith ,screeningfor inheritedthrombophiliasis notindicatedbefore startingHRT15 conditionsthat requirecautionwith use of HRT include: shouldnot be startedinwomenwith may often cause unscheduledbleedinginthe first six monthsof use.

10 Persistentor new onset (aftersix months)unscheduledbleedingon HRT requiresinvestigationto excludepelvic disease Abnormalliver oral HRT productssincethese are metabolisedin the liver does not seem to be exacerbatedby HRTso migraineis not a contraindication,but low dosetransdermalpreparationsmay be preferable27 Historyof endometrialor specialistreviewbefore consideringHRT High risk of HRT mayincreasethis risk further,althoughthe risk may be lowerwith HRT?HRTisprincipallyatreatmentformenopau salsymptoms, (QALYs)gainedintheUnitedKingdomand the US have used data from the Women sHealthInitiativestudyandconsideredfract urereduction,breastcancer,colorectalcanc er,coronaryheart disease,stroke,and venousthromboembolicevents over five years of HRT 28 Theyshow that HRT is cost effectivein all womencomparedwithnotreatmentbutthattheco steffectivenesswasgreaterinthosewith more severe vasomotorsymptoms(UK data, estimatedcost per QALY gained: 580 ( 700; $920) for womenwith anintact uterus and 205 for womenwho had had ahysterectomy).