6/4/18 12416thWCMPre-CongressWorkshop
Case2:BreastCancerintheperimenopause
Dr.MarlaShapiroC.M.CCFP,MHSc,FRCPC,FCFP,NCMP
Professor,UniversityofToronto
6/4/18 12516thWCMPre-CongressWorkshop
FinancialDisclosures
SpeakerBureau:Merck,Amgen,AMAG,Pfizer,BayerAdvisoryBoard:Merck,Amgen,Pfizer,Mithra,AMAG,GSKOther:CTVMedicalConsultant
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“TheThreeSeasonsofSurvival”
FitzhughMullanNEJM1985
Acute
Extended
Permanent
6/4/18 12716thWCMPre-CongressWorkshop
Needs of Breast Cancer Survivors
Late effect RiskRecurrence 0-100%
2nd primary 1-2%
Psychological distress 30%
Lymphedema 10-25%
Premature menopause, infertility and osteoporosis
45%
Estrogen deprivation >50%
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Needs of Breast Cancer Survivors
Late effect Risk
Weight gain 50% 2.5-5Kg20% 10-20Kg
CVS disease 0.5-1% CHF
Fatigue 30% 1-5 yrs after diagnosis
Cognitive impairment 30%
Familial risk 5-10%
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SymptomManagement
ü Women with breast cancer have many adverse symptoms, of which some are specific to premenopausal patients
ü Hot flushes: non-hormonal drugs, such as antidepressants and anti-seizure compounds
ü Vaginal dryness and dyspareunia-Non-estrogenic vaginal lubricants
ü Cancer-related fatigue- exercise
Loprinzi, C. L., S. L. Wolf, et al. (2008). "Symptom management in premenopausal patients with breast cancer." Lancet Oncol 9(10): 993-1001
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MeetJoan
• 52,3yearspostER/PRpositivebreastcancer• TAHBSO,BilateralMastectomy• Chemotherapeuticregime• Onarimidex
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Concerns
• Hotflashesandnightsweats• Whatareheroptions?
6/4/18 13216thWCMPre-CongressWorkshop
NonprescriptionProductsHave LimitedDatatoSupportEfficacyinRelievingVasomotorSymptomsAgent Study Design Efficacy Adverse Events
Soy-derived isoflavones1Systematic review of 25 randomized controlled trials of phytoestrogens (≥4 weeks) involving 2,348 symptomatic women
7 of 8 soy food trials, 3 of 5 soy extract trials, and 3 of 5 red clover trials showed no significant difference from placebo
Most common adverse events were gastrointestinal disorders
Black cohosh2N=80 late perimenopausal or postmenopausal women; 160 mg/day
No significant difference from placebo
Both groups reported gastrointestinal symptoms; nausea and vomiting; fatigue, asthenia, or malaise; and headaches
Evening primrose oil3 N=56 menopausal women; 4000 mg/day for 6 monthsNo significant difference from placebo
Minimal side effects, including slight nausea
Dong quai4 N=71 menopausal women; 4.5 g/day for 6 monthsNo significant difference from placebo
Both treatment groups reported burping, gas, and headaches
Ginkgo biloba5,6N=87 menopausal women;120 mg/day for 6 weeks5
N=31 menopausal women;120 mg/day for 1 week6
No significant difference from placebo
None reported
Ginseng7 N=384 menopausal women; 100 mg/day for 4 monthsNo significant difference from placebo
Both treatment groups reported influenza or colds, headaches or migraines, and gastrointestinal disorders
Vitamin E8Alpha E, Amino-Opti-E, Aquasol E, Aquavite-E, Centrum® Singles-Vitamin E, E Pherol, E-400 Clear, Nutr-E-Sol
N=120 women with a history of breast cancer; 800 IU/day for 4 weeks in a crossover design
No significant difference from placebo
Both groups reported headaches, fatigue, and nausea
1. Krebs EE, et al. Obstet Gynecol. 2004;104:824-836.
2. Newton KM, et al. Ann Intern Med. 2006;145:869-879.
3. Chenoy R, et al. BMJ. 1994;308:501-503. 4. Hirata JD, et al. Fertil Steril. 1997;68:981-986. 5. Elsabagh S, et al. J Psychopharmacol.
2005;19:173-181. 6. Hartley DE, et al. Pharmacol Biochem Behav.
2003;75:711-720. 7. Wiklund IK, et al. Int J Clin Pharmacol Res.
1999;19:89-99. 8. Barton DL, et al. J Clin Oncol. 1998;16:495-500.
There are limited data comparing the above referenced products to one another or to approved FDA treatments. Therefore, comparative efficacy cannot be determined based on the above.
6/4/18 13316thWCMPre-CongressWorkshopNorthAmericanMenopauseSociety.Menopause.2015;22(11).
Twomind-bodytherapieshavelevelIevidenceshowingpositiveeffectsn Cognitivebehavioraltherapy(CBT)protocols(MENOS1andMENOS2)
n Clinicalhypnosis:Elkinsprotocol
© 2015
Recommend:NonRx
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North American Menopause Society. Menopause. 2015;22(11).
n FDA-approved low-dose paroxetine salt
n Other SSRIs and SNRIs yielding significant VMS reductions in large RCTs
n Gabapentin and pregabalin
© 2015
Recommend:PrescriptionTherapies
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OtherSSRIs,SNRIs
n LargeRCTsshowsignificantVMSreductions with— Paroxetine— Escitalopram— Citalopram— Venlafaxine— Desvenlafaxine
North American Menopause Society. Menopause. 2015;22(11).
© 2015
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North American Menopause Society. Menopause. 2015;22(11).
Dependson
n Prioreffectivetherapyn Patienthistoryn Adverseeventsprofileandtoleranceofadverseeffects
n Co-administeredmedications
©2015
PrescriptionTherapies:Choice
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Concerns
• Vaginaldryness
6/4/18 13816thWCMPre-CongressWorkshop
Concerns
• Vaginaldrynessoptions………..• MoisturizersandLubricants• Vaginalestrogen• VaginalDHEAS• Lasertherapy
6/4/18 13916thWCMPre-CongressWorkshop
Concerns
• Sexualissues
6/4/18 14016thWCMPre-CongressWorkshop
6/4/18 14116thWCMPre-CongressWorkshop
Concerns
•Experiences a degree of distress and depression
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BreastCancerandDepression:TamoxifenandAntidepressantsviaCytochromeP4502D6
ü Women taking tamoxifen for the treatment or prevention of recurrence of breast cancer are likely to take antidepressants either for a psychiatric disorder or for hot flashes
ü Some antidepressants inhibit the metabolism of tamoxifen to its more active metabolites by the cytochrome P450 2D6 (CYP2D6) enzyme, thereby decreasing the anticancer effect
Desmarais, J. E. and K. J. Looper (2009). "Interactions between tamoxifen and antidepressants via cytochrome P450 2D6." J Clin Psychiatry 70(12): 1688-1697
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InteractionsbetweentamoxifenandantidepressantsviacytochromeP4502D6
2D6interaction
Fluoxetine +++ Strong:tobeavoided
Paroxetine +++ Strong:tobeavoided
Citalopram + Mild
Escitalopram + Mild:studieslacking
Bupropion +++ Strong:tobeavoided
Sertraline ++ Moderate
Fluvoxamine ++ Moderate2D6and3A4:studieslacking
Venlafaxine -/+ Minimal
Desvenlafaxine - Minimal:studieslacking
Mirtazapine + Minimal:studies lacking
Desmarais, J. E. and K. J. Looper (2010). "Managing menopausal symptoms and depression in tamoxifen users: implications of drug and medicinal interactions." Maturitas 67(4): 296-308
Desmarais, J. E. and K. J. Looper (2009). "Interactions between tamoxifen and antidepressants via cytochrome P450 2D6." J Clin Psychiatry 70(12): 1688-1697
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Concerns
• Whataboutboneloss?• Isdepressionanadditionalriskfactorforherbones?
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DepressionasaRiskFactorforOsteoporosis
ü Associationbetweendepressionandlowbonemineraldensity
üDepressionmayinducebonelossandosteoporoticfracturesü Viaspecificimmuneandendocrinemechanismsü Potentialeffectofspecificantidepressantsü Possibleroleofpoorlifestyle
Cizza, G., S. Primma, et al. (2009). "Depression as a risk factor for osteoporosis." Trends Endocrinol Metab 20(8): 367-373
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ManagementofMSKhealthWomenstartingaromataseinhibitortherapy
Baseline DXA scan of hip and spine (T score)
Normal Low Bone Mass Osteoporotic
Nutritional supplement
Lifestyle choices
BMD measurement: every 1-2 years
Nutritional supplement
Lifestyle choices
Annual BMD measurement
Candidate for bisphosphonate/denosumab treatment
Refer to rheumatologist or endocrinologist
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Concerns
• Sheisworriedaboutherhearthealth
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Concerns
• Sheisworriedaboutgettingcanceragain
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Evidence Based InterventionsLate effect InterventionsRecurrence and 2ndprimary
Mammo/hx/px22
Psychological distress Psychosocial interventions4
Lymphedema MLD, compression, complex decongestive therapy4
Premature menopause 7 Assessment of sexual reproductive technologies 4
Bone health programs Estrogen deprivation Diet/exercise and drugs
promising
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Evidence Based Interventions
Late effect Interventions
Weight Gain Diet /exercise
CVS disease Prevention strategies, cardiac work up
Fatigue Exercise promising
Cognitive impairment No evidence
Familial risk Genetic counseling 1
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Discussion
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Perimenopause—ChallengesandSolutionsCase3:CVDandDiabetesduringPerimenopause
CynthiaA.Stuenkel,MDUniversityofCalifornia,SanDiegoNothingtoDeclare
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Ihavenofinancialrelationshipstodisclose.
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NCDRiskFactorCollaboration.Lancet2016;387;1513-30
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TenCountrieswiththeLargestNumberofAdultswithDiabetesin1980and2014
NCDRiskFactorCollaboration.Lancet2016;387;1513-30.
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NationalDiabetesStatisticsReport
>100MillionUSAdultsAffected
§ Asof2015,intheU.S.§30.3million 9.5%diabetes§84.1million >33.3%pre-diabetes
§ AgerelatedDMprevalence
§18-44y 4%§45-64y 17%§> 65y 25%
www.cdc.gov/media/releases/2017/p0718-diabetes-report.html
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CriteriaforDiagnosisofDiabetes
§FPG> 126mg/dL 7.0mmol/L
§2-hPG> 200mg/dL 11.1mmol/L
§A1C > 6.5% 48mmol/mol
§RandomPG> 200mg/dL 11.1mmol/Lsymptoms
Diabetes Care 2018;41(Suppl 1)S13-S27
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CriteriaforDiagnosisofPrediabetes
§FPG> 100-125mg/dL 5.6- 6.9mmol/L
§2-hPG> 140-199mg/dL 7.8-11.0mmol/L
§A1C > 5.7-6.4%39-47mmol/mol
Diabetes Care 2018;41(Suppl 1)S13-S27
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CriteriaforTestingforDiabetesorPrediabetes inAsymptomaticAdults
ConsiderforalladultsBMI> 25*with> 1addedrisk:§First-degree relative with DM§High-risk race/ethnicity§Hx of cardiovascular disease§HTN > 140/90 or Rx HTN§HDL < 35 (0.90 mmol/L) and/or TG
> 250 (2.82 mmol/L)
§Polycystic ovary syndrome§Physical inactivity§Insulin resistance: severe obesity, acanthosis nigricans§Prediabetes test yearly§Gestational diabetes every 3y
Diabetes Care 2018; 41(Suppl 1):S13-S27. *Asian Americans, BMI > 23)
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CriteriaforTestingforDiabetesorPrediabetesinAsymptomaticAdults
§ Testingshouldbeginatage45yearsforallpatients1§ Repeattesting ataminimumof3yearintervals ifresultsarenormal1
§ InaSwedishpublichealthprogram,ageatDMdiagnosiswas4.6ylowerinthosewhowerescreen-detected2§ Clinicaldetectedcaseshadworsehealthoutcomes2
Diabetes Care 2018; 41(Suppl 1):S13-S27. *Asian Americans, BMI > 23); 2. Feldman AL, Diabetologia 2017
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ChallengesofPerimenopause andDM
§ Symptomsofestrogenwithdrawalcaninitiallybeconfusedwiththoseofhypoglycemia
§ Bloodglucosecontroloftendeterioratesduringtheluteal phase—perimenopausal hormonefluxescreatehavoc
§Weightgainchallengesglucose,BP,andlipidcontrol§Menstrualirregularitiesareofaddedconcernasriskofendometrialcanceriselevated
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MenopauseandDiabetesRisk
§Naturalmenopause,occurringattheaverageage,doesnotappeartoincreaseDMrisk1,2
§ DurationofreproductivelifespanmaycontributetoDM—bothshorter(<30yr)andlonger(> 45y)3,4
§HysterectomyisassociatedwithincreasedDMrisk;oophorectomy didnotconferaddedrisk5
1.StuenkelCA,Climacteric,2017;2.Mauvais-JarvisF,EndocrineReviews,2017;3.LeBlancES,Menopause,2017;4.Muka T,Diabetologia,2017;5.Luo J,AmJEpidemiol, 2017.
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MenopauseandDiabetesRisk
§Theexacteffectofmenopauseonglucosehomeostasis,independentfromchronologicalaging,isstillcontroversial1,2
§Relationshipsbetweenearlymenopauseanddiabetes(amongotherCVDriskfactors)maybebidirectional3
1.StuenkelCA,Climacteric,2017;2.Mauvais-JarvisF,EndocrineReviews,2017;3.MansonJEandWoodruffTK,JAMACardiol,2017.
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VasomotorSymptomsandDMRisk
§ InAustralianLongitudinalStudy,earlysevereVMSwereassociatedwithDMrisk;OR1.55(1.11-2.17)1
§ In2largecohortstudies,VMSwereassociatedwithincreasedriskofType2DM2
§ IntheWHIstudies,VMSwereassociatedwithDM,particularlynightsweats,possiblyrelatedtosleepdisturbance3
Herber-Gast GC,Menopause,2014;2.vanDijk GM,Maturitas,2015;3.GrayKE,Menopause,2018
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WomenwithDiabetes
§DiabetesisconsideredbytheAHAtobeaCHDriskequivalent§RCTevidenceofCVDoutcomeswithMHTinwomenwithDMismostlylacking§RCTofMHTshowneutralorbeneficialeffectsonglucosecontrol§Evidenceinadequatetomakefirmrecommendations
StuenkelCA,etal.JClin Endocrinol Metab 2015;100:3975-4011.
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RecommendationsforTreatingVMSwithMHTinDMOrganization Citation BottomLine
NAMS Menopause,2017 Not addressed
IMS Climacteric,2016 Not addressed
UKNICE PostReprod Health,2015 MHTnotadverseforglucose controlConsiderMHTaftertakingcomorbidities intoaccount
EndocrineSociety JCEM, 2015 EvidenceforsafetyinadequateSomewomenmaybecandidates forMHTafterassessingCVDriskPreferTDE2andMP
Canadian MenopauseSociety
JOGC ,2014 MayprescribeMHTforsymptomrelief
ACOG PracticeBulletin, 2014 NotaddressedStuenkelCA,Climacteric,2017;updatedJune,2018.
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WomenwithDiabetes
§Anindividualizedapproachtotreatingmenopausalsymptomscouldbeconsidered§Lowthresholdtorecommendnonhormonal therapies,particularlyinwomenwithconcurrentCVD§SomewomenwithDM,afterevaluationofCVDrisk,maybecandidatesforMHT§Prefertransdermal estrogenandmicronizedprogesterone—moremetabolically‘friendly’
StuenkelCA,etal.JClin Endocrinol Metab 2015;100:3975-4011.
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ACCEPTABLE
EVALUATECARDIOVASCULAR
RISK
HIGH *
CONSIDEROTHER OPTIONS
* Includes known CHD, CVD, PAD, etc.
ApproachtoPatientwithVMSConsideringMHT
StuenkelCA,etal.JClin Endocrinol Metab 2015;100:3975-4011.
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Cardiovascular RiskAssessment
§ BoththeEndocrineSociety1 andNAMS2 arealignedinrecommendingquantifying10yearCVDrisk
§UsetheAHA/ACCriskcalculatororothervalidatedcountryorpopulation-specificinstrument
§ Ifresourcesallow,CACdeterminationcancontributetoriskassessmentif> 40y3
§ Cardiovascular‘age’isaconceptunderdevelopment4
1. Stuenkel CA,JCEM,2015;2.NAMSHTPS,Menopause,2017;3.AmericanDiabetesAssociation,DiabetesCare,2018;4.SantenRJ,Menopause,2017
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Evaluate Cardiovascular Risk
StuenkelCA,etal.JClin Endocrinol Metab 2015;100:3975-4011;NAMSHTPS,Menopause,2017.
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TreatmentofMenopausalSymptomsinYoungWomenwithDiabetes
Mauvais-JarvisF,etal.EndocrineReviews, 2017
andnormalweight
orifobese
OralMHTOKTDpreferred
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SexDifferencesintheCVDConsequencesofDMComparedwithmen:§CVDriskprofileismoreadverseinwomen§WomenwithDMhave2-foldexcessriskCHD§MIoccursearlierandhashighermortality§Revascularizationrateslower;survivalless§Ratesofincidentheartfailurehigher§DMisstrongerriskfactorforstrokeandPVD
Regensteiner JG,etal.Circulation 2015;132:2424-2447.
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RecommendationsforCVDRiskFactorManagementinT2DM
Risk Recommendation§Nutrition Individualize;Mediterraneandiet§Obesity SurgeryBMI> 40or> 30glucose§Bloodglucose A1C < 7.0%(53mmol/mol)§Bloodpressure RxtoachieveBP<140/90§Cholesterol > 40yRxmoderateintensitystatin§Low-doseaspirin> 50y+1risk,Rx75-162mg/d
AmericanDiabetesAssociation.DiabetesCare,2018
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WhataboutnewdrugsforCVDriskreductioninT2DM?
SecondaryPreventionBenefitinRCTsLDLloweringasadjuncttostatin therapy§ Ezetimibe§ PCSK9inhibitor:evolocumab,alirocumab
Glucoseloweringagents§ SGLT2inhibitors:empagliflozin, canagliflozin*§ GLP-1agonists:liraglutide,semaglutide
Anti-inflammatoryagents§ Interleukin-1betablocker:canakinumab
AmericanDiabetesAssociation.DiabetesCare,2018;*2-foldincreasedamputations;boldFDAapprovedforCVDeventreduction.Dapagliflozin effectiveinobs studyinlowerriskpatients.
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HealthConsiderationsforWomenwithDM§Osteoporosisandfracturerisk§ Cancerrisk:breast,colorectal,andendometrial§Obstructivesleepapneacommon§ Cognitivedeclineanddepression§Genitourinarysyndromeofmenopause
StuenkelCA,Climacteric,2017
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PreventionorDelayofType2DiabetesForpatientswithprediabetes,referforintensivedietandexercisebehavioralcounseling§ Targetlossof7%initialbodyweight§ Increasemoderate-intensityphysicalactivityto150min/wk§ Technology-assistedtools(internetbasedormobileapps)
§Metformin maybeconsideredBMI> 35,age<60,GDM§MonitorVitaminB12deficiency(anemiaorneuropathy)
Diabetes Care 2018;41(Suppl 1)S51-S54
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MHTforPreventionofDM?
§Notgovernmentapprovedforthisindication§Notappropriateduetocomplexrisksandbenefits§Notaddressedbymostsocietyguidelines§Nottheendofthestory…
StuenkelCA,Climacteric,2017;Mauvis-JarvisF,EndocrineReviews,2017
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CVDandDMinthePerimenopauseSummaryandConclusions
§ Diabetesisaburgeoninghealthconcern,amenabletoreversalwithlifestyleinterventionsandweightloss
§ Theinteractionofmenopauseanddiabetesiscomplex§ Cardiovascularmorbidityandmortalityarethemostserioushealthsequelae forwomenwithDM
§Myriadhealthconcernsrequireadditionalclinicalemphasisandstudytodefineoptimalmanagement
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Discussion
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NutritionBreak
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MenopausalHormoneTherapyRegimensinthePerimenopause
Robert L Reid, MD FRCSCProfessor Ob/Gyn,
Division of REIQueen’s University,
Kingston ON
6/4/18 18216thWCMPre-CongressWorkshop
RobertReidDisclosures
Relationshipswithcommercialinterests:
Advisoryboards:Bayer,Merck,Mithra
Speaker’sBureau:Pfizer
6/4/18 18316thWCMPre-CongressWorkshop
Objectives
• Afterthispresentationparticipantswillbeableto:
• Describetheerraticonsetofmenopausalsymptomsthatmaycharacterizetheperimenopausal transition
• Definetheparticularsituationandselecthormonetherapyappropriatetotheunderlyingpathophysiology
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Perimenopausal MenstrualIntervalVariation
Treloar AE.Menstrualcyclicity andthepre-menopause.Maturitas 1981;3(3-4):249-64
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MenstrualIntervalVariationThroughReproductiveYears
Treloar AE.Menstrualcyclicity andthepre-menopause.Maturitas 1981;3(3-4):249-64
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MenstrualCyclicity OveraLifetime
16 40 45 50Regularmonthlycycles-every
28–30d
Shortenedfollicularphase-
22-24daycycles
Irregularunpredictable
cycles
Menstrualperiodscease
8-12Thelarcheindicatesfirstestrogenexposure
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OvulatoryCycles
Menses Menses
EstrogenProgesterone
Ovulation CL
DominantFollicle
ProgesteronecausesformationofcytosolicvacuolescontainingPG
ProgesteronewithdrawaltriggersPGreleasewith
“Synchronousshedding”
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Perimenopausal Anovulatory Cycles
NoprogesteroneexposureHencenosynchronousendometrialSheddingandriskforhyperplasia
CirculatingEstrogen
Bleeding
Sustainedanovulation
Amenorrheaorgradualendometrialproliferation
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Perimenopause:aTimeofUnpredictability
Occasional ovulation mixed with periods of ovarian quiescence
The few remaining follicles are those that are most resistant to FSH stimulation
As FSH levels rise these follicles activate and estrogen levels riseWith cessation of hot flashes
Hot Flashes
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ClinicalSituationsforHRTinPerimenopause
1. HormonetherapyforthewomanwithirregularmensesandperiodicVMSa) WithcontraindicationstoCHCb) WithoutcontraindicationstoCHC
2. Womenwithpre-existinginsertionofLNGIUSforbleedingcontrolwhosubsequentlydevelopsVMS
3. Womenlessthan1yearfromLMPwithamenorrheaandcontinuousVMS
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DefiningtheClinicalSituation
• Notalwaysprecise• FSHnothelpfulbeyondage45
• inyoungerwomenmayhelpdifferentiatePOIfromothercausesofamenorrhea• Durationofamenorrhea
• After6monthsamenorrheaabout50%havehadFMP;at12months90%• Needforcyclecontrolorcontraception?
6/4/18 19216thWCMPre-CongressWorkshop
1.HormoneTherapyfortheWomanwithIrregularMensesandPeriodicVMS
• InthissituationCHClevelsofhormonesarerequiredtooverrideoccasionalspontaneousovulationthusmaintainingcyclecontrolwhilepreventingVMS
• Alsoaffordscontraceptionandsomenon- contraceptivebenefits(boneprotection,reducedriskofendometrialanduterinecancer)
• IfacontraindicationtoCHC:• LNGIUSforcontraceptionandbleedingcontrol• SystemicestrogenforVMS
• IfnocontraindicationtoCHC:• ConsiderextendedcycleorcontinuousCHC
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2.VMSDevelopinginaWomanwithLNGIUSforHMB
• LNGprovidingcyclecontrolandcontraception• OfflabeladditionofsystemicestrogenforcontrolofVMS
LNGIUSInsertedVMS
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3.ContinuousVMSandAmenorrheabutNotMeetingCriteriaforMenopause
• Do not need to wait for 1 year of amenorrhea to start treatment for VMS
• Start with standard menopausal HRT and only switch to CHC (or LNG IUS and estrogen if contraindications to CHC exist) for troublesome bleeding (periodic menses)
7 months since LMP
EstrogenVMS
Progesterone
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Conclusions
• Doyourbesttodefinetheindividualsituationbasedonhistory(age,durationofamenorrhea,onsetandseverityofVMS)
• SelectatherapythatwillrelieveVMSwhilealsoaddressingissuesofcyclecontrolandcontraception(ifneeded)
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Discussion