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European Journal of Endocrinology 10.1530/EJE-17-1072 established ( analogues inthetreatment ofprostatecancer(PCa)are (ADT) with -releasing hormone (GnRH) metabolic adverseeffectsofandrogen deprivationtherapy The benefitsfordiseasecontrolandthebone Introduction mitigate ADT-associated adverseeffects withoutE2-related . reduced hotflushesandboneresorption.Largerstudies willberequiredtotestwhetherlow-doseE2treatmentcan concentrations intothereferencerangereportedforhealthymen,butwithsubstantialvariability. E2treatment Conclusion type 1collagentelopeptide. interquartile range:144–660).E2treatmentreducedhotflushfrequencyandseverityaswellbetacarboxyl-terminal dose group(median:208 Results end. baseline, days14and28.Hotflushdiariesotherbiochemicalmeasurementswerecompletedatbaseline study Fasting morningserumhormones,qualityoflifequestionnaires,andtreatmentsideeffects wereevaluatedat Methods Design without increasingcirculatingTS. deprivationtherapy(ADT).Secondarily, weaimedtoassessshort-termbiologicaleffects ofE2add-back circulating E2concentrationsinmenwithprostatecancersuppressedendogenousproductionarisingfrom are mediatedbyestradiol(E2).ThisstudyusedtwolowdosesofdailytransdermalE2geltoassesstheeffects on Objective Abstract University ofSydney, ConcordHospital,Concord,NSW, Endocrinology, 1 Jeffrey D Zajac Nicholas Russell -controlled trial therapy forprostate cancer:arandomized men undergoingandrogen deprivation Short-term effects oftransdermalestradiolin Department ofMedicine(AustinHealth),TheUniversityMelbourne,Heidelberg,Australia, https://doi.org/10.1530/EJE-17-1072 www.ej Clinical Study e-online.org : 28-dayrandomised,placebo-controlledtrial. : E2significantlyraised serumE2frombaselinetoday28comparedplacebointhe0.9 : 37participantswererandomisedtoeither0.9or1.8 : Thereisincreasingrecognitionthat,inmen,somebiologicalactionsattributedtotestosterone(TS) : InmenwithcastratelevelsofE2andTS,dailytransdermalE2:0.9–1.8 3 1 Pharmacy Department,AustinHealth,Heidelberg,Australia,and , 2 1 ). GnRHanaloguesproduce castrate levels , 2 1 , David J Handelsman , 2 , Rudolf Hoermann pmol/L; interquartilerange:157–332)andinthe1.8 5 © 2018EuropeanSociety ofEndocrinology N Russellandothers 1 , Ada S Cheung 4 and Printed inGreatBritain Mathis Grossmann 1 , 2 , Michael Ching has progressivelybeenreplaced bymedicalcastration, advanced prostatecancerin the1940s,surgicalcastration report ofcastrationasaneffective palliativetreatmentfor men. OverdecadessinceHuggins’ NobelPrize-winning of (T),anditsmetaboliteestradiol(E2) in add-backduringADT mg of0.1%E2gelperdayormatchedplacebogel. Published byBioscientifica Ltd. 4 ANZAC ResearchInstitute, 1 , 2 2 Department of 3 , mg dosegroup(median:220 mg increasedmedianserumE2 Downloaded fromBioscientifica.com at09/23/202110:07:18AM (2018) Endocrinology European Journal of [email protected] Email to NRussell should beaddressed Correspondence 178

178 :5 , 565–576

pmol/L; mg 565 –576 via freeaccess European Journal of Endocrinology www.eje-online.org Health, a tertiary referralhospitalaffiliatedwithThe Health, atertiary controlled, multi-arm,parallel-group trialatAustin We conducteda 28-day, randomised,blinded,placebo- Subject andmethods (IGF-1). resistance and lower insulin-like growth factor 1 of life, reduce biomarkers of resorption, reduce that E2treatmentwouldimprovehotflushesandquality of castrate circulating T concentrations. We hypothesised assess biological effects of E2 occurring in the presence analog treatment.Thisprovidedtheopportunity to suppressed endogenousE2productionduetoGnRH circulating E2concentrations inmenwithPCa 0.9 and1.8 doses ofdailytransdermalE2gel(providingrespectively men. circulating E2achievedby transdermalE2dosinginolder or .Furthermore,littleisknownaboutsteady-state may haveotherundesirableeffects,suchasgynecomastia even transdermalE2,ifgivenatsupraphysiologicdoses pro-thrombotic hepaticfirstpassmetabolism,however, Transdermal E2, in contrast to oral E2 is not subject to back’ approach( enrolling 12–25 men have tested the low-dose E2 ‘add- ADT usingGnRHanalogs( patches alonetoproducecastrateTlevelswithstandard ofADTcomparinghigh-doseE2viatransdermal controlled trial (RCT) designed to assess the safety and in thePATCH study, aphase2single-blindedrandomised to mitigateadverseeffects( addition toGnRHanalogs to restoreE2levelssufficient (replacing GnRHanalogs)orlow-doseE2‘add-back’in use ofhigh-dosetransdermalE2asasolemodeADT effects ofADT( E2 tomitigatethebone,brainandmetabolicadverse deficiency ( are duetoestrogendeficiencyaswellandrogen recognition thatsomecomponentsofmedicalcastration clotting factors( withconsequentupregulationofliver-derived attributed tohepaticfirstpassmetabolismofingested superseded duetoincreasedthromboembolicevents High-dose oralestrogentreatmenthasbeenlargely using GnRHanalogstoachievecastrateTlevels( initially usinghigh-doseoralestrogensbutmorerecently Clinical Study This RCTwasdesignedtoassesstheeffectsoftwolow ofPCacombinedwith The longnaturalhistory 6 mg E2perday)compared with placeboon ) hasrenewedinterestintheuseofnon-oral 7 3 10 , , 8 5 , ). Two alternativeapproachesarethe ). 11 , 12 ), andtheseRCTs usedoralE2. 9 ). Theformerapproachisused 8 ). OnlytwosmallRCTs, N Russellandothers 3 , 4 ). preregistered withtheAustralianNewZealandClinical provided writteninformedconsent.Thetrialwas committee (HREC/16/Austin/89)andeachparticipant orillicitdrugabuse. months;glucocorticoidtreatment; within12 transient ischaemicattack,myocardialinfarction or blood pressure ranelate use; systolic bloodpressure ; ,antiresorptiveorstrontium (VTE); breastcancer;humanimmunodeficiencyvirus (ECOG) Cooperative OncologyGroupPerformanceStatus mellitus;impairedperformancestatus(Eastern weeks.Exclusioncriteriawere PCa foraminimumof4 receiving GnRH agonistsorantagonists for non-metastatic wereeligibleforthestudyiftheyhadbeen 55–85 years outpatient clinicsfromJune2016toJuly2017.Menaged University ofMelbourne.Participantswererecruitedfrom for thedurationofstudy. Blindingwasremoved blinding ofparticipants, investigators andclinicians allocation withineachvolume groupandmaintained chest orupperarms.This process concealedtreatment use the specified volume once daily on the of the labelled as‘estradiolorplacebo’,withinstructions to dose syringesbypharmacyanddispensedtopatients E2 andplacebowerere-packagedintoidenticalmetered- and matchedtheE2gelforcolour, smellandconsistency. was a- (Fresenius Kabi, North Ryde, NSW, Australia) Pharmacare, StLeonards,NSW, Australia).Placebogel clinical involvementinthetrial. scheme administeredbyaninvestigator(MC)withno performed usingacomputer-generatedrandomization in aratioof2:1.ThefinalallocationtoE2orplacebowas randomisation, usingblocksofsize3,toE2orplacebo volume group,participantswereallocatedbyrestricted to adailygelvolumeof1or2 (coin toss),participantswerethenallocatedina1:1ratio or into categoriesbeloworabovetheclinicmedian( participants werestratifiedbybodymassindex(BMI) day. Randomisation( E2 2 (0.9 groups: E2 1 fashion, to one of four intervention reporting arandomisedtrial. the CONSORTchecklistofinformationtoincludewhen Trials (identifier 12616000373471). Registry We followed Estradiol add-backduringADT > The trialprotocolwasapprovedbythelocalethics E2 gel was Sandrena 1 Participants wererandomlyallocated,inaconcealed mg) perdayormatchingplacebo 1 29 kg/m mL (1.8 >

1); pastorcurrentvenousthromboembolism 2 ); secondly, usingsimplerandomisation mg) perdayormatchingplacebo2 >

100; symptomaticheartfailure;, i. 1 Fig. Downloaded fromBioscientifica.com at09/23/202110:07:18AM ) occurredasfollows:first, mg/g estradiol (Aspen mL; thirdly, withineach 178 > :5

160 ordiastolic mL perdayor 566 mL/ ≤ mL 29 via freeaccess European Journal of Endocrinology at eachvisit.Serumwasstored at Events, version4.03( according to Common Terminology Criteria for Adverse supplementation status.Adverse eventsweregraded not tomakechangestheirVitamin Dorcalcium calciumintakeof1300 daily dietary given standardwrittenadvicerecommending a volume was recorded to assess adherence. Men were described ( was derivedfromhotflushfrequencyandseverity as Average21–28 oftheintervention. dailyhotflushscore priortogelcommencementandduring days the 7 days asdescribedbyLoprinzi a hotflushdiary indicating betterqualityoflife.Participantscompleted grades qualityoflifefrom0to156,withhigherscores to ascertaintreatmentsideeffects.FACT-P totalscore the FACT-P questionnaire ( Ateachvisit,mencompleted 28 oftheintervention. had beencleanedandlocked. immediately priortodataanalysis,afterthedatabase represented ineachofthe4interventiongroups,A,B,C,andD. (1ml/2ml) ormatching-volumeplacebo(step2).MenwithBMIaboveandbelowtheclinicmedianof29werethusequally toss togel1mLor2mL(step1)andsecondly, bycomputer-generated randomisationalgorithm,ina2:1ratio(blocksize3),toE2 Study diagram.ParticipantswerestratifiedbyBMI(≤29or>29).Withineachcategory, menwerefirstrandomisedbycoin Figure 1 Clinical Study Gel syringeswerecollectedatday28andresidual Participants wereseenatbaseline,anddays14 Fasting morningpre-doseblood samplesweredrawn 13 ). 14 ). 12 ) and were interviewed ) andwereinterviewed N Russellandothers − 80°C forbatched mg andadvised et al. ( 13 ) for telopeptide (CTX)andpro collagentype1amino- assay CV3.9–19.5%. Cobas 8000,RocheDiagnostic International),withinter was measuredbychemiluminescent immunoassay(Roche standard methodologies.Atbaseline,25-OHVitamin D3 (LDL)cholesterolwerecalculatedusing of insulinresistance(HOMA2-IR)( Austin Health.Updatedhomeostaticmodelassessment Department, standard methodologiesattheBiochemistry lipoprotein (HDL)cholesterolweremeasuredusing c-peptide, IGF-1,triglyceridesandtotalhigh-density (LH), follicle-stimulatinghormone(FSH),insulin,glucose, including hemoglobin,hematocrit,luteinisinghormone of qualitycontrolsamples. respectively for within-run reproducibility at three levels (DHT). CVswere5–10%,4–9%,2–8%and7–13% for Tand0.350.17 11 and 4 and detectionwere1811 (LC–MS)( mass spectrometry analysis ofsexsteroidprofilebyliquidchromatography Estradiol add-backduringADT Serum betacarboxyl-terminal type1collagen At baselineandday28,hematologybiochemistry pmol/L for (E1); 0.10 and 0.03 Downloaded fromBioscientifica.com at09/23/202110:07:18AM nmol/L fordihydrotestosterone 15 pmol/L respectivelyforE2; ). Limitsofquantification 16 178 ) andlow-density www.eje-online.org :5 nmol/L 567 via freeaccess European Journal of Endocrinology www.eje-online.org E2 groupsshowingcomparable outcomeswerecombined in caseoffrequencydata. For furtheranalysis,thetwo Wallis testformore thantwogroupsorFisher’s exacttest Wilcoxon–Mann–Whitney testfortwogroups,Kruskal– group differencesweretested usingtheexactunpaired limit of detection value for data analysis. Between- Undetectable steroidconcentrationswereassignedthe data arereportedasmedian(interquartilerange). Main outcomeswerenon-normallydistributed,and Statistical analysis were similar, asexpected. combining thetwoE2groups,providedtheiroutcomes 17 participants( frequency of7withastandarddeviation7,requiring of hotflushes,weaimedtodetectachangeindaily outcomean alphalevelof0.05.Forthesecondary with apooledstandarddeviationof100 reporting a substantial increase inE2levelsof150 treated menbasedondatafromtheliterature( circulating E2concentrations betweenE2andplacebo- the trialwithapowerof80%todetectdifferencein We determinedthat8menpergroupwouldprovide Power analyses . markers, hotflushesandprostatecancer-specific gonadotrophins, HOMA2-IR,IGF-1,boneremodelling serum sex steroidsmeasuredbyLC–MS(T, DHT, E1), outcomes werechanges,baselinetostudyend,inother for the symptomatic outcome. Pre-specified secondary respective placebogroupandcombinedthegroups from baselinetoday28ineachE2groupwithits We reportserumE2concentrationsinthe4groups by LC–MSandthechangeindailyhotflushscore. E2 concentrationfrombaselinetoday28measured outcomesweretheserumThe pre-specifiedprimary Study designandpre-specified outcomes osteoblastic boneformation. osteoclastic activityandP1NPreflectingsubsequent basic multicellular units, with CTX primarily reflecting different componentsofcoupledboneremodellingby 2.5–3.9%. CTXandP1NParebiomarkersreflecting Diagnostic International)withinterassayCVsof and day 28 on a Roche Cobas e602 platform (Roche terminal propeptide(P1NP)weremeasuredatbaseline Clinical Study 17 ). Thisappearedtobeachievableby N Russellandothers pmol/L, at pmol/L 10 , 12 ) In our clinic database,we identified 48menmeeting Results lmerTest 2.0–36( ( using thestatisticalbasepackageR,version3.4.3forMac denoted statisticalsignificance.Analyseswereconducted plus 95% . Two-sided reported asrobustmeanadjusteddifference(robustMAD) trial betweentheE2groupandplaceboare Outcomes refer to the change from start to the end of the secondary outcomes. secondary were combined to increasepowerintheanalysisof groups andintheE2 respectively, thesegroups there werecomparableE2concentrations intheplacebo of 1008 prescribed doses were administered. Because from the36participantswhocompletedfollow-up,1003 (data notshown).Basedoninspectionofreturnedsyringes participant BMI,ageordurationofADTatenrolment no associationbetweenday28E2concentrationand 220 and 96–1814 (median: 208 from 106to870 and from baselinetoday28comparedplacebo( altered duringthestudy. hot flushes,butthesemedicationsortheirdoseswerenot (19%) werereceivingmedicationfromclassesusedtotreat 11 was 0.2 months).BaselinemedianT months,range:1–120 3 months(median: (49%) receivingADTformorethan3 1 Table visit ( randomised with1losstofollow-upaftertheday14 ( ( excluded onthebasisofpriorvenousthromboembolism the inclusioncriteriaofstudy. Elevenmenwere freedom weredeterminedbySatterthwaite’s method( outliers andadjustedforbaselinevalues( model toaccountforbothwithin-subjectvariationand referred toastheE2group.We usedarobustlinearmixed placebo groups.ThecombinedE2groupissubsequently to increasepowerandcomparedwiththecombined Estradiol add-backduringADT 18 n n ECOG =1), = pmol/L (rangeundetectableto65 ) with the added packages robustlmm 2.1–4 ( 2) orrefusaltoparticipate( pmol/L; interquartilerange:144–660).Therewas Both dosesofE2significantlyraisedserum Baseline characteristics by group are shown in al 2 Table Fig. 1 atcpn g ag a 08 yearswith18 . Participantagerangewas60–83 nmol/L (rangeof0.04–0.9 ). ). Day28serumE2 concentration ranged pmol/L inthe1.8 > pmol/L; interquartilerange:157–332), ( 1 20 n ). pmol/L inthe0.9

= 1), inabilitytoconsentinEnglish Downloaded fromBioscientifica.com at09/23/202110:07:18AM mg dosegroup(median: n ) Tit-ee were Thirty-seven =7). nmol/L) andE2was pmol/L). Sevenmen 178 :5 mg dosegroup 18 P values ). Degreesof 19 i. 2 Fig. < 568 ) and 0.05 19 via freeaccess ).

European Journal of Endocrinology GnRH analogueduration PCa stage FACT-P totalscore ECOG Prior strokeorMI Age serotonin reuptakeinhibitor;SNRI,Selectiveserotonin-noradrenaline inhibitor;SBP, Systolicbloodpressure;TS,Testosterone. Gonadotrophin-releasing hormone;IQR,Interquartilerange;LH,LuteinizingMI,Myocardialinfaction;PCa,ProstateCancer;SSRI,Selective Oncology GroupPerformanceStatus;FACT-P, FunctionalAssessmentofCancerTherapy–Prostate;FSH,Follicle-stimulatinghormone;GnRH, 25OH-Vit D3,25-hydroxyVitaminD3;BMI,BodyMassIndex;DBP, Diastolicbloodpressure;E1,Estrone;E2,Estradiol;ECOG,EasternCooperative a 25OH-Vit D3(nmol/L) E1 (pmol/L) E2 (pmol/L) FSH (IU/L) LH (IU/L) TS (nmol/L) Hot flushscores DBP (mmHg) SBP (mmHg) BMI (kg/m of 18 participants from theplacebo arm answered this question wasnotanswered byallparticipants.Thirteen return in completing participants, this additionaldiary Although therewas100% compliancewithhotflush their assignedtreatmentimproved hotflushesornot. day 28,blindedparticipantswereaskedtoindicate if at enrolmentandbaselinescore(datanotshown).At P placebo group(robustMAD: The scoredeclinedintheE2group,comparedwith Averaged dailyhotflushscoresareshownin Hot flushes Table 1 FACT-P totalscoreisaprostatecancer-specific qualityoflifescorerangingfrom0to156,withhigherscoresindicatinggreaterlife. (months)

= Clinical Study iai D Vitamin recurrence/ Biochemical advanced Locally Localised 1 0 Average dailyscore Average dailyfrequency Fish Ezetimibe Statin Gabapentinoid Clonidine SSRI/SNRI Calcium

salvage 0.02). TherewasnoassociationbetweenADTduration

Baseline characteristicsbygroup.Dataarepresentedasmedian(IQR). 2 ) a 0.30 0.23–0.82 Placebo (1 77.0 (68.8–106.0) 0.26 (0.22–0.53) 29.3 (27.6–32.0) 76.2 (73.4–79.4) − 164 (134–194) 138 (127–140) 128 (123–133) 2.9 (2.2–4.7) 2.7 (0.00–6.2) 2.1 (0.00–5.1) 8.5 (2.3–18.5) 11 (11–11) 80 (76–82) 2.2 (95%CI: N Russellandothers A 1 0 0 2 0 0 0 0 1 3 2 2 2 0 6 1

mL) ( n

=

6) − 3.6 to 74.9 (68.9–75.5) 77.0 (61.8–99.2) 0.10 (0.10–0.32) 0.14 (0.11–0.22) 28.8 (27.0–34.4) i. 3A Fig. 122 (118–132) 151 (116–216) 126 (120–142) E2 (1 3.0 (1.8–10.2) 3.6 (2.7–4.3) 1.4 (0.21–6.6) 1.1 (0.11–4.1) 11 (11–11) 80 (78–83) − 0.8;

mL) ( B 6 0 0 1 1 1 5 7 2 3 4 8 2 2 1 0 . n

=

12) groups inFACT-P totalscoreorsubscales measuring there werenosignificantchanges betweenE2andplacebo group and124( Baseline median(IQR)scores were122( Quality oflife indicated thatthetreatmentwashelpful( a totalof21participantanswerswhich16(76%) who did not answer this question in theE2 arm for was helpful.There1dropoutand2participants question, with3(23%)indicatingthattheirtreatment Estradiol add-backduringADT Placebo (2 72.7 (66.7–74.5) 72.0 (60.5–73.0) 0.10 (0.10–0.40) 0.21 (0.16–0.31) 29.0 (26.2–29.9) 121 (118–124) 124 (98.0–216) 147 (141–148) 2.0 (1.0–9.5) 3.0 (2.4–4.4) 1.9 (1.6–5.4) 1.7 (1.3–5.4) 11 (11–11) 82 (78–87) C 2 0 0 0 1 1 1 5 3 0 0 7 1 1 0 0

mL) ( 120 n

– =

128 7) ) intheplacebogroup.Atday 28, Downloaded fromBioscientifica.com at09/23/202110:07:18AM 12.0 (1.0–20.2) 71.4 (68.7–79.1) 88.5 (74.2–121) 0.10 (0.10–0.20) 0.17 (0.16–0.19) 29.0 (26.6–29.7) 124 (118–134) 115 (83.0–138) 131 (129–141) 3.6 (2.3–4.2) 4.3 (3.1–13.0) 3.3 (2.6–6.8) E2 (2 11 (11–11) 78 (74–81)

mL) ( 11 D 2 0 0 1 3 2 3 6 3 3 1 1 0 1 0 n

= 178

12) 118 www.eje-online.org :5 – P 133 P

value =

0.007). ) intheE2 0.449 0.312 0.892 0.996 0.208 0.063 0.494 0.609 0.590 0.131 0.766 0.485 1.000 0.378 1.000 0.401 1.000 0.501 0.573 0.750 0.579 0.174 1.000 0.617 – – –

(overall) 569 via freeaccess European Journal of Endocrinology www.eje-online.org CI, Confidenceinterval;E2,Estradiol; IQR,Interquartilerange. P Day 28 Day 14 Baseline detection wereassignedthevalueoflimit(11 Table 2 in P1NP( compared toplacebo,withasmallerrelativeincrement lipids. CTXdecreasedsignificantlyintheE2group haemoglobin, glucose, insulin, HOMA2-IR,IGF-1or small increaseinserumLH.Therewasnochange and SHBGdecreasedserumFSHwithapossible T andDHT( different betweencombinedE2andplacebogroupsfor endpoints, changesfrombaselinetoday28werenot For h-ematologicalandbiochemicalsecondary Laboratory secondaryendpoints symptoms (datanotshown). being, functional well-being or prostatecancer-specific social well-being,physicalemotionalwell- E2 concentrationbytreatmentassignmentandtimepoint. Figure 2

value E2 pmol/L C vsD: A vsB: Clinical Study 1000 1500 500 0 < < E2 (pmol/L)medianandinterquartilerangebytreatmentassignment andtimepoint.Values belowthelowerlimitof D0 Fig. 3B 0.001 0.001 Placebo 1mL D14 Table 3 D28 and ). E2treatmentincreasedserumE1 D0 C E2 1mLP and D14 Placebo (1 11 (11–11) 11 (11–11) 11 (11–11) D28 Table 3 11–103 11–65 11–11 A N Russellandothers mL) ( D0 lacebo 2mL ). D14 n =6) D28 D0 E2 2mL D14 D28 E2 (1 208 (157–332) 139 (99–175) 11 (11–11) pmol/L). 106–870 74–525 11–50 mL) ( B young and older men using the same laboratory andLC– young andoldermenusingthesamelaboratory that havebeenderivedfrompopulation-basedcohortsof compared ourfindingstoreferencerangesforserumE2 of menwithPCanotundergoingADT. Therefore,we ADT, itwasnotpossibletoincludeamatchedgroup analogue treatment. Due to the inherent indication for concentrations in men with castrate T levels due to GnRH daily dosesofboth0.9and1.8 This short-termRCTfoundthattransdermalE2gelin Discussion were noincidentcardiovascularorVTEevents. day 28.Noparticipantdevelopedbreastswelling.There grade 1nippletendernessbyday14,whichpersisteduntil E2 2 One participant(8%)intheE21 Adverse effects reference rangesforyoungandoldermen.Maximum groupswerewithinthereported in theintervention ( 22–174 pmol/L years),22–166 (65–75 were 38–196 age-specific centiles, derived malereference ranges for E2 Australian population-basedstudiesreportingsmoothed ( median serumE2was86 ( 147 young Australianmenaged19–22, median serumE2was MS assay. Estradiol add-backduringADT 22 21 n =12) ). In a pooled analysis of over 10 000 samples from 3 ). In a pooled analysis of over 10 000 ). Inastudyof325healthyolderAustralianmen, pmol/L (95% confidence interval 57–273 pmol/L (95% confidence interval In ourstudy, minimumandmedianE2concentrations In theRaineBirthCohortStudyof382healthy mL group and none in the placebo group developed pmol/L (menaged > 85 years) ( Placebo (2 Downloaded fromBioscientifica.com at09/23/202110:07:18AM 11 (11–11) 11 (11–11) 11 (11–11) pmol/L (95%CI39–153 mlL(58 years)and pmol/L (75–85 11–18 11–27 11–13 23 C mL) ( ). < mL group,2(17%)inthe 65 years), 23–154 pmol/L 65 years), n mg increasedserumE2 =7) 178 :5 E2 (2 D 220 (144–660) 170 (113–586) 11 (11–11) 96–1814 87–1083 11–17 mL) ( pmol/L) pmol/L) 570 n =12) via freeaccess European Journal of Endocrinology the box.Thepointsareindividual outliers.(A)Average daily interquartile rangebelowand above thebottomandtopof percentiles respectively. Thewhiskersextend 1.5timesthe lower andupperbordersofthe boxesarethe25thand75th Box-and-whisker plots.Thedarklinesshowthemedian, Figure 3 C B A

P1NP mcg/L CTX ng/L Average Daily Hot Flush Score Clinical Study 1000 1500 100 500 10 20 30 40 50 50 0 Baseline Day 0 Day 0 Placebo Placebo Placebo Day 28 Day 28 End N Russellandothers Day 0 Baseline Day 0 E2 E2 E2 Day 28 Day 28 End compared withplacebogroup was 8.9μg/L(5.0–12.7), 95% CI).Robustmeanadjusted difference ofE2group (−130 to−84), of E2groupcomparedwithplacebo groupwas−107 and day28(median95%CI).Robustmeanadjusteddifference placebo groupwas−2.2(−3.6to−0.8), mean adjusteddifference betweenE2groupcomparedand hot flushscoreatbaselineandend(median95%CI).Robust metabolised. absorbed E2thathasnotbeendistributed to tissuesor serum E2reflectsthatcomponentoftranscutaneously minimal duetothesuppressionofcirculating TS,and GnRH analoguesemployedhere, context of pharmacologic E2 add-back in men receiving tissue metabolismanddiffusedintotheblood( proportion oftotalsynthesisedE2thathasescapedlocal occurring inhealthymen,serumE2onlyreflectsthe ( 1788 pmol/L) higher (median685 the transdermalE2armofPATCH trialwerealso to 4500 for ADT in men with PCa, reported to range from 1400 intramuscular polyestradiolphosphateusedpreviously are substantially lower than those achieved with high-dose reference limits.Overall,theseserumE2concentrations concentrations rangedfrom3to7timestheupper circulating levelsachieved. between meanCminandCmaxwidevariability in ( ( reports ofE2gelapplicationinpostmenopausalwomen circulating hereisconsistentwith E2levelsobserved inthisstudy.observed Notably, thevariabilityin for thesubstantialvariabilityincirculating E2levels participants hadhigherendogenousE2levels. in thisstudy( male serumE2comparedwithLC–MSmeasurementsused performed withanE2immunoassay, whichoverestimates estimate serumE2bothbecausethemeasurementswere up to514 and peakserumE2levelsat2 elevated serumE2levelscomparedwithplaceboat1 Pharma) in8healthyyoungmenproducedsignificantly A single2 of transdermalE2gelonserumconcentrationsinmen. Estradiol add-backduringADT 30 29 ), andTgelinmen( , In thecontextof We areunabletodefinitivelyexplainthemechanism We areawareofonlyonestudyassessingtheeffects 30 ). Evenwithsteady-statedosingofE2gelinwomen pmol/L ( pmol/L) ( mg doseoftransdermalE2gel(Divigel,Orion P 28

< 25 0.001. (C) P1NP at day 0 and day 28 (median 0.001. (C)P1NPatday0and 28(median ) aswellthefactthatnon-castrate ). 24 27 in vivo ). ReportedE2concentrationsin pmol/L, 5th–95thpercentile: 350– ). Thosefindingsarelikelytoover- Downloaded fromBioscientifica.com at09/23/202110:07:18AM 31 E2synthesisbytissuearomatase ), thereare2-folddifferences h (mean290 in vivo P

= 178 0.02. (B) CTX at day 0 0.02. (B)CTXatday0 www.eje-online.org :5 E2synthesisis pmol/L, range 26 ng/L ng/L P ). Inthe <0.01. 571 via freeaccess h European Journal of Endocrinology www.eje-online.org what extentlong-term low-dose transdermal E2 add-back of menreceivingGnRHanalogues ( analogues, experiencedgynaecomastia comparedto19% to inducecastrate TS concentrations without GnRH receiving ahigh-dosetransdermal E2regimen,sufficient placebo gelinthisstudy. InthePATCH trial,75%ofmen 0.9 dosing considerationsinsuchmen. they mayhaveclinicalimplicationsregardingoptimalE2 examine thesehypotheses.Futurestudiesshoulddoso, as with E2levels,butourstudywasnotdesignedtorigorously our study, BMIanddurationofADTwerenot correlated include durationofpriorhypogonadismandfatmass.In doses. 1.8 mg was substantialoverlapinlevelsachievedwith0.9and E2. AgedidnotcorrelatewithserumE2levels,andthere contributed tothebetween-personvariabilityinserum the timebetweenlastdoseandbloodsamplingmayhave the gelatvarioustimesduringpreviousdaysothat have applied the disallowed morning dose or had applied morning bloodtest,itispossiblethatsomemenmay to withholdtheirdosepriordays14and28 addition, whileparticipantsinourstudywereinstructed transcutaneous absorptionandmetabolismofE2.In TS (nmol/L) median (IQR). Table 3 HOMA2-IR Insulin (IU/L) FBGL (mmol/L) SHBG (nmol/L) FSH (IU/L) LH (IU/L) DHT (nmol/L) binding globulin;TS,Testosterone; TG,. cholesterol; LH,Luteinizinghormone;MAD,Meanadjusteddifference; P1NP, procollagentype1amino-terminalpropeptide;SHBG,Sexhormone- Homeostatic ModelAssessmentofInsulinResistance;IGF-1,Insulin-likegrowthfactor1;IQR,Interquartilerange;LDL-C,Low-densitylipoprotein Estradiol; FBGL,Fastingbloodglucoselevel;FSH,Follicle-stimulatinghormone;HDL-C,High-densitylipoproteincholesterol;HOMA2-IR,Updated CI, Confidenceinterval;CTX,betacarboxyl-terminaltype1collagentelopeptide;D0,Day0;D28,28;DHT, ;E1,Estrone;E2, a P1NP (µg/L) CTX (ng/L) TG (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) IGF-1 (nmol/L) E1 (pmol/L) MAD wasnotestimableduetosingularity. Clinical Study mg, 2of12menreceiving1.8 Nipple tenderness was noted in 1 of 12 men receiving Other factorscontributingtoE2variabilitymight variabilityislikelyduetodifferencesin Observed Change frombaselinetoendinmenreceivingE2comparedwithplacebo.Dataarepresentedas 0.16 (0.13–0.20) 21.3 (17.6–24.1) 1.48 (1.23–1.82) 10.8 (9.1–14.0) 0.17 (0.17–0.17) 131 (91–160) 552 (408–757) 4.8 (4.5–5.2) 3.6 (2.3–4.2) 0.1 (0.1–0.2) 1.4 (1.2–2.0) 1.6 (1.3–1.8) 2.9 (2.2–3.6) 65 (45–70) 58 (38–68) Combined E2groups D0 N Russellandothers 0.17 (0.13–0.24) 18.8 (16.2–23.7) 1.36 (1.00–1.96) 10.8 (7.9–15.8) 0.17 (0.17–0.17) 706 (435–923) 433 (334–541) mg andnoneusing 8 4.9 (4.6–5.4) 0.9 (0.7–1.5) 0.1 (0.1–0.4) 1.3 (1.2–1.7) 1.6 (1.5–1.7) 2.5 (2.0–3.6) 82 (51–89) 66 (45–82) ). Itisunknownto ( n D28 =24) 0.26 (0.18–0.33) 18.2 (16.2–22.9) 1.29 (1.17–1.42) 0.17 (0.17–0.17) 144 (122–198) 505 (449–527) 9.9 (8.9–10.9) 5.1 (4.8–5.2) 3.0 (2.1–4.5) 0.2 (0.1–0.6) 1.0 (0.9–1.2) 1.6 (1.4–1.9) 2.2 (1.8–3.1) 70 (56–86) 51 (40–57) Combined placebogroups D0 35 reduced quality of life in men undergoing ADT ( increased hotflusheswith sleepdisturbance( flushing. Yet, despiteprevious reports associating men continuingtoreceive othermedicationsforhot selecting menfortroublesomehotflushingorexcluding This beneficialeffectoccurreddespitethestudy not reported beneficialeffectsthanthosereceivingplacebo. corroborated bythefactthatmoremenreceivingE2 for dailyhotflushscore( There weresubstantialimprovementsintherobustMAD Hot flushesandqualityoflife outcomes inmenwithPCareceivingADT. increasing circulating E1 has relevance for clinical longer-term studiesareneededtodeterminewhether deterioration inself-ratedhealthstatus( dwelling men,lowcirculating E1butnotE2predicteda For example, ina longitudinal study of 1637 community- have associatedlowE1withadversehealthoutcomes. studies potent bioactiveoestrogen,someobservational 17 hydroxysteroiddehydrogenase.WhileE2isthesole expected givenE2andE1undergointerconversion by that causedbyGnRHanaloguesalone. will increasetheincidenceofbreastadverseeffectsabove Estradiol add-backduringADT ), thesebenefitsdidnot translate intoadetectable The increaseincirculating hereis E1observed 10.6 (8.0–13.4) 0.19 (0.16–0.26) 1.33 (1.05–1.77) 0.17 (0.17–0.17) 15.1 (14.7–20.1) 506 (480–594) 159 (110–182) 5.0 (4.7–5.4) 3.9 (2.5–4.5) 0.1 (0.1–0.2) 1.2 (0.9–1.5) 1.6 (1.6–2.0) 2.5 (1.8–3.2) 68 (62–81) 50 (44–57) D28 ( n =13) Downloaded fromBioscientifica.com at09/23/202110:07:18AM − − − − − − 0.06 ( 11.6 (6.6–16.5) 0.18 (0.05–0.32) 0.03 ( i. 2A Fig. 0.14 ( 0.19 ( 0.16 ( 0.37 ( Robust MAD 107 ( 671 (583–758) 8.9 (5.0–12.7) 1.0 ( 2.3 ( 0 ( − − − − − − − − − − 0.6 to0.7) 0.19 to0.30) 2.9 to 0.01 to+0.07) 130 to 0.15 to0.15) 0.39 to0.01) 0.26 to 2.3 to1.5) 0.32 to0.04) N/A ) withE2treatment 178

a (95% CI) :5 − − − 1.7) 32 84) 0.07) ). Largerand 33 For MAD

< < < < < P value N/A 0.43 0.66 0.001 0.001 0.01 0.001 0.16 0.01 0.001 0.14 0.08 0.001 0.98 0.71 ) and 572 34 a via freeaccess , European Journal of Endocrinology or phosphatelevelsin Vitamin Dsupplementation. P1NP withE2treatment,without changesinPTH,calcium There weresignificantreductions inCTXandincreases Biomarkers ofboneremodelling controversial ( direct non-reproductive biological roles ofFSHremain of ADThavebeenproposed( tumour progressionandbonemetabolicsideeffects phenomenon is not known. Direct roles of FSH in levels ofT. WhetherthisFSHescapeisaclinicallyrelevant E2 hasFSH-suppressiveeffectsinmenwhohavecastrate ( decline ininhibinBseenduringGnRHagonisttreatment negative feedback on FSH from the progressive long-term long-term GnRHagonistuseandattributedtolossof ( further reducedinmenreceivingE2butnotplacebo by studyE2treatment,thelowbaselineserumFSHwas the pre-studyGnRHanaloguetreatmentand unaffected Although baselineTSandDHTwerefullysuppressedby andgonadotrophins function atthecostofmoregynecomastia. assigned toE2hadlessdeclineinphysicalandsexual difference in hot flushes between arms, although men PCa ( analogues for treatment of locally advanced or metastatic life inmenreceivingtransdermalE2ratherthanGnRH PATCH indicatelessseveredeclinesinglobalqualityof in treatingvasomotorsymptoms.Furthermore,datafrom non- ADTforPCahavealsosuggestedabenefit a synthetic non-steroidal estrogen, in men undergoing studies ( effects ofE2intheabsenceTSdirectly. Uncontrolled placebo controlforthedrug,whereasourstudytested by drug-inducedaromataseinhibitionbutwithouta ( the predominanttriggerforvasomotorsymptomsinmen indicating thatE2deficiency, notandrogendeficiency, is graded TSadd-backwithorwithoutaromataseinhibition, of inducedhypogonadisminhealthyyoungmenwith comparison withothermenPCa( of lifewasalreadyrelativelyhighinourcohortby short durationofthisstudyorbecausebaselinequality disparity may be dueto a lack of power because of the improvement inoverallquality-of-lifescores.This 37 41 Table 3 Clinical Study , ). However, that study inferred E2 effects indirectly These dataareconsistentwithanexperimentalstudy 42 34 ). Thesepresentfindingsindicatethatexogenous ). So-called‘FSHescape’hasbeendescribedduring ). Thiseffectseemedtobedrivenprimarilybya 38 , 39 44 ) andasmallRCT( ). 43 ). However, theproposed N Russellandothers 40 ) ofdiethylstilbestrol, 36 ). Hepatic protein synthesis bonedensity.or preserve todeterminewhetherthisstrategywillimprove necessary analogue treatment,longer-termtreatmentwillbe approach oflow-doseE2add-backinadditiontoGnRH compared withGnRHanalogue( bone densityformenreceivinghigh-dosetransdermalE2 the PATCH study have indicated a beneficial effect on E2-dependent effect ( lines ofevidencesuggestthisislargelybutnotsolelyan results inacceleratedboneremodelling,andmultiple receiving GnRHanalogues.Inmen,sexsteroiddeficiency suggests anantiresorptiveeffectofE2add-backinmen men ( healthy decrease inboneformationolderotherwise reverse, i.e. an increase in bone resorption and transient with thefactthatacutely, medicalcastrationproducesthe The acute effect with E2 add-back seen here is consistent such effects. this hypothesis,itmayhave beentooshorttodetect ( beneficial effectsbyreducing visceralfataccumulation effects ( to contributethesebodycompositionandmetabolic Combined deficiencyofandrogensandestrogensislikely sensitivity ( fat mass( by HOMA2-IR.ADTreducesmusclemassandincreases glucose, insulin,c-peptideorinsulinresistanceestimated We nodifferences infastinglipids,blood observed Insulin resistance andlipid are neededtoconfirmthatE2treatmentissafe( risk ofthromboembolic events, although larger studies in thePATCH trialwasnotassociatedwithanincreased transdermal E2( factoractivationwith andinflammatory alackof in thisstudybutpriorstudieshaveobserved hepatic E2 effect. We didnotmeasure clotting factors a small,butsignificantincreaseinSHBGconsistentwith cytokines andbindingproteins( synthesis ofSHBG,clottingfactors,inflammatory (or highparenteral)dosesofestrogensincreasehepatic with supraphysiologicalhepaticestrogenexposure.Oral while highparenteralE2dosescanachievesimilareffects hepatocytes tonon-physiologicalestrogenconcentrations, Due tofirstpassmetabolism,oralestrogensexpose Estradiol add-backduringADT 6 , 52 ). Whileourstudydoesnot provide datatosupport 45 ). Thispatternofchangeinboneremodelling 6 49 ). Theoretically, E2add-backmighthave 50 ) andisassociatedwithworseninginsulin ) andincidentdiabetesmellitus( 48 ). Moreover, high-dosetransdermalE2 46 ). Notably, datafrom preliminary Downloaded fromBioscientifica.com at09/23/202110:07:18AM 5 , 25 47 ). Forthealternative 178 ). Ourstudyshowed www.eje-online.org :5 8 ). 573 51 via freeaccess ). ). European Journal of Endocrinology www.eje-online.org Healthcare. Ada Cheung has received speaker’s honoraria from Merck, Novartis, Weight Watchers, Lillyand speaker’s honoraria from Besins Mathis Grossmannhasreceivedresearch fundingfromBayerPharma, Declaration ofinterest fewer adverseeffects. here andthehypothesis that alower dose mayresult in based onthelargelyoverlappingserumlevelsachieved proceed witha0.9 in alonger-termRCT. Furthertrialswouldreasonably adverse effectsofADTduetoGnRHanaloguetreatment benefit menby mitigating bone and,possibly metabolic rationale totestthehypothesisthatsuchE2add-backwill serum FSHintheabsenceofTS.Thesefindingsprovide a with PCa,andfurthersuppressespartiallysuppressed vasomotor symptoms and bone remodelling in older men but withsubstantialvariability. E2geltreatmentreduces reference range reportedforhealthyyoungoroldermen, increases medianserumE2concentrationsintothe levels ofbothE2andTS,dailytransdermal0.9–1.8 Our study demonstrates that in men who have castrate Conclusion comparing overallmortality( efficacy fromGnRHanaloguesororchiectomy when PCa foundnoevidencethatE2treatmentdifferedin parenteral E2asADTforlocallyadvancedormetastatic a systematicreviewof20RCTs oftheusehigh-dose treatment. Whilepreclinicaldataarenotconclusive( was too short to evaluate the oncologic outcomes of E2 clinical benefits from a strategy of E2 add-back. Our study conclusions aboutthepresenceordurabilityofany small samplesizeofthisstudy, preventingdefinitive MS technology. E2 concentrationsweremeasuredbyvalidatedLC–MS/ relatively largenumberofoutcomeswereassessed,and induced aromataseinhibition( seminal workinferredE2effectsindirectlybydrug- direct actionsofE2intheabsenceT, whereasprevious effects. Moreover, thestudydesignallowedustoevaluate may beassociatedwithanincreasedriskofundesirable leads tosupraphysiologicE2concentrations,which dose E2 as a sole mode of ADT ( analogue-based ADT, whichisincontrasttousinghigh- given tomenwithprostatecancerreceivingGnRH design ofrelativelylow-dosetransdermalE2add-back Strengths ofthestudyincludeitsuniquerandomised Strengths andlimitationsofthestudy Clinical Study The principallimitationsaretheshortdurationand mg E2doseratherthan1.8 53 ). N Russellandothers 6 8 , ). The latter strategy 37 ). Inaddition,a mg dose, mg 9 ), Acknowledgements to studydesign. A SCassistedinrecruitmentandrevisedthemanuscript;JDZcontributed manuscript; MCperformedtherandomisationandrevised revised themanuscript;DJHperformedLC–MSassaysand revised themanuscript;MGdesignedtrial,analysedresultsand results and wrote the manuscript; R H performed statistical analysis and N R contributed to study design, coordinatedthe trial, analysed the Author contributionstatement Medical ResearchCouncil(#APP1099173). This trialwasfundedbyaprojectgrantfromtheNationalHealthand Funding conflict ofinterest. Russell, RudolfHoermann,andJeffrey DZajacdeclarethattheyhaveno testimony inanti-dopingtribunalsandtestosteronelitigation.Nicholas research fromBesinsHealthcareandLawleyhasprovidedexpert institutional funding for investigator-initiated testosterone pharmacology Sharpe, Dohme and Astra Zeneca. DavidHandelsman has received References an EndocrineSocietyofAustraliaPostdoctoralAward. NR issupportedbyanAustralianPostgraduateAward. ASissupportedby

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Accepted 15March2018 Revised versionreceived7March2018 Received 26December2017

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