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Anxiety dan premenopause ganti 1.

menopause dg aspek psikiatrik

ARTIGO ORIGINAL

Depresso e ansiedade em mulheres climatricas: fatores associados

Depression and anxiety in menopausal factors

omen: associated

!l"aro #ernando $olisseniI% Dimas Au&usto 'ar"alho de Ara()oII% #ernanda $olisseniI% 'arlos Al*erto +ouro ,uniorIII% ,uliana $olisseniI-% .duardo /i0ueira #ernandes-% +artha de Oli"eira Guerra-I
I

Professores Adjuntos da disciplina de Ginecologia da Faculdade de Medicina da Universidade Federal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasil II !outor, Professor Adjunto da disciplina de "#stetr$cia da Faculdade de Medicina da Universidade Federal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasil III P%s-doutorado, Professor Adjunto do !eparta&ento de Fisiologia da Universidade Federal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasil I' P%s-graduando (!outorado) do (entro de iologia da )eprodu*+o da Universidade Federal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasil ' P%s-graduando (Mestrado) do (entro de iologia da )eprodu*+o da Universidade Federal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasil 'I !outora, Professora de P%s-gradua*+o da Universidade Federal de Juiz de Fora UFJF - Juiz de Fora (MG), rasil (orrespond,ncia

R./1+O

O2,.TI-O: deter&inar a preval,ncia de depress+o e ansiedade e& &ul-eres cli&at.ricas e os prov/veis fatores respons/veis por sua ocorr,ncia0 +3TODO/: e& estudo transversal, fora& selecionadas 12 &ul-eres 3ue fre3uentara& u& a&#ulat%rio de cli&at.rio no per$odo de &aio de 4556 a agosto de 45570 (o&o crit.rio de inclus+o fora& consideradas &ul-eres na fai8a et/ria de 95 a 6: anos e 3ue concordara& e& participar do projeto0 "s crit.rios de e8clus+o fora&; pacientes e& uso de terapia -or&onal, -or&onioterapia por i&plantes, !IUs e injet/veis de dep%sito nos <lti&os seis &eses, endocrinopatias 3ue levasse& a irregularidades &enstruais, -epatopatias, coagulopatias, uso de drogas 3ue interferisse& no ciclo &enstrual, ansiol$ticos e antidepressivos (pois o uso dessas drogas era indicativo de diagn%stico pr.vio de altera*=es do -u&or), -isterecto&izadas, ooforecto&izadas, portadoras de c>ncer e de enfer&idades psi3ui/tricas, pacientes 3ue tivesse& sido su#&etidas ? radioterapia ou 3ui&ioterapia0 Fora& aplicados 3uatro 3uestion/rios durante a entrevista; Ana&nese, contendo dados sociode&ogr/ficos, cl$nicos e -/#itos de vida@ Andice Menopausal de latt-Bupper&an, co& o o#jetivo de diagnosticar as pacientes portadoras de s$ndro&e cli&at.rica@ a su#escala para Ansiedade, derivada da escala Cospitalar para Ansiedade e !epress+o (CA!D-A), co& a finalidade de diagnosticar os casos de Ansiedade e o Invent/rio de !epress+o de ecE, co& o intuito de diagnosticar as &ul-eres portadoras de depress+o0 Fora& realizadas as an/lises descritivas e de correla*+o entre as vari/veis@ o teste do 4 e de Cos&er-Fe&es-oG, usando o progra&a DoftGare Dtatistica vers+o 60 R./1LTADO/: a &.dia de preval,ncia de depress+o entre as pacientes avaliadas foi de 26,HI en3uanto 3ue da ansiedade foi de :2,7I0 J+o -ouve diferen*a significativa entre a preval,ncia de depress+o e ansiedade e as tr,s fases do cli&at.rio0 "#servou-se rela*+o significativa entre a presen*a de sinto&as cli&at.ricos de intensidade &oderada e o apareci&ento dessas altera*=es do -u&or (pK5,55L)0 A depress+o foi &ais fre3uente e& &ul-eres portadoras de ansiedade (")M9,4) e insNnia (")M9,1) sendo a atividade re&unerada considerada fator de prote*+o (")M5,4)0 "s fatores de risco relacionados ? ansiedade fora& a presen*a de depress+o (")M6,L) e os antecedentes de tens+o pr.-&enstrual (")M7,5)0 'ON'L1/4./: a preval,ncia de depress+o e ansiedade . elevada no cli&at.rio, sendo poss$vel detectar fatores de risco relacionados ? sua ocorr,ncia0 $ala"ras5cha"e: MenopausaOpsicologia@ (li&at.rioOpsicologia@ !epress+o@ Ansiedade@ Preval,ncia

A2/TRA'T $1R$O/.: to deter&ine t-e prevalence of depression and an8ietP in cli&acteric Go&en and t-e pro#a#le factors responsi#le for its occurrence0 +.T6OD/: a transversal studP t-at -as selected 12 Go&en attended at a cli&acteric outpatient clinic, fro& MaP 4556 to August 45570 Inclusion criteria Gere; Go&en fro& 95 to 6: Pears old G-o agreed Git- participating in t-e project0 Q8clusion criteria; patients in -or&onal t-erapP, -or&one-t-erapP #P i&plant, !IUs and depo injections in t-e preceding si8 &ont-s, endocrinopat-ies leading to &enstrual irregularities, -epatopat-ies, t-ro&#opat-ies, use of drugs G-ic- interfere in t-e &enstrual cPcle, an8iolPtics and antidepressants (as t-eir use indicates previous diagnosis of &ood disorders), -Psterecto&P, oop-orecto&P, cancer or psPc-iatric disease, and patients G-o -ad #een su#&itted to radio or c-e&ot-erapP0 !uring t-e intervieG, four 3uestionnaires Gere applied; Ana&nesis, containing socio-

de&ograp-ic, clinical and living -a#its data@ latt-Bupper&anRs Menopausal Inde8 for cli&acteric sPndro&e diagnosis@ An8ietP su#-scale of t-e Cospital An8ietP and !epression scale (CA!D-A) for an8ietP diagnosis@ and ecERs !epression InventorP for t-e diagnosis of depression0 !escriptive and correlation analPsis a&ong t-e varia#les, 4 and Cos&er-Fe&es-oG tests Gere perfor&ed using t-e Dtatistica DoftGare progra&, version 60 R./1LT/: t-e average depression prevalence a&ong t-e patients Gas 260HI, G-ile t-at of an8ietP Gas :207I0 S-ere Gas no significant difference #etGeen t-e prevalence of depression and an8ietP in t-e t-ree p-ases of cli&acteriu&0 S-ere Gas a significant relations-ip #etGeen t-e presence of &oderate cli&acteric sP&pto&s and t-e presence of &ood alterations (pK5055L)0 !epression Gas &ore fre3uent in Go&en Git- an8ietP (")M904) and inso&nia (")M901), -aving a jo# #eing a protection factor (")M504)0 )isE factors related to an8ietP Gere t-e presence of depression (")M60L) and antecedents of pre-&enstrual tension (")M705)0 'ON'L1/ION/: t-e prevalence of depression and an8ietP is -ig- in cli&acteriu&, #eing possi#le to detect risE factors related to t-eir occurrence0 7ey ords: MenopauseOpsPc-ologP@ (li&acteriu&OpsPc-ologP@ !epression@ An8ietP@ Prevalence

Introdu8o
" cli&at.rio representa u& pro#le&a de sa<de p<#lica, pela sua &agnitude e pelas repercuss=es sociais produzidas, surgindo e& conse3u,ncia do au&ento da e8pectativa de vida ocorrida &undial&ente0 Jos pa$ses desenvolvidos, 25I da popula*+o . representada por &ul-eres cli&at.ricas0 Degundo o Instituto rasileiro de Geografia e Qstat$stica (I GQ), -/ cerca de 49 &il-=es de &ul-eres co& &ais de 95 anos, de acordo co& o censo realizado no ano de 45550 Jo rasil, sendo a perspectiva de vida e& torno dos 74,9 anos, u& ter*o da vida dessas &ul-eres ser/ vivido no cli&at.rio, predo&inante&ente na fase de defici,ncia estrog,nicaL0 " cli&at.rio representa a transi*+o do per$odo reprodutivo para o n+o-reprodutivo0 Inicia-se aos 95 anos e ter&ina aos 6: anos0 !entro desse espa*o de te&po, ocorre a &enopausa, 3ue corresponde ? <lti&a &enstrua*+o fisiol%gica da &ul-er, apro8i&ada&ente aos :5 anosL,40 (o&o conse3u,ncia do -ipoestrogenis&o 3ue se instala, surge& sinto&as vaso&otores, atrofia vaginal, disfun*=es se8uais, sinto&as urin/rios, al.& do au&ento de risco para doen*a cardiovascular e osteoporose0 Fatores #iopsicossociais pode& deter&inar a ocorr,ncia de &anifesta*=es ps$3uicas, e8teriorizadas por irrita#ilidade, nervosis&o, depress+o e ansiedade20 Qsti&a-se 3ue u& ter*o das &ul-eres sofrer/, pelo &enos, u& epis%dio de depress+o durante a vida, co& preval,ncia de 1I no cli&at.rio0 Jessa .poca, alguns fatores favorece& o surgi&ento dessa condi*+o, co&o o &edo de envel-ecer, senti&ento de inutilidade, e car,ncia afetiva90 As co&plica*=es de u& epis%dio

depressivo &aior, al.& do risco de suic$dio, s+o as dificuldades sociais, &atri&oniais, profissionais, tendo co&o conse3u,ncia a redu*+o da 3ualidade de vida9,:0 " estudo dos sinto&as depressivos e ansiosos no cli&at.rio . &uito antigo0 MaudsleP, na Inglaterra, e& LH76, descreveu u&a for&a de &elancolia 3ue ocorreria nessa fase da vida0 " conceito de &elancolia involutiva foi introduzido por Braepelin e& L14L co&o u&a entidade nosol%gica distinta, diferenciando-a da psicose &an$aco-depressiva por crit.rios evolutivos0 Qsse conceito foi &uito 3uestionado e ele o refor&ulou, concluindo 3ue o surgi&ento desse 3uadro cl$nico, ap%s os 9: anos, se devia ao au&ento de n<&ero de casos de doen*a afetiva e n+o de u&a nova condi*+o cl$nica60 Qssa afir&ativa . 3uestionada por v/rios pes3uisadores0 (o& os diversos estudos realizados so#re os sinto&as depressivos e de ansiedade, n+o se encontrou #ase cient$fica para apoiar u& conceito <nico70 A associa*+o entre o cli&at.rio e instala*+o da depress+o e ansiedade continua sendo foco de controv.rsias0 Qssa confus+o reflete o apareci&ento de diversas teorias 3ue t,& esti&ulado v/rias pes3uisas nesse ca&po0 U&a delas enfatiza as flutua*=es -or&onais 3ue ocorre& nessa fase de vida co&o respons/veis pelas altera*=es do -u&orH0 Jesse conte8to, a peri&enopausa . u& per$odo de &aior vulnera#ilidade para os transtornos ps$3uicos10 Alguns autores acredita& 3ue a peri&enopausa esteja forte&ente associada ao apareci&ento de sinto&as de ansiedade e depress+o e& &ul-eres se& -ist%ria pr.via de doen*a &ental, 3uando presentes outros fatores de risco, co&o elevado $ndice de &assa corp%rea, antecedentes de D$ndro&e de tens+o pr.-&enstrual (SPM), ondas de calor, dist<r#ios do sono, dese&prego e estado &aritalL5,LL0 "utros autores valoriza& a presen*a de sinto&as vaso&otores (fogac-os) 3ue, interferindo no sono da &ul-er, deter&inaria&, e& longo prazo, o apareci&ento dos 3uadros depressivos e ansiosos (Seoria !o&in%)L40 A partir de u&a perspectiva psicossocial, alguns pes3uisadores argu&enta& 3ue a depress+o e a ansiedade no cli&at.rio n+o ocorre& devido ?s flutua*=es -or&onais, &as devido ?s &udan*as no &eio fa&iliar, co&o separa*+o, s$ndro&e do nin-o vazio, doen*a ou &orte de fa&iliares, di&inui*+o de rendaL20 Qstudos de&onstra& 3ue a pr/tica regular de e8erc$cios f$sicos di&inui os n$veis de estresse, ansiedade e depress+o durante o per$odo de &enopausa70 " custo econN&ico dos 3uadros de depress+o e ansiedade para a sociedade . consider/vel, sendo co&par/vel ?3uele de outras doen*as, co&o as coronariopatiasL90 As repercuss=es sociais 3ue essas altera*=es do -u&or deter&ina&, acrescidas do au&ento da &or#i&ortalidade, faze& co& 3ue seu estudo seja e8tre&a&ente i&portante e priorit/rio dentre as outras doen*as 3ue ocorre& nesse per$odo de vida70 Pes3uisas de&onstrara& 3ue depress+o e ansiedade s+o a 3uarta causa &undial de incapacita*+o social e o principal pro#le&a de sa<de p<#licaL20 !essa for&a, tendo e& vista ser este t%pico foco de &uitas controv.rsias, n+o estando esta#elecidos, ao certo, os fatores direta&ente relacionados ao apareci&ento dessas altera*=es do -u&or, al.& do custo consider/vel e das repercuss=es sociais e fa&iliares deter&inadas pela depress+o e ansiedade, decidi&os pela realiza*+o deste estudo, visando, ainda, a per&itir a interven*+o do ginecologista na preven*+o e diagn%stico, au8iliando no trata&ento dos 3uadros0 " principal o#jetivo do estudo foi descrever as ta8as de preval,ncia e o perfil cl$nico para depress+o e ansiedade e& &ul-eres atendidas e& u& a&#ulat%rio de cli&at.rio de u& servi*o universit/rio0

+todos

)ealizou-se u& estudo cl$nico, prospectivo e transversal, sendo a popula*+o estudada constitu$da por 12 &ul-eres selecionadas dentre 255 &ul-eres atendidas no Dervi*o de (li&at.rio do Cospital Universit/rio da Universidade Federal de Juiz de Fora (CUOUFJF), no per$odo de &aio de 4556 a agosto de 4557, selecionadas de acordo co& os crit.rios de inclus+o e e8clus+o e -ist%ria &enstrual de tal for&a 3ue fosse poss$vel distri#u$-las e3uitativa&ente nas tr,s fases do cli&at.rio0 Fora& inclu$das no estudo &ul-eres na fai8a et/ria dos 95 aos 6: anos e 3ue concordara& e& participar do projeto0 Fora& utilizados co&o crit.rios de e8clus+o; pacientes e& uso de terapia -or&onal, -or&onioterapia por i&plantes, !IU e injet/veis de dep%sito nos <lti&os seis &eses, endocrinopatias 3ue levasse& a irregularidades &enstruais, -epatopatias, coagulopatias, uso de drogas 3ue interferisse& no ciclo &enstrual, ansiol$ticos e antidepressivos (pois o uso dessas drogas era indicativo de diagn%stico pr.vio de altera*=es do -u&or), -isterecto&izadas, ooforecto&izadas, portadoras de c>ncer e de enfer&idades psi3ui/tricas, pacientes 3ue tivesse& sido su#&etidas a radio ou 3ui&ioterapia0 " diagn%stico de cli&at.rio foi e&inente&ente cl$nico, #aseado na fai8a et/ria da paciente@ j/ a &enopausa foi caracterizada pela aus,ncia de &enstrua*+o por per$odo &$ni&o de L4 &eses0 Utilizara&-se 3uatro instru&entos para esta pes3uisa; Ana&nese contendo dados sociode&ogr/ficos, infor&a*=es cl$nicas e -/#itos de vida@ Andice Menopausal de latt-Bupper&an (IM B)@ Invent/rio de !epress+o de ecE ( !I) e a Du#escala Cospitalar para Ansiedade, derivada da Qscala Cospitalar de Ansiedade e !epress+o (CA!D-A)0 Ja ana&nese fora& avaliados; a idade das participantes, ra*a, escolaridade, estado &arital, atividade re&unerada, antecedente de tens+o pr.-&enstrual e de depress+o p%s-parto, antecedente de depress+o, -ist%ria de depress+o entre fa&iliares, &edo de envel-ecer, separa*+o, &orte de fa&iliar, a#orreci&ento &arcante, s$ndro&e do nin-o vazio, di&inui*+o da renda fa&iliar, atividade f$sica, art$stica, religiosa, -/#ito de fu&ar e de ingerir #e#ida alco%lica e relato de insNnia0 A -ist%ria &enstrual distri#uiu a popula*+o nas tr,s fases do cli&at.rio; pr.-&enopausa, peri&enopausa e p%s-&enopausa, co& #ase na classifica*+o da Dociedade Internacional de Menopausa0 !e acordo co& essa classifica*+o, a pr.-&enopausa . iniciada aos 95 anos e se caracteriza pela presen*a de regularidades &enstruais@ a peri&enopausa se inicia co& o apareci&ento das irregularidades &enstruais (ciclos &enstruais curtos ou longos) e ter&ina u& ano ap%s a &enopausa@ a p%s-&enopausa te& co&o caracter$stica a aus,ncia de &enstrua*+o, iniciando co& a &enopausa e ter&inando aos 6: anos, fazendo li&ite co& a senilidade0 " Andice Menopausal de latt-Bupper&an (IM B) teve co&o o#jetivos diagnosticar as pacientes portadoras de s$ndro&e cli&at.rica e classific/-las confor&e a intensidade dos sinto&as e& leve, &oderada e intensa, de acordo co& a pontua*+o o#tida na aplica*+o do 3uestion/rio40 Qsse instru&ento encontra-se adaptado e validado para seu uso, sendo a&pla&ente utilizado tanto para prop%sitos de pes3uisa co&o na pr/tica cl$nica, para &onitoriza*+o de efeitos dos diversos trata&entos institu$dos no cli&at.rio20 As respostas para cada sinto&a investigado segue a seguinte escala de escores; 5 (aus,ncia de sinto&as)@ L (sinto&as leves)@ 4 (sinto&as &oderados) e 2 (sinto&as intensos)0 Para o c/lculo do escore total, os sinto&as pes3uisados apresenta& pesos diferenciados, nos 3uais as ondas de calor (fogac-os) assu&e& &aior relev>ncia (peso 9), parestesia, insNnia e nervosis&o u&

valor inter&edi/rio (peso 4) e os de&ais sinto&as, co&o depress+o, vertigens, fadiga, artralgiaO&ialgia, cefaleia, palpita*+o e zu&#ido, peso L (u&)0 Multiplicando a intensidade do sinto&a pelo respectivo fator de convers+o e, e& seguida, fazendo a so&a dos resultados o#tidos, alcan*a-se u&a pontua*+o capaz de classificar a s$ndro&e cli&at.rica e& leve, &oderada e intensa0 (onsiderou-se s$ndro&e cli&at.rica de intensidade leve a pontua*+o at. L1, &oderada entre 45 e 2: e intensa &aior 3ue 2:L:0 " Invent/rio de !epress+o de ecE ( !I) . u& dispositivo psico&.trico de autoavalia*+o co&posto por 4L itens 3ue se refere& ? sinto&atologia depressiva; tristeza, pessi&is&o, sensa*+o de fracasso, falta de satisfa*+o, sensa*+o de culpa, sensa*+o de puni*+o, autodeprecia*+o, autoacusa*=es, ideias suicidas, crises de c-oro, irrita#ilidade, retra*+o social, indecis+o, distor*+o de i&age& corporal, ini#i*+o para o tra#al-o, dist<r#io do sono, fadiga, perda de apetite e de peso, preocupa*+o so&/tica e di&inui*+o da li#ido0 " Invent/rio de ecE foi traduzido e validado para o portugu,s nu&a popula*+o de estudantes universit/rios e ve& sendo a&pla&ente aplicado e& &uitas pes3uisas co& a finalidade diagnosticar e classificar os 3uadros de depress+o0 Pacientes co& pontua*+o &aior 3ue L: fora& diagnosticadas co&o portadoras de depress+o0 (onsiderou-se depress+o leve valores entre L6 e 45, &oderada entre 4L e 41 e grave igual ou &aior 3ue 25L60 A su#escala Cospitalar para Ansiedade, derivada da Qscala Cospitalar de Ansiedade e !epress+o (Cospital An8ietP and !epression Dcale CA!D-A) foi utilizada para diagnosticar os casos de ansiedade0 Se& co&o caracter$stica ser co&posta por duas su#escalas@ a su#escala de ansiedade e a su#escala de depress+o0 Qsta su#escala e8clui sinto&as &entais graves, detecta graus leves de transtornos afetivos e& a&#ientes n+o-psi3ui/tricos, e os 3uadros de ansiedade e depress+o, por.& n+o faz sua classifica*+o #aseada na intensidade dos sinto&as co& alta sensi#ilidade (12,7I) e especificidade (74,6I), tendo sido validada para o portugu,s L70 Jeste estudo, foi utilizada a su#escala de Ansiedade (CA!D-A), co& o o#jetivo de diagnosticar os 3uadros de s$ndro&e ansiosa0 Pontua*+o igual ou &aior 3ue oito confir&ava o diagn%stico0 "s principais sinto&as avaliados por esse instru&ento s+o; tens+o, &edo, inseguran*a, preocupa*+o, rela8a&ento, agita*+o e p>nico0 Sodas as entrevistas e aplica*=es dos 3uestion/rios fora& realizadas por u& &es&o pes3uisador0 U&a c%pia dos 3uestion/rios foi entregue ? entrevistada, para 3ue ela aco&pan-asse as 3uest=es, lidas e& voz alta, e as respostas assinaladas nos for&ul/rios, pelo &es&o0 " projeto foi aprovado pelo (o&it, de Ttica e& Pes3uisa da Universidade Federal de Juiz de Fora ((QP-UFJF) so# o n0 5:504556 e& a#ril de 45560 A coleta de dados ocorreu no per$odo de &aio de 4556 a agosto de 4557, no a&#ulat%rio de (li&at.rio do CU-UFJF0 Sodas as &ul-eres participantes do estudo fora& devida&ente esclarecidas e assinara& o ter&o de consenti&ento livre e esclarecido0 "s dados o#tidos fora& o#jetos de an/lise descritiva para deter&ina*+o da preval,ncia da depress+o e ansiedade nas tr,s fases do cli&at.rio0 Para esta#elecer as rela*=es entre fatores de risco e a sua ocorr,ncia, as vari/veis categ%ricas fora& e8pressas e& porcentage& (I) e suas &edidas de associa*+o fora& avaliadas pelo teste do 40 'ari/veis nu&.ricas fora& e8pressas co&o &.dia U desvio padr+o0 Jeste estudo, as vari/veis-resposta s+o ansiedade e depress+o0 Foi realizada u&a an/lise de regress+o log$stica #in/ria para cada u&a das vari/veis-resposta,

incluindo-se no &odelo as vari/veis preditoras 3ue apresentara& associa*+o significativa pelo teste do 40 A <nica vari/vel nu&.rica do estudo (idade) n+o foi inclu$da no &odelo de regress+o, u&a vez 3ue sua &.dia n+o foi significativa&ente diferente e& rela*+o ao fator ansiedade (teste t; tML,29@ gFM1L@ pM5,51) e ne& e& rela*+o ao fator depress+o (teste t; tM5,41@ gFM1L@ pM5,7H)0 " &odelo de regress+o n+o-linear foi utilizado para avaliar o risco ("dds )atio), co& os respectivos intervalos de confian*a de 1:I de cada vari/vel preditora inclu$da no &odelo 3ue pudesse interferir no desfec-o (ansiedade ou depress+o)0 " ajuste do &odelo foi verificado pelo teste de Cos&er-Fe&es-oG (pV5,L)0 Sodos os testes fora& #icaudais, respeitando-se todos os pressupostos estat$sticos0 Adotou-se co&o significante u& n$vel de :I para o erro alfa0 Sodas as an/lises fora& realizadas atrav.s do softGare DtatisticaW vers+o 60 A -ip%tese nula foi rejeitada 3uando pK5,5:0

Resultados
A popula*+o do estudo constou de 12 &ul-eres, distri#u$das nas tr,s fases do cli&at.rio; pr.-&enopausa (2L pacientes), peri&enopausa (24 pacientes) e p%s&enopausa (25 pacientes)0 A &.dia e o desvio padr+o de idade das &ul-eres na pr.-&enopausa era& de 9:,:U2,7 anos, na peri&enopausa de 9H,2U2,L e na p%s&enopausa de :9,7U:,5 anos0 " estudo foi co&posto de &ul-eres e& sua &aioria #ranca (74,5I), 3ue &orava& co& o co&pan-eiro (66,6I) e tin-a& atividade re&unerada (H5,6I)0 !esse total, u&a era analfa#eta, 91 -avia& co&pletado o pri&eiro grau, 24 o segundo grau e LL o terceiro grau0 Do# o ponto de vista cl$nico, 69,:I relatou antecedentes de tens+o pr.-&enstrual, 2L,4I antecedentes de depress+o e :6,1I u& a#orreci&ento &arcante nos <lti&os L4 &eses0 (o& rela*+o aos -/#itos de vida, 92,5I das &ul-eres afir&ara& ter 3uadro de insNnia pelo &enos tr,s vezes por se&ana (Sa#ela L)0 (onsiderando-se a totalidade da a&ostra estudada, a preval,ncia de depress+o foi de 26,HI, ao passo 3ue a preval,ncia de ansiedade foi de :2,7I0 J+o -ouve associa*=es significativas entre a ocorr,ncia de depress+o (pM5,L4) e ansiedade (pM5,HH) co& as tr,s fases do cli&at.rio consideradas, confor&e de&onstrada na Sa#ela 40

As vari/veis preditoras avaliadas na ana&nese das participantes do estudo e sua correla*+o co& depress+o e ansiedade est+o listadas nas Sa#elas 2 e 90 (o&o n+o -ouve associa*+o significativa entre a ocorr,ncia de depress+o (pM5,L4) e ansiedade (pM5,HH) co& as tr,s fases do cli&at.rio consideradas, n+o foi realizada a an/lise das vari/veis preditoras e& cada fase e si& de toda a &assa de dados da a&ostra0

Q& rela*+o ? depress+o, as pacientes co& ansiedade apresentara& risco apro8i&ada&ente 3uatro vezes &aior e as pacientes co& insNnia, u& risco apro8i&ada&ente cinco vezes &aior0 Por outro lado, o tra#al-o re&unerado &ostrou-se u& fator de prote*+o, tendo essas pacientes u& risco cerca de cinco vezes &enor de apresentar depress+o0 Xuanto ? ansiedade, as pacientes co& depress+o apresentara& risco apro8i&ada&ente seis vezes &aior e as pacientes co& s$ndro&e pr.-&enstrual, u& risco apro8i&ada&ente sete vezes &aior (Sa#ela :)0

"#servou-se u&a rela*+o significativa entre a presen*a de sinto&as cli&at.ricos de intensidade &oderada e a ocorr,ncia de depress+o e ansiedade (pK5,55L)0

Discusso
Jo rasil, sendo a perspectiva de vida e& torno dos 74,9 anos, u& ter*o da vida das &ul-eres ser/ vivido no cli&at.rio0 Qsti&a-se 3ue 22I das &ul-eres sofrer+o pelo &enos u& epis%dio de depress+o durante a vida, co& preval,ncia de 1I no cli&at.rio:0 Jeste estudo, o#servou-se u&a preval,ncia significativa de depress+o e ansiedade nas pacientes@ 26,H e :2,7I, respectiva&ente, apesar do #o& n$vel educacional (apenas u&a . analfa#eta), de encontrare&-se ainda e& fase produtiva e de a &aioria delas ter u&a atividade re&unerada0 Jo presente estudo, n+o -ouve diferen*a na ocorr,ncia de depress+o e ansiedade nas tr,s fases do cli&at.rio, apesar de ser o#servada u&a elevada preval,ncia0 "s resultados s+o co&pat$veis aos encontrados por outros pes3uisadores e& a&#ulat%rios especializados e p<#licos, co&o o estudadoL,LH0 Q& contrapartida, alguns estudos encontrara& u&a &aior preval,ncia e& &ul-eres na peri&enopausaL1,450 A alta preval,ncia dessas altera*=es do -u&or, encontrada nessa pes3uisa, pode ser resultado de v/rios fatores, co&o as altera*=es e flutua*=es -or&onais 3ue ocorre& nessa fase da vida, os aspectos sociais e e&ocionais dessa fai8a et/ria e a dificuldade 3ue t,& essas &ul-eres de procurar atendi&ento psi3ui/trico para transtornos predo&inante&ente leves e &oderados, diante do estig&a 3ue a especialidade ainda carrega0 "utra e8plica*+o para esse ac-ado seria o fato de as &ul-eres portadoras de depress+o ou ansiedade sere& &ais 3uei8osas e tere& &enor toler>ncia e& rela*+o aos sinto&as do cli&at.rio #uscando &ais fre3uente&ente o atendi&ento ginecol%gico4L0 Sa&#.& foi o#servada u&a rela*+o significativa entre a presen*a de sinto&as cli&at.ricos de intensidade &oderada e o apareci&ento de tais s$ndro&es (pK5,55L), corro#orando estudos anteriores:,LH,L10 "s dados a3ui apresentados de&onstrara& 3ue a ansiedade . fator de risco para a s$ndro&e depressiva, confir&ando os dados da literatura evidenciados e& outras pes3uisasLL,4L00 Ficou de&onstrado 3ue a insNnia . fator predisponente para a ocorr,ncia da depress+o, pelas altera*=es so&/ticas e ps$3uicas 3ue o deter&ina&, fato ta&#.& o#servado por outros pes3uisadoresL5,450 '/rios estudos de&onstrara& 3ue o dese&prego . fator preditivo para o desenvolvi&ento de sinto&as de depress+oLH,4L0 Sa&#.& co&provou-se, a3ui, 3ue a atividade re&unerada atua co&o fator de prote*+o0 A falta de u&a atividade re&unerada na fa&$lia . u& fator 3ue levaria a pro#le&as de autoesti&a, tendo-se e& vista as d$vidas e outras dificuldades decorrentes do pro#le&a econN&ico 3ue estaria direta&ente relacionado ? presen*a de rea*=es depressivas0 Gallicc-io et al0: e (o-en et al04L relatara& 3ue as altera*=es -or&onais 3ue ocorre& no cli&at.rio poderia&, e& &ul-eres predispostas, desencadear sinto&as ansiosos, atrav.s de &ecanis&o id,ntico ao da ocorr,ncia da s$ndro&e de tens+o pr.&enstrual, no &enac&e0 Foi o 3ue se o#servou neste tra#al-o0 Algu&as li&ita*=es &etodol%gicas deste estudo &erece& considera*=es; o desen-o transversal do presente estudo avalia associa*=es entre depress+o e ansiedade no cli&at.rio co& fatores de risco, &as n+o per&ite interfer,ncias so#re casualidade0 "

ta&an-o a&ostral pode co&pro&eter algu&as poss$veis associa*=es estat$sticas, &as ainda assi& fornece infor&a*=es i&portantes a respeito do te&a0 A partir dos resultados encontrados, o#serva&os 3ue -/ a necessidade de u&a &aior interfase entre esse p<#lico, os ginecologistas e os psi3uiatras, a fi& de se au&entare& a detec*+o e a oferta de trata&ento desses transtornos 3ue s+o alta&ente co&pro&etedores da 3ualidade de vida da &ul-er cli&at.rica atrav.s da identifica*+o dos fatores relacionados ?s altera*=es do -u&or0 (onclui-se, co& este estudo, 3ue n+o -ouve diferen*a significativa entre a ocorr,ncia de depress+o e ansiedade nas tr,s fases do cli&at.rio0 A depress+o foi &ais fre3uente e& &ul-eres portadoras de ansiedade e insNnia, sendo a atividade re&unerada considerada fator de prote*+o0 "s fatores de risco relacionados ? ansiedade fora& a presen*a de depress+o e os antecedentes de tens+o pr.&enstrual0 "#servou-se rela*+o significativa entre a presen*a de sinto&as cli&at.ricos de intensidade &oderada e o apareci&ento das altera*=es do -u&or0

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2 Pdf 3 Korean Journal of Family Medicine Korean Academy of Family Medicine

The Relationship between Menopausal Symptoms and Heart Rate Variability in Middle Aged Women
Jin Oh Lee, Sung Goo Kang, [...], and Sang Wook Song
Additional article information

Abstract
Background
T e study of t e correlation of menopausal symptoms !it eart rate "aria#ility $%&'( as not #een ade)uate. T e aim of t is study !as to in"estigate t e relations ip #et!een postmenopausal symptoms measured #y t e menopause rating scale $M&*( and %&'.

Methods
+e assessed postmenopausal symptoms $using M&*( !it age, -M., educational status, occupation, marital status, alco ol and caffeine consumption, smoking istory, exercise, duration of sleep and amenorr ea, degree of anxiety and depression, menarc eal age, and eart rate "aria#ility. For e"aluation of %&', t e record of electrocardiogram for / minutes in t e resting state !as di"ided into temporal categories and fre)uency categories, and analy0ed.

Results
1o significant differences in age, -M., duration of amenorr ea, eart rate, systolic #lood pressure, diastolic #lood pressure, fasting #lood sugar, triglyceride, and ig 2density lipoprotein !ere o#ser"ed #et!een t!o groups, ! ic !ere di"ided according to menopausal symptoms. 3o! fre)uency4 ig fre)uency $3F4%F( ratio !as significantly ig er in symptomatic !omen, compared !it asymptomatic !omen $P 5 6.6/(. 1o significant differences of %&' index #y t e se"erity of postmenopausal symptoms !ere

o#ser"ed. 3F4%F ratio of %&' parameters s o!ed a significant increase in moderate or se"ere degree of 7 ot flas es7 and 7sleep pro#lem7 score $P 5 6.6/(. Anxiety scale in symptomatic !omen !as significantly ig er t an in asymptomatic !omen $P 5 6.6/(.

Conclusion
T e a#o"e data suggest t at postmenopausal symptoms are associated !it altered autonomic control of eart rate. .n particular, ot flas es and sleep pro#lems in moderate or se"ere degree are related to increase of sympat etic ner"e acti"ity. Key!ords8 Postmenopausal *ymptoms, Menopause &ating *cale, %eart &ate 'aria#ility

!TR"#$CT "!
A !oman spends 143 of er life in t e postmenopausal state. %ealt management during t is period could #e considered important #ecause it affects t e entire )uality of life.1( Menopause starts ! en menstruation is terminated permanently due to loss of o"ary function, and its onset age is almost constant.2( .n Korea, t e mean age of menopause is 9: years, and it occurs !it in /216 years around t e age of 9: years. T e menopausal state could #e #roadly di"ided into 3 stages8 premenopause, perimenopause, and postmenopause. -ased on t e last menstrual period, if t e period of amenorr ea is longer t an 12 mont s, it is considered postmenopause. First 3 mont s of amenorr ea is considered premenopause. Perimenopause is amenorr ea of 3212 mont s, and t e "olume or fre)uency of menstruation #ecomes irregular due to estrogen deficiency during perimenopause.3( Many !omen present !it di"erse p ysical as !ell as psyc ological symptoms during perimenopause and postmenopause. T ey are referred to as climacteric symptoms or menopausal symptoms. According to t e sur"ey conducted #y t e Korean *ociety of Menopause, of ;6; !omen ! o under!ent natural menopause, :<= ans!ered t at t ey experienced menopausal symptoms or a"e symptoms currently.1( *uc menopausal symptoms include ot flas es, irregular eart #eats, insomnia, and fatigue, in addition to myalgia and art ralgia, decreased desire, mood c anges, ypersensiti"ity, anxiety, depression, memory impairment, etc., and urogenital symptoms, suc as dry "agina, dyspareusia, cystitis, urodynia, and urinary urgency. To estimate suc climacteric symptoms, )uestionnaire sur"ey met ods, suc as t e >reene9( menopause index, Kupperman index, and t e menopause rating scale $M&*(, etc. a"e #een used./( ?uestionnaire sur"ey met ods a"e ad"antages in t at t ey could #e simply and readily used for assessment of menopausal symptoms. T e #asic cause of menopausal symptoms is t e complex relations ip of estrogen meta#olism and t e autonomic ner"ous system. T erefore, im#alance of t e autonomic ner"ous system may correlate !it menopausal symptoms. @is armony of t e autonomic ner"ous system could #e e"aluated #y measurement of eart rate "aria#ility $%&'(.A( %eart rate "aria#ility is cyclic inter"al c anges of t e eart rate.;( T is is t e "alue t at measures c anges from one cardiac cycle to t e next cycle or c ange of t e && inter"al !it electrocardiogram. T e acti"ity le"el of t e autonomic ner"ous system could #e )uantified #y analysis of eart rate "aria#ility using po!er spectral analysis $time and fre)uency domain analysis(.:( Bntil no!, study of t e correlation of suc menopausal symptoms !it eart rate "aria#ility as not #een ade)uate. .n t is study, t e relations ip of menopausal symptoms !it eart rate "aria#ility !as examined using a )uestionnaire sur"ey met od.

M%TH"#S
&' Study Sub(ects and )eriods
Among female patients ! o under!ent p ysical examination at an uni"ersity ospital or "isited an outpatient clinic of t e department of family from January 2616 to August 2616, t is study !as conducted on /1 patients ! ose amenorr ea !as longer t an A mont s, #ut less t an 3 years. Cf t ese, 1/ patients !ere excluded #ecause of follo!ing reasons8 past experience of medications t at may mediate an effect on %&-D ormone replacement t erapyD total ysterectomy or #ilateral oop rectomyD cases of t yroid diseaseD cases in"ol"ing endocrine diseases suc as dia#etes, arr yt mia, cardio"ascular diseaseD se"ere anemia !it emoglo#in lo!er t an 16 mg4d3D and cases in"ol"ing a istory of psyc ological disease suc as insomnia, depression, or sc i0op renia. T e final num#er of study su#Eects !as 3A.

*' Study Methods


&+ The scale o, menopausal symptoms
@ata !ere collected #y t e su#Eects ! o agreed to participate in t e study and filled out t e )uestionnaire #y t emsel"es. *ocial and demograp ic c aracteristics of study su#Eects, and diseases currently under treatment, past surgical istory, #ody mass index, education, profession, marital status, smoking, drinking, regular exercise, coffee drinking, sleeping ours, age of menarc e, and t e amenorr ea period !ere included in t is )uestionnaire. .n addition, for assessment of depression symptoms and anxiety symptoms, t e ospital anxiety depression scale $%A@*( !as employed simultaneously.<( T e M&* Korean "ersion, !as used to measure climacteric symptoms.16( T e M&* as #een used as an e"aluation tool for screening of menopausal syndrome and treatments. T is tool consists of items for total 11 symptoms, and pre"ious di"erse menopausal symptoms !ere di"ided into t ree categories8 psyc ological domain, somato2"egetati"e domain, and urogenital domain.16( Fac )uestion as a se"erity scale of symptoms as none $6 point(, slig t $1 point(, moderate $2 points(, se"ere $3 points(, or "ery se"ere $9 points(. T e total point is t e sum of t e points of eac )uestion, and it is distri#uted from a minimum of 6 to a maximum of 99 points. %ig er scores reflect se"ere le"els of symptoms. T e mean total score for Asians is ;.2 points, psyc ological symptoms is 2.< points, p ysical symptoms is 3.3 points, and urogenital symptoms is 1.6 point.16( .n our study, / points of t e M&* !as considered as t e cut2off point, and scores ig er t an / points !ere classified into t e group !it menopausal symptoms. .n addition, in regard to t e se"erity of menopausal symptoms, 629 points !ere classified as t e group !it no4little symptoms, /2: points as t e mild group, <21A points as t e moderate group, and ig er t an 1; points as t e se"ere group.16(

*+ Measurement o, HRV
To control t e influence of circadian r yt m, %&' !as measured in t e fasting condition, after 16 minutes of sufficient rest, and #et!een : AM and 12 PM using t e *A22666F $Medicore, *eoul, Korea(.11( *u#Eects !ere instructed not to drink alco ol on t e day #efore measurement, and not to smoke on t e day of measurement. For measurement,

participants !ere seated on a c air, and an electrode !as attac ed to t e rig t !rist and t e left ankleD measurement !as performed for / minutes in t e resting state. For temporal analysis of t e &2& inter"al c ange during a period of / minutes, !e measuered t e standard de"iation of normal to normal inter"als in milliseconds $*@11(, ! ic simultaneously reflects t e c ange caused #y t e parasympat etic system primarily and t e s)uare root of t e mean s)uared differences of successi"e normal to normal inter"als in milliseconds $&M**@(. As for t e fre)uency category, t e lo! fre)uency area $3F, 6.6926.1/ %0(, t e ig fre)uency area $%F, 6.1/26.9 %0(, and t e 3F4%F ratio !ere o#tained, and statistically analy0ed.

-+ Statistical analysis
For statistical analysis, t e *P** "er. 12.6 $*P** .nc., G icago, .3, B*A( !as used. &egularity !as examined using t e * apiro2+ilk test, and, if it follo!ed t e normal distri#ution, t e score difference among t e groups !as analy0ed #y t2test. For cases t at did not follo! t e normal distri#ution, significance !as examined #y Mann2+ itney test. For comparison of t e symptom se"erity, t e non2parametric test Kruskal2+allis test !as applied. .n eac analysis, a P2"alue of 56.6/ !as considered statistically significant.

R%S$.TS
&' Characteristics o, Study Sub(ects
T e final num#er of study su#Eects !as 3AD ouse!i"es !ere most pre"alent, and all !ere married. T e Gron#ac H of M&* !as 6.:91. .n t e %A@*, internal consistency of anxiety scale !as 6.<21, and internal consistency of depression scale !as 6.A;6. According to t e standard of M&* score, t e group !it menopausal symptoms included 2A patients $;2.2=(, and t e group !it out menopausal symptoms included 16 patients $2;.:=(. T e mean "alue of M&* index of t e group !it menopausal symptoms and t e group !it out menopausal symptoms !as :.9 and 2.;, respecti"ely. Age, #ody mass index, amount of coffee consumption, eart rate, #lood pressure, fasting #lood glucose, triglycerides, and %@3 c olesterol "alue did not differ significantly. .n t e group !it menopausal symptoms, sleep ours !ere less and anxiety trait !as ele"ated in comparison !it t e group !it out menopausal symptoms $P 5 6.6/( $Ta#le 1(.

Ta#le 1 -aseline c aracteristics of su#Eects.

*' Association between the )resence or Absence and the .e/el o, Menopausal Symptoms and HRV

T e 3F4%F ratio of t e group !it menopausal symptoms !as found to #e significantly ig er t an t at of t e group !it out menopausal symptoms $Ta#le 2(.

Ta#le 2 %eart rate "aria#ility of asymptomatic !omen "s. symptomatic !omen. To examine t e difference of %&' according to t e le"el of climacteric symptoms, t ey !ere compared using t e non2parametric Kruksal2+allis test. %&' according to t e le"el of climacteric symptoms did not s o! significant differences $Ta#le 3(.

Ta#le 3 %eart rate "aria#ility according to se"erity of postmenopausal symptoms.

-' Association between the .e/el o, Hot 0lashes and HRV


*u#Eects !ere di"ided into t!o groupsD t ose !it a lo!er2t an2mild le"el of ot flas es, and t e group !it a ig er2t an2moderate le"el of ot flas es. According to t e results comparing differences of %&' index, t e 3F4%F ratio !as found to #e ele"ated in t e group ! ose ot flas es !ere ig er t an moderate, and ot er indexes of %&' #et!een t e t!o groups did not differ $Ta#le 9(.

Ta#le 9 %eart rate "aria#ility according to se"erity of ot flas es.

1' Association between the .e/el o, Sleep #isorders and HRV


As in ot flas symptoms analysis, su#Eects !ere di"ided into t!o groupsD a lo!er2t an2 mild le"el of sleep distur#ance, group and a ig er2t an2moderate le"el of sleep distur#ance group. According to t e results comparing differences of %&' index, t e

3F4%F ratio in a ig er2t an2moderate le"el of sleep distur#ance group s o!ed statistically significant ele"ation. Ct er indexes did not differ $Ta#le /(.

Ta#le / %eart rate "aria#ility according to se"erity of sleep pro#lems.

# SC$SS "!
%eart rate is determined #y t e proprietary autonomy of t e sinoatrial node and t e autonomic ner"ous system. T e autonomic ner"ous system, ! ic controls t e sinoatrial node, is constantly influenced #y di"erse c anges of en"ironment, and t e cyclic inter"al c ange of eart rate t at appears at t at time is referred to as %&'.12( Analysis of suc %&', ! ic could #e used in assessing t e acti"ity le"el of t e autonomic ner"ous system, could #e performed relati"ely inexpensi"elyD it is non2in"asi"e and )uantitati"eD t us, numerous studies a"e #een conducted. Gonse)uently, t e task force of t e Furopean *ociety of Gardiology and t e 1ort American *ociety of Pacing and Flectrop ysiology standardi0ed t e met od for measurement of %&' and its p ysiological and clinical uses in 1<<A.13( Glinical application of 3F is contro"ersialD nonet eless, 3F as #een used as t e index of control of t e sinoatrial node of t e eart #y t e sympat etic ner"e, and %F as t e index of control of t e sinoatrial #y t e "agus ner"e. And t e 3F4%F ratio, ! ic reflects acti"ity of sympat etic ner"es, as #een used as t e index of t e #alance state of t e autonomic ner"ous system.19( .t as #een reported t at t e general c aracteristic of %&' is s o!n in general #y time domain analysisD nonet eless, fre)uency domain analysis #etter s o!s t e #alance state of t e sympat etic ner"e and t e parasympat etic ner"e.12( .n t is study, t e relations ip of menopausal symptoms and %&' !as examined. .n t e menopausal group, t e 3F4%F ratio !as found to #e significantly ele"ated in comparison !it t e group !it out menopausal symptoms. Bntil no!, studies comparing t e %&' of young premenopausal !omen !it t at of postmenopausal !omen a"e reported t at t e 3F4%F ratio !as ele"ated in postmenopausal !omen.19( %o!e"er, studies comparing %&' of t e group !it menopausal symptoms and t e group !it out menopausal symptoms in perimenopausal and postmenopausal !oman, suc as our researc , a"e not #een conducted. &esults of t is study a"e s o!n t at t e group !it menopausal symptoms s o!ed a greater increase in sympat etic ner"e acti"ity. 1o significant differences of %&' index !ere o#ser"ed according to se"erity of postmenopausal symptoms. &esults of t is study do not concur !it results of a study reported #y A n et al. in 266/,1/( ! ic applied %&' as a standard of climacteric symptoms. T ey reported t at in t e group !it se"ere menopausal symptoms, t e *@11 and t e &M**@ !ere reduced. 1e"ert eless, t e study #y A n et al.1/( as a limitation in t at t e num#er of su#Eects !as small $n I 1A(. Cur study also as a small num#er of su#EectsD t us, it is difficult to dra! a concrete conclusion in regard to t e association of t e le"el of menopausal symptoms !it %&'. *tudies !it larger num#er of su#Eects !ill #e re)uired in t e future.

According to our results t at s o! t e association of t e 11 su#categories of t e M&* and t e index of %&', t e 3F4%F ratio !as found to increase in t e group ! ose le"els of ot flas es and sleep disorders !ere ig er t an moderate. T e results concur !it results reported #y %oikkala et al.1A( in 266< t at s o!ed t e normali0ed 3F and normali0ed %F "alue !ere different #y t e le"el of ot flas es. .n addition, alt oug direct comparison is difficult, t e findings are similar to t ose of t e study #y &e#ecca et al. in 266<, ! ic !as on ot flas es and control of t e eart #y t e "agus ner"e and s o!ed t at %F decreased ! en ot flas es !ere se"ere. Ct er studies and ours found t at, according to ot flas symptoms, one of ! ic is menopausal symptoms, im#alance of t e autonomic ner"ous system suc as reduction of t e acti"ity le"el of t e parasympat etic ner"e may #e present. T e mec anism of postmenopausal sleep disorders as not #een elucidated. %o!e"er, se"eral studies speculate t at ot flas es induce !akefulness during sleep, resulting in c ronic sleep depri"ation and fatigue.1;( Gonse)uently, deterioration of t e sleep )uality lo!ers t e le"el of acti"ity of t e parasympat etic ner"es.12( + en t e autonomic ner"ous system, ! ic maintains t e electrical sta#ility of eart, is impaired, arr yt mia or conse)uent deat may increase.12( T erefore, our study found t at t e le"el of im#alance of t e autonomic ner"ous system !as different #y t e se"erity of ot flas es or sleep disorder symptoms. T e group !it menopausal symptoms ad ig er anxiety traits !it statistical significance t at t e group !it out menopausal symptoms. + en postmenopausal p ysical symptoms manifest, anyone experiences negati"e self2esteem suc as urt pride, uselessness, lack of self2confidence, etc.D t us, a state of emotional crisis, suc as anxiety, depression, etc. may #e induced.1:( T is study as se"eral limitations. First, alt oug /2minute measurement of %&' as #een applied as a useful tool for e"aluation of t e autonomic ner"ous system function, ! ic controls t e eart, t e area of "ery 3F, ! ic directly s o!s t e le"el of acti"ity of t e sympat etic ner"ous system, could #e measured !it accuracy using 292 our measurement.13( *o, our study measured *@11 and t e 3F area among measurements of /2minute %&'D t en attempted indirect analysis. For more accurate studies, measurement of 292 our %&' is re)uired. *econd, t e num#er of su#Eects !as not sufficientD t us, t e association of t e le"el of menopausal symptoms !it %&' !as analy0ed using a non2parametric testing met od. .t is suggested t at studies on a larger num#er of su#Eects s ould #e conducted. @espite suc limitations, our study o#ser"ed t at t e presence or a#sence of menopausal symptoms !as associated !it %&'. T e 3%4%F ratio #ecame different depending on t e se"erity of ot flas es and sleep disorders, and t e ele"ation of anxiety trait and ot er emotional disorders !ere o#ser"ed in t e group !it menopausal symptoms. T e association of menopausal symptoms !it cardio"ascular disease could not #e directly compared only #y %&'D nonet eless, in cases experiencing a ig er2 t an2moderate le"el of ot flas es and sleep disorders, #ased on t e increase of t e 3F4%F ratio, t e increased le"el of acti"ity of t e sympat etic ner"ous system could #e confirmed in our study.

Article in,ormation
Korean J Fam Med. 2611 JulyD 32$/(8 2<<J36/. Pu#lis ed online 2611 July 2:. doi8 16.96:24kEfm.2611.32./.2<< PMG.@8 PMG33:3191 Jin C 3ee, *ung >oo Kang, *e %ong Kim, *eo Jin Park, and *ang +ook *ong

@epartment of Family Medicine, *t. 'incentKs %ospital, T e Gat olic Bni"ersity of Korea *c ool of Medicine, *u!on, Korea. Gorresponding aut or. Gorresponding Aut or8 *ang +ook *ong. Tel8 :2231229<2;A:1, Fax8 :2231229:2;969, Fmail8 ss!koE4at4unitel.co.kr &ecei"ed August 36, 2616D Accepted July 12, 2611. Gopyrig t L 2611 T e Korean Academy of Family Medicine T is is an Cpen Access article distri#uted under t e terms of t e Greati"e Gommons Attri#ution 1on2Gommercial 3icense $ ttp844creati"ecommons.org4licenses4#y2nc43.6( ! ic permits unrestricted non2commercial use, distri#ution, and reproduction in any medium, pro"ided t e original !ork is properly cited. Articles from Korean Journal of Family Medicine are pro"ided ere courtesy of Korean Academy of Family Medicine

Re,erences
1. Kim MJ, Kim J%. %o! long do menopausal ot flus es really lastM J Korean *oc Menopause. 266<D1/8;3J;:. 2. *peroff 3, >lass &%, Kase 1>. Glinical gynecologic endocrinology and infertility. /t ed. -altimore8 +illiams N +ilkinsD 1<<9. 3. McKinlay *M, -ram#illa @J, Posner J>. T e normal menopause transition. Maturitas. 1<<2D198163J11/. OPu#MedP 9. >reene J>. A factor analytic study of climacteric symptoms. J Psyc osom &es. 1<;AD26892/J936. OPu#MedP /. %einemann K, &ue#ig A, Pott off P, *c neider %P, *trelo! F, %einemann 3A, et al. T e Menopause &ating *cale $M&*( scale8 a met odological re"ie!. %ealt ?ual 3ife Cutcomes. 2669D289/. OPMG free articleP OPu#MedP A. Farnest GP, 3a"ie GJ, -lair *1, G urc T*. %eart rate "aria#ility c aracteristics in sedentary postmenopausal !omen follo!ing six mont s of exercise training8 t e @&F+ study. P3o* Cne. 266:D38e22::. OPMG free articleP OPu#MedP ;. 3ee QJ, Kim M*, Kim -T, K!ak T%, * im JQ, 3ee %&. %eart rate "aria#ility in meta#olic syndrome. J Korean Acad Fam Med. 2662D2381932J193<. :. Pomeran0 -, Macaulay &J, Gaudill MA, Kut0 ., Adam @, >ordon @, et al. Assessment of autonomic function in umans #y eart rate spectral analysis. Am J P ysiol. 1<:/D29:8%1/1J%1/3. OPu#MedP <. %errmann G. .nternational experiences !it t e %ospital Anxiety and @epression *cale22a re"ie! of "alidation data and clinical results. J Psyc osom &es. 1<<;D9281;J91. OPu#MedP 16. -erlin Genter for Fpidemiology and %ealt &esearc . -erlin8 RF> -erlinD Ocited 266< Jun 26P. M&*2t e menopause rating scale O.nternetP A"aila#le from8 ttp844!!!.menopauserating2scale.info. 11. G oi GJ, G oi +*, Kim K*. T e c anges in eart rate "aria#ility #et!een morning and afternoon. J Korean Acad Fam Med. 266:D2<8/;<J/:9. 12. *eo A&, Kang *>, * in J%, *ong *+. T e relations ip #et!een sleep )uality and eart rate "aria#ility in middle2aged men. Korean J %ealt Promot @is Pre". 266<D<82:<J 2</. 13. Task Force of t e Furopean *ociety of Gardiology and t e 1ort American *ociety of Pacing and Flectrop ysiology. %eart rate "aria#ility. *tandards of measurement, p ysiological interpretation, and clinical use. Fur %eart J. 1<<AD1;83/9J3:1. OPu#MedP

19. 1e"es 'F, *il"a de *a MF, >allo 3, Jr, Gatai AM, Martins 3F, Grescencio JG, et al. Autonomic modulation of eart rate of young and postmenopausal !omen undergoing estrogen t erapy. -ra0 J Med -iol &es. 266;D9689<1J9<<. OPu#MedP 1/. A n *J, %!ang J%, G oi JF, G o J%, Jang J-, 3ee K*. Practical use of %&' as #arometer of climacteric symptom. J Crient C#stet >ynecol. 266/D1:81<2J262. 1A. %oikkala %, %aapala ti P, 'iitasalo M, 'aananen %, *o"iEar"i A&, Qlikorkala C, et al. Association #et!een "asomotor ot flas es and eart rate "aria#ility in recently postmenopausal !omen. Menopause. 2616D1;831/J326. OPu#MedP 1;. 3im +J. *leep in menopause. *leep Med Psyc op ysiol. 2662D<8<AJ<<. 1:. -eck GT. T e occurrence of depression in !omen and t e effect of t e !omenKs mo"ement. J Psyc iatr 1urs Ment %ealt *er". 1<;<D1;819J1A. OPu#MedP

9 -MG &esearc 1otes -ioMed Gentral T e effect of ormone t erapy on !omenKs )uality of life in t e first year of t e Fstonian Postmenopausal %ormone T erapy trial Piret 'eerus, *irpa23iisa %o"i, O...P, and Flina %emminki Additional article information A#stract -ackground For postmenopausal !omen, t e main reason to start ormone t erapy $%T( is to reduce menopausal symptoms and to impro"e )uality of life $?C3(. T e aim of t is study !as to analyse t e impact of %T on different aspects of symptom experience and ?C3 during a randomised trial. A total of 1:23 postmenopausal !omen !ere recruited into t e Fstonian Postmenopausal %ormone T erapy $FP%T( trial in 1<<<J2661. +omen !ere randomised to #lind %T, open2la#el %T, place#o or non2treatment arm. After one year in t e trial, a )uestionnaire !as mailed and 13/< !omen $;/=( responded, A:A in t e %T arms and A;3 in t e non2%T arms. Mean age at filling in t e )uestionnaire !as /<.: years. T e )uestionnaire included +omenKs %ealt ?uestionnaire $+%?( to assess menopause specific ?C3 of middle2aged !omen toget er !it a 1;2item )uestionnaire on symptoms related to menopause, a )uestion a#out painful intercourse, and a )uestion a#out !omenKs self2rated ealt . &esults After one year in t e trial, fe!er !omen in t e %T arms reported ot flas es, trou#le sleeping, and s!eating on t e symptom )uestionnaire. According to +%?, !omen in t e %T arms ad fe!er "asomotor symptoms, sleep pro#lems, and pro#lems !it sexual #e a"iour, #ut more menstrual symptomsD %T ad no effect on depression, somatic symptoms, memory, attracti"eness, or anxiety. A smaller proportion of !omen reported painful intercourse in t e %T arms. T ere !ere no significant differences #et!een t e trial arms in !omenSs self2rated su#Eecti"e ealt . Gonclusions

T e results from t e FP%T trial confirm t at %T is not Eustified for treating symptoms, ot er t an "asomotor symptoms, among postmenopausal !omen. +%? pro"ed to #e a useful and sensiti"e tool to assess ?C3 in t is age group of !omen. Key!ords8 &andomised controlled trial, Postmenopausal ormone t erapy, ?uality of life -ackground -ased on results from long2term randomised trials, t e main indication for ormone t erapy $%T( among postmenopausal !omen is currently t e treatment of menopausal symptoms O1P. At t e same time, %T can a"e ad"erse outcomes, suc as "aginal #leeding and #reast tenderness O2P, so its o"erall #enefit on su#Eecti"e !ell2#eing can #e estimated #y comparing symptom experience as !ell as t e )uality of life $?C3( of !omen using %T !it t ose ! o do not. T e aim of t e present study, ! ic !as part of t e Fstonian Postmenopausal %ormone T erapy $FP%T( trial, !as to determine ! et er !omen recei"ing %T in a randomised trial experienced fe!er symptoms and #etter ?C3 after one year of use t an !omen recei"ing a matc ed place#o or no drug. Menopause specific ?C3, assessed using t e +omenSs %ealt ?uestionnaire $+%?( O3P, !as defined as !omenSs perceptions of t eir p ysical and emotional !ell #eing. Farlier, ?C3 as #een reported in t e FP%T trial at year t!o using Furo?o3 O3P ! ic is a generic ealt 2related ?C3 measurement tool. +omenSs ?C3 at t e end of t e first trial year !as assessed using a mailed )uestionnaire ! ic included t e +omenSs %ealt ?uestionnaire $+%?( O9P, ! ic as #een de"eloped to in"estigate psyc ological and somatic symptoms experienced #y peri2 and postmenopausal !omen and its psyc ometric properties a"e already #een !ell documented O/,AP. .n addition, information on self2rated ealt status, specific symptoms related to menopause and painful intercourse !as compared among !omen in different trial arms. .n pre"ious studies, t e effect of %T on ?C3 among postmenopausal !omen as #een studied in t e +.*@CM trial in t e Bnited Kingdom and in t e PFP. trial and t e +%. trial in t e Bnited *tates O2,;2<P. All t ese trials reported a positi"e effect of %T on "asomotor symptoms. T e participants in t e FP%T trial !ere younger t an t e !omen participating in t e +.*@CM and +%. trial, and t e num#er of participants in t e PFP. trial !as relati"ely small. @espite t e age differences t e results from t e FP%T Trial are consistent !it pre"ious findings from ot er trials. Met ods +omen !ere recruited into t e trial #y means of a )uestionnaire sent to all /62A9 year old Fstonian speaking !omen in t!o areas $Tallinn and Tartu and t eir surrounding counties( in 1<<<22661 $n I 3<,;13( toget er !it an in"itation to participate in a randomised pre"enti"e %T trial. T ey !ere sent an information leaflet containing information on %T a"aila#le at t at time and a detailed description of t e trial, in"iting !omen to participate in t is long2term trial studying t e effects of %T on !omenSs ealt . T e names and addresses !ere o#tained from t e Fstonian population registry. A detailed description of t e recruitment procedure, inclusion and exclusion criteria as #een pu#lis ed else! ere.O16P +omen !ere asked a#out t eir education, li"ing area, marital status, ealt status, last menstrual period $3MP(, "ie!s a#out menopause, and 1; different symptoms t at a"e #een associated !it menopause. +omen ! o responded and !ere eligi#le according to t e )uestionnaire data $n I 9,2</( !ere

randomised to one of t e four trial arms8 eit er to #lind %T arm, place#o arm, non2#lind %T arm or non2treatment arm $Figure 1(, and t en in"ited to t e #aseline assessment. Figure 1 Figure 1 FP%T trial flo! c art. For t e present analysis, !omen in t e #lind and t e non2#lind %T arms !ere com#ined and t ese arms !ere named %T arms, ! ereas !omen participating in t e place#o and t e non2treatment arm !ere analysed toget er and t is group !as named non2%T arms. From t e 2,3:3 !omen ! o came to see t e trial p ysician, 1,:23 !ere recruited after secondary assessment of eligi#ility $<1: to t e %T arms and <6/ to t e non2%T arms(. &egardless t eir ysterectomy status $13= of !omen ad undergone su#total ysterectomy(, !omen in t e %T arms recei"ed 6.A2/ mg conEugated oestrogen $GFF( plus 2./ mg medroxyprogesterone acetate $MPA(, or 6.A2/ mg GFF and / mg of MPA if t ey !ere !it in 3 years from t eir last period. +omen in t e non2%T arms recei"ed eit er place#o or no treatment. At t e end of t e first trial year, nearly alf of t e !omen in t e %T arms reported to a"e used more t an :6= of t eir trial medication, and anot er 3;= !ere of medium ad erence using 162;<= of allocated treatment. .n t e non2%T arms, "ery fe! !omen $2= used it for more t an :6= of trial duration( started %T, mainly due to menopausal symptoms O11P. After one year in t e trial !omen recei"ed a postal )uestionnaire and 1,3/< $;9./=( responded, A:A in %T and A;3 in non2%T arms. +omen !ere asked a#out symptoms related to menopause !it a 1;2item symptom list $t e same as at #aseline(, and a#out menopause specific ?C3 using t e +%?, t e same "ersion as used in t e BK in t e +.*@CM2trial O;P. *elf2rated ealt status !as to #e ranked as "ery good, good, moderate, satisfactory, poor, or "ery poor. T e +%? is a 3A item scale de"eloped to measure emotional and p ysical symptoms in middle2aged !omen and it contains nine su#scales. T e +%? !as translated into Fstonian #y t!o Fstonian researc ers !it good Fnglis skills. T e feasi#ility of t e translation !as tested #y a fe! Fstonian lay !omen aged /62A/ years, and t ey ad no difficulties completing on t e )uestionnaire. 3ater, t e )uestionnaire !as #ack2translated into Fnglis #y a nati"e Fnglis speaking Fstonian translator. T e +%? su#scales include8 depressed mood $; items(, anxiety4fears $9 items(, sleep pro#lems $3 items(, somatic symptoms $; items(, menstrual symptoms $9 items(, "asomotor symptoms $2 items(, memory4concentration $3 items(, attracti"eness $2 items(, sexual #e a"iour $3 items(. T e attracti"eness su#scale includes )uestions a#out self2esteem. T e )uestionnaire ans!ers a"e a 92point scale8 1 I yes, definitely, 2 I yes, sometimes, 3 I no, not muc and 9 I no, not at all. According to t e scale aut orSs recommendation, item scores are transformed into a dic otomous scale8 if t e response is 1 or 2, it is scored 6. .f t e response is 3 or 9, it is scored 1. For eac su#scale t e mean is calculatedD 6 is interpreted as good and 1 as poor )uality of life. For certain items t e scoring is re"ersed as some items are !orded positi"ely and some negati"ely OAP. T e statistical significance of t e differences #et!een t e different arms !as determined using t2test, T22tests, +ilcoxon rank sum tests, and odds ratios !it </= confidence inter"als. All analyses !ere done #y intention2to2treat principle. 1o adEustment !as used during t e statistical analysis. Gorrelation #et!een sleeping pro#lems and "asomotor

symptoms !as assessed #y Pearson correlation coefficient. T e soft!are used !as *A* "ersion <. &esults T e o"erall response rate to t e first year )uestionnaire !as ;9./=. T ere !ere no differences #et!een t e trial arms in response rate. .n t e #lind %T arm, 31/ !omen $;/.<=(, in t e place#o arm, 2;: !omen $;3.6=(, in t e non2#lind %T arm, 3;1 !omen $;3.:=(, and in t e non2treatment arm, 3</ !omen $;/.9=( returned t e mailed )uestionnaire. T ere !ere no differences #et!een t e respondents in different trial arms regarding t eir education $3/= ad a uni"ersity degree(, marital status $A3= #eing married or co a#iting( or years since menopause $a#out one tent of !omen !ere !it in 3 years from menopause( $Ta#le (Table1).1). The mean age of respondents in the HT arms was statistically significantly lo!er t an t at in t e non2%T arms $/<./ "ersus A6.1 years, *@ 9.6(, still t e median age of respondents !as t e same in %T and non2%T arms and t ere !as no difference #et!een t e trial arms as regards time since menopause. Also, t e mean age of all !omen participating in t e %T arms of t e trial !as a #it lo!er t an t ose in t e non2%T arms. @etailed #aseline c aracteristics of trial participants are presented else! ere O16P. Ta#le 1 Ta#le 1 Gomparison of first year sur"ey respondentsS #ackground c aracteristics in different trial arms, FP%T Trial T e means for t e +%? scales !ere compared at t e end of t e first trial year in different arms $Ta#le (Table2).2). Women in HT arms had better scores for "asomotor symptoms $p 5 6.6661(, sleep pro#lems $p I 6.66/( and sexual #e a"iour $p I 6.661(. A separate analysis s o!ed t at !omen !it "asomotor symptoms tended to report sleep pro#lems $r I 6.2:, p 5 6.661(, in %T arms $r I6.2<, 56.661( as !ell as in non2%T arms $r I 6.2/, p 5 6.661(. Ta#le 2 Ta#le 2 ?uality of life according to mean scales of +%? at t e end of t e first trial year, FP%T Trial T ere !as no difference in t e mean +%? scales for depressed mood, somatic symptoms, memory4concentration, anxiety4fears, and attracti"eness su#scales. %o!e"er, !omen in %T arms ad ig er mean scales for menstrual symptoms $p I 6.62(. + en asking a#out specific symptoms !it in past t!o !eeks, fe!er !omen in t e %T arms reported s!eating $C& I 6.A<D </=G.8 6.//26.:A(, trou#le sleeping $6.A3D6.9<2 6.:6(, and ot flas es $6.2:D6.2126.3;( at t e end of t e first trial year, compared !it !omen in t e non2%T arms $Ta#le (Table3).3). There were no differences in the reporting of other symptoms. In general the symptoms t at !ere most often reported #y respondents !ere ac es or stiffness in Eoints, lack of energy and #ackac e. Ta#le 3 Ta#le 3 1um#er and proportion of !omen reporting symptoms !it in past t!o !eeks at t e end of t e first trial year in different trial arms, FP%T Trial

At t e end of t e first trial year, "ery fe! !omen complained a#out painful intercourseD t ose in %T arms reported painful intercourse less fre)uently t an !omen in t e non2%T arms $p 5 6.69(, ! ile t e num#er of !omen ! o !ere not sexually acti"e $a#out one )uarter( !as nearly t e same in all arms of t e trial $Ta#le (Table44). Ta#le 9 Ta#le 9 1um#er and proportion of !omen reporting painful intercourse during t e first trial year in different trial arms, FP%T Trial T ere !ere no differences #et!een t e trial arms in self2rated ealt status $Ta#le (Table ). ). !ore than one third of women stated their health was good or "ery good# and more than half moderate or satisfactory. The n$mber of women who stated their health to be poor or "ery poor !as "ery small. Ta#le / Ta#le / +omenSs self2rated ealt status in different trial arms at t e end of t e first trial year, FP%T Trial @iscussion +omen participating in t e FP%T Trial !ere generally younger t an t ose in t e +%. and +.*@CM trials O2,;,:,16P. T e results from t ese trials s o! t at %T impro"es specific symptoms of menopause. %o!e"er, no effect of %T on self2rated ealt status or any ot er psyc ological $anxiety, depressed mood, memory4concentration( or somatic symptom !as o#ser"ed. T e mean age at recruitment in t e FP%T trial !as /< years, ! ereas in t e +.*@CM trial it !as A9 years O;P. T e response rate in t e FP%T trial !as ;/= compared to t e /;= in t e BK trial. T e same +%? )uestionnaire !as used #ot in t e FP%T trial and in t e +.*@CM trial to assess ealt related ?C3. Gom#ined %T started after menopause reduced "asomotor symptoms, sexual and sleep pro#lems #ot in t e +.*@CM trial and in t e FP%T trial after one year of use. *imilarly in #ot trials, no significant differences !ere found in ot er menopausal symptoms, depression, or o"erall )uality of life O;P. T e mean age in t e +%. trial at recruitment !as A3 years. T e response rate to different )uestions ranged from :;= to <6= in t e +%. trial. ?C3 !as assessed !it t e use of t e &A1@ 3A2item ealt sur"ey. .n t e +%. trial, more !omen assigned to com#ined %T and symptomatic at #aseline reported relief of ot flas es, nig t s!eats, "aginal dryness at t e end of t e first trial year, #ut !omen in %T arms !ere more likely to de"elop #reast tenderness, "aginal disc arge, and eadac es O2P. %T ad no effect on depression, somatic symptoms, memory, or anxiety O2P. T e use of %T !as not associated !it a meaningful #enefit in ?C3D t ere !as only a small #enefit in terms of sleep distur#ance, p ysical functioning, and #odily pain after one year in trial O:P. Among !omen /6 to /9 years of age !it moderate to se"ere symptoms at #aseline, com#ined %T impro"ed "asomotor symptoms and ad a small #enefit in terms of sleep distur#ance, #ut not in ot er )uality2of2life outcomes O:P. T e mean age of !omen participating in t e PFP. Trial !as /A.1 years at #aseline, and /2 symptoms !ere self2reported according to a c eck2list at year one and t ree. T e :;/ !omen participating in t e trial !ere assigned to one of t e fi"e trial arms, and

analysis !as restricted to ad erent !omen only. 1o #aseline assessment of symptoms !as reported. T e results from t e PFP. trial suggested a protecti"e effect of postmenopausal %T for "asomotor symptoms, an increase in #reast discomfort among users of progestin2containing regimens, and little influence on anxiety, cognition, or affect O<P. T us t e results of t e current study add to t e findings of pre"ious researc and confirm t e pattern of results t at appears to #e consistent for a range of ages of !omen starting %T. T e current FP%T results are also similar to t ose reported after t e second trial year of t e FP%T trial except for painful intercourse O12P. At t e end of t e first trial year, painful intercourse !as impro"ed #y %T, ! ereas at t e end of t e second trial year, t e effect !as re"ersed O12P. A possi#le reason for t is could #e t e decrease in ad erence rates #et!een t e first and second yearsD at t e end t e first trial year, t e proportion of !omen taking more t an :6= of allocated drugs in treatment arms !as 9A= ! ereas at t e end of t e second trial year it !as 32= O11P. All analyses !ere done according to intention2to2treat principle. T e +%? !as used in t e Fstonian language for t e first time, and it pro"ed to #e a useful and sensiti"e tool to assess )uality of life in t is specific age group of !omen. .n contrast t e Furo?o3 )uestionnaire, ! ic measures generic ealt related ?C3, t at !as used at t e end of t e second trial year of t e FP%T trial did not detect any differences #et!een t e trial arms O12P. .ncluding #ot menopause specific and generic ?C3 measures is recommended for )uality of life measurements in t is target group. To examine t e impact of #linding on recruitment, randomisation occurred #efore signing t e informed consent. A large num#er of randomised !omen declined t eir participation and did not enter t e trial, #ut since t is appened #efore recruitment, it could a"e not #een related to t eir treatment allocation. At recruitment, t ere !ere no #aseline differences in t e pre"alence of symptoms during past t!o !eeks in different trial arms except for s!eating ! ic !as reported more often #y !omen in t e non2#lind %T arm t an in t e non2treatment arm O12P. T ere !ere no differences #et!een #ackground c aracteristics of t e !omen in four trial arms O16,12P. Cne of t e limitations of t is study is t at ?C3 !as not assessed at #aseline. +e presume t at t ere !ere no significant differences #et!een t e trial arms in t at aspect due to randomisation. 3o! ad erence rates may a"e diluted to some extent t e differences #et!een t e trial arms. T e differences in t e results of t e menstrual pro#lems $+%? su#scale( #et!een %T and non2%T groups at one year are likely to reflect "aginal #leeding, caused #y %T. T erefore, t ey !ere not regarded irrele"ant for postmenopausal !omen and !ere included in t e present analysis. Pre"ious analysis s o!ed t at %T increased t e risk of #leeding su#stantially O12P. Cur )uestionnaire did not include )uestions on ot er ad"erse e"ents of %T, suc as #reast tenderness, #ut t ese a"e #een t e most often cited reasons for non2ad erence to %T in earlier studies O11P. Gonclusions .n t e lig t of pre"ious researc in t is area, t e results from t e FP%T trial confirm t at %T is not Eustified for treating symptoms ot er t an "asomotor symptoms among postmenopausal !omen. Cur study s o!s t at many symptoms t at are often attri#uted to menopause, suc as psyc ological and p ysical symptoms, are not c anged #y %T

and t erefore %T s ould not #e recommended as a treatment for t ese symptoms ! ic are likely to a"e ot er causes. +%? allo!ed a detailed insig t on "arious aspects of life )uality of in t is target group. .t could #e used more !idely in e"aluations of medical and non2medical inter"entions among peri2 and postmenopausal !omen. A"aila#ility of supporting data Ad"antages and disad"antages of postmenopausal ormone t erapy8 a pre"enti"e trial 2 t e Fstonian Postmenopausal %ormone T erapy trial. ttp844!!!.controlled2 trials.com4.*&GT13/33:;/;43/33:;/; %o"i *irpa23iisa. Pre"enti"e Trial on Postmenopausal %ormone T erapy in Fstonia. A study of treatment preferences and trial process !it in a c anging en"ironment. ttp844!!!.stakes.fi4"erkkoEulkaisut4muut4Tu1/;*takes266A.pdf 'eerus Piret. T e impact of postmenopausal ormone t erapy on ealt and use of ealt ser"ices8 experience from t e Fstonian Postmenopausal %ormone T erapy $FP%T( trial. ttp844acta.uta.fi4pdf4<;:2</12992;1392A.pdf Aut orsS contri#utions P' accepts full responsi#ility for t e !ork and for t e conduct of t e study, ad full access to all data, and controlled t e decision to pu#lis . P', *3% and F% are responsi#le for t e study concept and design, P' and *3% for ac)uisition of data. T*, M%, P', *3% and F% contri#uted to t e data analysis and interpretation of data, *3% and P' drafted t e manuscript and all aut ors read and appro"ed t e final manuscript. Gompeting interests All aut ors declare t at t ey a"e no competing interests. @etails of Ft ics Appro"al T e trial design !as appro"ed #y Tallinn Medical &esearc Ft ics Gommittee, Fstonia on January 22, 1<<: $appro"al 1o 2(. All participants ga"e !ritten informed consent. Ackno!ledgements +e sincerely t ank eac and e"ery !oman for t eir participation in t e trial. +e also t ank t e colla#orators from t e clinical centres and from t e 1ational .nstitute for %ealt @e"elopment in Fstonia and from t e 1ational .nstitute for %ealt and +elfare in Finland. T e trial !as funded #y t e Academy of Finland $grants 1o A<:3:, 2619<6(, *TAKF* $1ational &esearc and @e"elopment Gentre for +elfare and %ealt ( in Finland, and t e Fstonian Ministry of Fducation and &esearc $target funding no *F6<9662As6;(. T e funding #odies ad no role in t e study design, data collection, data analysis, data interpretation, !riting of t e report or in t e decision to su#mit t e paper for pu#lication. Article information -MG &es 1otes. 2612D /8 1;A. Pu#lis ed online 2612 April 3. doi8 16.11:A41;/A26/662/21;A PMG.@8 PMG339<9A/ Piret 'eerus,corresponding aut or1,2 *irpa23iisa %o"i,3 Tiina *e"Un,9 Myra %unter,/ and Flina %emminki9,A

1@epartment of epidemiology and #iostatistics, 1ational .nstitute for %ealt @e"elopment, %iiu 92, 11A1<, Tallinn, Fstonia 2%Eelt .nstitute, Bni"ersity of %elsinki, PC -CV 96 $KytWsuontie 11(, F.266619 Bni"ersity of %elsinki, %elsinki, Finland 31ational .nstitute for %ealt and +elfare $T%3(4Finnis Cffice for %ealt Tec nology Assessment $Fino ta(, PC- 36 $3intula denkuEa 9(, F.2662;1, %elsinki, Finland 91ational .nstitute for %ealt and +elfare $T%3(, PC- 36 $3intula denkuEa 9(, F.2662;1, %elsinki, Finland /@ept Psyc ology, .nstitute of Psyc iatry $>uySs Gampus(, KingSs Gollege 3ondon, *F1 <&T, 3ondon, BK ATampere *c ool of Pu#lic %ealt , F.233619, Bni"ersity of Tampere, Tampere, Finland corresponding aut orGorresponding aut or. Piret 'eerus8 piret."eerus4at4tai.eeD *irpa23iisa %o"i8 sirpa2liisa. o"i4at4t l.fiD Tiina *e"Un8 tiina.se"on4at4 otmail.comD Myra %unter8 myra. unter4at4kcl.ac.ukD Flina %emminki8 elina. emminki4at4t l.fi &ecei"ed August 29, 2611D Accepted April 3, 2612. Gopyrig t L2612 'eerus et al.D licensee -ioMed Gentral 3td. T is is an Cpen Access article distri#uted under t e terms of t e Greati"e Gommons Attri#ution 3icense $ ttp844creati"ecommons.org4licenses4#y42.6(, ! ic permits unrestricted use, distri#ution, and reproduction in any medium, pro"ided t e original !ork is properly cited. Articles from -MG &esearc 1otes are pro"ided ere courtesy of -ioMed Gentral &eferences *c enck2>ustafsson K, -rincat M, Frel GT, >am#acciani M, 3am#rinoudaki ., Moen M%. et al. FMA* position statement8 Managing t e menopause in t e context of coronary eart disease. Maturitas. 2611DA:8<9J;. OPu#MedP -arna#ei 'M, Goc rane --, Aragaki AK, 1ygaard ., +illiams &*, Mc>o"ern P>. et al. Menopausal symptoms and treatment2related effects of estrogen and progestin in t e +omenSs %ealt .nitiati"e. C#stet >ynecol. 266/D16/816A3J;3. OPu#MedP . F?2/@. A standardised instrument for use as a measure of ealt outcome. A"aila#le at8 ttp844!!!.euro)ol.org4$accessed Ccto#er 26, 2611( D 8 . %unter M*. T e +omenKs %ealt ?uestionnaire8 a measure of mid2aged !omenKs perceptions of t eir emotional and p ysical ealt . Psyc ol %ealt . 1<<2D;89/J/9. %unter M*. T e !omenKs ealt )uestionnaire $+%?(8 t e de"elopment, standardi0ation, and application of a measure of mid2aged !omenKs emotional and p ysical ealt . ?ual 3ife &es. 2666D<8;33J:. %unter M*. T e +omenSs %ealt ?uestionnaire $+%?(8 fre)uently asked )uestions $FA?( -MG %ealt ?ual 3ife Cutcomes. 2663D1891. OPMG free articleP OPu#MedP +elton AJ, 'ickers M&, Kim J, Ford @, 3a!ton -A, Mac3ennan A%. et al. %ealt related )uality of life after com#ined ormone replacement t erapy8 randomised controlled trial. -MJ. 266:D33;8a11<6. OPMG free articleP OPu#MedP %ays J, Cckene JK, -runner &3, Kotc en JM, Manson JF, Patterson &F. et al. Fffects of Fstrogen plus Progestin on %ealt 2&elated ?uality of 3ife. 1FJM. 2663D39:81:3<J/9. OPu#MedP >reendale >A, &e#oussin -A, %ogan P, -arna#ei 'M, * umaker *, Jo nson *, -arrett2Gonnor F. *ymptom relief and side effects of postmenopausal ormones8 results from t e Postmenopausal Fstrogen4Progestin .nter"entions Trial. C#stet >ynecol. 1<<:D<28<:2J:. OPu#MedP

'eerus P, %o"i *3, Fisc er K, &a u M, %akama M, %emminki F. &esults from t e Fstonian Postmenopausal %ormone T erapy $FP%T( Trial O.*&GT13/33:;/;P Maturitas. 266AD//81A2J;3. OPu#MedP 'oro#Eo" *, %o"i *3, 'eerus P, Pisare" %, &a u M, %emminki F. Treatment ad erence in t e Fstonian postmenopausal ormone t erapy trial O.*&GT13/33:;/;P Maturitas. 266/D/282:AJ</. OPu#MedP 'eerus P, Fisc er K, %o"i *3, Karro %, &a u M, %emminki F. *ymptom reporting and )uality of life in t e Fstonian Postmenopausal %ormone T erapy Trial. -MG +omenSs %ealt . 266:D:8/. OPMG free articleP OPu#MedP / Arc i"es of >ynecology and C#stetrics *pringer T e symptomatology of climacteric syndrome8 ! et er associated !it t e p ysical factors or psyc ological disorder in perimenopausal4postmenopausal patients !it anxietyJdepression disorder -orong R ou, Viaofang *un, O...P, and JiaEia %u Additional article information A#stract Purpose To explore ! et er t e symptoms of climacteric syndrome associated !it its p ysical factors or psyc ological disorder in perimenopausal4postmenopausal patients !it anxietyJdepression disorder. Met ods +e recruited ;: climacteric patients !it anxietyJdepression disorder and ;2 control participants in perimenopausal4postmenopausal !it out anxietyJdepression disorder for t is study. +e measured symptoms using t e >reene Glimacteric *ymptom *cale in all cases. +e also collected demograp ic data and tested sexual ormone, #lood pressure, #one density, cogniti"e, estrogen receptor2alp a $F&H( gene polymorp ism as p ysiological factors, using %A&*219 and G%@* assessed psyc ological disorder degree. &esults G2MM*F scores as !ell as Fstradiol and progesterone le"els in t e anxietyJdepression disorder group !ere significantly lo!er compared to t e control group $P 5 6.61(. .n addition, t e anxietyJdepression disorder group ad significantly ig er >reene Glimacteric *cale scores, as !ell as somatic symptoms compared to controls $P 5 6.61(. Moreo"er, t e anxiety, depression and somatic symptoms of t e >reene Glimacteric *cale !ere positi"ely correlated !it %A&*219 and G%@* scores $P 5 6.661( and negati"ely !it estrogen le"el and G2MM*F scores $P 5 6.6/( in t e anxietyJdepression disorder group. >reene Glimacteric *cale *ymptoms !ere not significantly correlated !it #lood pressure, #one density or ot er factors $P X 6.6/(. T ere !as no significant c ange in t e allele fre)uency or t e estrogen receptor2alp a gene polymorp isms, #et!een t e t!o groups $P X 6.6/(D o!e"er, t e Pp genotype !as negati"ely associated !it G2MM*F scores $r I appraises, P I 6.633(. 3imitations

T e sample si0e !as relati"ely small. Gonclusions T e symptoms of somatic symptoms in patients !it climacteric syndrome and anxietyJ depression disorder are associated !it t e emotional disorder #ut not !it a p ysical disease. T e Pp F&H polymorp ism P"u .. is associated !it a cogniti"e decrease. Key!ords8 Glimacteric, AnxietyJdepression, *omatic symptoms, Gogniti"e, P ysical disease .ntroduction +omen in perimenopausal or postmenopausal, !it t e gradual degradation of o"arian function in t e female ormone decreasing, can appear some p ysiological and psyc ological aspects of symptoms, main performance8 ot, s!eaty, tired, eadac e, di00iness, num#, sore lim#s, attention poor, anxious and ner"ous, insomnia, mood s!ings, and sorro! depression, clinical called Ymenopause syndromeZ or Yclimacteric syndromeZ O1, 2P. @epression or anxiety or depression com#ined anxiety $anxietyJ depression( is a common psyc ological disorder in menopausal !omen. .n *+A1 2616, 1:= of elderly !omen ad psyc ological disorders O3P, and anxietyJdepression in addition to a"e maEor depression, dropping interest, outside self2e"aluation, anxiety, ner"ousness, tendency to get angry, and also may #e associated !it fatigue, insomnia, inattention, memory loss, pain and so on menopause syndrome2like symptoms. T!o diseases a"e common some syndromes c aracteristic $especial somatic syndrome( easily confused in clinic, #ut also a"e difference risk for ealt y. Alt oug emotional disorders occur fre)uently in climacteric syndrome, climacteric syndrome t at se"erely compromises life and !ork is rare. .n contrast, anxietyJdepression disorder as serious risk for !omen O9P. Cn t e ot er and, decline in t e ealt of patients $e.g., ypertension and osteoporosis( often accompanies mild cogniti"e dysfunctions O/, 1:, 26P. *ome patients are excessi"ely concerned a#out t eir ealt and "isit clinics fre)uently, ! ic can lead to many misdiagnoses and !aste medical resources OA, ;P. @o t ese patients a"e multisystem symptoms resulted from somati0ed anxietyJ depression disorder or from truly organic diseasesM &eports on syndromes c aracteristic patients !it anxietyJdepression disorder in perimenopausal are limited. Are t e multisystem symptoms of patients !it anxietyJ depression disorder in perimenopausal4postmenopausal as se"ere as t eir psyc ological onesM T is )uestion needs to #e in"estigated furt er. Fstrogen receptor $F&( polymorp isms are associated !it many disorders including Al0 eimerSs disease $A@(, osteoporosis and coronary eart disease O:J11PD o!e"er, little is kno!n a#out t e association #et!een F& polymorp isms and anxietyJdepression comor#id !it climacteric syndrome. .n t is study, !e analy0ed F& polymorp isms, sex ormone le"els, psyc ological symptoms, cogniti"e function, #lood pressure, #one density, menopausal transition $MT( stages and diseases course #ased on t e >reene Glimacteric *cale categories O12P. T is study !ould #e to recognise syndromes c aracteristic and pro"ide t e t eoretical #ase for t e early diagnosis of depression or anxiety in perimenopausal4postmenopausal. Met ods Participants and sampling -ased on our study aim and re)uirements for statistical analyses, #et!een 266; and 2616, !e recruited o"er ;: patients !it anxiety and depression in perimenopausal and

postmenopausal, as !ell as control participants !it climacteric syndrome only. Goncerning menopausal status !e used t e follo!ing definitions8 perimenopausal !omen a"ing irregular menses, less t an 12 menses during t e last 12 mont s and postmenopausal8 no more menses in t e last 12 mont s. All participants meet t e *tages of &eproducti"e Aging +orks op $*T&A+( criteria for peri4postmenopause, MT score of *T&A+ #e [1 to \2 O2P, com#ined !it at least one symptom of climacteric syndrome. T e age range of t is sample !as 96JA6 years old. Fxclusion criteria of All participants undergoing ormonal t erapy, ormone t erapy #y implant in t e preceding A mont s, endocrinopat ies leading to menstrual irregularities, epatopat ies, t rom#opat ies, use of drugs ! ic interfere in t e menstrual cycle, anxiolytics and antidepressants $as t eir use indicates pre"ious diagnosis of mood disorders(, ysterectomy, oop orectomy, cancer or psyc iatric disease or ot er se"erely organic diseases. T is study !as appro"ed #y t e institutional re"ie! #oard of t e T ird Affiliated %ospital of >uang0 ou Medical Gollege $>uang0 ou, G ina( and !ritten informed consent !as o#tained from e"ery participant. +e placed participants in t e anxietyJdepression group using t e anxiety and depression diagnosis standard listed in .G@216 O13P. T e criteria include t e follo!ing8 $1( use of t e %amilton Anxiety &ating *cale219 items $%A&*219( O19, 1/P and t e G inese "ersion of t e 1;2item %amilton @epression &ating *cale $G%@*( O1AP, all patients %A&*219 scores ]19 and or G%@* ]1;D $2( experience of maEor anxiety symptoms for at least 3 mont s or maEor depression symptoms for at least 2 !eeksD and $3( decline in functioning at !ork and ome. Bsing t ese standards, !e recruited ;: patients !it maEor anxiety and or depression symptoms as anxietyJdepression group, of ! om /: ad mixed anxiety and depression disease$MA@@, .G@216 code F91.2(, 13 of ! om ad anxiety only $.G@216 code F91.:( and ; of ! om ad depression only $.G@216 code F32.6(.T e a"erage age of t ese patients !as /2.19 ^ /.;9 years. Alt oug somati0ation disorder is a somatoform disorder t at o"erlaps !it a num#er of functional somatic syndromes and as ig comor#idity !it maEor depression and anxiety disorders O1;P. T e study anxietyJdepression patients !ere not coincided !it somati0ation or somati0ation form disorder diagnosis criterion $.G@216 code F9/.6, F9/.1(. Procedure +e recorded patient demograp ic information including age, education, disease course and menopausal status. Fducation le"el !as defined as time spent in sc ool. @isease course !as defined as t e duration of t eir symptoms in yearsD a disease course of o"er A mont s !as considered to #e 1 year. Menopause !as defined as t e cessation of menses for o"er 12 mont s according to *&TA+ O2P. T e early postmenopausal cases !as 2A $33.33=( and 2: $3:.:<=( in anxietyJdepression group and control group. T ere !ere no difference #et!een t em $P 5 6.61(. +e used t e %A&*219 and G%@* to determine anxiety and depression le"els O19J1AP. T e >reene Glimacteric *cale +e analy0ed t e c aracteristics of climacteric syndrome #ased on t e >reene Glimacteric *cale. .n 2616, t e "alidation and relia#ility of >reene Glimacteric *cales $"alidation 6.A:J6.;A, relia#ility 6.:3J6.:; in G inese population( !as reported #y R eng et al. in %ongKang. T e >reene Glimateric *cale measures a total of 21 symptoms $Ta#le 1( O12, 1:P. Fac symptom is rated #y t e !oman erself according to its current se"erity using a four2point rating scale8 not2at2all symptoms $6(D a little symptoms $1(D

)uite a #it symptoms $2(D extreme symptoms $3(. T e >reene Glimacteric *cale scores include 21 items scores and an indi"idual score !it in fi"e symptom clusters8 $1( anxiety symptoms $symptoms 1JA(, $2( depression symptoms $symptoms ;J11(, $3( somatic symptoms $symptoms 12J1:(, $9( "asomotor symptoms $symptoms 1<J26( and $/( sexual function $symptoms 21(. T e mean score for eac symptom is calculated #y t e sum of all indi"idual scores di"ided #y t e num#er of su#Eects. T e mean score of eac symptom clusters are t e mean scores of t e symptoms !it in t at cluster. Ta#le 1 Ta#le 1 >reene Glimacteric *cale score comparisons #et!een t e anxietyJdepression group and t e control group $x ^ s( T e organic diseases diagnosis !as #ased on t e 266; F*%2F*G $Furopean *ociety of %ypertension2Furopean *ociety of Gardiology( Practice >uidelines O1<P, t e 266< Csteoporosis >uidelines O26, 21P and t e standard for early detection of dementia, including mild cogniti"e impairment O22P, #lood pressure, poor recognition a#ility and lo! #one density. Cur study used t e G inese Mini Mental *tate Fxamination $G2MM*F( O23, 29P to assess t e patient recognition function and t e Fan -eam V2ray -one @ensitometer to assess #one density. +e measured real2time #lood pressure o"er 29 to calculate patientsS a"erage systolic and diastolic measurements. *exual ormone determination +e measured estradiol $F2(, progesterone and testosterone le"els using radioacti"e immunoassays. Perip eral "ein #lood !as collected #et!een ;866 and :866 am. -lood from non2menopausal !omen !ere collected 3 days after t eir menstrual cycles. T e "ariation of estradiol, progesterone and testosterone le"els !it in anyone group !as /.A, ;.2 and :.61=, respecti"ely. T e differences of estradiol, progesterone and testosterone le"els #et!een t e groups !ere A./, ;.: and :./=, respecti"ely. T e sensiti"ity of eac F3.*A assay !as 6.61, 6.661 and 6.6661 pg4ml, respecti"ely. T e analysis of polymorp isms in F&H genes, P"u.. and V#a. primer design and synt esis T e se)uence for t e estrogen receptors is as follo!s8 P18 /_2 GT>GGAGGGTATGT>TATGTTTTGGTATTGTGG23_D and P28 /_2 TGTTTGTGT>GGAGGGT>>G>TG>ATTATGT>A23_. .n descending order, t e @1A molecular !eig t $Mark * en0 en, Qis engtang -iological Fnterprises 3td.( of t ese receptors are 2,666 #p41,A66 #p41,266 #p4:66 #p4A66 #p4966 #p4266 #p. T e met od for genotyping estrogen receptors uses t ree steps. $1( + ole genomic @1A !as extracted using t e fast extraction met od. $2( A polymerase c ain reaction $PG&( ! ere t e total reaction estrogen receptor "olume !as /6 `3 and comprised 39.3 `3 sterile deioni0ed !ater, / `3 16a PG& #uffer, 266 bmol43 d1TP 9 `3, 96 pmol primers, 166 ng @1A template and 1 B Ta)@1A polymerase. &eaction conditions consisted of a denature step at <9cG for 3 min, follo!ed #y 3/ cycles of <9cG for 36 s, A1cG for 96 s, ;2cG for <6 s, and a final extension at ;2cG for / min. T e extension product si0e !as 1.3 k#. $3( Finally, a restricted en0ymatic reaction !as performed using A B P"u.. and 16 B V#a. for en0ymatic digestion, follo!ed #y a 1.2 agarose gel !it et idium #romide electrop oresis for 96 min, ! ic !as t en p otograp ed.

T!o professional psyc ologists tested patientsS neurological and psyc ological statuses. Prior to t ese tests, #ot psyc ologists !ere trained to adEust and unify t eir standards. *tatistical analysis All data !ere recorded as mean ^ standard de"iation $x ^ s(. +e used *P** 1;.6 soft!are for all statistical analyses. $1( A1C'A and A1GC'A rank2sum tests $i.e., "ariance arr yt mias( analy0ed t e demograp ic and symptomatic differences #et!een t e anxietyJdepression group and t e control group. $2( PearsonSs correlation analy0ed t e relations ips #et!een symptoms, psyc ological scores and p ysiological status. $3( G i2s)uare tests analy0ed t e fre)uency of estrogen receptor2alp a polymorp isms. $9( Multifactorial logistic analyses analy0ed t e relations ip #et!een t e F&H polymorp ism and ot er symptoms suc as sex ormone le"els, psyc ological scores $%A&*219 and G%@*( and cogniti"e functions. A P "alue of less t an 6.6/ !as considered significantly different. &esults @ifferences in demograp ic information, %A&*219, G%@*, G2MM*F, >reene Glimacteric *cale scores and sexual ormone le"els #et!een groups As s o!n in Ta#le 1, t ere !ere significant differences #et!een t e anxietyJdepression group and t e control group $P 5 6.661( in all areas except difficulty in concentrating and sexual interest. T e "asomotor symptoms scores as !ell as t e facial redness and e"ening s!eating scores for t e anxietyJdepression group !ere significantly lo!er $P 5 6.6/( compared to t e control groupD all ot er anxietyJdepression group scores !ere ig er t an t e control group $P 5 6.61(. As s o!n in Ta#le 2, t e >reene climacteric *cale scores of anxiety, depression and somatic symptoms !ere significantly ig er in t e anxietyJdepression group $P 5 6.661( compared to control group, alt oug t e "asomotor symptoms scores !ere significantly lo!er $P 5 6.6/(. T e %A&*219 and G%@* scores of t e anxietyJdepression group !ere significantly ig er t an t e control group $P 5 6.661( ! ereas t e F2 and progesterone le"els !ere significantly lo!er $P 5 6.661(. T e cut2off score for t e statistics in Ta#le 2 is 2; $mild cogniti"e difficulty O21P. An A1GC'A rank sum test $"ariance arr yt mias( s o!ed t at t e G2MM*F score in t e anxietyJdepression group !as significantly lo!er t an t e control group $P 5 6.61(. T ere !ere no significant differences in age, testosterone le"el, #one density, systolic and diastolic #lood pressure #et!een t e t!o groups. Ta#le 2 Ta#le 2 Gomparison of >reene Glimacteric *cale, %A&*219, G%@*, and G2MM*F scores, as !ell as sexual ormone le"els, #one density and a"erage #lood pressure $x ^ s( Gorrelation analysis #et!een >reene Glimacteric *cale symptoms !it general condition, psyc ological score, #one density, a"erage #lood pressure in anxietyJ depression disorder group As s o!n in Ta#le 3, PearsonSs correlational analyses, re"ealed positi"e correlations #et!een >reene Glimacteric *cale anxiety, depression and somatic symptoms scores !it %A&*219 and G%@* scores $P 5 6.661( as !ell as negati"e correlations #et!een F2 and progesterone le"els and G2MM*F scores $P 5 6.6/( !it in t e anxietyJ depression group. T ere !as also a positi"e correlation #et!een education years in t e anxietyJdepression group. T ere !as an additional correlation #et!een "asomotor symptoms and %A&*219 scores, ! ereas sexual factors !ere correlated !it G%@* scores $P 5 6.6/(. T ere !as no significant correlation #et!een >reene Glimacteric

*cale scores and #lood pressure, #one density, menopause, disease course or ot er factors $P X 6.6/(. Ta#le 3 Ta#le 3 Gorrelation analysis #et!een t e >reene Glimacteric *cale symptoms !it general condition, psyc ological score, #one density and a"erage #lood pressure in anxietyJ depression disorder group Polymorp ism analyses on t e F&H gene +e used P, pV or x to indicate restriction en0ymes. 3o!ercase letters indicated t e digestion sites of t e en0yme, ! ereas capital letters indicated t e a#sence of restricted en0yme sites. T e P"u.. restriction en0yme distinguis es #et!een t ree genotypes8 PP $1.3 k#(, Pp $1.3 k# \ :/6 #p \ 9/6 #p( and pp $:/6 #p \ 9/6 #p(. T e V#a. restriction en0yme distinguis es #et!een t ree genotypes8 VV $1.3 k#(, Vx $1.3 k# \ <16 #p \ 3<6 #p(, and xx $<16 #p \ 3<6 #pD Fig. 1(. Fig. 1 Fig. 1 3eft t e endonuclease P"u.. distinguis ed t ree genotypes8 PP $1.3 k#(, pp $:/6 #p \ 9/6 #p( and Pp $1.3 k# \ :/6 #p \ 9/6 #p(. &ig t t e Fndonuclease V#a ... F& gene polymorp isms and t e allele fre)uency distri#ution Ta#le 9 s o!s t e allele fre)uency of t e F&H P"u .. and V#a polymorp isms. T e allele fre)uencies of t e studied sample !ere consistent !it t e %ardyJ+ein#erg >enetic e)uations and representati"e populations. T e genotype distri#ution in t e anxietyJ depression group !as PP1;.</=, Pp3<.;9=, pp92.31=, VV16.2A=, Vx32./6= and xx/;.A<=. T e allele fre)uency for P and V is 3;.:1 and 2A.2:=, respecti"ely. -ot groups a"e a maEority of p and x gene sites. As s o!n in Ta#le 9, t ere !ere no significant differences #et!een t e anxietyJdepression and control groups in t e genotypes of t e F&H P"u.. or V#a . polymorp isms. Ta#le 9 Ta#le 9 T e analysis of F&H P"u .. genotypes and allele fre)uencies T e correlation #et!een F& gene polymorp isms and anxietyJdepression symptoms Cne2!ay factorial analyses indicated t at t e Pp and pp genotypes !ere correlated !it anxiety, depression, and organic diseases, as !ell as G%@*, %A&*219 and G2MM*F scores. T e xx genotype !as correlated only !it organic disease and "asomotor symptoms. + en !e introduced t e ten factors a#o"e into a multifactorial logistic model, only t e Pp genotype and G2MM*F scores !ere negati"ely correlated $y I 9./1 a 1.693 [ 2.22, r I [6.16:, </= G. 6.619 d 6.::3, P I 6.633(. @iscussion Cur study s o!s t at %A&*219, G%@* and >reene Glimacteric *cale scores of anxiety, depression and somatic symptoms !ere significantly ig er in perimenopausal4postmenopausal patients !it anxietyJdepression disorder compared to a control group, ! ereas F2 and Progesterone le"els !ere significantly lo!er $P 5 6.61(. T ese findings indicate t at, in addition to anxiety and depression disorders, somatic symptoms are c aracteristics of climacteric patients !it anxietyJdepression disorders. T is finding is also consistent !it a pre"ious report using >reene Glimacteric *cale results O2/, 2AP. Bsing a PearsonSs correlation analysis, !e found t at a decreased F2 le"el is correlated !it anxiety, depression and somatic symptoms, ! ic in turn mig t

#e correlated !it t e onset of anxietyJdepression disorder. Pre"ious !ork #y ot er researc er corro#orates t is finding O2;, 2:P. Additionally, our study indicates t at anxiety, depression and somatic symptoms are correlated !it psyc ological scores #ut not !it #lood pressure, #one density, menopause or disease course. T ese findings indicate t e follo!ing8 $1( t e >reene Glimacteric *cale is "alid for determining climacteric patients !it anxiety and depression disordersD and $2( t e somatic symptoms in climacteric patients !it anxietyJdepression disorders mig t #e correlated !it emotional disorders only O2:, 2<P and not !it organic diseases, suc as ypertension and osteoporosis. T e anxietyJdepression group s o!ed a significant decrease in "asomotor symptoms, ! ic is positi"ely correlated !it t e %A&*219 score. T is result is inconsistent !it our ot er findings. -ased on t e symptoms of patients !it anxietyJdepression disorder, our study s o!s t at t ere is correlation #et!een "asomotor symptoms and t e occurrence of anxiety disorders. Patients !it lig t anxiety may keep t eir symptoms idden, ! ereas patients !it se"ere anxiety may s o! "asomotor. %o!e"er, patients !it anxietyJdepression disorder s o!ed a significant decrease in "asomotor symptoms, indicating t at t ese symptoms may #e c aracteristic of climacteric syndrome. *eritan and ot ers a"e s o!n t at "asomotor symptoms in patients !it climacteric syndrome are closely associated !it psyc ological status O2:, 36P. Alt oug !e sampled patients !it climacteric syndrome and anxietyJdepression disorder, our results are consistent !it pre"ious findings. A recent report as s o!n t at t e somatic symptoms in climacteric syndrome mig t #e t e accumulati"e effect of anxiety and facial redness, ! ic is also consistent !it our o#ser"ations O2<P. Cur study found a correlation #et!een education le"el and anxiety and depression symptoms, indicating t at people !it more education are more likely to #e anxious during menopause. T is finding is inconsistent !it t e study #y Kakkar et al. O1P. +e did not find a significant c ange in sexual interest in t e anxietyJdepression group compared to t e control groupD t is finding is also not consistent !it t e *+A1 report. Asian attitudes to!ard sex2related issues tend to #e conser"ati"e, ! ic could explain our results. T ere seems to #e no c ange in t e sexual interest of patients !it anxiety and depression. Moreo"er, our study indicated t at sexual #e a"ior is negati"ely correlated !it depression scores, ! ic is consistent !it pre"ious findings O3, 31P. T e transcription factor of F& is located in t e cytosol and nucleus and includes t!o isoforms8 F&H and F&e. %uman F&H is located on t e A)29J2; gene O:P and includes eig t exons and se"en introns, at a total lengt of 196 k#. .n t e first F&H gene intron, !e found a T to G mutation at 6.9 k# upstream of t e second exon, and an A to > mutation /6 #p do!nstream of t e locus, resulting in t e restriction sites for P"u.. and V#a., respecti"ely, t us creating a restriction site polymorp ism O:, <P. Pre"ious studies a"e s o!n t at t e F&H gene polymorp ism is correlated !it ot flas es and "aginal dryness #ut not !it emotional disorders in patients !it climacteric syndrome O32P. Cur study indicates t at t e allele distri#ution of anxietyJdepression genotypes is PP1;.</=, Pp3<.;9=, pp92.31=, VV16.2A=, Vx32./6= and xx/;.A<=. T e allele distri#ution fre)uency for t e P and V alleles is 3;.:1 and 2A.2:=, respecti"ely. T e maEority of alleles are p and x. *tatistical analysis re"ealed no significant differences in t e genotypes of t e F&H P"u.. and V#a. genes. Moreo"er, t ere !as no correlation #et!een t e F&H allele and anxiety or depression symptoms. T is finding is consistent !it Malacara O32P. -ased on a multifactorial logistic analysis, t ere is a negati"e

relations ip #et!een t e Pp genotype in t e F&H gene and t e G2MM*F score in t e anxietyJdepression group $r I [6.16:, P I 6.633(. -randi et al. O:P s o!ed t at t e PPVV genotype of F&H !ere more fre)uent in patients !it Al0 eimerSs disease $A@(, compared to a control group O:P. Fstrogen le"el decrease is correlated to A@. Fstrogen protects neurons. Fstrogen t erapy as positi"e effects on anxietyJdepression disorder, cogniti"e malfunction and A@ in patients !it climacteric syndrome O33P. @epression related to aging may #e a symptom of early2onset A@ O:P. T e *+A1 report found t at 1:= of older !omen a"e emotional disorders and t at depression !as significantly correlated !it impaired cogniti"e function O/PD o!e"er, t ere !as no suc correlation #et!een emotional symptoms and cogniti"e malfunction in patients !it climacteric syndrome O39P. .n our study, !e s o!ed t at anxiety, depression and somatic symptoms !ere negati"ely correlated !it G2MM*F scores in t e anxietyJdepression groupD o!e"er, t ere !as no suc correlation in t e control group. T us, t ese findings are consistent !it *+A1 report ! ic suggest cogniti"e decline correlation !it anxiety and or depression, #ut not climacteric syndrome. T ere is a negati"e correlation #et!een t e Pp genotype in t e F&H gene and G2MM*F scores, ! ic is inconsistent !it ClsenSs report. .n ClsenSs study, t e V#a. genotype VV !as negati"ely correlated !it impaired cogniti"e function in postmenopausal O3/P. &ecently, Kim et al. O3AP reported similar results. T e inconsistent results may #e relation to t e difference of samples. .s t ere a correlation #et!een impaired cogniti"e function of emotion disorder and t e occurrence of mild cogniti"e impairment $e.g., MG. or early2 onset A@(M Are t e F&H polymorp ism and decreased estrogen le"els common or different mec anisms in patients !it climacteric syndrome as !ell as anxietyJ depression disorders and patients !it A@M T ese )uestions need to #e furt er in"estigated in perimenopausal4postmenopausal patients !it anxietyJdepression disorders. Gonclusion T e somatic symptoms in patients !it climacteric syndrome are correlated !it emotional disorders #ut not !it organic diseases. T ere !as no correlation #et!een t e F&H allele polymorp ism and anxiety or depression symptoms, ! ereas t e Pp genotype of t e F&H P"u .. gene may #e related to impaired cogniti"e function in patients !it anxiety or depression symptoms. Ackno!ledgments T is !ork !as supported #y t e 1atural *cience Foundation of >uangdong Pro"ince, in G ina $6A6223:/(. Gonflict of interest T e aut ors declare t at t ey a"e no conflict of interest. Cpen Access T is article is distri#uted under t e terms of t e Greati"e Gommons Attri#ution 1oncommercial 3icense ! ic permits any noncommercial use, distri#ution, and reproduction in any medium, pro"ided t e original aut or$s( and source are credited. Article information Arc >ynecol C#stet. 2612 MayD 2:/$/(8 139/J13/2. Pu#lis ed online 2611 1o"em#er 2<. doi8 16.166;4s669692611221/120 PMG.@8 PMG332/91:

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2:. *eritan A3, .osif AM, Park J%, et al. *elf2reported anxiety, depressi"e, and "asomotor symptoms8 a study of perimenopausal !omen presenting to a speciali0ed midlife assessment center. Menopause. 2616D1;8916J91/. doi8 16.16<;4gme.6#613e31:1#f/aA2. OPu#MedP OGross &efP 2<. 3ermer MA, Morra A, Moineddin &, Manson J, -lake J, Tierney MG. *omatic and affecti"e anxiety symptoms and menopausal ot flas es. Menopause. 2611D1:812<J132. OPu#MedP 36. >old F-, Gol"in A, A"is 1, -rom#erger J, >reendale >A, Po!ell 3, et al. 3ongitudinal analysis of t e association #et!een "asomotor symptoms and race4et nicity across t e menopausal transition8 study of !omenSs ealt across t e nation. Am J Pu#lic %ealt . 266AD<A8122AJ123/. doi8 16.216/4AJP%.266/.6AA<3A. OPMG free articleP OPu#MedP OGross &efP 31. Kat02-earnot *. Menopause, depression, and loss of sexual desire8 a psyc odynamic contri#ution. J Am Acad Psyc oanal @yn Psyc iatry. 2616D3:8<<J11A. doi8 16.1/214Eaap.2616.3:.1.<<. OPu#MedP OGross &efP 32. Malacara JM, Pere023u)ue F3, Martine02>ar0a *, *anc e02Marin FJ. T e relations ip of estrogen receptor2alp a polymorp ism !it symptoms and ot er c aracteristics in post2menopausal !omen. Maturitas. 2669D9<81A3J1A<. doi8 16.161A4E.maturitas.2669.61.662. OPu#MedP OGross &efP 33. * er!in --, %enry JF. -rain aging modulates t e neuroprotecti"e effects of estrogen on selecti"e aspects of cognition in !omen8 a critical re"ie!. Front 1euroendocrinol. 266:D2<8::J113. doi8 16.161A4E.yfrne.266;.6:.662. OPu#MedP OGross &efP 39. >reendale >A, +ig t &>, %uang M%, et al. Menopause2associated symptoms and cogniti"e performance8 results from t e study of !omenSs ealt across t e nation. Am J Fpidemiol. 2616D1;181219J1229. doi8 16.16<34aEe4k!)6A;. OPMG free articleP OPu#MedP OGross &efP 3/. Clsen 3, &asmussen %-, %ansen T, et al. Fstrogen receptor alp a and risk for cogniti"e impairment in postmenopausal !omen. Psyc iatr >enet. 266AD1A8:/J::. doi8 16.16<;461.ypg.66661<999/.2;///.;1. OPu#MedP OGross &efP 3A. Kim JJ, Pae GB, Kim M&, et al. Association #et!een Fstrogen &eceptor >ene Polymorp isms and @epression in Post2Menopausal +omen8 A Preliminary *tudy. Psyc iatry .n"estig. 2616D;$3(8229J22;. doi8 16.936A4pi.2616.;.3.229. OPMG free articleP OPu#MedP OGross &efP A T e .nternational Journal of -e a"ioral 1utrition and P ysical Acti"ity -ioMed Gentral @ietary !eig t loss and exercise inter"entions effects on )uality of life in o"er!eig t4o#ese postmenopausal !omen8 a randomi0ed controlled trial .kuyo .mayama, Gat erine M Alfano, O...P, and Anne McTiernan Additional article information A#stract -ackground Alt oug lifestyle inter"entions targeting multiple lifestyle #e a"iors are more effecti"e in pre"enting un ealt y !eig t gain and c ronic diseases t an inter"ening on a single #e a"ior, fe! studies a"e compared indi"idual and com#ined effects of diet and4or

exercise inter"entions on ealt 2related )uality of life $%&?C3(. .n addition, t e mec anisms of o! t ese lifestyle inter"entions affect %&?C3 are unkno!n. T e primary aim of t is study !as to examine t e indi"idual and com#ined effects of dietary !eig t loss and4or exercise inter"entions on %&?C3 and psyc osocial factors $depression, anxiety, stress, social support(. T e secondary aim !as to in"estigate predictors of c anges in %&?C3. Met ods T is study !as a randomi0ed controlled trial. C"er!eig t4o#ese postmenopausal !omen !ere randomly assigned to 12 mont s of dietary !eig t loss $n I 11:(, moderate2to2 "igorous aero#ic exercise $22/ minutes4!eek, n I 11;(, com#ined diet and exercise $n I 11;(, or control $n I :;(. @emograp ic, ealt and ant ropometric information, aero#ic fitness, %&?C3 $*F23A(, stress $Percei"ed *tress *cale(, depression O-rief *ymptom .n"entory $-*.(21:P, anxiety $-*.21:( and social support $Medical Cutcome *tudy *ocial *upport *ur"ey( !ere assessed at #aseline and 12 mont s. T e 122mont c anges in %&?C3 and psyc osocial factors !ere compared using analysis of co"ariance, adEusting for #aseline scores. Multiple regression !as used to assess predictors of c anges in %&?C3. &esults T!el"e2mont c anges in %&?C3 and psyc osocial factors differed #y inter"ention group. T e com#ined diet \ exercise group impro"ed 9 aspects of %&?C3 $p ysical functioning, role2p ysical, "itality, and mental ealt (, and stress $p f 6.61 "s. controls(. T e diet group increased "itality score $p 5 6.61 "s. control(, ! ile %&?C3 did not c ange differently in t e exercise group compared !it controls. %o!e"er, regardless of inter"ention group, !eig t loss predicted increased p ysical functioning, role2p ysical, "itality, and mental ealt , ! ile increased aero#ic fitness predicted impro"ed p ysical functioning. Positi"e c anges in depression, stress, and social support !ere independently associated !it increased %&?C3, after adEusting for c anges in !eig t and aero#ic fitness. Gonclusions A com#ined diet and exercise inter"ention as positi"e effects on %&?C3 and psyc ological ealt , ! ic may #e greater t an t at from exercise or diet alone. .mpro"ements in !eig t, aero#ic fitness and psyc osocial factors may mediate inter"ention effects on %&?C3. Key!ords8 ealt 2related )uality of life, exercise, dietary !eig t loss, postmenopausal !omen -ackground 1early t!o2t irds of B* adults are o"er!eig t or o#ese O1P. T ese indi"iduals are at increased risk for a "ariety of c ronic diseases including meta#olic disease, eart disease, cancer, and psyc osocial disorders O2P, ! ic may significantly reduce ealt 2 related )uality of life $%&?C3(. A re"ie! of : studies examining %&C?3 among !omen aged o"er // years old concluded t at postmenopausal !omen, especially t ose !it -M. greater t an 36 kg4m2, a"e lo!er %&?C3 in p ysical functioning, energy, and "itality compared !it normal2!eig t !omen O3P. 3ifestyle modification including dietary !eig t loss or p ysical acti"ity as #een s o!n to impro"e %&?C3 O92AP. @espite t e num#ers of studies reporting positi"e effects of

lifestyle modification on %&?C3, limited studies a"e in"estigated possi#le mec anisms of c ange in %&?C3. Furt er, t e optimal lifestyle prescription for impro"ing %&?C3 as not #een esta#lis ed O;P. .ncreasing e"idence suggests t at t e com#ination of diet and exercise may #e superior to diet or exercise alone !it respect to reducing !eig t O:,<P, impro"ing lipid profile O16,11P and pre"enting type 2 dia#etes O12P. %o!e"er, t e fe! inter"ention studies t at compared t e effects of dietary !eig t loss and4or exercise inter"entions on %&?C3 a"e s o!n mixed results O1321/P. Among ;A patients !it type 2 dia#etes, diet\exercise and diet2only inter"ention groups significantly impro"ed in a general )uality of life measure O13P. .n 31A older adults !it osteoart ritis, indi"iduals assigned to a diet\exercise inter"ention impro"ed %&?C3 $p ysical functioning, general ealt , role2 p ysical, #ody pain, and social functioning( compared !it controls O19P. Among 1/; ealt y men, no differences in c ange in %&?C3 !ere o#ser"ed among men randomi0ed to diet\exercise, diet2only, exercise2only, or control groups O1/P. @espite numerous exercise and dietary !eig t loss inter"entions reporting positi"e c anges in %&?C3, t e mec anisms #e ind o! exercise and dietary !eig t loss programs impro"e %&?C3 are not clear. + ile some inter"ention studies a"e s o!n t at !eig t loss is associated !it impro"ed %&?C3 O1A,1;P, ot ers a"e s o!n t at people impro"e %&?C3 !it out ant ropometric c anges O1:,1<P. T e primary aim of t is study !as to examine t e indi"idual and com#ined effects of dietary !eig t loss and exercise inter"entions on %&?C3. @efining t e indi"idual and com#ined effects of diet and exercise inter"entions on %&?C3 !ill elp inform researc ers, practitioners and policy makers on optimal lifestyle prescriptions for impro"ing %&?C3. T e secondary aim !as to explore p ysical and psyc osocial factors associated !it c anges in %&?C3 during t e inter"ention. T e findings !ould pro"ide information to explain potential mec anisms of o! diet and exercise inter"entions affect %&?C3. Met ods T e 1utrition and Fxercise for +omen $1F+( trial !as a 122mont , randomi0ed controlled trial conducted at t e Fred %utc inson Gancer &esearc Genter, *eattle, +A from 266/ to 266<. Participants !ere recruited from t e greater *eattle, +A area t oug mass mailing and media placements from 266/ to 266:, and 93< !ere enrolled in t e study $Figure (%ig$re1).1). The st$dy incl$sion criteria included8 age /62;/ years oldD #ody mass index $-M.( ] 2/.6 kg4m2 $if Asian2American ] 23.6 kg4m2(D 5 166 minutes per !eek of moderate or "igorous intensity p ysical acti"ityD postmenopausalD not taking ormone replacement t erapy for t e past 3 mont sD no istory of #reast cancer, eart disease, dia#etes mellitus, or ot er serious medical conditionsD fasting glucose 5 12A mg4d3D currently not smokingD alco ol intake of fe!er t an 2 drinks per dayD a#le to attend diet4exercise sessions at t e inter"ention siteD and normal exercise tolerance test. Figure 1 Figure 1 Flo! diagram of t e trial. +omen !ere randomi0ed to8 $1( dietary !eig t loss !it a goal of 16= !eig t reduction $1 I 11:(, $2( moderate2to2"igorous intensity aero#ic exercise for 9/ minutes4day, / days4!eek $1 I 11;(, $3( com#ined exercise and diet $1 I 11;(, and control groups $1 I :;(. *tudy staff performed randomi0ation t roug a computer program de"eloped #y t e

study statistician. &andomi0ation !as #locked on -M. $5 36.6 kg4m2 or ] 36.6 kg4m2( and race4et nicity $+ ite, -lack, and ot ers(. .n addition, to ac ie"e a proportionally smaller num#er of !omen assigned to t e control group, a permuted #locks randomi0ation !it #locks of 9 !as used, ! ere in t e control assignment !as randomly eliminated from eac #lock !it a pro#a#ility of approximately 1 in 9. T e 1F+ trial !as designed to a"e sufficient po!er to detect a difference of 16= c ange in serum estrone, t e primary study outcome, o"er a 122mont period making t ree primary pair!ise comparisons8 diet \ exercise "s. exerciseD diet \ exercise "s. dietD and diet "s. exercise inter"ention groups. -ased on t e num#er of participants ! o completed t e 122mont assessments, !e estimate t at !e a"e <<.<= po!er to detect 16 points c ange in t e p ysical functioning scale $%&?C3(. All study procedures !ere re"ie!ed and appro"ed #y t e Fred %utc inson Gancer &esearc Genter .nstitutional &e"ie! -oard in *eattle, +A, and all participants pro"ided signed .nformed Gonsent. .nter"entions T e diet group recei"ed a reduced calorie !eig t loss inter"ention, a modification of t e @ia#etes Pre"ention Program $@PP( lifestyle O26P and 3ook A%FA@ $Action for %ealt in @ia#etes( trial O21P inter"entions !it goals of8 total caloric intake of 12662 2666 kcal4day #ased on #aseline !eig t, f36= calories from fat, and 16= !eig t loss !it in t e first 29 !eeks !it maintenance for t e rest of inter"ention period. T e diet inter"ention !as conducted #y dietitians !it training in #e a"ior modification. Participants ad indi"idual sessions !it t e dietitians at least t!ice, t en met !eekly in small groups $a"erage /216 !omen( until !eek 29, and after!ard communicated !it t e dietitians at least t!ice per mont eit er "ia group sessions or "ia email4p one contact. T e diet inter"ention in"ol"ed sessions designed to de"elop strategies and skills to ac ie"e caloric and !eig t loss goals, ! ic included self2monitoring, goal setting, coping strategies, and pro#lem sol"ing. T e exercise inter"ention !as 9/ minutes per day of moderate2to2"igorous intensity aero#ic exercise, / days per !eek including 3 exercise p ysiologist2super"ised sessions per !eek at t e facility. C"er t e first : !eeks, participants gradually increased t e intensity and duration of exercise training to ;62:/= of maximal eart rate $using Polar eart rate monitors, 3ake *uccess, 1Q( for 9/ minutes per session and maintained t is le"el t ereafter. +omen in t e diet\exercise group recei"ed #ot t e reduced2calorie !eig t loss and exercise inter"entions. T e diet sessions !ere pro"ided separately for diet\exercise and diet only groups. Alt oug t e diet and exercise group used t e exercise facility !it !omen assigned to t e exercise2only group, participants !ere instructed not to discuss t e diet inter"ention. Gontrols !ere not gi"en an inter"ention during t e trial, #ut !ere offered 9 group diet sessions and : !eeks of super"ised exercise sessions after 12 mont sK data collection. Measures .nformation on demograp ics, medication use, ant ropometrics, aero#ic fitness, lifestyle #e a"iors, psyc osocial factors, and %&?C3 !ere assessed at #aseline and 12 mont s. *tudy staff in"ol"ed in t ese assessments !ere #linded to randomi0ation. .nformation on age, race4et nicity, education, marital status, and employment !ere collected using a

standardi0ed )uestionnaire. Participants !ere asked to #ring t eir current prescription and o"er2t e2counter medications to t e clinic, and information on drug name, dose, fre)uency, and duration of use !ere a#stracted. %eig t and !eig t !ere measured !it a stadiometer and digital scale, and -M. !as calculated as kg4m2. Aero#ic fitness !as assessed !it a maximum grade treadmill test using t e modified #ranc ing protocol O22,23P. P ysical acti"ity !as measured using an inter"ie! adapted from t e Minnesota 3eisure Time P ysical Acti"ity ?uestionnaire O29P. @ietary intake !as assessed using t e +omenKs %ealt .nitiati"e 1262item food fre)uency )uestionnaire O2/P. Psyc osocial factors examined included depression, anxiety, percei"ed stress, and social support. @epression and anxiety !ere assessed #y t e -rief *ymptom .n"entory2 1: O2AP. &a! scores !ere calculated and T scores !ere assigned according to t e scoring manual O2;P !it ig er scores indicating more symptoms of depression and anxiety. Percei"ed stress !as assessed !it t e Percei"ed *tress *cale O2:PD scores ranged from 6 to 9 !it larger scores indicating greater percei"ed stress. C"erall social support !as assessed #y t e s ort "ersion of t e Medical Cutcomes *tudy $MC*( *ocial *upport *ur"ey OA,2<P. A mean of all item scores !as calculated and con"erted to a score ranging from 6 to 166. %ig er social support scores suggest greater perception of social support. %&?C3 !as assessed #y t e MC* 3A2.tem * ort2Form %ealt *ur"ey $*F23A( O36P. Fig t su#scales $p ysical functioning, role2p ysical, #odily pain, "itality, general ealt , social functioning, role2emotional, and mental ealt ( !ere calculated, per standard scoring protocol. *cores ranges from 6 to 166 !it ig er scores indicating a #etter state of %&?C3. For t e #odily pain su#scale, ig er scores represent less pain. *tatistical analyses +e performed analyses using last o#ser"ation carried for!ard. For comparison, !e also performed t e analyses using a"aila#le data and using multiple imputation. All randomi0ed participants !ere included in t e analyses follo!ing t e intention2to2treat principle. T e #aseline c aracteristics !ere compared across t e 9 study arms using analysis of "ariance $A1C'A( and c i2s)uare tests, as appropriate. T2tests !ere used to compare differences in #aseline %&?C3 and psyc osocial factors $depression, anxiety, percei"ed stress, and social support( #y su#groups defined #y #aseline c aracteristics8 age $defined #y median split as 5 /; years "s. ] /; years(, et nicity $non2%ispanic + ite, ot ers(, education $no college degree, college degree(, employment $employed, unemployed(, marital status $no partner, married or !it partner(, #aseline -M. $2/ f -M. 5 36, ] 36 kg4m2(, and use of antidepressants or anxiolytics $no, yes(. -aseline c aracteristics t at significantly altered %&?C3 scores and psyc osocial factors !ere included as co"ariates in t e su#se)uent analyses. +e also tested models !it out t ese co"ariates $unadEusted model(. T e 122mont c anges in %&?C3 !ere compared among t e 9 study arms using t e analysis of co"ariance $A1GC'A( adEusting for #aseline scores and co"ariates identified in t e analysis gi"en a#o"e. +e used t e -onferroni correction to adEust for multiple comparisons $P2"alue I 6.6/43 I 6.61; for 3 comparisons(. @ata for all participants !ere used in t e follo!ing analyses. For %&?C3 su#scales ! ic significantly differed across inter"ention groups, PearsonKs correlation coefficients !ere calculated to assess t e #i"ariate associations #et!een c anges in %&?C3 and p ysical and psyc ological factors $!eig t, aero#ic fitness, depression, percei"ed stress and social support(. Multiple regression analysis !as used to assess predictors of

%&?C3 c ange. All analyses !ere performed !it *A* soft!are $"ersion <.1D *A* .nstitute, Gary, 1G(. &esults -aseline )uestionnaire data !as a"aila#le from 93: participants. Cf t e 93< !omen randomi0ed to t e 9 study arms, 3<< completed p ysical exams, 3;6 completed a treadmill test, and 3:2 returned t e )uestionnaire at 12 mont s $Figure (%ig$re1).1). There were no differences in baseline %&?C3 score or psyc osocial "aria#les $depression, anxiety, percei"ed stress, and social support( #et!een t ose ! o completed "s. did not complete t e 122mont s )uestionnaire $all p2"alues X 6.6/(. -aseline c aracteristics of study participants Ta#le Table11 displays the baseline characteristics of the st$dy participants. &articipants were a mean age of ' years( mostly non)Hispanic white (' *)( and highly ed$cated (+ * with college degree). There were no differences in baseline characteristics among t e 9 study arms $all p2"alues X 6.6/(. T ere !ere no differences in psyc osocial factors and %&?3 #et!een t e four study arms except t e mental ealt score. T e exercise group ad ig er mental ealt scores compared !it diet and control groups at #aseline $p 5 6.6/(. Ta#le 1 Ta#le 1 -aseline c aracteristics of study participants stratified #y trial arm .nter"ention effects on !eig t, aero#ic fitness and ad erence T e inter"ention effects on !eig t and aero#ic fitness and ad erence !ere reported else! ere O31P. .n #rief, t e diet, exercise, and diet\exercise groups decreased #ody !eig t #y ;.2 kg o"er 12 mont s $percent c ange from #aseline #ody !eig t =g@iet I :./=D p 5 6.61(, 2.6 kg $=gFxercise I 2.9=, p I 6.63(, and :.< kg $=g@iet\Fxercise I 16.:=, p 5 6.61(, respecti"ely compared !it controls. Approximately alf of t e participants in t e diet groups $diet 91./=D diet \ exercise groups /<./=( ac ie"ed t e goal of 16= !eig t reduction at 12 mont s. T e exercise and diet \ exercise groups met a mean :6= and :/= of t e goal of 22/ minutes per !eek of moderate intensity aero#ic exercise, respecti"ely. Aero#ic fitness increased #y 6.1; 34min and 6.12 34min, respecti"ely in exercise and diet\exercise groups $all p 5 6.661, "s. control(. -aseline %&?C3 scores and psyc osocial factors stratified #y su#groups Ta#le Table22 displays mean H,-./ scores at baseline stratified by baseline characteristics. .lder women (0 1 years) had lower role)physical scores and percei"ed stress# and higher "itality scores compared to younger !omen $5 /; yearsD p 5 6.6/(. 1one of t e psyc osocial factors and %&?C3 scores !ere different #et!een su#groups defined #y et nicity or education. Fmployed !omen ad lo!er social functioning t an unemployed !omen $p I 6.62(. +omen ! o !ere married or !it partner reported ig er le"els of social support $p 5 6.6/D "s. no partner(. C#ese !omen ad lo!er p ysical functioning and role2p ysical scores $p 5 6.6/D "s. o"er!eig t(. +omen taking antidepressants or anxiolytics reported a ig er le"el of #odily painD lo!er p ysical functioning, "itality, role2emotional, and mental ealt scoresD and ig er le"els of depression and anxiety $all p 5 6.6/(. Ta#le 2 Ta#le 2

-aseline scores of ealt 2related )uality of life $measured #y *F23A( and psyc osocial factors $depression and anxiety measured #y -*.21:, percei"ed stress measured #y t e Percei"ed *tress *cale, social support measured #y MC* *ocial *upport *ur"ey(, ... .nter"ention effects on : aspects of %&?C3 C"erall, t e 122mont s c anges in 9 su#scales of %&?C3 differed among t e 9 groups8 p ysical functioning $p 5 6.661(, role2p ysical $p 5 6.661(, "itality $p 5 6.661(, and mental ealt $p I 6.6A( $Ta#le (Table3).3). 2ompared with controls# the diet3e4ercise gro$p increased physical f$nctioning $p 5 6.661(, role2p ysical $p 5 6.661(, "itality $p 5 6.661(, and mental ealt scores $p I 6.61( and decreased #odily pain $p I 6.69(. Alt oug #ot t e diet and diet\exercise groups increased "itality, t e diet\exercise group s o!ed a larger increase t an t e diet only group $p I 6.69 comparing t e t!o groups(. T e diet only group increased "itality $p 5 6.661D "s. controls( and mental ealt $p I 6.6/D "s. controls(. T e exercise group did not impro"e any su#scales of %&?C3 compared !it controls. Ta#le 3 Ta#le 3 .ndi"idual and com#ined effects of diet and4or exercise inter"ention on ealt 2related )uality of life scores $measured #y *F23A( .nter"ention effects on psyc osocial "aria#les T e 122mont c ange in percei"ed stress differed #y study arm $p I 6.69(. T e diet\exercise group significantly decreased percei"ed stress $26.// points( ! ile t e control group increased t eir stress le"els $6.32 points( $p I 6.66A( $Ta#le (Table4).4). 5ltho$gh the o"erall and pairwise comparisons among 4 st$dy arms did not reac statistical significance $due to t e -onferroni correction for multiple comparisonD p f6.61; !as considered statistically significant in t e pair!ise comparision(, t e diet\exercise group reduced depression $g@iet\Fxercise I 21.; points, p I 6.63D "s. control gGontrol I 6.; points( and increased social support $g@iet\Fxercise I 1.6 points, p I 6.6/D "s. control gGontrolI 22.: points(. Ta#le 9 Ta#le 9 .ndi"idual and com#ined effects of diet and4or exercise inter"ention on psyc osocial factors $depression and anxiety measured #y -*.21:, percei"ed stress measured #y t e Percei"ed *tress *cale, social support measured #y MC* *ocial *upport *ur"ey( -i"ariate correlations #et!een c anges in %&?C3 and p ysical and psyc osocial factors -i"ariate correlations !ere examined for 122mont c anges in %&?C3 and factors t at significantly c anged during t e inter"ention using com#ined data of all 9 study groups $Ta#le (Table ). ). Weight loss was positi"ely associated with changes in physical f$nctioning (r I 6.2:, p 5 6.661(, role2p ysical $r I 6.1:, p 5 6.661(, "itality $r I 6.3A, p 5 6.661( and mental ealt scores $r I 6.13, p I 6.66A(. +eig t loss !as also associated !it an impro"ement in depression scores $r I 26.11, p I 6.62(. .ncreased aero#ic fitness !as positi"ely associated !it p ysical functioning scores $r I 6.1A, p I 6.666;(. @ecreased depression and percei"ed stress, and impro"ed social support !ere associated !it increases in p ysical functioning, role2p ysical, "itality and mental ealt scores $all p 5 6.661(. @ecreased depression !as associated !it increased p ysical functioning $r I 26.21, p 5 6.661(, role2p ysical $r I 26.23, p 5 6.661(, "itality $r I 26.92, p 5 6.661(, and mental ealt scores $r I 26.//, p 5 6.661(. .ncreased stress !as in"ersely associated !it p ysical functioning $r I 26.22, p 5 6.661(, role2p ysical $r I 26.26, p 5

6.661(, "itality $r I 26.32, p 5 6.661(, and mental ealt scores $r I 26./1, p 5 6.661(. .ncreased social support !as associated !it impro"ed p ysical functioning $r I 6.29, p 5 6.661(, role2p ysical $r I 6.22, p 5 6.661(, "itality $r I 6.22, p 5 6.661(, and mental ealt $r I 6.2/, p 5 6.661(. Ta#le / Ta#le / -i"ariate correlations #et!een 122mont c anges in ealt 2related )uality of life $measured #y *F23A( and potential predictors Predictors of 122mont c anges in %&?C3 T e 122mont c anges in t e four su#scales of %&?C3 t at significantly differed #y inter"ention arm $p ysical functioning, role2p ysical, "itality, and mental ealt ( !ere furt er examined to identify t e predictors of %&?C3 c ange $Ta#le (Table+).+). 2hange in an4iety le"els did not differ by inter"ention arm( therefore# it was not incl$ded in t e model O32P. .n multiple regression models, t e 122mont c anges in !eig t $e I 26./6, p 5 6.661(, aero#ic fitness $e I 9.A;, p I 6.61(, percei"ed stress $e I 26./:, p I 6.62(, and social support $e I 6.1;, p 5 6.661( predicted increased p ysical functioning. &educed !eig t $e I 26.A;, p I 6.661( and depression $e I 26./6, p I 6.661( and impro"ed social support $e I 6.29, p I 6.61( predicted increased role2p ysical score. &educed !eig t $e I 26.;9, p 5 6.661(, depression $e I 26.92, p 5 6.661( and percei"ed stress $e I 26.;<, p I 6.669( !ere associated !it impro"ed "itality. +eig t loss $e I 26.1/, p I 6.69( and decreases in depression $e I 26.93, p 5 6.661( and percei"ed stress $e I 21.2:, p 5 6.661( predicted positi"e c anges in mental ealt . Ta#le A Ta#le A Predictors of 122mont c anges in ealt 2related )uality of life $measured #y *F23A( +e also performed t e analyses using a"aila#le data and using multiple imputation. T ere !ere no su#stantial differences #et!een t e results on t ese analyses except for t e relations ip #et!een c anges in aero#ic fitness and t e p ysical functioning scale. T e correlation coefficient #et!een 122mont c anges in aero#ic fitness and t e p ysical functioning scale !as significant in t e last2o#ser"ation carried for!ard and complete case analyses $p 5 6.61(, ! ile it !as non2significant in t e multiple imputation analyses $p I 6.6<, data are a"aila#le on re)uest(. T erefore, !e presented t e results of last o#ser"ation carried for!ard analyses in t is paper. T e analysis results did not differ su#stantially ! en t e co"ariates !ere remo"ed from t e model $unadEusted model, supplementary ta#les are a"aila#le on re)uest(. @iscussion T is study examined t e indi"idual and com#ined effects of dietary !eig t loss and4or aero#ic exercise inter"entions on %&?C3 among sedentary, o"er!eig t4o#ese postmenopausal !omen. To our kno!ledge, t is trial is t e first to compare indi"idual and com#ined effects of dietary !eig t loss and exercise inter"ention on %&?C3 in o"er!eig t4o#ese, postmenopausal !omen !it out maEor medical conditions. +e found t at t e com#ined dietary !eig t loss and exercise group impro"ed more aspects of %&?C3 and psyc osocial factors $depression, stress and social support( !it larger increments compared !it diet or exercise alone. +e also found significant associations #et!een !eig t loss, increased aero#ic fitness, and impro"ements in %&?C3 and psyc ological factors, suggesting t at t ese factors may explain, at least in part, t e impro"ed %&?C3 o#ser"ed in t e diet and exercise inter"entions.

T e com#ined dietary !eig t loss and exercise group impro"ed more aspects of %&?C3 and !it larger increments compared !it diet or exercise alone. Cur findings !ere consistent !it pre"ious trials in clinical populations, among t ose !it type 2 dia#etes O13P or osteoart ritis O19P. T e latter trial reported up to a 1A./ point increase in all su#scales of *F23A !it a 1:2mont diet\exercise inter"ention O19P, ! ic !as greater t an t e o#ser"ed c anges in our sample $/211 points(. T is may #e caused #y differences in t e study sample, as t e o#ser"ed increase in %&?C3 scores among our com#ined diet\exercise group !as consistent !it pre"ious !eig t loss trials in general populations O9,1;P. .n a A2mont !eig t loss trial $lo! calorie diet and aero#ic exercise( among 2<: o#ese !omen $age /62;/(, !omen lost <.9= of #aseline !eig t and increased p ysical functioning and "itality scores #y A and : points, respecti"ely O1;P. Anot er A2mont !eig t loss trial in 199 o"er!eig t4o#ese adults reported a mean !eig t loss of /.A kg and 2 to 112point impro"ements in : su#scales of *F23A O9P. .n contrast to a num#er of studies reporting positi"e effects of exercise on %&?C3, !e did not find significant impro"ements in any aspects of %&?C3 in !omen randomi0ed to t e exercise2only group. .t is possi#le t at our participants ad ig #aseline %&?C3 ! ic could a"e caused a ceiling effect. Preference for type of exercise could also a"e affected t e results. Gourneya et al. found t at participants ! o preferred resistant training s o!ed greater increase in %&?C3 ! en assigned to resistant training group compared !it t ose assigned to aero#ic exercise or control groups O33P. Cur participants mig t a"e preferred to #e assigned to a group ot er t an t e exercise2only group, ! ic could a"e resulted in minimal c anges in %&?C3. T e com#ined diet\exercise inter"ention also impro"ed psyc osocial factors $depression, stress, and social support(, ! ile t ere !ere no effects on t ese factors in t e diet or exercise alone groups. Alt oug !e are not a!are of studies comparing t ese psyc ological outcomes in indi"idual "s. com#ined diet and exercise inter"entions, lifestyle modification programs in"ol"ing diet and exercise a"e #een s o!n to impro"e psyc ological ealt . A 122mont intensi"e lifestyle inter"ention program of t e 3ook A%FA@ $Action for %ealt in @ia#etes( Trial, mediated t roug !eig t loss $mean :.: kg !eig t loss among inter"ention group( and aero#ic fitness, impro"ed depression in 9223 o"er!eig t adults !it type 2 dia#etes O1:P. A cardiac re a#ilitation program reduced stress, ! ic !as associated !it !eig t loss and impro"ed aero#ic fitness O39P. Cur finding t at t e com#ined diet\exercise group impro"ed psyc ological factors is consistent !it t ese studies, #ut t e reasons for t e impro"ements are not clear. +e did not find any significant correlations #et!een !eig t loss or aero#ic fitness !it t ese psyc osocial factors except for a correlation #et!een !eig t loss and reduced depression. Future studies are recommended to in"estigate mec anisms #y ! ic lifestyle inter"entions may impro"e psyc ological ealt . Positi"e c anges in depression and stress !ere significantly associated !it 9 su#scales of %&?C3, ! ic remained significant after adEusting for c anges in !eig t and aero#ic fitness. *tudies a"e s o!n t at psyc ological disorders affect "arious aspects of %&?C3. An analysis of 11,292 outpatients in t e B.*. s o!ed t at indi"iduals ! o are depressed a"e lo!er p ysical functioning, role2p ysical and social functioning compared !it non2depressed indi"iduals O3/P. Anot er study as s o!n t at increased depressi"e symptoms !ere associated !it decline in all : aspects of *F23A among female patients !it remitted maEor depression disorder O3AP. Cur study confirmed t at psyc ological conditions a"e a significant impact on %&?C3 and t at a lifestyle

#e a"ioral c ange of a diet and exercise in com#ination, is a potential met od to impro"e psyc ological ealt . .mpro"ed aero#ic fitness !as an independent predictor of 122mont c anges in p ysical functioning. Gonsistent !it our findings, &oss et al. found t at c anges in -M. and aero#ic fitness independently explained a c ange in p ysical functioning score, and t at impro"ed aero#ic fitness ad independent effects #eyond -M. c ange only in p ysical functioning scale among : su#scales of *F23A in a A2mont lifestyle inter"ention among o#ese !omen O1;P. An analysis from t e 3ook A%FA@ trial found t at #ot !eig t loss and increased aero#ic fitness mediated t e inter"ention effects on p ysical composite scores O1:P. .n our pre"ious 122mont exercise trial in 1;3 postmenopausal !omen, !e found t at a c ange in aero#ic fitness !as associated !it a c ange in p ysical functioning #ut not !it c anges in eit er mental ealt or general ealt OAP. +eig t loss in t e present study !as associated !it impro"ements in #ot p ysical and mental aspects of %&?C3. A 122mont follo!2up of a A2mont lifestyle inter"ention found t at indi"iduals ! o continued to lose !eig t during t e follo!2up period s o!ed impro"ed "itality and general ealt of *F23A and t at !eig t loss !as associated !it impro"ements in t ese aspects of *F23A among /6: postmenopausal !omen O3;P. Cur findings confirmed t at o#esity is a risk factor for reduced %&?C3 and t at !eig t loss can impro"e #ot p ysical and mental aspects of %&?C3. Pre"ious studies a"e s o!n an important role of psyc osocial factors on explaining o! exercise impacts )uality of life O3:291P. .n multiple sclerosis patients, depression, social support, self2efficacy and fatigue mediated effects of exercise on )uality of life O91P. >reater social support !as associated !it stronger exercise self2efficacy in older adults in anot er study O92P. Fxercise self2efficacy mediated t e exercise effect on mental and p ysical aspects of %&?C3 in older !omen O96P. %ig er exercise self2 efficacy !as associated !it greater p ysical po!er score, a com#ined score of aero#ic fitness and fi"e items from t e *enior Fitness Test O93P among older adults O99P. .t is possi#le t at t e o#ser"ed associations of !eig t loss and impro"ed aero#ic fitness !it %&?C3 in our study could #e mediated t roug increase in exercise self2efficacy. Future studies may #enefit from testing psyc osocial predictors of )uality of life including self2 efficacy to furt er determine t e mec anism of o! inter"entions affect %&?C3. T e strengt s of t is trial include its large sample si0eD randomi0ed controlled designD t ree inter"ention arms allo!ing direct comparisons of indi"idual and com#ined exercise and diet groups to eac ot er and controlsD excellent ad erence to inter"ention prescriptionD lo! rate of drop2outs $<=(D and use of "alidated measures of %&?C3 and psyc osocial factors. .n particular, direct comparison #et!een com#ined diet\exercise and diet or exercise alone allo!ed us to understand t e indi"idual and com#ined contri#ution of t ese lifestyle #e a"iors on %&?C3. T is study is limited #y some factors t at s ould #e kept in mind ! en interpreting t e results. Cur sample consisted primarily of non2%ispanic + ite !omen !it a ig education le"el on a"erage. %ence, our findings may not #e generali0a#le to men, or !omen in ot er et nic groups or !it different education le"els. Anot er limitation is t e relati"ely ig %&?C3 scores among our sample. F"en t oug !e found significant effects on se"eral aspects of %&?C3, t e analysis may a"e suffered from a ceiling effect. -ased on t ese limitations, future studies are needed to test t e effects of t ese

dietary !eig t loss and exercise inter"entions in ot er populations suc as !omen of ot er race4et nicity groups or in men. Gonclusions Cur findings suggest t at t e com#ination of dietary !eig t loss and exercise may a"e a larger #eneficial effect on %&?C3 compared !it dietary !eig t loss or exercise alone. +eig t loss and impro"ements in aero#ic fitness and psyc osocial factors $depression, stress, and social support( !ere predictors of increased %&?C3, suggesting t at t ese factors could mediate t e inter"ention effects on %&?C3. A##re"iations A1GC'A8 analysis of co"arianceD A1C'A8 analysis of "arianceD -M.8 #ody mass indexD -*.8 -rief *ymptom .n"entoryD @PP8 @ia#etes Pre"ention ProgramD %&?C38 ealt related )uality of lifeD 3ook A%FA@8 Action for ealt in @ia#etesD MC*8 Medical Cutcome *tudy *ocial *upport *ur"eyD *F23A8 Medical Cutcomes *tudy 3A2.tem * ort2 Form %ealt *ur"ey. Gompeting interests T e aut ors declare t at t ey a"e no competing interests. Aut orsK contri#utions .. conducted data analyses, interpreted t e results and drafted t e manuscript. GMA interpreted t e results and drafted t e manuscript. AK and GF- ac)uired t e data. 3V performed analysis. >3- designed t e study. AM designed t e study, ac)uired t e data, interpreted t e results, and drafted t e manuscript. All aut ors a"e re"ised and appro"ed t e manuscript. Ackno!ledgements T e 1utrition and Fxercise for +omen $1F+( trial !as supported #y &61 GA16/2692 61A1 from t e 1ational Gancer .nstitute $1G.(. + ile !orking on t e trial, GMA !as employed at t e C io *tate Bni"ersity, and located to 1G. follo!ing completion of er effort on t e 1F+ trial. AK !as supported #y 1G. &2/GA6<9::6 at t e time of t is study and is currently supported #y 1G. 2&2/GA6/;A<<. KFF is supported #y /K32&&62/61/263 from 1ational Genter for &esearc &esources $1G&&(, a component of t e 1ational .nstitute of %ealt $1.%( and 1.% &oadmap for Medical &esearc . Article information .nt J -e a" 1utr P ys Act. 2611D :8 11:. Pu#lis ed online 2611 Ccto#er 2/. doi8 16.11:A419;<2/:A:2:211: PMG.@8 PMG321/A/A .kuyo .mayama,1 Gat erine M Alfano,2 Angela Kong,3 Karen F Foster2*c u#ert,9 Garolyn F -ain,1 3iren Viao,1 Gat erine @uggan,1 G ing2Qun +ang,1,/ Kristin 3 Gamp#ell,A >eorge 3 -lack#urn,; and Anne McTiernancorresponding aut or1,9,: 1Pu#lic %ealt *ciences @i"ision, Fred %utc ison Gancer &esearc Genter, *eattle, +A, B*A 2Cffice of Gancer *ur"i"ors ip, 1ational Gancer .nstitute, 1ational .nstitutes of %ealt , -et esda, M@, B*A 3Gancer Fducation and Gareer @e"elopment Program, Bni"ersity of .llinois at G icago, G icago, .3, B*A 9@epartment of Medicine, *c ool of Medicine, Bni"ersity of +as ington, *eattle, +A, B*A

/@epartment of -iostatistics, *c ool of Pu#lic %ealt , Bni"ersity of +as ington, *eattle, +A, B*A A@epartment of P ysical T erapy, Bni"ersity of -ritis Golum#ia, 'ancou"er, -G, Ganada ;@epartment of *urgery, -et .srael @eaconess Medical Genter, %ar"ard Medical *c ool, -oston, MA, B*A :@epartment of Fpidemiology, *c ool of Pu#lic %ealt , Bni"ersity of +as ington, *eattle, +A, B*A corresponding aut orGorresponding aut or. .kuyo .mayama8 iimayama4at4f crc.orgD Gat erine M Alfano8 alfanoc4at4mail.ni .go"D Angela Kong8 akong4at4uic.eduD Karen F Foster2*c u#ert8 kfoster4at4u.!as ington.eduD Garolyn F -ain8 ce#ain4at4f crc.orgD 3iren Viao8 lxiao4at4f crc.orgD Gat erine @uggan8 cduggan4at4f crc.orgD G ing2Qun +ang8 cy!ang4at4f crc.orgD Kristin 3 Gamp#ell8 kristin.camp#ell4at4u#c.caD >eorge 3 -lack#urn8 g#lack#u4at4#idmc. ar"ard.eduD Anne McTiernan8 amctiern4at4f crc.org &ecei"ed January 11, 2611D Accepted Ccto#er 2/, 2611. Gopyrig t L2611 .mayama et alD licensee -ioMed Gentral 3td. T is is an Cpen Access article distri#uted under t e terms of t e Greati"e Gommons Attri#ution 3icense $ ttp844creati"ecommons.org4licenses4#y42.6(, ! ic permits unrestricted use, distri#ution, and reproduction in any medium, pro"ided t e original !ork is properly cited. T is article as #een cited #y ot er articles in PMG. Articles from T e .nternational Journal of -e a"ioral 1utrition and P ysical Acti"ity are pro"ided ere courtesy of -ioMed Gentral &eferences Flegal KM, Garroll M@, Cgden G3, Gurtin 3&. Pre"alence and trends in o#esity among B* adults, 1<<<2266:. JAMA. 2616D363$3(823/J291. doi8 16.16614Eama.266<.2619. OPu#MedP OGross &efP A"enell A, -room J, -ro!n TJ, Poo#alan A, Aucott 3, *tearns *G, *mit +G, Jung &T, Gamp#ell MK, >rant AM. *ystematic re"ie! of t e long2term effects and economic conse)uences of treatments for o#esity and implications for ealt impro"ement. %ealt Tec nol Assess. 2669D:$21(81J1:2. iii2i". OPu#MedP Jones >3, *utton A. ?uality of life in o#ese postmenopausal !omen. Menopause .nt. 266:D19$1(82AJ32. doi8 16.12/:4mi.266;.66;639. OPu#MedP OGross &efP -lissmer -, &ie#e @, @ye >, &uggiero 3, >reene >, Gald!ell M. %ealt 2related )uality of life follo!ing a clinical !eig t loss inter"ention among o"er!eig t and o#ese adults8 inter"ention and 29 mont follo!2up effects. %ealt ?ual 3ife Cutcomes. 266AD9893. doi8 16.11:A419;;2;/2/29293. OPMG free articleP OPu#MedP OGross &efP Kaukua J, Pekkarinen T, *ane T, MustaEoki P. %ealt 2related )uality of life in o#ese outpatients losing !eig t !it "ery2lo!2energy diet and #e a"iour modification22a 22y follo!2up study. .nt J C#es &elat Meta# @isord. 2663D2;$16(81233J1291. doi8 16.163:4sE.iEo.6:623;<. OPu#MedP OGross &efP -o!en @J, Fesinmeyer M@, Qasui Q, T!oroger *, Blric GM, .r!in M3, &udolp &F, 3aGroix K3, *c !art0 &&, McTiernan A. &andomi0ed trial of exercise in sedentary middle aged !omen8 effects on )uality of life. .nt J -e a" 1utr P ys Act. 266AD3839. doi8 16.11:A419;<2/:A:23239. OPMG free articleP OPu#MedP OGross &efP Fontaine K&, -arofsky .. C#esity and ealt 2related )uality of life. C#es &e". 2661D2$3(81;3J1:2. doi8 16.169A4E.19A;2;:<x.2661.66632.x. OPu#MedP OGross &efP 1orris *3, R ang V, A"enell A, >regg F, -o!man -, *erdula M, -ro!n TJ, *c mid G%, 3au J. 3ong2term effecti"eness of lifestyle and #e a"ioral !eig t loss inter"entions

in adults !it type 2 dia#etes8 a meta2analysis. Am J Med. 2669D11;$16(8;A2J;;9. doi8 16.161A4E.amEmed.2669.6/.629. OPu#MedP OGross &efP +ing &&. P ysical acti"ity in t e treatment of t e adult ood o"er!eig t and o#esity8 current e"idence and researc issues. Med *ci *ports Fxerc. 1<<<D31$11 *uppl(8*/9;J //2. OPu#MedP *tefanick M3, Mackey *, * ee an M, Flls!ort 1, %askell +3, +ood P@. Fffects of diet and exercise in men and postmenopausal !omen !it lo! le"els of %@3 c olesterol and ig le"els of 3@3 c olesterol. 1 Fngl J Med. 1<<:D33<$1(812J26. doi8 16.16/A41FJM1<<:6;6233<6163. OPu#MedP OGross &efP +ood P@, *tefanick M3, +illiams PT, %askell +3. T e effects on plasma lipoproteins of a prudent !eig t2reducing diet, !it or !it out exercise, in o"er!eig t men and !omen. 1 Fngl J Med. 1<<1D32/$;(89A1J9AA. doi8 16.16/A41FJM1<<16:1/32/6;63. OPu#MedP OGross &efP Cro0co 3J, -uc leitner AM, >imene02Pere0 >, &o)ue .FM, &ic ter -, Mauricio @. Fxercise or exercise and diet for pre"enting type 2 dia#etes mellitus. Goc rane @ata#ase *yst &e". 266:. p. G@6636/9. OPu#MedP Kaplan &M, %art!ell *3, +ilson @K, +allace JP. Fffects of diet and exercise inter"entions on control and )uality of life in non2insulin2dependent dia#etes mellitus. J >en .ntern Med. 1<:;D2$9(8226J22:. doi8 16.166;4-F62/<A993. OPu#MedP OGross &efP &eEeski +J, Foc t -G, Messier *P, Morgan T, Pa or M, Penninx -. C#ese, older adults !it knee osteoart ritis8 !eig t loss, exercise, and )uality of life. %ealt Psyc ol. 2662D21$/(891<J92A. OPu#MedP %ellenius M3, @a lof G, A#erg %, Krakau ., de Faire B. ?uality of life is not negati"ely affected #y diet and exercise inter"ention in ealt y men !it cardio"ascular risk factors. ?ual 3ife &es. 1<</D9$1(813J26. doi8 16.166;4-F669393;:. OPu#MedP OGross &efP Palmeira A3, Markland @A, *il"a M1, -ranco T3, Martins *G, Minderico G*, 'ieira P1, -arata JT, *erpa *C, *ardin a 3-. et al. &eciprocal effects among c anges in !eig t, #ody image, and ot er psyc ological factors during #e a"ioral o#esity treatment8 a mediation analysis. .nt J -e a" 1utr P ys Act. 266<DA8<. doi8 16.11:A419;<2/:A:2A2<. OPMG free articleP OPu#MedP OGross &efP &oss KM, Milsom 'A, &ickel KA, @e#ragan0a 1, >i##ons 3M, Mura!ski MF, Perri M>. T e contri#utions of !eig t loss and increased p ysical fitness to impro"ements in ealt 2related )uality of life. Fat -e a". 266<D16$2(8:9J::. doi8 16.161A4E.eat#e .266:.12.662. OPMG free articleP OPu#MedP OGross &efP +illiamson @A, &eEeski J, 3ang +, 'an @orsten -, Fa#ricatore A1, Toledo K. .mpact of a !eig t management program on ealt 2related )uality of life in o"er!eig t adults !it type 2 dia#etes. Arc .ntern Med. 266<D1A<$2(81A3J1;1. doi8 16.16614arc internmed.266:./99. OPMG free articleP OPu#MedP OGross &efP *egal &J, &eid &@, Gourneya K*, Malone *G, Parliament M-, *cott G>, 'enner PM, ?uinney %A, Jones 3+, @KAngelo MF. et al. &esistance exercise in men recei"ing androgen depri"ation t erapy for prostate cancer. J Glin Cncol. 2663D21$<(81A/3J1A/<. doi8 16.12664JGC.2663.6<./39. OPu#MedP OGross &efP Kno!ler +G, -arrett2Gonnor F, Fo!ler *F, %amman &F, 3ac in JM, +alker FA, 1at an @M. &eduction in t e incidence of type 2 dia#etes !it lifestyle inter"ention or metformin. 1 Fngl J Med. 2662D39A$A(83<3J963. OPMG free articleP OPu#MedP &yan @%, Fspeland MA, Foster >@, %affner *M, %u##ard '*, Jo nson KG, Ka n *F, Kno!ler +G, Qano"ski *R. 3ook A%FA@ $Action for %ealt in @ia#etes(8 design and met ods for a clinical trial of !eig t loss for t e pre"ention of cardio"ascular disease in type 2 dia#etes. Gontrol Glin Trials. 2663D29$/(8A16JA2:. doi8 16.161A4*61<;2 29/A$63(666A923. OPu#MedP OGross &efP

Pate &&, -lair *1, @urstine J3, Fddy @3, %anson P, Painter P, *mit 3K, +olfe 3A. >uidelines for Fxercise Testing and Prescription. 9. P iladelp ia, PA8 3ea N Fe#igerD 1<<1. *c auer JF, %anson P. Bsefulness of a #ranc ing treadmill protocol for e"aluation of cardiac functional capacity. Am J Gardiol. 1<:;DA6$1A(813;3J13;;. doi8 16.161A466622 <19<$:;(<6A222<. OPu#MedP OGross &efP Taylor %3, Jaco#s @&, *c ucker -, Knudsen J, 3eon A*, @e#acker >. A )uestionnaire for t e assessment of leisure time p ysical acti"ities. Journal of c ronic diseases. 1<;:D31$12(8;91J;//. doi8 16.161A466212<A:1$;:(<66/:2<. OPu#MedP OGross &efP Patterson &F, Kristal A&, Tinker 3F, Garter &A, -olton MP, Agurs2Gollins T. Measurement c aracteristics of t e +omenKs %ealt .nitiati"e food fre)uency )uestionnaire. Annals of epidemiology. 1<<<D<$3(81;:J1:;. doi8 16.161A4*169;2 2;<;$<:(666//2A. OPu#MedP OGross &efP @erogatis 3&, Melisaratos 1. T e -rief *ymptom .n"entory8 an introductory report. Psyc ol Med. 1<:3D13$3(8/</JA6/. doi8 16.161;4*66332<1;6669:61;. OPu#MedP OGross &efP @erogatis 3&. -rief *ymptom .n"entory 1:8 Administration, scoring, and procedures manual. Minneapolis8 1G* Pearson, .ncD 2661. Go en *, Kamarck T, Mermelstein &. A glo#al measure of percei"ed stress. J %ealt *oc -e a". 1<:3D29$9(83:/J3<A. doi8 16.236;4213A969. OPu#MedP OGross &efP * er#ourne G@, *te!art A3. T e MC* social support sur"ey. *ocial science N medicine $1<:2( 1<<1D32$A(8;6/J;19. doi8 16.161A462;;2</3A$<1(<61/62-. OPu#MedP OGross &efP +are JF. *F 3A ealt sur"ey8 manual and interpretation guide. -oston, MA8 T e %ealt .nstitute 1e! Fngland Medical GenterD 1<<3. Foster2*c u#ert KF, Alfano GM, @uggan G&, Viao 3, Gamp#ell K3, Kong A, -ain GF, +ang GQ, -lack#urn >3, McTiernan A. Fffect of @iet and Fxercise, Alone or Gom#ined, on +eig t and -ody Gomposition in C"er!eig t2to2C#ese Postmenopausal +omen. C#esity $*il"er *pring( 2611. OPMG free articleP OPu#MedP MacKinnon @P, 3ock!ood GM, %offman JM, +est *>, * eets '. A comparison of met ods to test mediation and ot er inter"ening "aria#le effects. Psyc ol Met ods. 2662D;$1(8:3J169. OPMG free articleP OPu#MedP Gourneya K*, McKen0ie @G, Mackey J&, >elmon K, &eid &@, Friedenreic GM, 3ad a A-, Proulx G, 'allance JK, 3ane K. et al. Moderators of t e effects of exercise training in #reast cancer patients recei"ing c emot erapy8 a randomi0ed controlled trial. Gancer. 266:D112$:(81:9/J1:/3. doi8 16.16624cncr.233;<. OPu#MedP OGross &efP @au#enmier JJ, +eidner >, *umner M@, Mendell 1, Merritt2+orden T, *tudley J, Crnis @. T e contri#ution of c anges in diet, exercise, and stress management to c anges in coronary risk in !omen and men in t e multisite cardiac lifestyle inter"ention program. Ann -e a" Med. 266;D33$1(8/;JA:. doi8 16.126;4s1/329;<Aa#m3361h;. OPu#MedP OGross &efP +ells K-, *te!art A, %ays &@, -urnam MA, &ogers +, @aniels M, -erry *, >reenfield *, +are J. T e functioning and !ell2#eing of depressed patients. &esults from t e Medical Cutcomes *tudy. Jama. 1<:<D2A2$;(8<19J<1<. doi8 16.16614Eama.2A2.;.<19. OPu#MedP OGross &efP ten @oessc ate MG, Koeter M+, -ockting G3, *c ene A%. %ealt related )uality of life in recurrent depression8 a comparison !it a general population sample. J Affect @isord. pp. 12AJ132. OPu#MedP

Qankura @J, Gonroy M-, %ess &, Pettee KK, Kuller 3%, Kriska AM. +eig t regain and ealt 2related )uality of life in postmenopausal !omen. C#esity $*il"er *pring( 266:D1A$16(822/<J22A/. doi8 16.163:4o#y.266:.39/. OPu#MedP OGross &efP + ite *M, +oEcicki T&, McAuley F. P ysical acti"ity and )uality of life in community d!elling older adults. %ealt ?ual 3ife Cutcomes. 266<D;816. doi8 16.11:A419;;2;/2/2;2 16. OPMG free articleP OPu#MedP OGross &efP McAuley F, Konopack JF, Motl &+, Morris K*, @oerksen *F, &osengren K&. P ysical acti"ity and )uality of life in older adults8 influence of ealt status and self2 efficacy. Ann -e a" Med. 266AD31$1(8<<J163. doi8 16.126;4s1/329;<Aa#m3161h19. OPu#MedP OGross &efP McAuley F, @oerksen *F, Morris K*, Motl &+, %u 3, +oEcicki T&, + ite *M, &osengren K&. Pat !ays from p ysical acti"ity to )uality of life in older !omen. Ann -e a" Med. 266:D3A$1(813J26. doi8 16.166;4s121A6266:2<63A2<. OPMG free articleP OPu#MedP OGross &efP Motl &+, McAuley F, *nook FM, >liottoni &G. P ysical acti"ity and )uality of life in multiple sclerosis8 intermediary roles of disa#ility, fatigue, mood, pain, self2efficacy and social support. Psyc ol %ealt Med. 266<D19$1(8111J129. doi8 16.16:6413/9:/66:62291<62. OPMG free articleP OPu#MedP OGross &efP McAuley F, Jerome >J, Mar)ue0 @V, Fla"sky *, -lissmer -. Fxercise self2efficacy in older adults8 social, affecti"e, and #e a"ioral influences. Ann -e a" Med. 2663D2/$1(81J ;. doi8 16.126;4*1/329;<AA-M2/61h61. OPu#MedP OGross &efP &ikli &F, Jones GJ. *enior fitness test manual. G ampaign, .38 %uman KineticsD 2661. Konopack JF, Mar)ue0 @V, %u 3, Fla"sky *, McAuley F, Kramer AF. Gorrelates of functional fitness in older adults. .nt J -e a" Med. 266:D1/$9(8311J31:. doi8 16.16:6416;6//66:623A///;. OPMG free articleP OPu#MedP OGross &efP ; Glinics %ospital das Glinicas da Faculdade de Medicina da Bni"ersidade de *ao Paulo Fffect of massage in postmenopausal !omen !it insomnia J A pilot study @enise Cli"eira, %elena %ac ul, O...P, and 3ia -ittencourt Additional article information .1T&C@BGT.C1 1early :6= of !omen going t roug menopause experience some kind of clinical symptom and in 96= of cases t e symptoms are sufficiently intense to lead t e patient to seek medical assistance.1 T e most common symptoms are "asomotor insta#ility, ner"ousness, anxiety, irrita#ility, depression and insomnia, all significantly detrimental to !ell2#eing. .nsomnia is ig ly pre"alent and affects #et!een 2:= and A3= of postmenopausal !omen.2 T e searc for complementary t erapies is increasing, massage t erapy #eing among t ese. T e effects of massage on t e acti"ation of arterial and "enous #lood flo!, t e lymp atic system, in addition to impacting oedema, t e conEuncti"e tissue and muscles,3 are !ell kno!n. T roug acting on t e somatic, autonomic and central ner"ous system, massage promotes impro"ed "isceral functioning and re2esta#lis es omeostasis.9

T roug cutaneo2muscle stimulation on t e surface of t e #ody, t e receptors of touc , pressure, eat, "i#ration and pain are acti"ated and t ese stimuli are transported to t e autonomous and central ner"ous systems, unleas ing neuro2c emical reactions./ A recent study s o!ed t at !omen !it complaints of insomnia principally c ose corporal t erapies,A ! ereas anot er one concluded t at massage promotes relaxation and sleep and is identified as an agreea#le inter"ention #y t e elderly.; Alt oug t e #enefits of massage !ere descri#ed in a study, no o#Eecti"e parameters of sleep !ere e"aluated.: Furt ermore, t ere are t us far no studies ! ic e"aluate t e effects of massage specifically on postmenopausal !omen. Ct er studies o#ser"ed t at yoga impro"ed climacteric symptons in !omen in peri2and post2menopause.<216 T e o#Eecti"e of t is pilot study !as to e"aluate t e effect of t erapeutic massage on insomnia, depression, and anxiety t roug su#Eecti"e and o#Eecti"e parameters in postmenopausal patients !it insomnia. MATF&.A3* A1@ MFT%C@* *u#Eects .n t is study, !e selected se"en postmenopausal !omen !it insomnia8 difficulty in falling sleep or insomnia symptoms for at least t ree times a !eek $mean age ^ *@8 /A.2: ^ 1.<;$*@(, range /6 to A/ years, mean #ody2mass index $-M.( 5 36 kg4m2(. T e study !as appro"ed #y t e Ft ical Gommittee of t e Federal Bni"ersity of *ao Paulo $GFPi696:46;(. .nclusion criteria re)uired t at indi"iduals #e in postmenopause $at least 1 year of amenorr ea #efore enrollment and an F*% le"el a#o"e 36 mlB4m3(, !it no pre"ious exposure to exogenous ormones. Fxclusion criteria !ere serious ealt pro#lems and use of antidepressants or sleep2 inducing aids. +e also excluded !omen !it sleep apnea $apnea ipopnea index in polysomnograp y ig er t an 1/4 our(. Protocol design *tudy su#Eects accordingly under!ent t e follo!ing8 a screening inter"ie! t at included a complete medical istory, anamnesis, and Kupperman index11, as !ell as complete gynecological and ematological examinations. T erapeutic massage T ese "olunteers !ere su#mitted to sixteen one2 our sessions of massage t!ice !eekly and e"aluated on psyc ological and p ysiological parameters. ?uestionnaires ?uestionnaires !ere applied #efore and after inter"ention. T e .n"entories of *elf2 e"aluation $*piel#erger *tate Trait Anxiety .n"entory2 *TA. . and ..,12 and -eck @epression .n"entory13(, ! ic e"aluate t e degree of anxiety and depression of t e "olunteers, !ere applied in t e pre2trial, 9t , :t , 12t and 1At sessions. T e *leep @iary $Morin, G. "ersion( e"aluates sleeping a#its, as !ell as t e c aracteristics and )uality of sleepD19 t is )uestionnaire !as responded to on a daily #asis #y t e "olunteers. T e *tate Trait Anxiety .n"entory $*TA.( is made up of 96 affirmations ! ic relate to t e feelings of t e indi"idual and is di"ided into t!o partsD *TA. . and *TA. .. 2 eac is

composed of 26 affirmations to ! ic a score of one to four must #e gi"en. T e first part e"aluates state2anxietyD t e second e"aluates anxious2trait. T e -eck @epression .n"entory is made up of 21 )uestions J t e ig er t e score attri#uted to eac )uestion, t e more depressed is t e indi"idual. T e *leep @iary is an easily completed )uestionnaire ! ic s ould prefera#ly #e responded to soon after t e patient !akes up and carried out for a minimum period of t!o !eeks. T is )uestionnaire contains information suc as t e time of going to #ed, t e time taken to fall asleep, o! many times t e patient a!akens during t e nig t, t e time of !aking up, of getting out of #ed, t e num#er of sleep ours, t e )uality of sleep and t e consumption of alco ol and4or coffee, t us descri#ing t e c aracteristics of sleep in t e period analysed.1/ Polysomnograp y $P*>( P*> !as performed !it a computeri0ed system consisting of surface electrodes for electroencep alograp y, electromyograp y, electrooculograp y, electrocardiograp y, impedance pneumograp y to record a#dominal4c est mo"ement, t ermal sensors and nasal cannula to measure nasal and oral air flo!, a sensor to detect #ody position, a !rist infrared oximeter attac ed to t e patientKs distal p alange to gauge oxy emoglo#in, and a snoring sensor. After t e exam, a p ysician trained in P*> analy0ed t e sleep stage according to t e criteria set fort #y &ec tsc affen and Kales.1A &espiratory e"ents !ere analy0ed #y criteria esta#lis ed #y t e Gommittee of t e American Academy of *leep Medicine, as !ere arousals and periodic leg mo"ements.1; T e ot er sleep parameters !ere8 sleep latency, &FM sleep latency, sleep efficiency, stages 3 and 9, &FM sleep. *tatistical analysis .n t e statistical analysis of t e data, non2parametric tests !ere utili0ed due to t e "aria#ility of t e "aria#les studied. For t e analysis of t e in"entories, t e Friedman Test !as utili0ed and for t e analysis of t e polysomnograp ia t e +ilcoxon Test !as used.1: &F*B3T* *leep and clinical complaints a( *u#Eecti"e )uestionnaires T ere !as a significant $p56.6/( impro"ement in t e symptoms of anxiety and depression. Figure 1 *TA. . Figure 1 Figure 1 Anxiety scores of "olunteers as e"aluated #y *TA.2* )uestionary during sessions !it t erapeutic massage. Figure 2 *TA. .. Figure 2

Figure 2 Anxiety scores of "olunteers as e"aluated #y *TA.2T )uestionary during sessions !it t erapeutic massage. Figure 3 -@. Figure 3 Figure 3 @epression scores of "olunteers as e"aluated #y -@. )uestionary during sessions !it t erapeutic massage. T e *leep @iary s o!ed t at all of t e participants fell asleep more rapidly, presented a gradual impro"ement in )uality of sleep and a!oke feeling #etter. #( Polysomnograp y $P*>( For sleep arc itecture "aria#les, o#Eecti"e measure #y P*> indicated t at t ere !as a significant difference in &FM latencyD sleep stage 1D sleep stage 3 and 9. Ta#le 1 Follo!2up Ta#le 1 Ta#le 1 Polysomnograp y results #efore and after t erapeutic massage $TM(. T e "olunteers !ere re2e"aluated after a period of one year. T ey did not undergo any ot er t erapy during t is time. T ey !ere asked a#out t eir sleep complaints8 t!o !omen stated alt oug t ey ad impro"ed sleep during massage treatment, no! t ey are suffering from insomnia. T!o !omen stated t at t ey !ere sleeping #etter and t ree stated t at t ey ad no pro#lems at all !it t eir current sleep patterns. @.*GB**.C1 T e present study s o!ed t at t erapeutic massage decreased t e se"erity of su#Eecti"e sleep distur#ance related to menopause. First, t ere !as a decrease in insomnia and anxiety2depressi"e symptomsD t e treatment also suppressed ot er menopausal symptoms. *econd, P*> findings re"ealed a decrease in &FM latency and increased stages t ree and four. .n lig t of t e large num#er of !omen suffering from climacteric syndrome, t ere is a surprisingly skeletal literature on alternati"e treatments to sleep difficulties in postmenopausal !omen. Alt oug menopausal !omen a"e #een t e su#Eect of endocrinological researc , less attention as #een gi"en to treatment #y e"aluating sleep $su#Eecti"e and o#Eecti"e(. A recent study s o!ed t at a large num#er of postmenopusal !omen seek complementary and alternati"e t erap ies. .n t is researc , /A3 !omen !ere inter"ie!ed and 13.;= preferred t e use of massage. Among t ese !omen, :1.:= stated impro"ement in climacteric symptons after t erapeutic massage.1< T erapeutic massage reduced stress in "arious clinical situations suc as t at of depression, pain syndromes and auto2immune diseases.26 T ese parameters !ere assayed !it t e measurement of su#stances like cortisol, serotonin and dopamine. .n a study !it elderly su#Eects, it !as o#ser"ed t at foot massage $reflexot erapy( impro"ed )uality of sleep, reduced depression and increased t e le"el of serotonin.21 +it t e

same tec ni)ue, a significant difference !as also o#ser"ed in climacteric symptoms, in fatigue, in total c olesterol and in t e le"el of cortisol.22 .n a multi2centric controlled study, massage !as done to treat insomnia and t e Pitts#urg *leep ?uality .ndex and t e *leepless Anxiety *cale *leepless @epression *cale !ere used to e"aluate patient symptoms. T ey concluded t at t ere !as a significant impro"ement in <A= of t e cases, similar to t e trend o#ser"ed in t is study.: .n t e post2+omenKs %ealt .nitiati"e era,23 considera#le de#ate as #een directed at t e risks of %T. T is leads !omen in menopause to seek #eneficial ealt ad"ice and make positi"e lifestyle c anges. .n our study, 1A t erapeutic massage sessions s o!ed a significant impro"ement $p56.6/( in t e symptoms of anxiety and depression. +it regard to t e @iary, t ere !as an impro"ement in )uality of sleep, since all participants fell asleep more rapidly, presented a gradual impro"ement in )uality of sleep and referenced impro"ed !ell2#eing upon a!akening. Polysomnograp y re"ealed a significant difference in &FM latency in t e first sleep stage and in sleep stages t ree and four. Cne limitation of t e present study is t e limited num#er of !omen as !ell as t e a#sence of a control group. 1e"ert eless, t ese preliminary results indicate t at massage can #e an alternati"e in treating postmenopausal !omen !it insomnia. -ased on t e present results, !e suggest t at t erapeutic massage is #eneficial for impro"ing su#Eecti"e sleep )uality in postmenopausal !omen, as !ell as for alle"iating symptoms of depression and anxiety. *ince sleep complaints are common during menopause, future studies s ould include a control group to assess t e potential of massage as treatment or complementary treatment for insomnia in postmenopausal !omen. AGK1C+3F@>MF1T* T is !ork !as supported #y grants from Associajko Fundo de .ncenti"o l Psicofarmacologia $AF.P(, G1P) and FAPF*P $GFP.@ i<:41936323 to *.T.(. Article information Glinics $*ao Paulo(. 2611 Fe#ruaryD AA$2(8 393J39A. doi8 16.1/<64*1:6;2/<32261166626662A PMG.@8 PMG36/<:;/ @enise Cli"eira,. %elena %ac ul,.,.. *ergio Tufik,. and 3ia -ittencourt. .Bni"ersidade Federal de *ko Paulo, @epto de Psico#iologia, *ko Paulo, *P, -ra0il ..Bni"ersidade Federal de *ko Paulo, @epto de >inecologia, *ko Paulo, *P, -ra0il F2mail8 elena ac ul4at4psico#io.epm.#r Tel.8 P one8 // 11 219<61// Gopyrig t L 2611 %ospital das Glmnicas da FMB*P T is is an Cpen Access article distri#uted under t e terms of t e Greati"e Gommons Attri#ution 1on2Gommercial 3icense $ ttp844creati"ecommons.org4licenses4#y2nc43.64( ! ic permits unrestricted non2commercial use, distri#ution, and reproduction in any medium, pro"ided t e original !ork is properly cited. T is article as #een cited #y ot er articles in PMG. Articles from Glinics are pro"ided ere courtesy of %ospital das Glinicas da Faculdade de Medicina da Bni"ersidade de *ao Paulo &FFF&F1GF*

1. %arrison. Medicina interna. .n8 Garr - &, -rads a! K @, editors. @istnr#ios do o"orio e do trato reproduti"o feminino 19t ed. &io de Janeiro8 Mc>ra!2%ill .nteramericana do -rasil 3tdaD 1<<:. p. 13:6. 2. Gampos %%, -ittencourt 3&A, %aidar MA, Tufik *, -aracat FG. Pre"alpncia de distnr#ios do sono na pUs menopausa. &e" -ras >inec C#stet. 266/D2;8;31JA. 3. >oats >G. Massage t e scientific #asis of an ancient art8 part 2. P isiological and t erapeutic effects. -r J *p Med. 1<<9D2:81/3JA. 16.113A4#Esm.2:.3.1/3 OPMG free articleP OPu#MedP 9. Mantle F. *leepless and unsettled. 1ursing times. 1<<AD<289AJ;. OPu#MedP /. >uimarkes GM, Pinge MGM, Qamamura Q, Mello 3FAM. Fffects of acupuncture on #e a"ioral, cardio"ascular and ormonal responses in restraint2stressed +istar rats. -ra0 J Med &es. 1<<;836. OPu#MedP A. 1e!ton KM, -uist @*M, Keenan 13, Anderson 3A, 3aGroix AR. Bse of alternati"e t erapies for menopause symptoms8 &esults of a population2#ased sur"ey. C#stet >ynecol. 2662D16681:J2/. 16.161A4*662<2;:99$62(6266/2; OPu#MedP ;. *c iff A. 3iterature re"ie! of #ack massage and similar tec ni)ues to promote sleep in elderly people. Pflege. 266AD1<81A3J;3. 16.1629416122/362.1<.3.1A3 OPu#MedP :. R ou QF, +ei Q3, R ang P3, >ao *, 1ing >3, R ang R?, et al. Multi2central controlled study on t ree2part massage t erapy for treatment of insomnia of deficiency of #ot t e eart and spleen. R ongguo R en Jiu. 266AD2A83:/J:. OPu#MedP <. -oot 23aForce G, T urston &G, Taylor M&. A pilot study of a %at a yoga treatment for menopausal symptoms. Maturitas. 266;D/;82:AJ</. 16.161A4E.maturitas.266;.61.612 OPu#MedP 16. Go en -F, Kanaya AM, Macer J3, * en %, G ang AA, >rady @. Feasi#ility and accepta#ility of restorati"e yoga for treatment of ot flus es8 A pilot trial. Maturitas. 266;D/A81<:J269. 16.161A4E.maturitas.266A.6:.663 OPu#MedP 11. Kupperman %*, +etc ler --, -latt M%>. Gontemporary t erapy of t e menopausal syndrome. JAMA. 1</<D1;181A2;J3;. OPu#MedP 12. *piel#erger G@, >orsuc &3, 3us ene &F. Galifornia8 Gonsulting2Psyc ologists PressD 1<;6. Manual for t e state2trait anxiety in"entory $Yself2e"aluating )uestionnaire( 13. -eck AT. Filadelfia8 Genter for Gogniti"e T erapyD 1<;:. @epression in"entory. 19. Morin G, Fspie GA. 1e! Qork8 *pringerD 2669. .nsomnia J A Glinical guide to assessment and treatment. 1/. 2663. . Gonsenso -rasileiro de .nsqnia. %ypnos J &e"ista do *ono. 1A. &ec tsc affen A, Kales A, editors. 3os Angeles8 -rain .nformation *er"ice, -rain &esearc .nstituteD 1<A:. A manual of standardi0ed tec nology tec ni)ues and scoring systems for sleep stages of uman su#Eects. 1;. .#er G, Ancoli2.srael *, G esson A, Jr, ?uan *. +estc ester8 American Academy of *leep MedicineD 266;. T e AA*M Manual for t e *coring of *leep and Associated F"ents8 &ules, Terminology and Tec nical *pecifications, First Fdition. 1:. *iegel *, Gastellan 1J., Jr Porto Alegre8 ArtmedD 266A. Fstatmstica nko paramrtrica para cipncias do comportamento. 2t ed. p.99:. 1<. @aley A, MacArt ur G, McManis &, *tokes23ampard %, +ilson *, &oalfe A, et al. Factors associated !it t e use of complementary medicine and non2p armacological inter"ention in symptomatic menopausal !omen. Glimacteric. 266AD<833AJ9A. 16.16:6413A<;136A66:A96;9 OPu#MedP 26. Field T, &eif M%, @iego M, *c angerg *, Ku n G. Gortisol decreases and serotonin and dopamine increase follo!ing massage t erapy. .nt J 1eurosci. 266/D11/813<;J913. 16.16:646626;9/6/<6</A9/< OPu#MedP

21. *ong &%, Kim @%. T e effects of foot reflexion massage on sleep distur#ance, depression disorder and t e p ysiological index of t e elderly. Tae an Kan o %ak oe G i. 266AD3A81/J29. OPu#MedP 22. 3ee QM. Fffects of foot reflexology massage on climacteric symptom, fatigue and p ysiologic parameters of middle aged !omen. J Korean Acad Adult 1urs. 266AD1:82:9J<2. 23. +omenSs %ealt .nitiati"e. +riting >roup for t e +omenSs %ealt .nitiati"e in"estigators. &isks and #enefits of estrogen plus progestogin in ealt y postmenopausal !omen8 principal results from t e +omenSs %ealt .nitiati"e randomi0ed controlled trial. JAMA. 2662D2::8321J33. 16.16614Eama.2::.3.321 OPu#MedP : *eminars in reproducti"e medicine Aut or Manuscript 1.% Pu#lic Access F"aluation and Management of *leep @istur#ance @uring t e Menopause Transition %adine Joffe, M.@., M.*c., Anda Massler, M.@., M.*c., and Kat erine M. * arkey, M.@., P .@. Additional article information A#stract *leep distur#ances in midlife !omen are common and a"e #een associated !it t e menopause transition itself, symptoms of ot flas es, anxiety and depressi"e disorders, aging, primary sleep disorders $i.e., o#structi"e sleep apnea, periodic lim# mo"ement disorder(, comor#id medical conditions and medications, as !ell as !it psyc osocial and #e a"ioral factors. -ecause t ere are se"eral common sources of sleep pro#lems in midlife !omen, t e cause of an indi"idual !omanKs sleep distur#ance may #e multifactorial. Fffecti"e #e a"ioral and p armacological t erapies are a"aila#le to treat sleep distur#ances of different etiologies. T is re"ie! pro"ides an o"er"ie! of different types of sleep distur#ance occurring in midlife !omen and presents data supporting t e use of ormone t erapy, ypnotic agents, and #e a"ioral strategies to treat sleep pro#lems in t is population. T e re"ie! aims to e)uip clinicians e"aluating menopause2 age !omen !it t e kno!ledge and e"aluation tools to diagnose, engage sleep experts ! ere appropriate, and treat sleep distur#ance in t is population. *leep disorders in midlife !omen s ould #e treated #ecause su#stantial impro"ements in )uality of life and ealt outcomes are ac ie"a#le. .ntroduction *leep complaints increase dramatically in !omen during midlife,O1P suggesting a potential association #et!een sleep distur#ance and t e menopause transition. .n t e 266/ 1ational .nstitutes of %ealt *tate2of2t e2*cience Gonference panel report on menopause2related symptoms,O2P sleep distur#ance !as identified as a key symptom of t e menopause transition. 1octurnal ot flas es a"e #een ypot esi0ed to #e a primary source of menopause2associated sleep distur#ance. %o!e"er, ot er contri#utors to sleep disruption must also #e considered in midlife !omen ! o report sleeping pro#lems. Gommon etiologies of persistent sleep distur#ance in t is population include ot flas es, age2related factors, primary sleep disorders, and psyc iatric illness.O3P

Additional nonpat ological causes of sleep disruption may result from psyc osocial, #e a"ioral, and stress2related factors. T is re"ie! pro"ides an o"er"ie! of different types of sleep distur#ance occurring in midlife !omen. *leep2related concerns associated !it $1( "asomotor symptomsD $2( depressi"e and anxiety symptomsD $3( primary sleep disorders, and $9( aging and medical illness are descri#ed. @ata supporting t ese common sources of sleep distur#ance during t e menopause transition, as !ell as ot er nonpat ological contri#utors, are re"ie!ed. T roug out t e article, differences #et!een percei"ed and o#Eecti"ely measured sleep are discussed. T e re"ie! aims to e)uip clinicians e"aluating menopause2age !omen !it t e kno!ledge and e"aluation tools to diagnose, engage sleep experts ! ere appropriate, and treat sleep distur#ance in midlife !omen. Terminology and @efinitions T e term sleep distur#ance descri#es su#Eecti"ely percei"ed sleep pro#lems t at do not necessarily meet criteria for a clinical disorder #ut are #ot ersome to t e indi"idual. .n contrast, insomnia is a clinically defined disorder t at is diagnosed ! en an indi"idual reports a constellation of symptoms t at meets criteria for an insomnia syndrome.O9P T e insomnia diagnosis re)uires a report of difficulty initiating sleep, maintaining sleep, or experiencing nonrestorati"e sleep, despite ade)uate opportunity for sleep. @aytime functional impairments resulting from nocturnal sleep distur#ance must also #e reported. O9P .nsomniacs commonly descri#e excessi"e daytime sleepiness and4or fatigue t at co2 occurs !it t eir diminis ed a#ility to sleep at nig t. A diagnosis of insomnia does not re)uire t at sleep distur#ance #e documented o#Eecti"ely.O/P .n fact, ! en polysomnograp y $P*>( is conducted, a#normalities may or may not #e detected and, e"en if documented, may not correspond to t e clinical complaints.O/P T us P*> is not recommended routinely to diagnose insomnia.OAP 1e"ert eless, P*> can sometimes #e useful in insomnia patientssespecially t ose ! o fail to respond to treatments#ecause it as t e potential to re"eal an occult sleep disorder t at !as not suspected #ased on istory and p ysical examination ! en t e initial diagnosis of insomnia !as made.O;P Anot er common sleep disorder t at does not re)uire a P*> for diagnosis is restless legs syndrome $&3*(. &3* is a sleep disorder c aracteri0ed #y an urge to mo"e t e legs during periods of rest or inacti"ity.O9P -y definition, &3* symptoms a"e a circadian pattern !it increasing se"erity at nig t. &3* is considered a sleep disorder #ecause deli#erate lim# mo"ements initiated to pro"ide relief from &3* discomfort delay t e onset of sleep. .ndi"iduals !it &3* fre)uently report sleep2onset insomnia and su#se)uent daytime sleepiness and fatigue. .n contrast to insomnia and &3*, ot er primary sleep disorders $e.g., sleep apnea and periodic lim# mo"ement disorder OP3M@P( are diagnosed using o#Eecti"e measurements of sleep. Gon"entional P*> detects sleep stages $rapid eye mo"ement O&FMP, non2&FM lig t Ostage 1 and 2, also called 11 and 12P, and non2&FM deep sleep Ostage 3 and 9, also called 13P( #y measuring #rain acti"ity using electroencep alograp y $FF>( com#ined !it electro2oculograp y and electromyograp y to measure eye mo"ements and muscle acti"ity, respecti"ely.O:,<P &espiratory effort and airflo! indicators and pulse oximetry are used concurrently to diagnose sleep2disordered #reat ing, most commonly o#structi"e sleep apnea $C*A(, ! ic is defined #y repetiti"e episodes of complete $apnea( or partial $ ypopnea( air!ay o#struction t at are associated !it transient oxygen desaturations and s ort arousals from sleep. Multiple arousals related to air!ay o#struction t roug out t e nig t lead to snoring and sleep fragmentation, ! ic can

result in sleepiness, let argy, and mood distur#ances during t e daytime.O9P A P*> e"aluation for C*A s ould #e considered ! en indi"iduals report snoring toget er !it a!akenings from sleep, unrefres ing sleep, and4or daytime sleepiness. A diagnosis of P3M@ s ould #e considered ! en an indi"idual reports a!akenings and kicking during t e nig t, restless sleeping, and daytime fatigue. P3M@ is diagnosed #ased on repetiti"e, stereotyped lim# mo"ements $P3Ms( t at last up to se"eral seconds and lead to fragmentation of and repeated a!akenings from sleep, ! ic results in daytime sleepiness and fatigue. %o!e"er, P3Ms are considered pat ological only if t ey occur fre)uently at nig t and produce arousals from sleep. T e pat op ysiology of P3M@ is unkno!n, #ut it fre)uently co2occurs !it &3*, &FM #e a"ior disorder, or narcolepsy. Bp to :6= of patients !it &3* also a"e P3M@, and 36= of indi"iduals !it P3M@ also a"e &3*.O16P *econdary, re"ersi#le causes of P3Ms, including antidepressant medication use and C*A, also exist. .n contrast to &3*, P3M@ is a disorder associated !it a!akenings after sleep is initiated, and P3M@ re)uires a P*> to esta#lis t e diagnosis. Actigrap y is an alternate tec nology to P*> t at is used to document rest and acti"ity states. T e de"ice is !orn like a !rist!atc and measures acti"ity counts !it an accelerometer. *leep and !akefulness are estimated from t e acti"ity counts using algorit ms t at !ere de"eloped #y correlating patterns of mo"ement !it FF>2#ased determination of sleep. Actigrap y pro"ides an estimate of sleep time, sleep onset, sleep offset, and sleep efficiency and also detects sleep distur#ance associated !it increased mo"ement. .t does not measure sleep arc itecture, o!e"er, and t e accrued data are not fully concordant !it t ose procured #y P*>.O11J 1AP Alt oug actigrap y cannot #e used to make a diagnosis of sleep apnea or P3M@, it offers ad"antages o"er P*> for measuring sleep distur#ance and insomnia, including t e capacity to monitor sleep #e a"ior o"er multiple nig ts and t e a#ility to measure sleep in an indi"idualKs usual sleeping en"ironment. Association #et!een *leep @istur#ance and t e Menopause Transition .n contrast to men, sleep complaints increase dramatically during midlife in !omen, !it t e pre"alence increasing from d12 to 96= in !omen during t e late 96s and early /6s, O1P consistent !it t e typical age of t e menopause transition. Fpidemiological studies indicate t at !omen are more likely to report sleeping pro#lems as t ey transition from late reproducti"e age into t e perimenopause.O1;J21P .n epidemiological studies documenting t e presence of an insomnia syndrome, peri2 and early postmenopausal !omen are more likely to meet criteria for an insomnia disorder t an older reproducti"e2 age !omen $2A= "ersus 13=(.O22P T ese results ig lig t t e "ulnera#ility to percei"ed sleep distur#ance and insomnia during t e menopause transition. %o!e"er, in contrast to t e percei"ed sleep distur#ance associated !it t e menopause transition, studies examining differences in o#Eecti"ely measured sleep patterns using P*> a"e not found clear e"idence t at peri2 and postmenopausal !omen a"e !orse measured sleep t an premenopausal !omen.O1:,23,29P .n one large epidemiological study t at found compara#le P*> sleep among !omen in different menopause status groups,O1:P postmenopausal !omen o#tained an a"erage of 19 minutes more sleep per nig t t an premenopausal !omen and ad slig tly more deep sleep $1A= "ersus 13=(. O1:P T ese differences are consistent !it #etter P*> sleep in t e postmenopausal group, #ut, in lig t of t e ig er rate of su#Eecti"e sleep complaints in t is sample of

postmenopausal !omen, t ese P*> findings may represent a compensatory response to ot er unmeasured sleep differences. Alt oug t e a#sence of a#normalities in P*>2measured sleep in perimenopausal !omen mig t appear inconsistent !it t e percei"ed sleep distur#ance reported during t e menopause transition, it is nota#le t at percei"ed and o#Eecti"ely defined sleep measures capture different parameters of sleep and fre)uently do not coincide among !omen !it "asomotor symptomsO2/P or in indi"iduals !it sleep disorders suc as C*A.O2AP .ndi"iduals reporting insomnia fre)uently do not a"e a#normalities on P*>,O/P and, in older adults, significant sleep a#normalities can #e seen on P*> among indi"iduals ! o do not identify t emsel"es as a"ing a sleep pro#lem.O2;P G anging le"els of sex ormones across t e menstrual cycle and t roug t e menopause transition a"e #een associated !it differences in percei"ed sleep )uality and o#Eecti"ely measured sleep patterns.O26,2:J31P lists findings from studies reporting associations #et!een reproducti"e ormone le"els and sleep in !omen during t e menopause transition. Taken toget er, results of t ese studies suggest t at decreases in estradiol and increases in follicle2stimulating ormone, progesterone, and testosterone may ad"ersely modulate sleep2!ake #e a"iors and contri#ute to t e eig tened risk for sleep distur#ance and insomnia in !omen undergoing t e menopause transition. Factors Associated !it Percei"ed and Measured *leep @istur#ance in +omen during t e Menopause Transition *e"eral clinical c aracteristics a"e #een associated !it sleep complaints in peri2 and postmenopausal !omen $(. *tudies in"estigating sources of percei"ed and P*>2 measured sleep distur#ance in midlife !omen ! o report sleep pro#lems a"e found a "ariety of associated factors.O3,21,32,33P T e specific conditions associated !it sleep distur#ance "ary depending on t e particular sleep parameter in"estigated. Psyc ological symptoms and ot flas es are associated most strongly !it percei"ed sleep distur#ance, ! ereas C*A and P3M@ are associated !it o#Eecti"e a#normalities in P*>2measured sleep. *uc studies suggest t at midlife !omen !it sleep pro#lems are a eterogeneous group. >i"en t e !ide range of potential sleep pro#lems, it is expected t at sleep distur#ance during midlife is multifactorial and t at se"eral sleep2 disrupting causes may co2occur e"en !it in an indi"idual !oman. T e c allenge of making attri#utions of sleep distur#ance to specific ealt conditions is made e"en more complicated #y age2related increases in sleep t at can #e difficult to disentangle. *leep @istur#ance and %ot Flas es 1ig ttime ot flas es, or nig t s!eats, are almost uni"ersal in !omen !it daytime ot flas es. + en ot flas es persist during t e nig t, t ey fre)uently, #ut not uni"ersally, a!aken a !oman from sleep, alt oug not e"ery nocturnal ot flas is associated !it an a!akening. +omen !it ot flas es may also experience nocturnal a!akenings t at are unrelated to a "asomotor e"ent. %ot flas es occur in A6 to :6= of !omen during t e menopause transitionO39P and persist for 9 to / years on a"erage.O3/,3AP -ecause of t eir pre"alence, nocturnal ot flas es are t oug t to #e a common source of sleep distur#ance in midlife !omen. Multiple large epidemiological studies a"e concluded t at, alt oug ot flas es are associated !it reduced sleep )uality, including unrefres ing sleep and repeated #rief a!akenings from sleep, t ey are unlikely contri#utors to pro#lems !it falling asleep at t e #eginning of t e nig t.O3,1:J26,2<,31,33,3;,3:P %ot flas es4nig t s!eats correlate

!it t e se"erity of insomnia symptomsO3<P and are associated !it a greater likeli ood of an insomnia diagnosis $2:./= "ersus 16./=(.O22P For !omen !it se"ere ot flas es, :1.3= report poor sleep )uality, and 93.:= meet criteria for c ronic insomnia.O22P @espite t e strong association #et!een ot flas es and insomnia, only limited and contradictory e"idence supports an association #et!een ot flas es and o#Eecti"ely measured sleep distur#ance.O1:,23,29,3;J92P Alt oug percei"ed ot flas es correlate !it poor percei"ed sleep )uality, studies measuring ot flas es o#Eecti"ely a"e not linked ot flas es to percei"ed sleep distur#ance.O93P *imilarly, percei"ed ot flas es !ere not associated !it differences in P*> parameters of sleep in a large epidemiological study,O1:P and a smaller study found reduced sleep efficiency and longer &FM latency in !omen reporting ot flas es.O29P %o!e"er, ! en sleep !as measured using actigrap y, ot flas es !ere associated !it selected components of sleep disruption $i.e., greater nig ttime !akefulness and more !ake episodes(.O3<P + en ot flas es are measured o#Eecti"ely, data #earing on t e relations ip to o#Eecti"ely measured sleep are conflicting $ (.O3;,92,99J9AP T ese studies compared cross2sectional P*>2measured sleep parameters in symptomatic midlife !omen !it t ose o#ser"ed in !omen !it out o#Eecti"ely measured ot flas es. &esults from t ese studies are inconsistent, !it four identifying a deleterious effectO3;,96J92P and one s o!ing no effect of ot flas es on sleep.O3:P T e contradictory results of t ese studies may result from small sample si0es, cross2sectional designs, and "arying eligi#ility criteria and analytic approac es. Four studies of postmenopausal !omen did not re)uire sleep complaints for eligi#ility,O3:,96J92P and anot er study of #reast cancer patients !it insomnia did not re)uire ot flas es for eligi#ility.O3;P Additional studies are clearly needed to #etter elucidate and isolate t e impact of ot flas es on o#Eecti"e parameters of sleep. Alt oug t e a#sence of a clear2cut association #et!een ot flas es and o#Eecti"ely measured sleep appears to contradict t e strong association #et!een percei"ed ot flas es and su#Eecti"e sleep distur#ance, t ese sleep parameters measure different components of sleep t at may not necessarily #e o"erlapping. .n addition, alt oug P*> is t e gold standard for screening and )uantifying sleep distur#ance, P*> is typically conducted in t e la#oratory for 1 to 3 nig ts, potentially pro"iding insufficient sampling to ade)uately capture sleep distur#ance related to ot flas es. *upporting t is notion is t e o#ser"ation of nig t2to2nig t "aria#ility in t e se"erity of ot er disorders t at disrupt sleep suc as C*AO9;P and insomnia.O9:,9<P Future in"estigations may inform ! ic component of o#Eecti"ely measured sleep predicts t e perception of poor sleep )uality in !omen !it ot flas es. @ata on t e mec anism #y ! ic ot flas es may disrupt sleep are limited and contro"ersial.O2P %ot flas es can #e documented o#Eecti"ely during t e nig ttime e"en in t e a#sence of an a!akening, indicating t at not all ot flas es are e)ually disrupti"e to nocturnal sleep.O96P T e likeli ood of !aking up in association !it a ot flas may "ary in part !it t e sleep stage in ! ic t e ot flas occurs, !it a greater likeli ood of a!akening during sleep periods composed of less &FM sleep.O9/P G anges in core #ody temperature $TG( produced #y ot flas es may #e anot er mec anism t roug ! ic ot flas es produce sleep disruption. T ermoregulation is tig tly coupled to sleep, and some a"e ypot esi0ed t at an ina#ility to dissipate eat at nig t reflects a yperaroused state t at may lead to insomnia.O/6P %ot flas es are

commonly preceded #y a transient increase in TG.O/1P At ot flas onset, sternal s!eating occurs, ! ic dissipates eat and results in a decline in TG, sometimes transiently #elo! #aseline TG le"els. Alt oug it as #een ypot esi0ed t at fluctuations in TG precipitate an a!akening, data indicating t at a!akenings are e)ually likely to precede or follo! a nocturnal ot flas suggest t at t e TG increase fre)uently preceding a flas may not necessary #e responsi#le for inducing an a!akening.O3:P %o!e"er, it is plausi#le t at t e central ner"ous system c anges t at likely precede #ot t e fluctuation in TG and t e perception of a ot flas may #e responsi#le for precipitating an a!akening. C"erall, TG is lo!er among !omen !it ot flas es t roug out t e day and nig t,O/1P suggesting a disruption of t e typical circadian temperature r yt m. &esults of t ese preliminary studies are at odds !it ot er in"estigations indicating t at ig er TG during sleep is associated !it !orse P*>2measured sleep.O/2,/3P A potential link #et!een t ermoregulation, ot flas es, and sleep disruption !arrants furt er in"estigation to determine t e precise mec anism underlying t ese interrelated p ysiological processes. *leep @istur#ance, Anxiety, and @epressi"e *ymptoms .n addition to ot flas es, ig er le"els of depressi"eO26,21,2<,33P and anxietyO3,21,2<P symptoms a"e #een associated !it a perception of !orse sleep )uality in midlife !omen. *uc studies a"e not specifically distinguis ed ! et er !omen !it depressi"e and4or anxiety symptoms meet criteria for a psyc iatric disorder. Ct er studies confirm t at e"en mild psyc ological distress is linked to !orse sleep )uality.O2AP Psyc iatric disorders including maEor depression, dyst ymia, generali0ed anxiety disorder, panic disorder, and ot er mood and anxiety disorders all a"e sleep disruption $percei"ed and o#Eecti"ely measured( as a common symptom component.O/9,//P -ecause !omen are at increased risk for experiencing a maEor depressi"e episode during t e perimenopause,O/A,/;P sleep distur#ance during midlife may #e a marker of a clinically significant mood disorder t at !arrants furt er e"aluation. Moreo"er, #ecause ot flas es are strongly associated !it depression symptomsO/:,/<P and !omen !it ot flas es are more likely to de"elop a maEor depressi"e episode,O/AP sleep pro#lems may result from #ot ot flas es and depression in !omen ! o a"e multiple concurrent symptoms. Midlife !omen ! o a"e depression in addition to ot flas es and sleep disruption report !orse sleep )uality and o#Eecti"ely measured sleep t an t ose !it out depression,OA6P suggesting t at depression and ot flas es may a"e an additi"e effect on sleep distur#ance. To confound matters, !omen !it a prior istory of depression are more likely to report ot flas esOA1P and may de"elop sleep distur#ance #ecause of ot flas es ! en t ey are not depressed. Anot er potential temporal pattern is t at sleep distur#ance resulting from ot flas es may also increase t e risk of su#se)uent depression.OA2,A3P .ndeed, disrupted sleep as #een s o!n to precede t e onsetOA9P and recurrenceOA/P of depression in ot er populations. 3ike depression, anxiety correlates strongly !it insomnia. T is link as #een esta#lis ed for specific anxiety disorders, including panic disorder,OAAP generali0ed anxiety disorder,OA;P social p o#ia,OA:P and posttraumatic stress disorder.OA<P .n addition, trou#le sleeping is associated !it mild anxiety symptoms, presenting as ig er le"els of stress, tension, and self2consciousness.O21P Moreo"er, like depressi"e symptoms, anxiety also correlates !it and commonly precedes t e onset of ot flas es during t e

menopause transition,O;6,;1P raising t e possi#ility t at sleep distur#ance may result from anxiety, ot flas es, or #ot . -ecause anxiety and depressi"e symptoms commonly, #ut not uniformly, co2occur, it can #e difficult to disentangle t e indi"idual contri#utions of t ese psyc ological symptoms. T us, in e"aluating !omen ! o report sleep distur#ance during t e menopause transition, anxiety disorders, depressi"e disorders, and ot flas es s ould all #e considered as potential contri#uting factors t at may act independently or Eointly to disrupt sleep. Primary *leep @isorders Primary sleep disorders suc as C*A, &3*, and P3M@ are common in midlife !omen and contri#ute to complaints of distur#ed sleep in t is population. T e o"erall pre"alence of C*A is estimated at <= in !omen, #ut t is pre"alence increases as !omen transition into midlife, !it t e pre"alence increasing from A./= to :.;= to 1A= in !omen in t eir 36s, 96s, and /6s, respecti"ely.O;2P *e"eral p ysiological c anges t at occur in midlife !omen con"erge to increase C*A in t is population. For instance, C*A risk rises #ot !it age and !it increasing #ody mass index $-M.(.O;3P *tudies t at a"e examined C*A specifically in midlife !omen suggest t at #ody !eig t is a stronger predictor of C*A t an is menopausal status per se,O;9J;;P and t us !omen ! o experience excessi"e !eig t gain in midlife may experience more disrupted sleep and sleep2disordered #reat ing.O;:P 1onet eless, ! en controlling for age and -M., C*A is more common among postmenopausal !omen t an premenopausal !omen, suggesting t at t e menopause transition is also a factor in t e de"elopment of C*A.O;2J;<P F"idence suggests t at sleep2disordered #reat ing is underdiagnosed in !omen, O;2,:6,:1P per aps due to gender #iasO:1P or differing symptom presentations #et!een men and !omen.O:2,:3P Gompared !it men !it C*A, !omen !it C*A are more likely to a"e an initial complaint of insomnia or depression.O:3P .t is incum#ent on clinicians treating sleep distur#ances in midlife !omen not to o"erlook symptoms suggesti"e of sleep2disordered #reat ing and to refer suc patients for P*> gi"en t e medical risks associated !it C*A including coronary artery disease,O:9P ypertension, O:/P stroke,O:AP depression,O:;Pand deat .O::P &3* is anot er common sleep disorder t at disrupts sleep in midlife !omen. Alt oug &3* affects d16= of t e population, t e disorder is t!ice as common in !omen as men, O:<P and t e risk of &3* in !omen increases !it age and parity.O<6P @uring midlife, &3* occurs more fre)uently in !omen !it "asomotor symptoms, #ut t is disorder as not #een linked !it menopausal status or ormone t erapy.O<1P T e pat op ysiology in"ol"es iron meta#olism and dopaminergic neurotransmission primarily,O<2,<3P #ut secondary causes $e.g., t yroid disease, antidepressant medication use( also exist. A possi#le etiologic role of reproducti"e ormones in &3* is suggested #y an association #et!een &3* and increased endogenous estradiol le"els in pregnant !omen.O<9P -ecause &3* increases !it aging and secondary causes t at are common in midlife !omen, a clinical istory for &3* symptoms s ould #e o#tained ! en pro#lems initiating sleep are reported. P3M@ is anot er primary sleep disorder t at increases in pre"alence !it age and is common among menopausal !omen.O</P -ecause P3Ms may result from t e use of antidepressant medications and sleep2disordered #reat ing, #ot of ! ic are common

in midlife !omen, secondary causes of P3Ms s ould #e considered #ecause t ey may play a role in t e ig pre"alence of P3M@ in t is population. Alt oug a role for estrogen in t e etiology of P3M@ as #een suggested #y increased P3Ms during pregnancy,O<AP t e role of sex ormones in P3M@ as not #een !ell defined in !omen undergoing t e menopausal transition. T!o small randomi0ed controlled trials of ormone t erapy in postmenopausal !omen s o!ed t at estrogen plus progesterone,O<;P #ut not estrogen alone,O</P decreased P3Ms. T e link #et!een reproducti"e ormones and P3M@ is unclear, and furt er study of t e roles of estrogen and progesterone in t e etiology and treatment of P3Ms is needed. Age2related *leep G anges and Medical Gonditions Alt oug percei"ed sleep distur#ance in midlife !omen is associated !it t e menopausal transition, sleep complaints in t is population also correlate !it age2related sleep c anges and !it medical conditions t at increase during midlife.O<:P Gommon conditions t at may affect sleep t at increase !it age include o#esity,O<<P cancer,O166P gastroesop ageal reflux,O161P urinary incontinence and nocturnal micturition,O;;,162J 169P t yroid dysfunction,O16/P c ronic pain syndromes,O16AP and fi#romyalgia.O16;P As !omen age, increased use of neuroacti"e medications may also contri#ute to sleep difficulties. -e a"ioral and Psyc osocial Factors Ct er common causes of sleep distur#ances in midlife !omen t at may contri#ute to significant sleep disruption include poor sleep ygiene $i.e., irregular sleep2!ake sc edule, excessi"e napping, insufficient sleep(, decreased sleep due to "olitional factors $i.e., staying up late or rising early #y c oice or to meet !ork or social o#ligations(, and en"ironmental distur#ances $e.g., snoring #ed partner, sleeping !it lig ts, tele"ision, cell p one on(. Psyc osocial factors may also contri#ute to sleep distur#ances. @istur#ed sleep in midlife !omen as #een linked to marital dissatisfaction,O16:P and !omen in midlife are often sand!ic ed #et!een t e time2consuming demands of caring for t eir c ildren and t eir aging parents. T erefore, alt oug ot flas es, medical conditions, psyc iatric illness, sleep disorders, and medications may #e etiological in sleep distur#ance, #e a"ioral and psyc osocial factors are important in t e differential diagnoses for t e midlife !oman reporting nonrestorati"e sleep, sleep disruption, and4or daytime fatigue. O;;P Management *trategies for *leep @istur#ances during t e Menopause Transition &andomi0ed place#o2controlled trials a"e demonstrated t e efficacy of ormone t erapy $%T( and ypnotic agents for treatment of sleep distur#ance occurring in !omen during t e perimenopause and early postmenopause. .n t is section, !e summari0e results of randomi0ed controlled trials $&GT*( comparing %T and ypnotic t erapies to place#o in t e management of sleep disorders in perimenopausal and postmenopausal !omen. Also discussed #riefly are nonp armacological #e a"ioral inter"entions t at a"e #een studied !idely for t e management of insomnia $i.e., cogniti"e #e a"ioral t erapy, sleep ygiene(, al#eit not specifically in t e context of reproducti"e aging. -eyond t e scope of t is re"ie! is a discussion of ot er commonly used sleeping aids for sleep disruption, including #en0odia0epines, tra0odone, melatonin, melatonin agonists, dip en ydramine, and ot er o"er2t e2counter treatments. Many of t ese are

effecti"e ypnotics, #ut none a"e #een studied specifically in !omen !it sleep distur#ances related to t e menopause transition. Fstrogen and Progestin T erapy T e effect of %T on sleep as #een studied !idely in postmenopausal !omen $and(. T e "ast maEority of &GTs comparing %T to place#o a"e found t at %T impro"es percei"ed sleep )uality and self2reported sleeping pro#lems more t an place#o,O<;,16<J122P alt oug se"eral ot ers did not find an ad"antage of %T o"er place#o $(.O123,129P &esults of studies using P*> to measure %T effects on sleep parameters o#Eecti"ely a"e #een mixed $(, !it some reporting impro"ement in selected components of sleepO<;,11;,11:,121,122,12/,12AP and ot ers descri#ing eit er no effectO;A,</,122P or e"en deleterious effects of inter"entions on isolated components of P*>2measured sleep.O122,12;P C"erall, most of t e studies in"ol"ing P*> measures s o!ed small #ut fa"ora#le effects of %T on sleep. T e most consistent findings are less fragmentation of sleep, !it a reduction in !akefulness and arousals. T ese decreases in P*>2measured sleep fragmentation are consistent !it su#Eecti"e reports of impro"ed sleep )uality !it %T. %o!e"er, t e positi"e effects of %T on sleep as measured #y P*> !ere small in some studies, ! ic may limit t e clinical significance of t ese findings. .nconsistencies #et!een study results relating to selected P*>2measured sleep parameters are difficult to interpret in part #ecause of small sample si0es and due to "aria#ility in measurement approac es and outcome "aria#les. Additional studies are t us needed to gain a #etter understanding of t e effects of %T on P*>2measured sleep in !omen during and after t e menopause transition. Analyses of t e effects of %T on sleep a"e commonly #een conducted as part of larger in"estigations of multiple )uality2of2life domains and primarily in !omen ! o do not a"e a specific sleep complaint, alt oug someO112,11/,11<,126,12:P re)uired ot flas es for eligi#ility. Alt oug no sleep complaint !as re)uired, it is nota#le t at impro"ed sleep !as reported and4or measured #y P*> among study populations of predominantly asymptomatic !omen. %o!e"er, some studies found t at t e #eneficial effects !ere small and potentially not clinically meaningful. Finally, se"eral &GTs reported t at %T ad a more marked effect on sleep eit er among !omen !it ot flas es or for t ose !it sleep distur#ances associated !it ot flas es,O112J119P suggesting t at sleeping pro#lems co2occurring !it nocturnal ot flas es are most amena#le to treatment !it %T.O11AP Most studies administered com#ined estrogen and progestin t erapy, making it difficult to distinguis t e #eneficial effects of estrogen from t at of t e coadministered progestin. O<;,16<,116,112J11/,11;J121,129,12/,12;P %o!e"er, #eneficial effects on sleep !ere also seen in studies using estrogen aloneO</,111,122,12A,12<,136P or progestin alone, O121,12:P suggesting t at estrogen and progestins may a"e independent t erapeutic effects on sleep. >reater #enefit of natural progesterone o"er medroxyprogesterone on percei"ed sleep )uality and on selected P*>2#ased sleep parameters as #een s o!n in preliminary studies comparing %T preparations composed of different progestins. O11;,11<P @ata are limited on t e effect of %T on sleeping pro#lems among !omen !it primary sleep disorders $(. *tudies in postmenopausal !omen ! o a"e a clinical diagnosis of insomnia s o! #etter percei"ed sleep )uality and a trend to!ard impro"ement of P*>2 measured sleep parameters !it %T.O11:,12/P &esults of a fe! studies in"estigating t e

effects of ormone t erapy in postmenopausal !omen suggest t at %T may ameliorate apnea symptoms in !omen !it out a formal diagnosis of C*A.O<;,11:,12/,136P *tudies examining effects of %T on P3Ms in !omen !it out a P3M@ disorder a"e not s o!n !orsening of P3Ms,O</,<;P ! ic is important in lig t of t e suggested deleterious role of estrogen in younger !omen !it P3M@.O<AP T e mec anisms t roug ! ic estrogen and progestin t erapies may impro"e sleep are not kno!n. Fstrogen itself may a"e a direct sleep effect #y increasing omeostatic dri"e for sleepDO131P o!e"er t e specific mec anisms t roug ! ic t ese effects may occur a"e not #een descri#ed in umans. *tudies in rodents suggest t at t e effect of estradiol on sleep4!ake cycles may #e explained #y a reduction in prostaglandin synt esis in t e "entrolateral preoptic nucleus of t e ypot alamus.O132P Alternati"ely, for !omen !it co2occurring ot flas es, estrogen t erapy may impro"e sleep distur#ance as an indirect conse)uence of its salutary effects on nocturnal ot flas es. O11AP Progestins are kno!n to exert a direct sleep induction or ypnotic effect mediated t roug gamma2amino#utyric acid2acti"e meta#olites.O133P Progestins are also a potent respiratory stimulant t at decrease t e num#er of apnea episodes in men,O139P #ut little is kno!n a#out effects of progestins in !omen !it C*A. 1on2#en0odia0epine *edati"e2 ypnotics T e non2#en0odia0epines 0olpidem and es0opiclone a"e #een s o!n to #e more effecti"e t an place#o in t e treatment of insomnia in peri2 and early postmenopausal !omen.O13/J13;P *tudies s o! t at t ese ypnotic agents impro"e sleep in !omen ! o a"e difficulty initiating O13/,13AP and4or maintaining sleep.O13A,13;P Participants in t ese studies typically ad ot flas es t at co2occurred !it t eir sleep distur#ance and de"eloped in concert !it t e onset of ot flas es. .n addition to treating insomnia symptoms, use of es0opiclone reduced t e num#er of percei"ed ot flas es occurring at nig t, #ut not during t e daytime, suggesting t at !omen sleep t roug t eir nocturnal "asomotor symptoms, rat er t an t e agent a"ing a direct effect on ot flas es.O13AP *leep %ygiene and Gogniti"e -e a"ioral T erapy for .nsomnia .nsomnia and milder forms of sleep distur#ance may respond !ell to nonp armacological treatment suc as sleep ygiene approac es and cogniti"e #e a"ioral t erapy for insomnia. *leep ygiene in"ol"es targeted #e a"ioral modification approac es t at can #e taug t in t e office, re"ie!ed on multiple online resources suc as !!!.sleepfoundation.org, and implemented at ome. *leep ygiene addresses commonsense ealt practices suc as exercise, diet, cigarette smoking, alco ol use, as !ell as en"ironmental factors including lig t, noise, and temperature exposure t at may interfere !it sleep.O13:P Ct er components of good sleep ygiene include rituali0ed #edtime routines and strategies to a"oid frustration !it not #eing a#le to initiate sleep or return to sleep after an a!akening. Gogniti"e #e a"ioral t erapy for insomnia $G-T2.( is a structured s ort2term psyc ot erapy inter"ention conducted #y a licensed psyc ologist or #e a"ioral medicine practitioner. G-T2. identifies t e psyc ological and #e a"ioral factors t at play a role in an indi"idualKs insomnia. Gomponents include stimulus control, sleep ygiene, sleep restriction, paradoxical intention, relaxation training, and reframing of negati"e4false #eliefs a#out sleep and insomnia. G-T2. !orks #y modifying faulty #eliefs, expectations, and attri#utions a#out sleep and insomnia. &GTs of G-T2. s o! #enefit in ;6 to :6= of

indi"iduals !it primary insomnia.O13:P Multiple !ell2controlled trials a"e documented t e sustained efficacy of G-T2. up to A mont s after a course of treatment is completed. O13<J191P *ome studies suggest t at G-T2. is more efficacious t an ypnotic medications,O191P ! ereas ot ers report superior outcomes ! en G-T2. is com#ined !it a ypnotic medication.O13<P Alt oug G-T as #een s o!n to #e ig ly effecti"e for treating primary insomnia, including in midlife !omen, its #enefit for sleep distur#ances related specifically to menopause a"e yet to #e studied. @iscussion *leep distur#ance #ecomes more common in !omen during midlife and is specifically associated !it t e menopause transition, !it !orse percei"ed sleep )uality reported #y peri2 and early postmenopausal !omen t an #y similarly aged premenopausal !omen. Alt oug ot flas es are linked to percei"ed sleep pro#lems, t eir association to P*>2measured sleep remains unclear, and ot er common medical conditions, mental ealt pro#lems, age2related factors, and primary sleep disorders also correlate strongly !it sleep pro#lems in t is population. F"aluation of midlife !omen !it sleep complaints s ould in"ol"e consideration of t ese potential causes of sleep disruption, including t e possi#ility t at different sleep pro#lems may co2occur. Persistent sleep distur#ance and insomnia may arise from a com#ination of predisposing, precipitating, and perpetuating factors.O192P T erefore, !omen ! o report sleep pro#lems during t e menopause transition may #e predisposed to de"elop ne!2onset sleep distur#ance from ot flas es and ot er sleep2disrupting factors.O193P Treatment considerations for !omen !it menopause2associated sleep distur#ance include use of ormone t erapy, ypnotic agents, and #e a"ioral inter"entions. .n addition, concurrent t erapy may #e re)uired to target co2occurring symptoms of ot flas es, depression, and anxiety, ! ere present. .n some indi"iduals, t e constellation of co2occurring symptoms may #e t e primary determinant for treatment. For example, !omen !it prominent ot flas es may #e treated optimally !it %T, ! ic is likely to suppress #ot sleep and "asomotor symptoms.O11AP T ose !it concurrent ot flas es ! o are una#le to take %T can #e treated !it a com#ination of t erapies targeting #ot sleep distur#ance and ot flas es. Alternati"ely, ypnotic treatments can #e used alone, especially if "asomotor symptoms are not particularly #ot ersome or if ot flas es are primarily nocturnal, in ! ic case treatments targeting sleep can #e used to elp !omen sleep t roug ot flas es, rat er t an directly suppress ot flas es.O13AP +idely used non ormonal p armacological treatments for ot flas es include serotonergic antidepressants $i.e., selecti"e serotonin reuptake in i#itor O**&.P, selecti"e noradrenergic reuptake in i#itor O*1&P.( and selected antidepressants $i.e., ga#apentin, prega#alin(.O199,19/P .n some cases, use of t e **&.4*1&. to treat ot flas es may also impro"e sleep distur#ance, t ere#y eliminating t e need for ypnotic treatments.O19AP %o!e"er, ot er studies suggest t at augmentation of *1&.4**&. !it t e ypnotic agent 0olpidem impro"es sleep and )uality2of2life relati"e to use of t e *1&.4**&. alone in !omen !it ot flas es and associated sleep distur#ance.O19;P .n t is common scenario of co2occurring ot flas es and sleep distur#ance, t e need to prioriti0e targeting insomnia symptoms !it a specific ypnotic t erapy likely "aries according to t e degree of sleep impairment resulting from ot flas es. %o!e"er, com#ined treatments s ould #e considered #ecause concurrent t erapy may #e re)uired to optimi0e !ell2#eing. Analogous to t e approac used to target co2occurring ot flas es in !omen !it sleep distur#ance, com#ined treatments may also #e re)uired for !omen ! o a"e sleep pro#lems concurrent !it depression and anxiety disorders. +omen !it persistent

sleep disruption s ould #e e"aluated for suc psyc iatric illnesses and referred for treatment ! ere appropriate. *imilarly, !omen ! ose sleep pro#lems are part of a primary sleep disorder, suc as C*A, &3*, or P3M@, s ould #e referred for specific t erapies targeting treatments for t ese disorders. Gonclusions .n summary, sleep difficulties in midlife !omen are common and a"e #een associated !it t e menopause transition itself, symptoms of ot flas es, anxiety and depressi"e disorders, aging, primary sleep disorders, comor#id medical conditions and medications, as !ell as !it psyc osocial and #e a"ioral factors. Glinicians s ould #e a!are of t e pre"alence of sleep distur#ance and sleep disorders in t is population and refer !omen for e"aluation if a sleep disorder is suspected, particularly in lig t of t e mor#idity and mortality associated !it sleep apnea. Fffecti"e #e a"ioral and p armacological t erapies are a"aila#le to treat sleep distur#ances of different etiologies, and once a specific diagnosis is made, affected !omen s ould #e treated #ecause su#stantial impro"ements in )uality of life and ealt outcomes are ac ie"a#le. T ere are se"eral common sources of sleep pro#lems in midlife !omen, and an indi"idual !omanKs sleep distur#ance may #e multifactorial. Gareful e"aluation of t e nature of t e sleep distur#ance !ill elp identify t e underlying causes and determine priorities for e"aluation and treatment. Ta#le 1 Ta#le 1 Association #et!een &eproducti"e %ormones and *leep ?uality and Patterns in Midlife +omen Ta#le 2 Ta#le 2 Factors Associated !it *leep Gomplaints during and after t e Menopause Transition Ta#le 3 Ta#le 3 Fffect of C#Eecti"ely Measured %ot Flas es on C#Eecti"ely Measured *leep Ta#le 9 Ta#le 9 @ou#le2-lind &andomi0ed Place#o2Gontrolled Trials * o!ing Fffect of Fstrogen and4or Progestin T erapy on Percei"ed *leep ?uality Ta#le / Ta#le / @ou#le2-lind &andomi0ed Trials * o!ing Fffect of Fstrogen and4or Progestin T erapy on *leep Parameters Measured C#Eecti"ely !it Polysomnograp y and Percei"ed *leep ?uality Ackno!ledgments T is researc !as supported in part #y 1&61M%6:2<22 $%J(. T e aut ors t ank Fli0a#et 3. 3emon, M.A., and *tep anie Gonnors, -.A., for t eir administrati"e support. Article information *emin &eprod Med. Aut or manuscriptD a"aila#le in PMG 2613 August ;. Pu#lis ed in final edited form as8 *emin &eprod Med. 2616 *eptem#erD 2:$/(8 969J921. Pu#lis ed online 2616 *eptem#er 1/. doi8 16.16//4s26636212A2<66 PMG.@8 PMG3;3A:3; 1.%M*.@8 1.%M*/66/A6

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!omenKs ealt across t e nation. Am J Pu#lic %ealt . 266AD<A$;(8122AJ123/. OPMG free articleP OPu#MedP ;2. Qoung T, Palta M, @empsey J, *katrud J, +e#er *, -adr *. T e occurrence of sleep2disordered #reat ing among middle2aged adults. 1 Fngl J Med. 1<<3D32:$1;(81236J123/. OPu#MedP ;3. Qoung T, *katrud J, Peppard PF. &isk factors for o#structi"e sleep apnea in adults. JAMA. 2669D2<1$1A(82613J261A. OPu#MedP ;9. Garskadon MA, -earpark %M, * arkey KM, et al. Fffects of menopause and nasal occlusion on #reat ing during sleep. Am J &espir Grit Gare Med. 1<<;D1//$1(826/J216. OPu#MedP ;/. Kopelman P>, Apps MG, Gope T, Fmpey @+. T e influence of menstrual status, #ody !eig t and ypot alamic function on nocturnal respiration in !omen. J & Goll P ysicians 3ond. 1<:/D1<$9(8293J29;. OPu#MedP ;A. -lock AJ, +ynne J+, -oysen P>. *leep2disordered #reat ing and nocturnal oxygen desaturation in postmenopausal !omen. Am J Med. 1<:6DA<$1(8;/J;<. OPu#MedP ;;. Alexander J3, 1eylan T, Kot0 K, @ennerstein 3, &ic ardson >, &osen#aum &. Assessment and treatment for insomnia and fatigue in t e symptomatic menopausal !oman !it psyc iatric comor#idity. Fxpert &e" 1eurot er. 266;D;$11, *uppl(8*13<J *1//. OPu#MedP ;:. Andersen M3, -ittencourt 3&, Antunes .-, Tufik *. Fffects of progesterone on sleep8 a possi#le p armacological treatment for sleep2#reat ing disordersM Gurr Med G em. 266AD13$2<(83/;/J3/:2. OPu#MedP ;<. -ixler FC, 'gont0as A1, 3in %M, et al. Pre"alence of sleep2disordered #reat ing in !omen8 effects of gender. Am J &espir Grit Gare Med. 2661D1A3$3 Pt 1(8A6:JA13. OPu#MedP :6. &edline *, Kump K, Tis ler P', -ro!ner ., Ferrette '. >ender differences in sleep disordered #reat ing in a community2#ased sample. Am J &espir Grit Gare Med. 1<<9D19<$3 Pt 1(8;22J;2A. OPu#MedP :1. Qoung T, %utton &, Finn 3, -adr *, Palta M. T e gender #ias in sleep apnea diagnosis. Are !omen missed #ecause t ey a"e different symptomsM Arc .ntern Med. 1<<AD1/A$21(8299/J29/1. OPu#MedP :2. @ursunoglu 1, C0kurt *, *arikaya *. .s t e clinical presentation different #et!een men and !omen admitting to t e sleep la#oratoryM *leep -reat . 266<D13$3(82</J2<:. OPu#MedP :3. * epertycky M&, -anno K, Kryger M%. @ifferences #et!een men and !omen in t e clinical presentation of patients diagnosed !it o#structi"e sleep apnea syndrome. *leep. 266/D2:$3(836<J319. OPu#MedP :9. Peker Q, Garlson J, %edner J. .ncreased incidence of coronary artery disease in sleep apnoea8 a long2term follo!up. Fur &espir J. 266AD2:$3(8/<AJA62. OPu#MedP :/. Peppard PF, Qoung T, Palta M, *katrud J. Prospecti"e study of t e association #et!een sleep2disordered #reat ing and ypertension. 1 Fngl J Med. 2666D392$1<(813;:J13:9. OPu#MedP :A. Ar0t M, Qoung T, Finn 3, *katrud J-, -radley T@. Association of sleep2disordered #reat ing and t e occurrence of stroke. Am J &espir Grit Gare Med. 266/D1;2$11(8199;J 19/1. OPMG free articleP OPu#MedP :;. Peppard PF, *0klo2Goxe M, %la KM, Qoung T. 3ongitudinal association of sleep2 related #reat ing disorder and depression. Arc .ntern Med. 266AD1AA$1A(81;6<J1;1/. OPu#MedP ::. Qoung T, Finn 3, Peppard PF, et al. *leep disordered #reat ing and mortality8 eig teen2year follo!2up of t e +isconsin sleep co ort. *leep. 266:D31$:(816;1J16;:. OPMG free articleP OPu#MedP

:<. P illips M3, 3adouceur G@, @re"ets +G. A neural model of "oluntary and automatic emotion regulation8 implications for understanding t e pat op ysiology and neurode"elopment of #ipolar disorder. Mol Psyc iatry. 266:D13$<(8:2<, :33J:/;. OPMG free articleP OPu#MedP <6. -erger K, 3uedemann J, Trenk!alder G, Jo n B, Kessler G. *ex and t e risk of restless legs syndrome in t e general population. Arc .ntern Med. 2669D1A9$2(81<AJ 262. OPu#MedP <1. +esstrom J, 1ilsson *, *undstrom2Poromaa ., Blf#erg J. &estless legs syndrome among !omen8 pre"alence, comor#idity and possi#le relations ip to menopause. Glimacteric. 266:D11$/(8922J92:. OPu#MedP <2. Allen &. @opamine and iron in t e pat op ysiology of restless legs syndrome $&3*( *leep Med. 2669D/$9(83:/J3<1. OPu#MedP <3. Allen &P. &ace, iron status and restless legs syndrome. *leep Med. 2662D3$A(89A;J 9A:. OPu#MedP <9. @0aEa A, +e rle &, 3ancel M, Pollmtc er T. Fle"ated estradiol plasma le"els in !omen !it restless legs during pregnancy. *leep. 266<D32$2(81A<J1;9. OPMG free articleP OPu#MedP </. Polo2Kantola P, &au ala F, Frkkola &, .rEala K, Polo C. Fstrogen replacement t erapy and nocturnal periodic lim mo"ements8 a randomi0ed controlled trial. C#stet >ynecol. 2661D<;$9(8/9:J//9. OPu#MedP <A. 1ikkola F, Fk#lad B, Fk olm F, Mikola %, Polo C. *leep in multiple pregnancy8 #reat ing patterns, oxygenation, and periodic leg mo"ements. Am J C#stet >ynecol. 1<<AD1;9$/(81A22J1A2/. OPu#MedP <;. %ac ul %, -ittencourt 3&, Andersen M3, %aidar MA, -aracat FG, Tufik *. Fffects of ormone t erapy !it estrogen and4or progesterone on sleep pattern in postmenopausal !omen. .nt J >ynaecol C#stet. 266:D163$3(826;J212. OPu#MedP <:. -erecki2>isolf J, -egum 1, @o#son AJ. *ymptoms reported #y !omen in midlife8 menopausal transition or agingM Menopause. 266<D1A$/(81621J162<. OPu#MedP <<. Patel *&, -lack!ell T, &edline *, et al. Csteoporotic Fractures in Men &esearc >roup. *tudy of Csteoporotic Fractures &esearc >roup T e association #et!een sleep duration and o#esity in older adults. .nt J C#es $3ond( 266:D32$12(81:2/J1:39. OPMG free articleP OPu#MedP 166. *tepanski FJ, +alker M*, *c !art0#erg 3*, -lakely 3J, Cng JG, %outs AG. T e relation of trou#le sleeping, depressed mood, pain, and fatigue in patients !it cancer. J Glin *leep Med. 266<D/$2(8132J13A. OPMG free articleP OPu#MedP 161. Mody &, -olge *G, Kannan %, Fass &. Fffects of gastroesop ageal reflux disease on sleep and outcomes. Glin >astroenterol %epatol. 266<D;$<(8</3J</<. OPu#MedP 162. Asplund &, A#erg %. 1octurnal micturition, sleep and !ell2#eing in !omen of ages 96JA9 years. Maturitas. 1<<AD29$1J2(8;3J:1. OPu#MedP 163. Asplund &, A#erg %. @aytime sleepiness in 96JA9 year2old !omen in relation to somatic ealt and medical treatment. *cand J Prim %ealt Gare. 1<<:D1A$2(8112J11A. OPu#MedP 169. Asplund &, A#erg %F. 1octuria and ealt in !omen aged 96JA9 years. Maturitas. 2666D3/$2(8193J19:. OPu#MedP 16/. +inkelman J+, >oldman %, Piscatelli 1, 3ukas *F, @orsey GM, Gunning am *. Are t yroid function tests necessary in patients !it suspected sleep apneaM *leep. 1<<AD1<$16(8;<6J;<3. OPu#MedP 16A. Fis #ain @A, Gole -, 3e!is JF, >ao J. + at is t e e"idence for c ronic pain #eing etiologically associated !it t e @*M2.' category of sleep disorder due to a general medical conditionM A structured e"idence2#ased re"ie!. Pain Med. 2616D11$2(81/:J1;<. OPu#MedP

16;. G er"in &@, Teodorescu M, Kus !a a &, et al. C#Eecti"e measures of disordered sleep in fi#romyalgia. J & eumatol. 266<D3A$<(8266<J261A. OPMG free articleP OPu#MedP 16:. Troxel +M, -uysse @J, %all M, Matt e!s KA. Marital appiness and sleep distur#ances in a multi2et nic sample of middle2aged !omen. -e a" *leep Med. 266<D;$1(82J1<. OPMG free articleP OPu#MedP 16<. +elton AJ, 'ickers M&, Kim J, et al. +.*@CM team %ealt related )uality of life after com#ined ormone replacement t erapy8 randomised controlled trial. -MJ. 266:D33;8a11<6. OPMG free articleP OPu#MedP 116. 1ielsen TF, &a"n P, Pitkin J, G ristiansen G. Pulsed estrogen t erapy impro"es postmenopausal )uality of life8 a 22year place#o2controlled study. Maturitas. 266AD/3$2(81:9J1<6. OPu#MedP 111. -runner &3, >ass M, Aragaki A, et al. +omenKs %ealt .nitiati"e .n"estigators Fffects of conEugated e)uine estrogen on ealt 2related )uality of life in postmenopausal !omen !it ysterectomy8 results from t e +omenKs %ealt .nitiati"e &andomi0ed Glinical Trial. Arc .ntern Med. 266/D1A/$1;(81<;AJ1<:A. OPu#MedP 112. *c urmann &, %oller T, -enda 1. Fstradiol and drospirenone for climacteric symptoms in postmenopausal !omen8 a dou#le2#lind, randomi0ed, place#o2controlled study of t e safety and efficacy of t ree dose regimens. Glimacteric. 2669D;$2(81:<J1<A. OPu#MedP 113. 'estergaard P, %ermann AP, *tilgren 3, et al. Fffects of / years of ormonal replacement t erapy on menopausal symptoms and #lood pressuresa randomised controlled study. Maturitas. 2663D9A$2(8123J132. OPu#MedP 119. %ays J, Cckene JK, -runner &3, et al. +omenKs %ealt .nitiati"e .n"estigators Fffects of estrogen plus progestin on ealt 2related )uality of life. 1 Fngl J Med. 2663D39:$1<(81:3<J1:/9. OPu#MedP 11/. >am#acciani M, Giaponi M, Gappagli -, et al. Fffects of lo!2dose, continuous com#ined estradiol and noret isterone acetate on menopausal )uality of life in early postmenopausal !omen. Maturitas. 2663D99$2(81/;J1A3. OPu#MedP 11A. Polo2Kantola P, Frkkola &, %elenius %, .rEala K, Polo C. + en does estrogen replacement t erapy impro"e sleep )ualityM Am J C#stet >ynecol. 1<<:D1;:$/(81662J 166<. OPu#MedP 11;. Montplaisir J, 3orrain J, @enesle &, Petit @. *leep in menopause8 differential effects of t!o forms of ormone replacement t erapy. Menopause. 2661D:$1(816J1A. OPu#MedP 11:. *aletu -. *leep, "igilance and cognition in postmenopausal !omen8 place#o2 controlled studies !it 2 mg estradiol "alerate, !it and !it out 3 mg dienogest. Glimacteric. 2663DA$*uppl 2(83;J9/. OPu#MedP 11<. >am#acciani M, Giaponi M, Gappagli -, et al. Fffects of lo!2dose, continuous com#ined ormone replacement t erapy on sleep in symptomatic postmenopausal !omen. Maturitas. 266/D/6$2(8<1J<;. OPu#MedP 126. 3e"ine @+, @ailey MF, &ock ill -, Tipping @, 1aug ton MJ, * umaker *A. 'alidation of t e +omenKs %ealt .nitiati"e .nsomnia &ating *cale in a multicenter controlled clinical trial. Psyc osom Med. 266/DA;$1(8<:J169. OPu#MedP 121. *c ussler P, Kluge M, Qassouridis A, et al. Progesterone reduces !akefulness in sleep FF> and as no effect on cognition in ealt y postmenopausal !omen. Psyc oneuroendocrinology. 266:D33$:(81129J1131. OPu#MedP 122. Polo2Kantola P, Frkkola &, .rEala K, Pullinen *, 'irtanen ., Polo C. Fffect of s ort2 term transdermal estrogen replacement t erapy on sleep8 a randomi0ed, dou#le2#lind crosso"er trial in postmenopausal !omen. Fertil *teril. 1<<<D;1$/(8:;3J::6. OPu#MedP 123. @iem *, >rady @, ?uan J, et al. Fffects of ultralo!2dose transdermal estradiol on postmenopausal symptoms in !omen aged A6 to :6 years. Menopause. 266AD13$1(8136J13:. OPu#MedP

129. %einric A-, +olf CT. .n"estigating t e effects of estradiol or estradiol4progesterone treatment on mood, depressi"e symptoms, menopausal symptoms and su#Eecti"e sleep )uality in older ealt y ysterectomi0ed !omen8 a )uestionnaire study. 1europsyc o#iology. 266/D/2$1(81;J23. OPu#MedP 12/. *aletu2Ry lar0 >, Anderer P, >ru#er >, et al. .nsomnia related to postmenopausal syndrome and ormone replacement t erapy8 sleep la#oratory studies on #aseline differences #et!een patients and controls and dou#le2#lind, place#o2controlled in"estigations on t e effects of a no"el estrogen2progestogen com#ination $Glimodien, 3afamme( "ersus estrogen alone. J *leep &es. 2663D12$3(823<J2/9. OPu#MedP 12A. AntoniEe"ic .A, *talla >K, *teiger A. Modulation of t e sleep electroencep alogram #y estrogen replacement in postmenopausal !omen. Am J C#stet >ynecol. 2666D1:2$2(82;;J2:2. OPu#MedP 12;. Kalleinen 1, Polo C, %imanen *3, Joutsen A, Polo2Kantola P. T e effect of estrogen plus progestin treatment on sleep8 a randomi0ed, place#o2controlled, dou#le2 #lind trial in premenopausal and late postmenopausal !omen. Glimacteric. 266:D11$3(8233J293. OPu#MedP 12:. -lock AJ, +ynne J+, -oysen P>, 3indsey *, Martin G, Gantor -. Menopause, medroxyprogesterone and #reat ing during sleep. Am J Med. 1<:1D;6$3(8/6AJ/16. OPu#MedP 12<. Polo2Kantola P, Portin &, Polo C, %elenius %, .rEala K, Frkkola &. T e effect of s ort2term estrogen replacement t erapy on cognition8 a randomi0ed, dou#le2#lind, cross2o"er trial in postmenopausal !omen. C#stet >ynecol. 1<<:D<1$3(89/<J9AA. OPu#MedP 136. Polo2Kantola P, &au ala F, %elenius %, Frkkola &, .rEala K, Polo C. -reat ing during sleep in menopause8 a randomi0ed, controlled, crosso"er trial !it estrogen t erapy. C#stet >ynecol. 2663D162$1(8A:J;/. OPu#MedP 131. Paul K1, Turek F+, Kryger M%. .nfluence of sex on sleep regulatory mec anisms. J +omens %ealt $3arc mt( 266:D1;$;(81261J126:. OPu#MedP 132. Mong JA, @e"id0e 1, >ood!illie A, Pfaff @+. &eduction of lipocalin2type prostaglandin@synt ase in t e preoptic area of female mice mimics estradiol effects on arousal and sex #e a"ior. Proc 1atl Acad *ci B * A. 2663D166$2/(81/26AJ1/211. OPMG free articleP OPu#MedP 133. Friess F, Tagaya %, Trac sel 3, %ols#oer F, &upprec t &. Progesterone2induced c anges in sleep in male su#Eects. Am J P ysiol. 1<<;D2;2$/ Pt 1(8F::/JF:<1. OPu#MedP 139. *tro l KP, %ensley MJ, *aunders 1A, *c arf *M, -ro!n &, .ngram &%., Jr Progesterone administration and progressi"e sleep apneas. JAMA. 1<:1D29/$12(81236J 1232. OPu#MedP 13/. *oares G1, Joffe %, &u#ens &, Garon J, &ot T, Go en 3. Fs0opiclone in patients !it insomnia during perimenopause and early postmenopause8 a randomi0ed controlled trial. C#stet >ynecol. 266AD16:$A(81962J1916. OPu#MedP 13A. Joffe %, Petrillo 3, 'iguera A, et al. Fs0opiclone impro"es insomnia and depressi"e and anxious symptoms in perimenopausal and postmenopausal !omen !it ot flas es8 a randomi0ed, dou#le2#linded, place#o2controlled crosso"er trial. Am J C#stet >ynecol. 2616D262$2(81;1, e1Je1;1, e11. OPu#MedP 13;. @orsey GM, 3ee KA, *c arf M-. Fffect of 0olpidem on sleep in !omen !it perimenopausal and postmenopausal insomnia8 a 92!eek, randomi0ed, multicenter, dou#le2#lind, place#o2controlled study. Glin T er. 2669D2A$16(81/;:J1/:A. OPu#MedP 13:. Morin G. Gontri#utions of cogniti"e2#e a"ioral approac es to t e clinical management of insomnia. Prim Gare Gompanion J Glin Psyc iatry. 2662D9821J2A.

13<. Morin GM, 'allievres A, >uay -, et al. Gogniti"e #e a"ioral t erapy, singly and com#ined !it medication, for persistent insomnia8 a randomi0ed controlled trial. JAMA. 266<D361$1<(8266/J261/. OPMG free articleP OPu#MedP 196. *i"ertsen -, Cm"ik *, Pallesen *, et al. Gogniti"e #e a"ioral t erapy "s 0opiclone for treatment of c ronic primary insomnia in older adults8 a randomi0ed controlled trial. JAMA. 266AD2</$29(82:/1J2:/:. OPu#MedP 191. Fdinger J@, +o lgemut +K, &adtke &A, Mars >&, ?uillian &F. Gogniti"e #e a"ioral t erapy for treatment of c ronic primary insomnia8 a randomi0ed controlled trial. JAMA. 2661D2:/$19(81:/AJ1:A9. OPu#MedP 192. *pielman A. Assessment of insomnia. Glin Psyc ol &e". 1<:ADA811J2/. 193. @rake G, &ic ardson >, &oe rs T, *cofield %, &ot T. 'ulnera#ility to stress2 related sleep distur#ance and yperarousal. *leep. 2669D2;$2(82:/J2<1. OPu#MedP 199. 3oprin0i G3, ?in &, -alcue"a FP, et al. P ase ..., randomi0ed, dou#le2#lind, place#o2controlled e"aluation of prega#alin for alle"iating ot flas es, 16;G1. J Glin Cncol. 2616D2:$9(8A91JA9;. OPMG free articleP OPu#MedP 19/. 3oprin0i G3, *loan J, *tearns ', et al. 1e!er antidepressants and ga#apentin for ot flas es8 an indi"idual patient pooled analysis. J Glin Cncol. 266<D2;$1;(82:31J2:3;. OPMG free articleP OPu#MedP 19A. *u"anto23uukkonen F, Koi"unen &, *undstrWm %, et al. Gitalopram and fluoxetine in t e treatment of postmenopausal symptoms8 a prospecti"e, randomi0ed, <2mont , place#o2controlled, dou#le2#lind study. Menopause. 266/D12$1(81:J2A. OPu#MedP 19;. Joffe %, Partridge A, >io##ie2%urder A, et al. Augmentation of "enlafaxine and selecti"e serotonin reuptake in i#itors !it 0olpidem impro"es sleep and )uality2of2life in #reast cancer patients !it ot flas es8 a randomi0ed dou#le2#lind, place#o2controlled trial. Menopause. 2616 Jun 29D Fpu# a ead of print. OPu#MedP < Menopause $1e! Qork, 1.Q.( Aut or Manuscript 1.% Pu#lic Access Fstrogen Treatment .mpairs Gogniti"e Performance follo!ing Psyc osocial *tress and Monoamine @epletion in Postmenopausal +omen Paul A. 1e! ouse, M.@., Julie @umas, P .@., O...P, and *imon 1. Qoung, P .@. Additional article information A#stract C#Eecti"e &ecent studies a"e s o!n !omen experience an acceleration of cogniti"e pro#lems after menopause, and t at estrogen treatment can impro"e or at least maintain current le"els of cogniti"e functioning in postmenopausal !omen. %o!e"er, !e a"e pre"iously s o!n t at t e negati"e emotional effects of psyc osocial stress are magnified in normal postmenopausal !omen after estrogen treatment. T is study examined ! et er estradiol administration can modify cogniti"e performance after exposure to psyc ological stress and monoamine depletion. Met ods Participants consisted of 22 postmenopausal !omen placed on eit er oral place#o or 1;e2estradiol $F2( $1 mg4day for 1 mont , t en 2 mg4day for 2 mont s(. At t e end of t e

3 mont treatment p ase, participants under!ent t ree depletion c allenges in ! ic t ey ingested one of t ree amino acid mixtures8 deficient in tryptop an, deficient in p enylalanine4tyrosine, or #alanced. Fi"e ours later, participants performed t e Trier *ocial *tress Test $T**T(, follo!ed #y mood and anxiety ratings and cogniti"e testing. Gogniti"e measures included tests of attention, psyc omotor function, and "er#al episodic memory. &esults F22treated compared to place#o2treated participants ex i#ited significant !orsening of cogniti"e performance on tasks measuring attentional performance and psyc omotor speed. *imilar trends for impairment !ere seen in measures of long2term episodic memory compared to place#o2treated postmenopausal !omen. F22treated participants also s o!ed a significant increase in negati"e mood and anxiety compared to place#o2 treated !omen after #ut not #efore t e T**T, t oug t e !orsening of #ot cogniti"e and #e a"ioral functioning !ere not correlated. T ese effects !ere independent of tryptop an or tyrosine4p enylalanine depletion and !ere not manifest #efore t e T**T or at #aseline. Gonclusions T ese data suggest t at t e relations ip #et!een estrogen administration and cogniti"e4#e a"ioral performance in postmenopausal !omen may #e more complex t an initially appreciated and t at effects of psyc osocial stress may influence ! et er ormone effects are #eneficial. Key!ords8 estrogen, menopause, monoamines, stress, cognition .1T&C@BGT.C1 *tudies of t e cogniti"e effects of estrogen or of !omen follo!ing menopause a"e strongly suggested t at estrogen le"els are directly rele"ant to cogniti"e function. Fxperimental studies of postmenopausal estrogen or estrogen treatment a"e in general tended to s o! positi"e effects on cogniti"e functioning1. -eneficial effects of ormone t erapy on cognition after menopause a"e #een confirmed in a num#er of studies s o!ing t at administration of estrogen to ealt y postmenopausal !omen $PM+( impro"ed "isuospatial a#ilities, memory, and frontal lo#e function 2J; :J16, alt oug not all studies a"e not s o!n positi"e effects 11J1/ and studies examining estrogen t erapy specifically in older postmenopausal !omen a"e not s o!n significant #enefit, including t e large +omenKs %ealt .nitiati"e $+%.( study 1AJ26. Meta2analyses21, 22 demonstrated t at ormone t erapy s o!s cogniti"e #enefit in younger !omen #ut older !omen s o! less e"idence of #enefit or small negati"e effects. C"erall, studies support t e ypot esis t at estrogen elps to maintain aspects of attention, "er#al and "isual memory23J2/, and may a"e positi"e effects on tasks mediated #y t e prefrontal cortex2A and ippocampus2; especially in younger PM+, alt oug in t e recent *+A1 study, perimenopausal !omen did not s o! t e expected impro"ement !it estradiol treatment2:. Gertain estrogen receptor polymorp isms appear to #e associated !it t e risk of de"eloping cogniti"e impairment2< and estrogen reduces neuronal generation of e2amyloid peptides ! ic may #e rele"ant to t e onset of Al0 eimerKs disease $A@(36. PM+ appear to #e at ig er risk for A@, particularly if t ey carry t e APCF9 allele31, and t ere is considera#le epidemiologic e"idence from #ot prospecti"e and case2control studies t at F2 use in PM+ may decrease t e risk of t e de"elopment and4or expression of A@32J3A, !it an o"erall odds ratio of 6.AA29. .n memory clinics, ormone users s o!ed lo!er rates of dementia diagnoses "ersus mild

cogniti"e impairment t an nonusers, ! o deteriorated more rapidly t an ormone users3;. .n contrast to cogniti"e functioning, t e increased "ulnera#ility for depression seen in reproducti"e2age !omen in !omen declines after t e menopause3:, 3< alt oug t e perimenopause may #e associated !it increased "ulnera#ility for #ot depressi"e symptoms and a diagnosis of ne! onset depression96, 91. + ile some studies a"e supported positi"e mood effects of estrogen or ormonal t erapy in postmenopausal !omen92J9/, ot ers a"e not9AJ9:. %o!e"er, t ere are fe! studies regarding t e interaction #et!een mood effects and cogniti"e performance in postmenopausal !omen. A strong candidate for explaining t e cogniti"e and mood alterations after menopause is t e influence of declining le"els of gonadal steroids on neurotransmitter systems and mood regulatory systems3<, per aps interacting !it genetic "ulnera#ility and life stress9<. A potential ypot esis for o! estrogen or its loss after menopause exerts effects on cognition and mood is t roug interactions !it modulatory neurotransmitter systems. For example, significant !ork as #een done on examining o! estrogen interacts !it c olinergic system acti"ity to alter cogniti"e functioning in #ot animal models and umans $see >i##s/6 and @umas et al,/1 for re"ie!(. &ecently, t is la#oratory as s o!n t at estradiol $F2( appears to impro"e cogniti"e performance related to c olinergic function as measured #y increased cogniti"e resistance to anti2c olinergic #lockade in normal PM+/2. T is impro"ement may #e dose and domain specific, i.e. lo!er doses impro"es primarily attentional functioning, ig er doses may influence episodic memory/3. Fffects of F2 on c olinergic function related to episodic memory may #e age2specific !it younger !omen s o!ing #enefit #ut older !omen s o!ing no #enefit or impairment $pro"iding direct experimental support for t e 7critical period ypot esis7/3 of estrogen #enefit after menopause(. %o!e"er, ot er monoamine neurotransmitters appear to a"e su#stantial modulatory roles on mood, anxiety, and on cogniti"e performance and #e a"ior. For example, estrogen s o!s effects on modulation of serotonin and dopamine receptor density/9, dopamine release//, and potentiation of serotonin function/AJ/<. Postmenopausal !omen respond more #riskly to serotoninergic antidepressants if taking estrogensA6JA3. Gatec olamine and indolamine systems can #e in"estigated in umans utili0ing conceptually similar treatment2c allenge models to t ose t at a"e #een utili0ed to in"estigate c olinergic system2 ormone interactions. +e a"e pre"iously reported t e effects of estrogen and monoamine depletion on mood follo!ing psyc osocial stressA9. As an extension of t is study !e no! report t e effects of t e same manipulation on cogniti"e functioning. T e primary goal of t e o"erall proEect !as to test ! et er s ort2 term administration of F2 to normal PM+ !ould alter mood reacti"ity and cogniti"e performance to experimental psyc osocial stress and )uantitati"ely c ange t e #e a"ioral responses to G1* catec olamine and4or serotonin depletion, p armacological c allenges t at directly interact !it central monoamine systems. Fstrogen le"els "ary #ot !it in indi"iduals and compared to premenopausal le"els during t e perimenopause and postmenopause and t is "aria#ility is associated !it p ysical and #e a"ioral symptomatologyA/, AA. +e reasoned t at fluctuations in estrogen le"els may lead to alterations in le"els of monoamine neurotransmitters, ! ic may influence mood reacti"ity and cogniti"e performance to external e"ents. T us, to pro#e t e interaction of estrogen and monoamine neurotransmitters on cognition and mood, !e used t e tec ni)ue of monoamine depletion and experimentally2induced

psyc osocial stress. Acute tryptop an depletion $AT@( is a !ell2esta#lis ed tec ni)ue for examining t e role of serotonin systems in mood A;, A:. Acute p enylalanine4tyrosine depletion $APT@( is a ne!er tec ni)ue designed to examine t e effects of reduced catec olamine synt esis and transmission on #e a"ior and performance A<. Tryptop an depletion can, in some circumstances, produce ad"erse effects on mood and #e a"ior t at are considered rele"ant to understanding t e causes of affecti"e illness A:, ;6. Furt er, central catec olamine depletion as #een examined in normal premenopausal !omen and as #een found to produce negati"e effects on mood under stress A<. .n t is study, !omen ! o !ere postmenopausal $X /6 years( took a fixed dose of 1;e2 estradiol $F2( or place#o for t ree mont s and t en participated in t ree c allenges using monoamine depletion to #riefly c ange t e relati"e amounts of monoamine neurotransmitters in t e #rain $serotonin, dopamine, and norepinep rine(. Participants t en participated in a psyc osocial stress paradigm to potentiate negati"e mood $Trier *ocial *tress Test, T**T(;1 t at in"ol"es pu#lic speaking and as #een s o!n pre"iously to relia#ly produce mild2moderate psyc osocial stress. +e a"e reported pre"iously on t e mood effects of t is manipulationA9, in ! ic !e s o!ed significant en ancement of negati"e mood effects after t e psyc osocial stress maneu"er in t e F22treated participants. %ere !e report on t e cogniti"e results from t at study !it additional participants. +e ypot esi0ed t at t e psyc osocial stress manipulation $T**T( !ould en ance any negati"e mood and cogniti"e effects of monoamine depletion and t at estrogen administration !ould #lunt or #uffer potential negati"e effects produced #y t e com#ination of t e monoamine depletion and t e stress test in a measura#le and )uantifia#le !ay. *ince estrogen as #een noted to interact !it #ot serotonergic and catec olaminergic systems, it !as ypot esi0ed t at depletion of eit er monoamine system !ould interact !it estrogen treatment to alter cogniti"e performance. MFT%C@* T e #asic design consisted of a dou#le2#lind parallel group design $eac su#Eect !as randomly assigned to recei"e eit er 3 mont s of F2 or place#o( !it eac treatment group t en undergoing acute depletion and social stress c allenges. All participants signed fully informed consent after an explanation of all procedures, risks, and #enefits. Participants recei"ed w166 as compensation for t eir time and a small gift pack after eac study session. T e study !as appro"ed #y t e Bni"ersity of 'ermont Gommittee for %uman &esearc in t e Medical *ciences $.&-(. Participants Participants !ere recruited t roug ne!spaper ad"ertisement and ealt ne!sletters pu#lis ed #y our Medical Genter, pu#lic information sessions, ne!spaper ad"ertisements, and random mailings. *tudy participants !ere first screened #y p one for eligi#ility. Participants consisted of 22 normal PM+ ages /2J:3 $MIA9.3, *@I16.A(. *u#Eect demograp ics are descri#ed in Ta#le 1. Ta#le 1 Ta#le 1 *u#Eect @emograp ic @ata $nI22( Medical *creening

Participants !ere !it out menses for at least 1 year, ad an F*% le"el greater t an 36 m.B4ml, nonsmokers, ad a normal mammogram !it in t e last year, and !ere !it out surgically2induced menopause $#ilateral oop orectomy(. T ey !ere not taking %T, or oral contracepti"es, and !ere at least one year !it out suc treatment. Participants !ere p ysically ealt y, ad a #ody mass index f39 kg4m2, and ad no cardio"ascular disease ot er t an mild ypertension. Participants !it maEor concomitant illnesses !ere excluded on t e #asis of istory, p ysical exam, and la#oratory tests assessing ematopoietic, renal, epatic and ormonal function. $G-G, G em 26, T*%, B4A, FG>(. Participants !ere p ysically examined #y a gynecologic nurse2practitioner to esta#lis general p ysical ealt and for specific p ysical contraindications for F2 t erapy $e.g. adnexal mass, large uterine fi#roids, etc.( Participants !ere excluded if t ey ad specific contraindications for F2 treatment, or current or any past Axis . psyc iatric disorders. *pecific criteria for exclusion for t e F2 treatment included contraindications for ormone replacement including istory of #reast cancer or F22dependent neoplasiaD #lood pressure X 1A64166 $untreated(D istory of deep "ein t rom#osis or ot er t rom#oem#olic diseaseD epatomaD se"ere migraines or stroke on oral contracepti"esD concurrent use of #ar#iturates, rifampin, insulin, car#ame0epine, oral ypoglycemics, antidepressants, or lipid2lo!ering drugsD kno!n intolerance to conEugated F2sD dia#etesD untreated t yroid diseaseD clinical osteoporosisD se"ere menopausal symptoms. All participants !ere taking no centrally acti"e drugs. 1o participants !ere taking selecti"e estrogen receptor modulators $*F&Ms( or er#al menopause preparations. A minimum of 19 days elapsed #et!een discontinuing centrally acti"e or psyc oacti"e agents and participation in t is study. Gogniti"e4-e a"ioral *creening All participants !ere cogniti"ely and #e a"iorally assessed using standard tests designed to exclude participants !it cogniti"e or #e a"ioral impairment. Participants !ere e"aluated using t e Mini Mental *tate Fxam $MM*(;2, -rief Gogniti"e &ating *cale;3, t e Mattis @ementia &ating *cale;9, to esta#lis a >lo#al @eterioration *cale score $>@*( ! ic rates t e degree of cogniti"e impairment;/. Participants !ere re)uired to a"e a >@* score of 1J2 and a MM* score of greater t an or e)ual to 2;. Participants !ere excluded if t ey scored #elo! 123 on t e @ementia &ating *cale;9 scale and !ere matc ed across t e t!o groups in terms of educational #ackground. -e a"ioral screening consisted of a partial *tructured Glinical .nter"ie! for @*M2.'2T& $*G.@(;A to esta#lis t e presence4a#sence of present or past Axis . maEor psyc iatric disorders, particularly any present or past istory of mood disorders. .n addition, participants completed t e -eck @epression &ating *cale;; and a menopause symptom c ecklist modified from * er!in;: to detect su#clinical depressi"e symptoms. An exclusion cut off score of 16 !as used for t e -eck @epression &ating *cale. Fstrogen4Place#o Treatment After screening and acceptance into t e study, eac su#Eect !as placed randomly and #lindly on eit er oral place#o or 1;2e estradiol $F2( $using identical pink capsules( for 3 mont s. T ere !ere 11 !omen in t e F2 group and 11 !omen in t e place#o group. +omen !ere initially placed on F2 1 mg per day for 36 days, and t en !ere increased to 2 mg per day. T is !as done #ecause early pilot trials re"ealed t at estrogen2related side effects $e.g. #reast tenderness or spotting( tended to #e noticed #y participants if t e participant !as #egun on 2 mg of F2 from t e #eginning. Bsing 1 mg of F2 for t e first 36 days elped to protect t e #lind.. At t e end of t e 3 mont treatment period,

participants participated in a series of c allenge studies designed to examine differences in sensiti"ity to acute transmitter depletion and psyc osocial stress. F2 or place#o treatment continued t roug out t e c allenge4stress studies. T!el"e days of medroxyprogesterone acetate $MPA( $Pro"era( !as gi"en at t e end of t e study to produce s edding of t e endometrial lining. Acute @epletion G allenges All studies took place on t e Bni"ersity of 'ermont >eneral Glinical &esearc Genter $>G&G(. Fac participant under!ent t ree test days, at least se"en days apart, in ! ic t ey recei"ed t e eac of t e t!o amino acid depletion mixtures and t e nutritionally2 #alanced control mixture. T e depletion se)uence !as determined #y a random order procedure. T e procedure for t e administration of t e amino acid mixtures !as t e same as !e a"e used pre"iouslyA<. Participants !ere placed on a lo!2protein diet for t e e"ening meal prior to eac study day. Follo!ing an o"ernig t fast, t e study #egan at 6:66 !it #aseline testing and e"aluation. Participants t en ingested one of t ree amino acid $AA( mixtures8 $1( a nutritionally #alanced AA mixture, $2( a mixture deficient in tryptop an $AT@(, or $3( a mixture deficient in p enylalanine and tyrosine $APT@(. T e composition of t e AA mixtures !as t at used in prior studies, adEusted for t e generally lo!er !eig t of !omen. Mixtures consisted of amino acid suspended and !ater, !it t e !orst tasting amino acids $32 met ionine, 32 cysteine and 32 arginine( in capsules. T e li)uid suspensions !ere fla"ored !it noncaloric, no2protein fla"oring of orange, grapefruit, lemon, c ocolate, or cran#erry2lemon $su#EectSs c oice( to disguise t e unpleasant taste. +e a"e pre"iously demonstrated t e feasi#ility of administering 3 AA mixtures to female participants !it accepta#le tolera#ility;<. Testing concluded !it a ig protein snack for repletion of amino acid le"els. *ocial *tress Test Fi"e ours after amino acid ingestion, participants performed a mildly stressful psyc ological task, t e Trier *ocial *tress Test $T**T(;1. T e T**T consisted of t ree parts, a #rief .nstruction Period, a 162min Anticipation Period, and a 162min Test Period. For t e #rief .nstruction Period, participants !ere taken to t e T**T room ! ere 3 persons !ere already sitting at a ta#le and a "isi#le "ideo camera !as set up. T e su#Eect !as asked to stand on an YVZ on t e floor in front of t e panel of people. T e .nstructor presented t e su#Eect !it one of t ree scenarios and asked t e su#Eect to prepare a /2min speec a#out t e topic. Participants !ere told t at t e panel !as specially trained to monitor non"er#al #e a"ior and t at a "oice2fre)uency analysis of t e speec !ould #e performed. Follo!ing t e instructions, t e su#Eect returned to er room. @uring t e Anticipation Period, participants !ere asked to prepare t e /2min speec . T ey !ere gi"en 16 minutes to prepare and take notes in a separate room, #ut !ere not allo!ed to use t em during t eir speec . Participants presented t eir /2min speec follo!ed #y / minutes of arit metic pro#lems. T e T**T !as originally designed to #e conducted one time per su#Eect, utili0ing only t e first speec scenario and arit metic pro#lem. .n order to repeatedly confront t e su#Eect !it t e T**T on eac of t e t ree study "isit days, t e t!o additional scenarios and arit metic pro#lems !ere created. For eac of t e t ree scenarios, t e su#Eect !as asked to take on a role !it in a gi"en context and ad to con"ince a panel to grant er a specific re)uest8 1( &ole of a Eo# applicant for t e position of manager at a #anking firm. 2( &ole of t e director of a

re a#ilitation program for prisoners re)uesting a donation of a large sum of money to support t e program. 3( &ole of a #uilding de"eloper re)uesting a #uilding permit to #uild a strip mall in a rural 1e! Fngland to!n. For t e arit metic pro#lem portion of t e Test Period, t e pro#lems consisted of serial su#tractions of a t!o digit num#er from a four digit num#er, and upon e"ery mistake, t e su#Eect !as asked to #egin again at t e first num#er. &epeated exposure to t e T**T as #een s o!n to induce an e)ual p ysiologic stress response :6, :1. Gonsultation !it t e creators of t e T**T and t eir re"ie! of our scenarios produced general agreement t at t e repeated use of t e T**T !it our scenarios ad precedent and !ould produce repeated e)ui"alent stress $*c ommer, personal communication(. Participants !ere #riefed #efore t e study #egan a#out t e general nature of t e T**T and ! at !as expected of t em. T is !as done so as to e)uali0e t e anticipation of t e T**T across t e t ree study days. .t s ould #e noted t at t e actual performance of t e su#Eect during t e T**T !as not e"aluated. T e psyc ological stress induced !as a product of t e actual e"ent of standing in front of a panel of strangers and deli"ering a speec D t us, t e topic of t e speec !as less important. &egardless, t e speec scenarios and arit metic pro#lems !ere Eudged to #e e)ual in difficulty and e)ui"alently contro"ersial topics for t e population #eing studied. Furt er, t e order of scenarios !as randomi0ed across participants, decreasing t e possi#ility t at differences in scenarios !ould produce different stress outcomes. Participants !ere de#riefed at t e end of t e study regarding t e mild deception in t e stress test $i.e., no actual monitoring of test performance(. CBTGCMF MFA*B&F* GC>1.T.'F A cogniti"e testing #attery !as constructed to e"aluate a num#er of cogniti"e domains potentially sensiti"e to monoamine depletion and psyc osocial stress as !ell as affected #y loss of and su#se)uent treatment !it estrogen. T ese cogniti"e domains included tests of simple attention, complex attention and "er#al episodic memory. Fac task is descri#ed #elo!. T e cogniti"e #attery !as performed once eac study day, after t e psyc osocial stress maneu"er. Participants !ere pre2trained on t e entire cogniti"e #attery prior to study initiation to ensure sta#le asymptotic performance to ensure e)ui"alent cogniti"e performance at #aseline #et!een t e groups. *imple Attention T e Gritical Flicker Fusion $GFF( task:2 and t e G oice &eaction Time $G&T( task:3 from t e Milford Test -attery !ere used as t e measures of simple attention and !ere performed using t e 3eeds Psyc omotor @e"ice. @uring t e GFF task t ere !ere t!o different types of trials. .n an ascending trial, t e participant pressed a #utton t at indicated ! en t e fre)uency of flas ing lig ts ad increased to t e point t at t e lig ts appear to #e no longer flas ing #ut rat er appear continuously on $YfusedZ(. T e lig ts #egan flas ing at a rate of 12 %0 and t e fre)uency !as increased to /6 %0. .n a descending trial, t e participant pressed a #utton ! en t e fre)uency of apparently fused lig ts !as decreased suc t at lig ts #egan to appear to #e flas ing. T e lig ts #egan flas ing at /6 %0 and decreased to 12 %0. T e participant needed to respond #efore t e fre)uency it t e upper or lo!er limit in eac trial. T e participant !as presented !it t ree of eac trial type. @ependent measures for t is task !ere t e median detection fre)uency across all trials, as !ell as t e median detection fre)uency

on t e ascending and descending trials separately. 3o!er fre)uency "alues are generally understood to reflect impaired attention and4or arousal. T e G&T task !as a reaction time task in ! ic participants kept t eir index finger on a Y omeZ lig t sensiti"e diode $3*@( until one of six 3G@ lig ts arrayed in a semicircle, approximately 2/ cm from t e Y omeZ key, !as lit on t e response #ox. T e su#Eect lifted er index finger and mo"ed it to co"er t e 3*@ corresponding to t e illuminated 3G@. * e t en returned er finger to t e Y omeZ 3*@. T ree performance measures !ere o#tained from t e G&T. T e first !as t e median total reaction time $&T( per trial. T e second !as t e median recognition &T, t e amount of time it took t e su#Eect to lift er finger off of t e ome 3*@ once t e signal to respond appeared. T e t ird measure !as t e median motor &T, t e time it took t e participant to mo"e er finger and to co"er t e 3*@ corresponding to t e illuminated 3G@. Gomplex Attention T e measures of complex attention !ere t e @igit *ym#ol *u#stitution Test $@**T:9(, and t e Gonnors Gontinuous Performance Test $GPT:/(. .n t e @**T, participants !ere presented !it nine num#ers t at corresponded to nine sym#ols. Cn t e ans!er form t e participant !as instructed to !rite t e sym#ol t at corresponded to eac num#er and to complete as many as possi#le in <6 seconds. T e dependent measure !as t e total correct completions. .n t e computeri0ed GPT task, indi"idual letters appeared on t e computer screen for 366 ms !it a response period of t!o seconds for 126 trials. Participants !ere instructed to press a #utton ! en t ey sa! an A follo!ed #y an V. T e dependent measures !ere its, errors of omission and commission, and it reaction time. 'er#al Fpisodic Memory T e -usc ke *electi"e &eminding Task $*&TD -usc ke, 1<;3( and t e 'er#al Paired Associates Test $'PAD +ec sler Memory *cale ...( !ere used as measures of "er#al episodic memory. .n t e *&T, participants !ere read a list of 19 !ords, follo!ed #y an immediate recall trial. T e experimenter t en reminded t e participant of any !ords s e did not recall and s e !as instructed to recall all 19 !ords again. T is process !as repeated for eig t trials. T ree measures !ere o#tained from t is task8 t e total num#er of !ords recalled across all lists, t e recall consistency from one trial to t e next, and t e recall failure from one trial to t e next. .n t e 'PA, participants !ere read a list of eig t pairs of !ords. T en t ey !ere read t e first !ord in eac pair and asked t e recall t e associate. T e list !as read and recalled a maximum of A times. .f t e participant recalled all !ords on t e list !it in t e first t ree trials, t e tests !as discontinued after t ree trials. Four of t e !ord pairs !ere strong associates $easy pairs( ! ile t e ot er four !ere !eak associates $ ard pairs(. @ependent measures !ere num#er correct for t e strong and !eak associates after t ree and six trials. T e final test of "er#al memory !as a Paragrap &ecall test:A. Participants !ere read a s ort paragrap and t en asked to retell t e story from memory. T e dependent measure !as t e num#er of information units correctly recalled from memory.

Gogniti"e task !ere performed in t e follo!ing order8 GFF, *&T, G&T, 'PA, GPT, @**T, Paragrap &ecall. T is administration order !as t e same for all participants on all study days. A minimum of 16 e)ui"alent "ersions of t e testing forms !ere created so t at a ne! "ersion of eac test !as a"aila#le for eac of t e testing days. T ese forms !ere counter#alanced across study days for all participants. -e a"ior T e primary mood and anxiety measure !as t e su#Eect2completed Profile of Mood *tates $PCM*(:;. T is scale is a A/ item adEecti"e c ecklist t at generates A #ipolar factor2analytically deri"ed factors, $elated2depressed, composed2anxious, energetic2 tired, agreea#le2 ostile, confident2unsure, and clear eaded2confused( or 12 unipolar factors, plus total score. T is scale as #een used extensi"ely in c allenge study paradigms and is sensiti"e to t e effects of psyc otropic drugs and G1* state manipulations. .t !as administered 3 times during t e experimental session8 pre2 depletion, post2depletion prior to T**T, and post T**T. Participants completed a -eck @epression .ndex $-@.( ;; t!ice during t e day8 pre2depletion and post2depletion #ut prior to t e T**T. 1euroendocrine4p ysiologic Measures of estradiol and F*% !ere collected to assess compliance and t e effecti"eness of F2 t erapy. Fstradiol and F*% !ere measured !it an A@'.A Gentaur c emiluminescence competiti"e immunoassay $estradiol( and an A@'.A Gentaur t!o2 site sand!ic immunoassay $F*%( #ot utili0ing a la#eled acridinium ester. *amples !ere collected at screening and on t e first day of eac c allenge se)uence. -lood !as collected on eac study day for measures of plasma total tryptop an, p enylalanine, and tyrosine to assess t e ade)uacy of depletion. *amples !ere collected pre2depletion $[9/S( and end of session $\966S(. Plasma p enylalanine and tyrosine concentrations !ere determined using a -eckman *ystem >old amino acid analy0er using gradient %P3G !it precolumn deri"ati0ation and fluorometric detection. Tryptop an !as measured #y isocratic %P3G !it fluorometric detection. Gortisol !as measured #y radioimmunoassay $@iagnostic Products Gorporation(. 'ital signs !ere recorded pre2depletion at [9/S, pre2T**T at \366S, and post2T**T at \966S @ATA A1A3Q*.* T e general approac !as t at of mixed model repeated measures analysis of "ariance $A1C'A( utili0ing *A* P&CG M.VF@. .nitial analysis of cogniti"e measures !as a 2a3 treatmentD 2 $F2 "s P3G( a depletion 3 $AT@, ATP@, Mock( mixed model A1C'A as an o"erall test of t e effect of estradiol treatment and monoamine depletion effects on cognition follo!ing psyc osocial stress. Treatment $F2 "s. place#o( !as t e #et!een2 participants factor and depletion $AT@, APT@, and mock( !ere t e !it in2su#Eect factors. For t e mood measures only, time !as an additional factor as t ere !as a pre2depletion, pre2stress maneu"er mood assessment. Gogniti"e testing !as performed once on eac of t e t ree experimental days and t us eac su#Eect performed cogniti"e testing under eac monoamine depletion2psyc osocial stress condition. As t e primary effect of interest in t is study !as t e impact of F2 treatment on cogniti"e performance follo!ing monoamine depletion and psyc osocial stress, if no treatment2#y2depletion effect !as found, results !ere collapsed across depletions and t e analyses !ere redone as an

independent samples t2test. + en t ere !as a significant interaction $e.g. treatment a depletion(, non2ort ogonal a2priori contrasts !ere used to test for differences #et!een treatment across depletions. Gorrelations #et!een cogniti"e and mood measures !ere performed using Pearson product2moment correlations adEusted for multiple comparisons. T e alp a le"el for reEection of t e null ypot esis !as set at p5.6/. &F*B3T* Participants Participants !ere matc ed for age, education, !eig t, and years since menopause $Ta#le 1(. T e mean age of participants !as A9.3^ 16.A. -M. a"eraged 2A.23 ^ 9.9; kg4m2 and participants !ere an a"erage of 19.3 ^ 16./ years post menopause. T is !as a ig ly educated group !it an a"erage of 19.< years of education. Fifteen participants ad ad pre"ious experience !it ormone replacement t erapy $X1 year pre"iously( and ; did not. For t ose !omen ! o ad pre"iously used ormone t erapy, t e a"erage duration of ormone use !as 3.< ^ 9.< years. F*%, Fstradiol and Gortisol 3e"els Pretreatment F*% s o!ed a mean le"el of A/.;3 m.B4ml $menopausal le"el is considered a#o"e 36J3/ m.B4ml( and !as not significantly different #et!een treatment groups $t$1:( I.<:, p X .39. After t ree mont s of treatment, t e F22treated participants s o!ed a significantly reduced mean F*% le"el of 2<.A compared to t e place#o2treated participants ! o ad a mean le"el of A<.6 $t$1;(I/.3<, p 5 .661(. Mean plasma estradiol le"els after t ree mont s of treatment !ere significantly ele"ated at 13/.3A pg4ml for t e F22treated group compared to 1:.3 pg4ml for t e place#o2treated group $t$1<(I/.19, p5.661(. T e le"els of estradiol seen in t e F22treated !omen are compara#le to late follicular p ase le"els in premenopausal !omen, ! ereas t e le"el seen in t e place#o2 treated !omen is compara#le to t e early follicular p ase. Gortisol le"els !ere measured at #aseline and \926 minutes $post2T**T(. -aseline le"els $pre2depletion, pre2T**T( !ere ig er, $p5 .61( in t e F22treated participants #ut declined similarly across t e experimental day in #ot treatment groups. Amino Acid 3e"els Plasma concentrations of total tryptop an, p enylalanine, and tyrosine !ere measured at #aseline $pre2depletion( and at \966 minutes $post2depletion( $Ta#le 2(. After tryptop an depletion, plasma tryptop an le"els declined ;A=. After tyrosine4p enylalanine depletion, #ot tyrosine and p enylalanine le"els declined #y A6= suggesting t at an ade)uate depletion !as ac ie"ed A<, ::. Ta#le 2 Ta#le 2 Amino Acid 3e"els $nI22( Glinical Assessment of Mood across Treatment P ase A comparison of t e clinical depression ratings $-@.( from screening to t e end of t e treatment p ase for eac su#Eect re"ealed no significant time2#y2treatment interaction $F$1,1:(I./:, p X .9/(. Furt ermore, a comparison of t e end of treatment -@. scores $t e #aseline -@. score on t e first depletion c allenge day( #et!een treatment groups s o!ed a small numerical difference $P3G8 2.<1 ^ 3.AD F28 9.// ^ 2.<( t at !as not significantly different #et!een treatments $t$26(I1.1<, p X. 2/(. T ese data demonstrate t at t e treatment alone $F2 or place#o( did not produce significant or clinically manifest negati"e c anges in mood across t e t ree2mont treatment p ase nor did t e groups differ prior to #eginning t e monoamine depletion c allenges.

Gogniti"e Performance Gogniti"e testing results are presented in Ta#le 3. Gogniti"e testing !as only performed after t e T**T. .n general, significant impairment !as seen across many cogniti"e measures in t e F2 treated group, particularly on attention and psyc omotor measures. Ta#le 3 Ta#le 3 Gogniti"e performance scores #y treatment and depletion condition $n I 22D Place#o I 11D F2 I 11(. Attention4Psyc omotor Gritical Flicker Fusion $GFF( Attentional performance as measured #y t e median fre)uency of all trials s o!ed a significant main effect of treatment $F$1,26( I :.AA, p I .66:( !it F22treated participants s o!ing a reduced fre)uency compared to place#o2treated participants $Figure 1(, suggesting impaired attention. T ere !as a strong trend for a treatment2#y2c allenge interaction $F$2,26( I 3.1;, p X .6A( !it t e tyrosine4p enylalanine depletion condition s o!ing a slig tly poorer performance compared to tryptop an depletion and mock depletion after F2 treatment. Falling trials s o!ed a significant $F$1,26( I 11.A1, p I . 663( main effect of F2 treatment as !ell, producing a median fre)uency reduction, #ut rising trials did not $p X .11(. Figure 1 Figure 1 Gogniti"e performance measures follo!ing t e Trier *ocial *tress Test. @ata are presented for estradiol $F2( and place#o $P3G( treatment groups for eac monoaminergic depletion8 Acute Tryptop an @epletion $AT@(, Acute Tyrosine4P enylalanine @epletion ... G oice &eaction Time $G&T( For t e G&T, total median &T s o!ed no treatment2#y2c allenge interaction. Gollapsing t e data across c allenge conditions demonstrated a significant $t$26( I 2.A:, p 5 .6/( effect of F2 treatment !it t e pattern of means s o!ing t at estrogen treated participants performed slo!er across all depletion conditions t an place#o treated participants $Figure 1(. T e recognition component of t e G&T s o!ed a significant effect of c allenge, F$2,3;( I 16.69, p I .6663, on median recognition &T !it t e tyrosine4p enylalanine depletion s o!ing a slo!er &T t en eit er t e mock or tryptop an depletion conditions. %o!e"er t ere !as no significant treatment or c allenge2#y2treatment effects. Analyses collapsed across c allenge conditions re"ealed a significant effect of F2 treatment $t$26( I 2.2/, p 5 .6/( !it &T significantly greater $slo!er( for F22treated participants. For t e motor component of G&T, t ere !ere no significant treatment2#y2c allenge interaction effects on median &T, #ut as !it t e ot er components, collapsing across c allenge conditions re"ealed a significant $t$26( I 2.A:, p 5 .6/( slo!ing effect of F2 treatment. Gontinuous Performance Task $GPT( As t ere !ere no significant c allenge2#y2treatment interactions, !e examined treatment effects #y looking at t e data collapsed across c allenge conditions. T e proportion of its s o!ed a significant $t$26( I 2.A/, p 5 .6/( negati"e effect of estrogen treatment,

!it F2 treated participants demonstrating a reduced proportion of its across all conditions. A similar significant pattern $t$26( I 2.A/, p 5 .6/( !as seen in errors of omission !it errors s o!ing increases under all conditions for t e F2 treated participants. T ere !ere no significant or trend2le"el effects on commission errors, #ut t e proportion of commission errors !as "ery lo!. -y contrast, t ere !as a significant F$1,26( I A.1;, p I .62 positi"e main effect of F2 treatment on it &T !it F2 treated participants s o!ing a faster &T $#et!een A6 and 166 ms( across all depletion conditions. T e contrast in t ese results suggests t e possi#ility t at F2 treated participants demonstrated a speed2accuracy trade2off, #ecoming faster, #ut less accurate. 1o ot er parameters s o!ed significant effects. @igit *ym#ol *u#stitution Task $@**T( T ere !as a significant, F $1,26( I 9.A3, p I .69, main effect of treatment on t e num#er of items correctly completed !it F22treated participants s o!ing a significantly $p I . 661( reduced num#er of items correctly completed compared to t e place#o2treated participants $Figure 1(. .n addition, t ere !as a significant c allenge2#y2treatment interaction, F$2, 3:( I 3.::, p I .63, !it F22treated participants s o!ing significantly t$26( I 2./, p 5 .6/( fe!er correct completions after tyrosine4p enylalanine depletion. Memory *electi"e &eminding Task $*&T( T ere !ere no effects at F2 treatment on t is task. T ere !as a trend $p I .12( for :2trial recall to #e reduced under #ot tryptop an and tyrosine4p enylalanine depletion conditions. .n addition, recall consistency s o!ed a significant main effect of depletion c allenge, F$2, 3;( I 9.<3, p I .61(, !it consistency #eing significantly reduced under #ot tryptop an and tyrosine4 p enylalanine depletion conditions. T ere !as no interaction !it F2 treatment on t is parameter. &ecall Failure s o!ed a pattern of increased failure scores under F2 treatment, #ut t e effect of treatment !as not significant. 'er#al Paired Associate Task $'PA( + ile t ere !as no significant c allenge2#y2treatment interactions, collapsing across c allenge conditions, t ere !as a significant $t$26( I 2.1/, p 5 .6/( effect of F2 suc t at F22treated participants s o!ed a reduced recall of ard !ord pairs across all depletion conditions $Figure 1(. T ere !as a similar trend $p I.1A( for F22treated participants to s o! a similarly reduced recall for easy pairs of !ords. Paragrap &ecall T ere !ere no significant or a trend2le"el treatment, c allenge, or interaction effects on t is measure. Mood Fffects T e effects of t e ormone2monoamine depletions4psyc osocial stress manipulation on mood !ere pre"iously presented in detail in 1e! ouse et al. A9. +e #riefly re"ie! and update t ose findings ere, focusing on t e PCM* results.

An examination of t e entire model for t e PCM* total score and su#scales re"ealed no significant treatment2#y2depletion c allenge interactions. T us t e analyses !ere redone collapsing across c allenge conditions to examine ormone treatment effects. Total Mood @istur#ance score s o!ed a significant interaction of ormone treatment #y time, F$2, 26( I <.96, p I .661, !it F2 su#Eect s o!ing a significant increase in Total Mood @istur#ance scores follo!ing t e stress4monoamine depletion manipulation. Fxamining t e su#scale scores from t e PCM* re"ealed similar ormone treatment2#y2time interactions for @epression $F$2,26( I 9./6, p I.62(, Gonfusion $F I 3.<3. p I .69(, and 'igor $F I A.A;, p I .663(, !it F2 participants s o!ing significant score c anges indicating !orsening self2ratings follo!ing t e stress4monoamine depletion manipulation compared to place#o treatment. .n addition, on t e Tension su#scale, t ere !as a main effect of ormone treatment, F $1, 26( I A.:9, p I .62(, !it F22treated participants s o!ing ig er scores across time. T e Anger4%ostility su#scale s o!ed only tri"ial significant effects of time and did not s o! any treatment or ormone treatment2stress manipulation effects. Gorrelation !it Mood Fffects of Psyc osocial *tress and Monoamine @epletion +e examined ! et er group differences in cogniti"e performance correlated !it c anges in self2rated mood follo!ing t e psyc osocial stress manipulation and monoamine depletion. +e compared t e PCM* total score and su#scale scores at t e post2depletion rating in relations ip to t e performance measures t at !ere o#tained at t e same time. T e relations ips !ere inconsistent, !it some mood measures correlating !it performance under place#o on some tasks and under estrogen on ot ers. T ere !ere small correlations #et!een t e Tension su#scale of t e PCM* and impaired performance on t e *electi"e &eminding Task, t e G&T, and t e @**T, o!e"er t e pattern of treatment correlations !as inconsistent as t e Tension su#scale correlated !it performance on place#o on some tasks and estrogen on ot ers. A similar pattern !as seen for t e @epression, Fatigue, and Gonfusion su#scales. Furt ermore, none of t ese correlations sur"i"ed correction for multiple comparisons. T us it does not appear t at t e magnitude of t e mood c anges alone explained t e estrogen treatment2related negati"e effects on cogniti"e performance. +e also ad pre"iouslyA9 examined effects of age, T**T scenario, and t e effect of repeated administration of t e T**T on mood dependent "aria#les. 1eit er age, day, nor T**T scenario interacted !it ormone treatment or depletion c allenge. Moreo"er, t ere !as no significant effect of repeated administration of t e T**T and no significant interaction !it ormone treatment or depletion c allenge !as found. 'ital *igns Cnly minor effects of ormone treatment and amino acid depletion !ere seen on "ital signs. T ere !as a trend for a treatment2#y2c allenge interaction on diastolic #lood pressure $p X .6;( !it diastolic #lood pressure s o!ing a slig t increase after tyrosine2 p enylalanine depletion. 1o effects !ere seen on systolic #lood pressure. Pulse s o!ed significant main effects of c allenge $F$2,33( I 3.;;, p 5 .6/( and time $F$2,3:( I :.96, p 5 .661(, #ut no interactions !it ormone treatment !as found. T e pattern of means s o!ed t at t e mock depletion !as not associated !it an increase in pulse across t e psyc osocial stress maneu"er compared to t e AT@ or ATP@ depletions t at !ere associated !it a relia#le increase in pulse. Temperature s o!ed a small significant F$1,1< I A6.:1, p 5 .661( time2related c ange as expected #ut did not s o! any

significant F2 treatment2related effects or any systematic results of monoamine depletion. 1o clinically rele"ant c anges occurred. @.*GB**.C1 Post2menopausal !omen ! o !ere administered estradiol $F2( at a dose of 1 mg of oral 1;e2estradiol per day for 1 mont , t en 2 mg per day for 3 mont s generally ex i#ited poorer cogniti"e performance follo!ing a psyc ologically stressful e"ent compared to place#o2treated !omen. T is response !as independent of t e effects of monoamine depletion, ! ic appeared to a"e only a small o"erall effect on t e cogniti"e and emotional responses and did not interact !it t e effects of F2. T ese effects did not appear to #e secondary to #aseline mood differences prior to depletion or t e T**T, as participantsS end of treatment depression scores $-eck(, and pre2depletion mood scores $PCM*( and depression scales !ere not significantly different #et!een treatment groups. +e expected t at monoamine depletion and psyc osocial stress toget er !ould produce negati"e cogniti"e and mood c anges, as !as seen #y 3eyton et al.A< #ut t at mig t #e modified #y t e presence of F2. Monoamine depletion produced only minor negati"e cogniti"e c anges compared to mock depletion. -y comparison, t e effects of F2 treatment on cogniti"e performance follo!ing social stress !ere larger and appeared to #e largely independent of t e monoamine depletion maneu"ers. T e cogniti"e domains of impairment included #ot attention and to a lesser extent, memory. Attentional impairment included simple speed measures ! ic a"e generally #een s o!n to #e impro"ed #y F23, :<. T e current study relia#ly s o!ed t at estradiol treatment after psyc osocial stress lengt ened reaction time and decreased perceptual discrimination a#ility. @umas et al/2 s o!ed t at t ese measures !ere impro"ed #y estradiol treatment after c olinergic c allenge. %o!e"er, estradiol ad t e opposite effect on t ese measures after psyc osocial stress. Additionally, t ere !as also partial impairment on some "er#al episodic memory measures for t e estradiol group relati"e to t e place#o group. T ese data contrast !it prior data #y Maki and colleagues and * er!in and colleagues<, <6 ! o s o!ed t at F2 impro"ed "er#al episodic memory performance, alt oug t ese studies !ere not done !it a psyc osocial stress or neuro2 c emical stress maneu"er. T us, t e psyc osocial stress manipulation in t is study appeared to interact !it t e estradiol treatment to generally impair cogniti"e performance, ! ic !as t e opposite of ! at !e originally ypot esi0ed. -elo! !e discuss furt er t e implications for suc an interaction. T e one exception to t ese findings !as t e it &T measure during t e GPT task, ! ic impro"ed in F22treated participants after t e psyc osocial stress4amino acid depletion maneu"er, in contrast to t e &T for ot er tasks suc as t e G&T, ! ic s o!ed significant slo!ing. Cn t e GPT task participants displayed a speed2accuracy trade off t at interacted !it t e effects of estrogen treatment. T e F2 treated participants made fe!er its #ut ad faster it &Ts compared to t e place#o treated group. Additionally, differences in task specifics may explain t ese results. T e G&T task is a sensory detection and motor task. -y contrast, t e GPT test re)uires a deeper le"el of stimulus processing to make an appropriate decision on ! et er to respond to particular stimuli, and t us as greater test demands t an t e simpler G&T task. Furt er studies s ould in"estigate ! et er task complexity or dept of processing c anges t e effect of stress2 or ormone2related alterations on cogniti"e performance. T ese results differ from prior pu#lis ed findings from our la#oratory s o!ing t at t ree mont s of F2 administration to PM+ en ances cogniti"e performance follo!ing

c olinergic #lockade/2, /3, o!e"er, t ere !ere significant differences #et!een t e present study and our prior pu#lis ed !ork on F2 and cogniti"e performance. Alt oug t e pattern of F2 administration and t e su#Eect population !as "ery similar to our prior studies s o!ing cogniti"e en ancement, no psyc osocial stress manipulation !as used in our prior studies, rat er partial c olinergic #lockade pro"ided t e pro"ocati"e stimulus. T ese prior studies s o!ed t at F2 treatment reduced t e sensiti"ity to c olinergic #lockade and reduced t e cogniti"e impairment associated !it t at #lockade. T us, F2 appears to s o! e"idence of en ancing c olinergic2system related cogniti"e function. -y contrast, no c olinergic manipulation !as used in t e present study, rat er t e focus !as on emotional stress and monoamine neurotransmitter manipulations. T e impact of emotional or psyc osocial stress on t e a#ility of t e F2 to en ance c olinergic2related cogniti"e performance remains to #e examined. %o! @oes Psyc osocial or Fmotional *tress or *tress %ormones Affect Gognit"e PerformanceM A series of studies a"e s o!n t at psyc osocial stress can induce certain cogniti"e deficits #ot !orking memory and retrie"al deficits<1.<2, <3. G ronic stress appears to a"e long2term negati"e effects on memory functioning and #rain structure<9. %o!e"er, emotional arousal can result in en ancing as !ell as impairing effects on long term memory. T e directionality of t is effect may depend on t e #aseline state of arousal, t e type of emotion present, and t e p ase of t e cogniti"e or memory process t at is exposed to emotional arousal or stress. *ignificant gender differences exist in t e neuronal circuitry in"ol"ed in emotion2cognition interactions suggesting t e possi#ility t at sex steroids may play a role in t is process</. Kim and @iamond<A a"e suggested t at excess amygdala input and increased glucocorticoid secretion act to impair ippocampal plasticity and su#se)uent learning. *ince estrogen le"els can modulate %PA axis acti"ity in response to psyc osocial stress<; as !ell as t e acti"ity of lim#ic structures suc as t e amygdala response to negati"e emotional information<:, <<, it is likely t at F2 may directly affect t e #rain circuitry in"ol"ed in an acute stress response and su#se)uent emotional learning. *tudies of t e effects of F2 on emotional perception are also fe!. Pearson and 3e!is166 a"e s o!n t at recognition of emotional expressions is relia#ly altered across t e menstrual cycle !it t e recognition of fear impro"ing ! en F2 le"els !ere ig . Protopopescu and colleagues<< a"e s o!n t at specific su#regions of or#ital frontal cortex $CFG( c anged t eir pattern of acti"ity in reaction to negati"e emotional stimuli across t e menstrual cycle. T e aut ors interpreted t is data as premenstrual en ancement of top2do!n modulation of lim#ic acti"ity, !it t e accompanying suppression of sensory e"aluati"e function. .n a some! at differently designed menstrual cycle study, >oldstein and colleagues<: s o!ed t at #rain areas associated !it negati"e emotional responses including t e amygdala, anterior cingulate gyrus, and CFG s o!ed lo!er acti"ity during mid2late follicular p ase $! en estradiol le"els could #e expected to #e ig ( t an during early follicular p ase $! en estradiol le"els !ould #e lo!er(. 1o suc studies a"e examined t e #rain acti"ity associated !it emotional stimuli or emotional cognition in postmenopausal !omen or !it %T. Alterations in cortical acti"ity produced #y differing circulating le"els of ormones suc as F2 may t us play a role in regulating o! t e amygdala and ot er emotion2related structures respond to emotional stimuli and4or stressful e"ents<:, <<, 161. %o! t e processing of emotional stimuli c anges after menopause is at t is point unkno!n. T us, it may #e t at t e steady administration of F2 to postmenopausal !omen at a plasma le"el consistent !it

late follicular p ase, as in t is study, may a"e produced alterations in t e cortical or su#cortical processing of stressful or emotional experiences. .n t!o recent re"ie!s, P elps162, 163 as noted t at t e amygdala is responsi#le for t e emotional contri#ution to declarati"e memory. *pecifically, s e suggests t at t e amygdala can modulate #ot t e encoding and storage of ippocampal2dependent memories and t at #idirectionally t e ippocampus, #y forming episodic representations of emotional significance, can influence t e amygdala response ! en emotional stimuli are encountered162. -ased on our data and neuroimaging studies of premenopausal !omen, it is not unreasona#le to suggest t at sex ormone status may a"e significant impact on cogniti"e processes after emotional stress in PM+. Cur data suggests t at exogenously manipulated F2 le"els may a"e significant impact on #ot emotional reacti"ity and cogniti"e performance. .t is t erefore important in future studies to examine o! menopause and postmenopausal %T may affect emotional reacti"ity and emotional memory. Postmenopausal !omen appear to s o! greater sensiti"ity t an premenopausal !omen in t eir p ysiologic response to cogniti"e and speec tasks !it t e difference #eing ascri#ed to #ot age and ormonal status169. Pre"ious studies of t e effects of ormones on experimental stressors a"e found t at t e "arious forms of estrogen appear to reduce some of t e p ysiologic effects of mild la#oratory2induced stress $e.g. sol"ing arit metic pro#lems(16/, 16A. 3ind eim and colleagues16; s o!ed t at t e greater #iop ysical response of PM+ follo!ing stress !as reduced after six !eeks of transdermal estradiol treatment. Fstrogen treatment as #een s o!n to en ance parasympat etic responsi"eness to experimental stress, suggesting reduced sympat etic acti"ation16: alt oug in one study t e T**T !as not found to pro"oke a differential effect on p ysiological measures in estrogen treated !omen<;. KaEantie and P illips16< conclude t at t ere is an increase in sympat oadrenal responsi"eness after menopause ! ic is attenuated during oral ormone t erapy. T e lack of interaction of t e F22induced effect on cogniti"e impairment follo!ing psyc osocial stress !it monoamine depletion suggests t at ot er neurotransmitter systems may #e in"ol"ed in mediating t ese effects. + ile t e exact neuroc emical mec anisms responsi#le for t e negati"e cogniti"e and emotional responses seen ere cannot #e ascertained from t is particular study, t e lack of concomitant progesterone administration suggests t at t e impact of stress2related symptoms t at !ould normally #enefit from progesterone2deri"ed neurosteroid2>A-AA receptor interactions may a"e #een ad impact on t e effects seen in t is study. 3imitations + ile t e effects of estrogen on cognition after psyc osocial stress in t is study !ere large, caution is indicated in interpreting t ese results. Goncerns regarding t e repeata#ility of t e T**T as !ell as t e dose of F2 are similar to our prior studyA9. T e T**T !as not originally designed for repeated administration and repeated presentation may diminis t e stressful response to t e test. +e examined t is possi#ility in detail in our prior pu#lis ed !orkA9, and ! ile !ere small effects of t e day and scenario, t e magnitude !as small suggesting little a#ituation or sensiti0ation in t e current study. .n addition, t e negati"e effect of estradiol treatment remained across all depletion c allenges. +e also ad to use a #et!een2su#Eects design !it regard to estradiol treatment #ecause of limitations regarding o! often participants can perform t e depletion c allenges and T**T. T e cogniti"e #attery !as only performed after t e

psyc osocial stress maneu"er, #ecause t e primary comparison of interest !as #et!een treatments, rat er t an !it in2su#Eects. Additionally, t e lengt and difficulty of t e entire experimental procedure !as suc t at adding pre2depletion cogniti"e testing !as felt to #e too #urdensome for participants. T us !e do not a"e information a#out o! t e participants !ould a"e performed prior to t e monoamine depletion and psyc osocial stress. %o!e"er, participants !ere extensi"ely cogniti"ely screened at #aseline and trained on t e cogniti"e #attery prior to initiation of t e o"erall study and t us !e are confident t at cogniti"e performance !as essentially e)ui"alent #et!een t e t!o groups prior to estrogen or place#o treatment and amino acid4psyc osocial stress c allenge. Additionally, t e t e F2 dose used in t is study !as some! at ig er t an a"erage clinical doses, alt oug not #eyond t e normal clinical range. Fstradiol #lood le"els !ere not ig er t an is typically seen during t e late follicular p ase of a normal menstrual cycle. +e a"e s o!n pre"iously t at F2 le"els in t is range are #eneficial in a c olinergic c allenge model/2 o!e"er t e interaction !it psyc osocial stress in t e current study s o!ed t e opposite effects. Additional cortisol sampling #eyond t e t!o samples t at !e o#tained !ould a"e #een elpful to furt er c aracteri0e t e magnitude of t e stress response, #ut !e !ere una#le to do so in t is study design. Finally, alt oug t is !as t e #linded study, !e recogni0e t at t e su#Eecti"e effects of estradiol may a"e #een difficult to fully #lind. GC1G3B*.C1 T!enty t!o postmenopausal !omen ! o !ere administered F2 for 3 mont s ex i#ited marked !orsening of cogniti"e performance after a social stress test compared to place#o2treated PM+. T ese effects !ere generally independent of Tryptop an or Tyrosine4P enylalanine depletion and !ere not significantly correlated !it negati"e mood c anges. T ese data imply t at t e effect of F2 on cogniti"e performance after menopause is not straig tfor!ard and may interact significantly !it psyc ological stress or especially stressful e"ents. Fffects of t e ormone2stress interaction on cogniti"e performance did not appear to #e significantly modified "ia catec olamine or indoleamine mec anisms. Furt er researc !ill #e necessary to confirm and clarify t ese findings as !ell as explore underlying mec anisms. &eplication !it out t e depletion maneu"er, t e examination of t e effects of different doses of F2, com#ined F2 and progestin t erapy, and t e examination of !omen during different p ases of t e menstrual cycle !ill elp clarify t ese findings. Ackno!ledgements T is !ork !as supported #y an .ndependent .n"estigator a!ard from 1A&*A@ and &61 A>6219;A to P.1., G.%& grant MCP21/66/1 to *.1.Q, and >G&G M6126616<. T e aut ors !is to t ank t e staff of t e Bni"ersity of 'ermont >eneral Glinical &esearc Genter for t eir efforts in t e support of t is proEect and our researc "olunteers for t eir dedication to clinical researc . Footnotes Gonflicts of .nterest4@isclosures8 1one. .n addition, none of t e sponsors ad any role in t e design or conduct of t e study, management, analysis, and interpretation of t e data, or preparation, re"ie!, or appro"al of t e manuscript. A partial "ersion of t is !ork !as pre"iously presented as a poster at t e *ociety for 1euroscience Annual Meeting, +as ington, @G, 1o"em#er 1<, 266:

Article information Menopause. Aut or manuscriptD a"aila#le in PMG 2611 July 1. Pu#lis ed in final edited form as8 Menopause. 2616 JulyD 1;$9(8 :A6J:;3. doi8 16.16<;4gme.6#613e31:1e1/df9 PMG.@8 PMG2<9323: 1.%M*.@8 1.%M*22/;AA Paul A. 1e! ouse, M.@.,1 Julie @umas, P .@.,1 %eat er +ilkins, -.A.,1 Fmily Goderre, -.A.,1 Gynt ia K. *ites, M.@.,2 Magdalena 1aylor, M.@., P .@.,1 G a!ki -enkelfat, M.@.,3 and *imon 1. Qoung, P .@.3 1Glinical 1euroscience &esearc Bnit, @epartment of Psyc iatry, Bni"ersity of 'ermont Gollege of Medicine 2@i"ision of &eproducti"e Medicine, -aystate Medical Genter, Tufts Bni"ersity *c ool of Medicine 3@epartment of Psyc iatry, Mc>ill Bni"ersity *c ool of Medicine Address for Gorrespondence $P1(8 Glinical 1euroscience &esearc Bnit, @epartment of Psyc iatry, Bni"ersity of 'ermont Gollege of Medicine, 1 *out Prospect *t., -urlington, 'T 6/961, 'oice8$:62( :9;29/A6, Fax8 $:62( :9;2;::<, Mo#ile8 $:62( 3;329:92, Fmail8 Paul.1e! ouse4at4u"m.edu, %ome Page8 !!!.u"m.edu4dcnru Gopyrig t notice and @isclaimer T e pu#lis erKs final edited "ersion of t is article is a"aila#le at Menopause *ee ot er articles in PMG t at cite t e pu#lis ed article. &eference 3ist 1. * er!in --. Fstrogen and Gogniti"e Functioning in +omen. Fndocrine &e"ie!s. 2663D29$2(8133J1/1. OPu#MedP 2. &esnick *M, Metter FJ, Ronderman A-. Fstrogen replacement t erapy and longitudinal decline in "isual memory8 a possi#le protecti"e effect. 1eurology. 1<<;D9<819<1J19<;. OPu#MedP 3. *mit Q&, >iordani -, 3aEiness2CK1eill &, Ru#ieta J. 3ong2term estrogen replacement is associated !it impro"ed non"er#al memory and attentional measures in postmenopausal !omen. Fertility and *terility. 2661D;A$A(81161J116;. OPu#MedP 9. Jaco#s @M, Tang MV, *tern Q, et al. Gogniti"e function in nondemented older !omen ! o took estrogen after menopause. 1eurology. 1<<:D/683A:J3;3. OPu#MedP /. * ay!it0 *F, 1aftolin F, Relterman @, et al. -etter oral reading and s ort2term memory inmidlife, postmenopausal !omen taking estrogen. Menopause. 2663D16$/(8926J92A. OPu#MedP A. Krug &, -orn J, &asc -. A 32day estrogen treatment impro"es prerontal cortex2 dependent cogniti"e function in postmenopausal !omen. Psyc oneuroendocrinology. 266AD318<A/J<;/. OPu#MedP ;. *te"ens Glark, Prest!ood 3o!2dose estradiol alters #rain acti"ity. Psyc iatry &esearc 8 1euroimaging. 266/D13<$3(81<<J21;. OPu#MedP :. @uka T, Tasker &, Mc>o!an JF. T e effects of 32!eek estrogen ormone replacement on cognition in elderly ealt y females. Psyc op armacology. 2666D19<812<J13<. OPu#MedP <. * er!in --. Fstrogenic effects on memory in !omen. Annals of t e 1e! Qork Academy of *ciences. 1<<3D;938213J236. OPu#MedP 16. Kimura @. Fstrogen replacement t erapy may protect against intellectual decline in postmenopausal !omen. %ormones and -e a"ior. 1<</D2<8312J321. OPu#MedP 11. @itkoff FG, Grary +>, Gristo M, 3o#o &A. Fstrogen impro"es psyc ological function in asymptomatic postmenopausal !omen. C#stetrics and >ynecology. 1<<1D;:8<<1J <</. OPu#MedP

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9;. %ays J, Cckene JK, -runner &, et al. Fffects of estrogen plus progestin on ealt 2 related )uality of life. T e 1e! Fngland Journal of Medicine. 2663D39:$1<(81:3<J1:/9. OPu#MedP 9:. &esnick *M, Maki PM, &app *&, et al. Fffects of com#ination estrogen plus progestin ormone treatment on cognition and affect. Journal of Glinical Fndocrinology and Meta#olism. 266AD<181:62J1:16. OPu#MedP 9<. Gaspi A, *ugden K, Moffitt TF, et al. .nfluence of life stress on depression8 moderation #y a polymorp ism in t e /2%TT gene. *cience. 2663D36183:AJ3:<. OPu#MedP /6. >i##s &-. Fstrogen T erapy and Gognition8 A &e"ie! of t e G olinergic %ypot esis. Fndocr &e". 266< er.266<2663A. OPMG free articleP OPu#MedP /1. @umas J, Fdgren G, 1e! ouse PA. Fstrogen replacement after menopause8 role in normal cognition and Al0 eimerKs disease. Aging %ealt . 266AD28<//J<AA. /2. @umas JA, %ancur2-ucci G, 1aylor M, *ites G, 1e! ouse PA. Fstrogen treatment effects on antic olinergic2induced cogniti"e dysfunction in normal post2menopausal !omen. 1europsyc op armacology. 266AD31826A/J26;:. OPu#MedP /3. @umas JA, %ancur2-ucci G, 1aylor M, *ites G, 1e! ouse P. Fstrogen interacts !it t e c olinergic system to affect t e "er#al memory in postmenopausal !omen8 e"idence for t e critical period ypot esis. %ormones and -e a"ior. 266:D/381/<J1A<. OPMG free articleP OPu#MedP /9. Fink >, *umner -F%, &osie &, >race C, ?uinn JP. Fstrogen control of central neurotransmission8 effect on mood, mental state, and memory. Gellular and Molecular 1euro#iology. 1<<AD1A$3(832/J399. OPu#MedP //. Mc@ermott J3, Kreut0#erg J@, 3iu -, @lu0en @F. Fffects of estrogen treatment on sensorimotor task performance and #rain dopamine concentrations in gonadectomi0ed male and female G@21 mice. %ormones and -e a"ior. 1<<9D2:$1(81AJ2:. OPu#MedP /A. &u#ino! @, *c midt P, &oca G. Fstrogen2serotonin interactions8 implications for affecti"e regulation. -iological Psyc iatry. 1<<3D998:3<J:/6. OPu#MedP /;. McF!en -. Fstrogen actions t roug out t e #rain. &ecent Progress in %ormone &esearc . 2662D/;$1(83/;J3:9. OPu#MedP /:. -et ea G3, Mirkes *J, 3u 1R, *treic er JM, Gameron J3. @ifferences in central serotonergic acti"ity in stress2sensiti"e "ersus stress2resilient monkeys8 tryptop an ydroxylase $TP%(, serotonin reuptake transporter $*F&T( and serotonin 1A autoreceptor $/%T1A( m&1A expression. Paper presented at8 T e *ociety of -iological Psyc iatry 2663 Annual MeetingD 2663D 2663D *an Francisco, GA. /<. *c midt PJ. Mood, depression and reproducti"e ormones in t e menopausal transition. T e American Journal of Medicine. 266/D11:$12-(8/9*J/:*. OPu#MedP A6. *c neider 3*, *mall >+, %amilton *%, -ystritsky A, 1emeroff G-, Meyers -*. Fstrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. American Journal of t e >eriatric Psyc iatry. 1<<3D/8<;J16A. OPu#MedP A1. 1agata %, 1o0aki M, 1akano %. * ort2term com#inational t erapy of lo!2dose estrogen !it selecti"e serotonin re2uptake in i#itor $flu"oxamine( for oop orectomi0ed !omen !it ot flas es and depressi"e tendencies. Journal of C#stetrics N >ynaecology &esearc . 266/D31$2(816;J119. OPu#MedP A2. *oares G1, Poitras J&, Prouty J, Alexander A-, * ifren J3, Go en 3*. Ffficacy of citalopram as a monot erapy or as an adEuncti"e treatment to estrogen t erapy for perimenopausal and postmenopausal !omen !it depression and "asomotor symptoms. Journal of Glinical Psyc iatry. 2663DA9$9(89;3J9;<. OPu#MedP A3. &asgon 13, @unkin J, Fair#anks 3, et al. Fstrogen and response to sertraline in postmenopausal !omen !it maEor depressi"e disorder8 A pilot study. Journal of Psyc iatric &esearc . 266;D91$3J9(833:J393. OPu#MedP

A9. 1e! ouse PA, @umas J, %ancur2-ucci G, et al. Fstrogen Administration 1egati"ely Alters Mood Follo!ing Monoaminergic @epletion and Psyc osocial *tress in Postmenopausal +omen. 1europsyc op armacology. 266:D33$;(81/19J1/2;. OPu#MedP A/. Prior JG. Perimenopause8 t e complex endocrinology of t e menopausal transition. Fndocr &e". 1<<:D1<$9(83<;J92:. OPu#MedP AA. Maki PM. Menopause and anxiety8 immediate and long2term effects. Menopause. 266:D1/$A(81633J163/. 1616.16<;4gme.1636#1613e31:1:Ad31::23. OPu#MedP A;. Qoung *1, *mit *F, Pi l &C, Fr"in F&. Tryptop an depletion causes a rapid lo!ering of mood in normal males. Psyc op armacology. 1<<3D:;81;3J1;;. OPu#MedP A:. @elgado P. Monoamine depletion studies8 .mplications for antidepressant discontinuation syndrome. Journal of Glinical Psyc iatry. 266ADA; *upplement 9822J2A. $*upplement 9( OPu#MedP A<. 3eyton M, Qoung *1, Pi l &C, et al. Fffects on mood of acute p enylalanine4tyrosine depletion in ealt y !omen. 1europsyc op armacology. 1<<<D22$1(8/2JA3. OPu#MedP ;6. Qoung *, 3eyton M. T e role of serotonin in uman mood and social interaction8 insig t from altered tryptop an le"els. P armacology -ioc emistry and -e a"ior. 1<<3D;18:/;J:A/. OPu#MedP ;1. Kirsc #aum G, Pirke KM, %ell ammer @%. T e KTrier *ocial *tress TestK22a tool for in"estigating psyc o#iological stress responses in a la#oratory setting. 1europsyc o#iology. 1<<3D2:$1J2(8;AJ:1. OPu#MedP ;2. Folstein MF, Folstein *F, Mc%ug P&. 7Mini2mental state78 a practical met od for grading t e cogniti"e state of patients for t e clinician. Journal of Psyc iatric &esearc . 1<;/D12$3(81:<J1<:. OPu#MedP ;3. &eis#erg -, *c enk M, Ferris *, *c !art0 >, de3eon M. T e -rief Gogniti"e &ating *cale $-G&*(8 Findings in primary degenerati"e dementia $P@@( Psyc op armacology -ulletin. 1<<3D$1<(89;J/6. ;9. Jurica PJ, 3eitten G3, Mattis *. @ementia &ating *cale22. 3ut0, F38 Psyc ological Assessment &esources .nc.D 2661. ;/. &eis#erg -, Ferris *%, de 3eon MJ, Grook T. T e >lo#al @eterioration *cale for assessment of primary degenerati"e dementia. American Journal of Psyc iatry. 1<<3D13<$<(8113AJ113<. OPu#MedP ;A. First M-&3*, >i##on M, +illiams J-+. *tructured Glinical .nter"ie! for @*M2.'2T& Axis . @isorders2Patient Fdition. *G.@2.4P, 242661 ed. +as ington, @.G.8 American Psyc iatric Press .nc.D 2661. ;;. -eck AT, +ard G%, Mendelson M, Mock J, Fr#aug J. An in"entory for measuring depression. Arc i"es of >eneral Psyc iatry. 1<A1D98/3JA3. OPu#MedP ;:. * er!in --. T e impact of different doses of estrogen and progestin on mood and sexual #e a"ior in postmenopausal !omen. Journal of Glinical Fndocrinology and Meta#olism. 1<<1D;2$2(833AJ393. OPu#MedP ;<. Fllen#ogen MA, Qoung *1, @ean P, Palmour &M, -enkelfat G. Mood response to acute tryptop an depletion in ealt y "olunteers8 sex differences and temporal sta#ility. 1europsyc op armacology. 1<<AD1/$/(89A/J9;9. OPu#MedP :6. Kirsc #aum G, Pruessner JG, *tone AA, et al. Persistent ig cortisol responses to repeated psyc ological stress in a su#population of ealt y men. Psyc osomatic Medicine. 1<</D/;$/(89A:J9;9. OPu#MedP :1. &o leder 1, *c ommer 1G, %ell ammer @%, Fngel &, Kirsc #aum G. *ex differences in glucocorticoid sensiti"ity of proinflammatory cytokine production after psyc osocial stress. Psyc osomatic Medicine. 2661DA3$A(8<AAJ<;2. OPu#MedP

:2. Kupke T, 3e!is &. &elati"e influence of su#Eect "aria#les and neurological parameters on neuropsyc ological performance of adult sei0ure patients. Arc i"e of Glinical 1europsyc ology. 1<:<D983/1J3A3. OPu#MedP :3. %indmarc .. Psyc ological performance models as indicators of t e effects of ypnotic drugs on sleep. Psyc op armacology. 1<:9D*18/:JA:. OPu#MedP :9. +ec sler @. +ec sler Adult .ntelligence *cale2&e"ised. *an Antonio8 T e Psyc ological GorporationD 1<:1. :/. T e Gontinuous Performance Test Ocomputer programP. 'ersion 3.6. Toronto8 Multi2 %ealt *ystemsD 1<</. :A. 3e0ak M@. 1europsyc ological Assessment. 2nd ed 1<</. :;. Mc1air @M, 3orr M, @roppleman 3F. Profile of Mood *tates. *an @iego, GA8 Fducational and .ndustrial Testing *er"iceD 1<;1. ::. >olig tly K3, 3loyd JA, %o#son JF, >allag er P, Mercer >, Qoung A%. Acute tryptop an depletion in sc i0op renia. Psyc ological Medicine. 2661D318;/J:9. OPu#MedP :<. -aker 3@, G olerton -, >leason G, et al. Fstrogen fa"ora#ly affects selecti"e attention for ealt y postmenopausal !omen. *ociety for 1euroscience, 2662. 2662 <6. Maki P, Ronderman A, &esnick *. Fn anced "er#al memory in nondemented elderly !omen recei"ing ormone2replacement t erapy. American Journal of Psyc iatry. 2661D1/:$2(822;J233. OPu#MedP <1. -artolic Fi, -asso M&, *c efft -K, >lauser T, Titanic2*c efft M. Fffects of experimentally2induced emotional states on frontal lo#e cogniti"e task performance. 1europsyc ologia. 1<<<D3;$A(8A;;JA:3. OPu#MedP <2. *c oofs @, Preux @, +olf CT. Psyc osocial stress induces !orking memory impairments in an n2#ack paradigm. Psyc oneuroendocrinology. 266:D33$/(8A93JA/3. OPu#MedP <3. Ku lmann *, Piel M, +olf CT. .mpaired memory retrie"al after psyc osocial stress in ealt y young men. t e Journal of 1euroscience. 266/82<;;J2<:2. OPu#MedP <9. 3upien *J, Fiocco A, +an 1, et al. *tress ormones and uman memory function across t e lifespan. Psyc oneuroendocrinology. 266/D36$3(822/J292. OPu#MedP </. Koc K, Pauly K, Kellermann T, et al. >ender differences in t e cogniti"e control of emotion8 An fM&. study. 1europsyc ologia. 266;D9/$12(82;99J2;/9. OPu#MedP <A. Kim JJ, @iamond @M. T e stressed ippocampus, synaptic plasticity and lost memories. 1at &e" 1eurosci. 2662D3$A(89/3J9A2. OPu#MedP <;. Kudielka -M, *c midt2&ein!ald AK, %ell ammer @%, Kirsc #aum G. Psyc ological and endocrine responses to psyc osocial stress and dexamet asone4corticotropin2 releasing ormone in ealt y postmenopausal !omen and young controls8 t e impact of age and a t!o2!eek estradiol treatment. 1euroendocrinology. 1<<<D;6$A(8922J936. OPu#MedP <:. >oldstein JM, Jerram M, Poldrack &, et al. %ormonal cycle modulates arousal circuitry in !omen using functional magnetic resonance imaging. T e Journal of 1euroscience. 266/D2/8<36<J<31A. OPu#MedP <<. Protopopescu V, Pan %, Altemus M, et al. Cr#itofrontal cortex acti"ity related to emotional processing c anges across t e menstrual cycle. P1A*. 266/D162$99(81A6A6J 1A6A/. OPMG free articleP OPu#MedP 166. Pearson &, 3e!is M-. Fear recognition across t e menstrual cycle. %ormones and -e a"ior. 266/82A;J2;1. OPu#MedP 161. Amin R, Fpperson G1, Gonsta#le &T, Ganli T. Fffects of estrogen "ariation on neural correlates of emotional response in i#ition. 1euro.mage. 266AD32$1(89/;J9A9. OPu#MedP

162. P elps FA. %uman emotion and memory8 .nteractions of t e amygdala and ippocampal complex. Gurrent Cpinion in 1euro#iology. 2669D1981<:J262. OPu#MedP 163. P elps FA. Fmotion and cognition8 insig ts from studies of t e uman amygdala. Annual &e"ie! of Psyc ology. 266A82;J/3. OPu#MedP 169. *aa# P>, Matt e!s KA, *toney GM, Mc@onald &%. Premenopausal and postmenopausal !omen differ in t eir cardio"ascular and neuroendocrine responses to #e a"ioral stressors. Psyc op ysiology. 1<:<D2A$3(82;6J2:6. OPu#MedP 16/. Geresini >, Freddi M, Morganti *, et al. T e effects of transdermal estradiol on t e response to mental stress in postmenopausal !omen8 a randomi0ed trial. American Journal of Medicine. 2666D16<$A(89A3J9A:. OPu#MedP 16A. Komesaroff PA, Fsler M@, *ud ir K. Fstrogen supplementation attenuates glucocorticoid and catec olamine responses to mental stress in perimenopausal !omen. J Glin Fndocrinol Meta#. 1<<<D:9$2(8A6AJA16. OPu#MedP 16;. 3ind eim *&, 3egro &*, -ernstein 3, et al. -e a"ioral stress responses in premenopausal and postmenopausal !omen and t e effects of estrogen. American Journal of C#stetrics and >ynecology. 1<<2D1A;81:31J1:3A. OPu#MedP 16:. -urleson M%, Malarkey +-, Gacioppo JT, et al. Postmenopausal ormone replacement8 effects on autonomic, neuroendocrine, and immune reacti"ity to #rief psyc ological stressors. Psyc osomatic Medicine. 1<<:DA681;J2/. OPu#MedP 16<. KaEantie F, P illips @.+. T e effects of sex and ormonal status on t e p ysiological response to acute psyc osocial stress. Psyc oneuroendocrinology. 266AD31$2(81/1. OPu#MedP 16 T e American Eournal of geriatric psyc iatry 8 official Eournal of t e American Association for >eriatric Psyc iatry Aut or Manuscript 1.% Pu#lic Access T is article as #een corrected. *ee Am J >eriatr Psyc iatry. 2616 *eptem#er 2D 1:$/(8 9/A. Psyc iatric @isorders and Gogniti"e @ysfunction Among Clder, Postmenopausal +omen8 &esults From t e +omenSs %ealt .nitiati"e Memory *tudy G ristop er G. Golenda, M.@., M.P.%., Glaudine 3egault, P .@., O...P, and >loria F. *arto, M.@., P .@. Additional article information A#stract C#Eecti"e To estimate t e fre)uency of depressi"e symptoms and selected psyc iatric disorders in t e +omenSs %ealt .nitiati"e Memory *tudy $+%.M*( co ort and related t em to cogniti"e syndromes. @esign +%.M* !as a randomi0ed, dou#le2#linded, place#o2controlled pre"ention clinical trial examining ! et er opposed and unopposed ormone t erapy reduced t e risk of dementia in ealt y postmenopausal !omen. Participants scoring #elo! a designated cutpoint on a cogniti"e screener recei"ed a compre ensi"e neuropsyc iatric !orkup and

adEudicated outcome of no cogniti"e impairment, mild cogniti"e impairment, or pro#a#le dementia. Participants *e"en t ousand four undred se"enty2nine +%.M* participants #et!een age A/ and ;< years and free of dementia at t e time of enrollment in +%.M*. Fi"e undred t!enty2one uni)ue participants contri#uted complete data re)uired for t ese analyses. Measures @epressi"e symptoms !ere measured !it t e 1/2item >eriatric @epression *cale and t e presence of selected psyc iatric disorders $maEor depression, generali0ed anxiety, and panic and alco ol a#use( !as made using t e P&.MF2M@. &esults T e 1:= of !omen ad at least one psyc iatric disorder !it depression #eing t e most common $1A=( follo!ed #y general anxiety or panic $A=( and alco ol a#use $1=(. @epression and t e presence of a psyc iatric disorder !ere associated !it impaired cogniti"e status. Participants a"ing a psyc iatric disorder !ere more t an t!ice as likely to #e diagnosed !it cogniti"e impairment as t ose !it no psyc iatric disorder $odds ratio I 2.6A, </= confidence inter"al I 1.1;J3.A6(. Clder age, ! ite race, and dia#etes !ere also associated !it cogniti"e impairment. Gonclusion T e fre)uency of a psyc iatric disorder is associated !it poorer cogniti"e functioning among older !omen enrolled in +%.M*. T at approximately one in fi"e !omen ad a pro#a#le psyc iatric disorder, most typically depression, ig lig ts t e need for greater detection and treatment efforts in t is population. Key!ords8 Psyc iatric disorders, cognition, MG., risk of dementia, comor#idity Approximately one of e"ery se"en Americans older t an ;6 years suffers from some form of dementia.1 Moreo"er, t e pre"alence of dementia increases significantly !it age. *ome form of dementia is present in approximately 1./= adults at t e age of A/ years2 and rises to nearly 3:= in t ose aged <6 years and older.1 @iscrete psyc iatric disorders suc as depression or ot er affecti"e and anxiety disorders may cooccur !it dementia.3 T e pre"alence of clinically significant depression in patients !it Al0 eimer disease is #et!een 26= and 2/=.9,/ T e occurrence of psyc iatric comor#idities !it mild cogniti"e impairment $MG.( or early dementia is an area of increasing interest, especially t e relations ip #et!een depression and dementia.A Fpidemiologic studies a"e #een inconsistent, o!e"er. Farly studies from France and t e Bnited *tates s o!ed opposite findings. T e Frenc study failed to find an association !it depressi"e symptoms and cogniti"e deterioration o"er a 32year period,; ! ereas t e B.*. study found a t!ofold risk of incident dementia in persons !it preexisting depression.: Anot er study found t at depressi"e symptoms predicted future cogniti"e losses in elderly persons !it preexisting moderate cogniti"e impairment #ut did not find an association #et!een depressi"e symptoms and onset or rate of decline for cogniti"ely intact elderly.< .n contrast, t e Mononga ela 'alley .ndependent Flders *ur"ey demonstrated t at depressi"e symptoms !ere cross2 sectionally related to cogniti"e function #ut not associated !it decline, and for t ose ! o de"eloped dementia o"er time, #aseline depressi"e symptoms did not exert muc effect on decline.16 More recently, G odos et al.11 noted t at from #aseline to ;2year

follo!2up, ig er le"els of #aseline depressi"e symptoms !ere associated !it greater decline in cogniti"e performance among older adults aged ;6J;< years at #aseline. Finally, -ecker et al.12 found no consistent relations ip #et!een mood state and t e de"elopment of dementia in su#Eects participating in t e community2#ased co ort study, t e Gardio"ascular %ealt *tudy2Gognition $G%*2G(. T e relations ip #et!een depression and t e de"elopment of dementia is muc stronger in clinical studies ! ere patient diagnoses a"e #een esta#lis ed, and it as #een o#ser"ed t at patients !it Yre"ersi#le dementiaZ often fail to ac ie"e a complete cogniti"e reco"ery after remission of depression and during follo!2up. @uring follo!2up, an a"erage of 11=J23= of patients !it an initially re"ersi#le dementia #ecome irre"ersi#ly demented e"ery year.13J1; T e +omenSs %ealt .nitiati"e Memory *tudy $+%.M*(,1: a large, randomi0ed, dou#le2 #linded, place#o2controlled pre"ention clinical trial, examined ! et er postmenopausal ormone t erapy $%T( reduces t e risk of all2cause dementia in ealt y nondemented !omen aged A/J;< years at #aseline. T is study pro"ides an opportunity to examine t e association #et!een depression and se"eral psyc iatric disorders and pro#a#le dementia $P@( and MG.. .t is predicted t at depression !ill #e associated !it diagnosed P@ and MG.. .t is also predicted t at nondepressi"e disorders $anxiety, panic, and alco ol a#use( !ill also #e associated !it incident dementia and MG., #ut t e association !ill not #e as strong as !it depression. .n addition, !e !ill examine ! et er +%.M* treatment assignment or demograp ic or ealt "aria#les are related to psyc iatric mor#idity. MFT%C@* *ample Participants for +%.M* !ere recruited during +%. %T trial from t e estrogen plus progestin arm. 'isits occurred annually for ; years $1<</J2662(.1; T e ;,9;< +%.M* participants !ere A/J;< years of age at #aseline and free of P@ as ascertained #y t e +%.M* protocol. Potential +%.M* participants !ere asked ! et er t ere !ere any reasons, suc as serious emotional pro#lems, mental illness, or too muc stress, t at !ould make it ard for t em to #e in a researc study. Fxclusion from t e study #ased on t ese screening )uestions !as t us strictly self2report. Furt ermore, at t e final eligi#ility assessment, t e clinic staffs !ere asked to use t eir o!n Eudgment to determine ! et er t e !oman !as ineligi#le #ased on depression. 1o ot er inclusion4exclusion criteria !ere re)uired. A detailed description of t e +%.M* protocol for determining P@ and MG. as #een pu#lis ed.1; -riefly, in P ase 1 of t e +%.M* protocol, t e participants recei"ed a cogniti"e screening !it t e Modified Mini2Mental *tate Fxamination $3M*F( at #aseline and annually t ereafter. +omen ad"anced to P ase 2 of t e protocol if t ey scored #elo! an education2adEusted cutpoint on t e 3M*F.1<,26 T ere !ere /21 !omen ! o ad"anced once or more to P ase 2. Criginally, t e cut scores !ere f;2 for t ose !it f: years of formal education and f;A for t ose !it ]< years of education. %o!e"er, to increase sensiti"ity, after 1A mont s ne! cutpoints of f:6 for t ose !it f: years of education and f:: for t ose !it ]< years of education !ere implemented. T is resulted in an increase of A1 su#Eects t at !ere included in t e co ort of /21.

.n P ase 2, !omen under!ent a compre ensi"e neuropsyc iatric examination t at included t e Gonsortium to Fsta#lis a &egistry for Al0 eimerSs @isease #attery of neuropsyc ological tests and standardi0ed inter"ie!s of t e participant and a proxy to assess ac)uired cogniti"e and #e a"ioral impairments.21,22 P ase 3 consisted of a clinical e"aluation #y a #oard2certified p ysician2specialist. T e p ysician2specialist classified t e +%.M* participant as a"ing no cogniti"e impairment $1G.(, MG., or P@, #ased on @iagnostic and *tatistical Manual of Mental @isorders, Fourt Fdition, criteria.23 All clinical and test data !ere t en transmitted to t e +%.M* GGG for re"ie! and central adEudication #y a committee consisting of t ree #oard2certified specialists $t!o neurologists and one geriatric psyc iatrist( !it extensi"e experience in dementia. Measures @epressi"e *e"erity @epressi"e symptom se"erity !ere assessed !it t e 1/2item >eriatric @epression *cale $>@*(.29 Participants reporting ]/ symptoms and ]16 symptoms on t e >@* !ere classified as depressed, and t ose !it fe!er symptoms !ere considered not depressed. Psyc iatric @iagnoses T e P&.MF2M@ psyc iatric diagnostic inter"ie!2/ !as administered #y a trained and certified examiner and re"ie!ed #y t e clinician to identify t e follo!ing disorders8 maEor depression, generali0ed anxiety, and panic and alco ol a#use. YAny depressi"e2anxiety2 alco ol disorderZ !as a composite category created if !omen !ere classified as a"ing at least one of t e four psyc iatric diagnoses. T e P&.MF2M@ as #een used !it t e elderly including t ose !it cogniti"e impairment.2AJ2: *creening instruments for #ipolar disorders, t oug t disorders, personality disorders, or ot er su#stance a#use disorders !ere not used. Panic @isorder T e panic symptoms list from t e P&.MF2M@ includes 13 symptoms, so in addition to a categorical classification $panic disorder "ersus no panic disorder( a total symptom se"erity score ! ic is t e sum of t e symptoms reported during t e Ylast really #ad timeZ an anxiety attack occurred during t e past mont . Anxiety @isorder T e generali0ed anxiety scale includes six symptoms t at a"e #ot ered t e participant more t an alf t e days during t e last mont . T e score for t e symptoms ranges from 6 to A. A score 52 represents no anxiety. .f t e score is ]2, t e participant is t en asked ! et er 1( t e pro#lems make it ard to do er !ork, take care of t ings at ome, or get along !it ot er people, 2( s e as !orried a great deal a#out different t ings, and 3( s e as ad all t ese pro#lems for as long as A mont s. A positi"e ans!er to all t ree )uestions reflects pro#a#le generali0ed anxiety disorder. Cne of t e t ree ans!ers #eing negati"e reflects anxiety, not ot er!ise specified. Alco ol A#use @isorder

Alco ol a#use !as determined !it t e participant ans!ering a series of fi"e )uestions on alco ol use. .f any !as ans!ered positi"ely, anot er series of fi"e )uestions !ere asked a#out doctorSs suggestion of a drinking pro#lem, or drinking ! ile !orking or taking care of ot ers, or missing or #eing late at !ork #ecause of drinking, or pro#lems getting along !it ot ers ! ile drinking, or dri"ing a car after se"eral drinks. .f any of t e )uestions from t e second series !as ans!ered positi"ely, t e participant !as identified !it pro#a#le alco ol a#use4dependence. Ct er!ise, no alco ol pro#lem is registered. Analysis All analyses !ere conducted at t e +ake Forest Bni"ersity +%.M* Goordinating Genter. @ata !ere a#stracted from t e first #elo! t e cutpoint 3M* score. YCn2trialZ data from all /21 participants ! o recei"ed t e full e"aluation at least once after scoring #elo! t e cutpoint on t e 3M*F !ere analy0ed. Pre"alence rates !ere compared #et!een comparison groups using T2 or Fis erSs exact tests. To furt er in"estigate t e presence or a#sence of a disorder, logistic regression models !ere used to find t e #est fitting and most parsimonious model.2< T e response "aria#le, a disorder, is a dic otomous outcome $yes or no(. AdEustments for year of first #elo! t e cut2point 3M* score, age, and #aseline 3M* scores !ere included in models for t e t!o main outcomes, i.e., any depressi"e2anxiety2alco ol disorder and maEor depression. A multi"aria#le logistic regression model !as fitted to determine associations #et!een psyc iatric outcomes and cogniti"e outcomes and selected demograp ic and clinical factors. Parameters for t e logistic models !ere estimated using standard maximum likeli ood met ods. T e assessment of goodness of fit included computation and e"aluation of o"erall measures #ased on residuals, e.g., t e Pearson residual and t e de"iance residual. &F*B3T* @uring t e course of t e +%.M* clinical trial $1 I ;,9;<(, in total <;1 neuropsyc iatric e"aluations !ere completed. Cf t ese, <36 yielded a final diagnosis of 1G., MG., or P@. Cf t ese :<1 e"aluations, representing /21 uni)ue participants, contri#uted complete data re)uired for t ese analyses. Ta#le 1 includes t e num#er of follo!2up assessments at eac annual "isit. Missing data resulted from incomplete cogniti"e assessments #ecause of "arious reasons including refusals, transportation issues, and ot er ealt pro#lems. T!el"e $2=( of t e first a#normal 3M* scores occurred at #aseline and none resulted in a P@ diagnosis. T e follo!ing percents of first a#normal 3M* scores occurred at su#se)uent "isits8 23=, 36=, 1A=, 13=, <=, /=, and 1= at years 1J;, respecti"ely. TA-3F 1 TA-3F 1 Follo!2Bp Assessments of +omen Fntered into t e +%.M* Go ort T e pre"alence of psyc iatric mor#idities at first a#normal 3M* score is presented in Ta#le 2. T e most common disorder !as maEor depression affecting :9 $1A=( participants. >eneral anxiety or panic !as diagnosed in A= of t e sample, ! ereas alco ol a#use !as only found in 1=. Any depressi"e2anxiety2alco ol disorder !as present in <3 $1:=( !omen at first #elo! t e 3M* cutpoint score. 1one of t ese mor#idities differed #y treatment assignment to %T $data not s o!n(. TA-3F 2 TA-3F 2

Fre)uency of Psyc iatric Gomor#idities at First P ase 2 1europsyc iatric F"aluation $1 I /21( T e relations ip #et!een +%. #aseline demograp ic, life style, and clinical c aracteristics and psyc iatric mor#idity status !as examined $Ta#le 3(. T e presence of any depressi"e2anxiety2alco ol disorder !as associated !it race $p 56.61( !it ! ites less likely to #e affected t an non2! ites. Alco ol use !as lo! o"erall and less common among t ose !it any depressi"e2anxiety2alco ol disorder $2:= "ersus 96=, p I 6.62(. T ose !it any depressi"e2anxiety2alco ol disorder !ere more t an t!ice as likely to a"e reported a istory of dia#etes $2:= "ersus 13=, p 56.661(. T ere !ere no differences in t ese #aseline c aracteristics #y treatment assignment $data not s o!n(. TA-3F 3 TA-3F 3 @emograp ic, 3ifestyle, and Glinical Factors for Participants #y Any @epressi"e2Anxiety2 Alco ol @isordera at First P ase 2 1europsyc iatric F"aluation A total of 23< $9A=( participants !ere classified as 1G., 21/ $91=( as MG. and A; $13=( as P@. T e cogniti"e groups !ere significantly different in relation to some psyc iatric outcomes. %a"ing any depressi"e2anxiety2alco ol disorder $p 56.61( and a"ing maEor depression $p I 6.62( !ere significantly associated !it cogniti"e status. T e MG. group !as more likely to a"e maEor depression or any depressi"e2anxiety2 alco ol disorder t an t e 1G. group, significantly more likely to a"e maEor depression or any psyc iatric mor#idity t an !it t e P@ or 1G. groups $Ta#le 9(. T e num#er of !omen !it depressi"e se"erity scores a#o"e t e >@* cutpoint of 16 !as greater among !omen Eudged to #e cogniti"ely impaired $MG. and P@( t an !omen !it 1G. $p I 6.63(, #ut t e difference failed to reac statistical significance !it con"entional cutpoint of >@* I / $p I 6.21(. *imilar results !ere o#tained after controlling for year of first a#normal 3M* score, age, and #aseline 3M* scores for t e presence of any depressi"e2anxiety2alco ol disorder and maEor depression. TA-3F 9 TA-3F 9 Psyc iatric Gomor#idities at First P ase 2 1europsyc iatric F"aluation #y Gogniti"e *tatus As s o!n earlier, t ere !ere 2:2 participants classified !it cogniti"e impairment $P@ or MG.( at t e time of t eir first a#normal 3M* score and neuropsyc iatric e"aluation. .n addition, 3: ot er participants !ere su#se)uently classified !it impairment at a later annual assessment. T erefore, !e compared psyc iatric comor#idities, at t e time of first diagnosis, for t ose cogniti"ely impaired "ersus t ose ! o remained nonimpaired, at t e time of t eir last ad"ancement to t e neuropsyc iatric e"aluation $Ta#le /(. T e findings !ere similar to Ta#le 9 e"en after adEusting for year of first 3M* score #elo! cutpoint, age, and #aseline 3M* scores. T e cogniti"ely impaired group experienced ig er le"els of depression, #ased on >@* cutpoints ]/ and ]16, and maEor depression $p f6.69(. Any depressi"e2anxiety2alco ol disorder also s o!ed t e same pattern $p 56.61(. TA-3F / TA-3F / Psyc iatric Gomor#idities for Participants at First Gogniti"e .mpairment 'ersus T ose +it out .mpairment at 3ast 1europsyc iatric F"aluation

+e determined t e demograp ic, life style, and clinical factors associated !it cogniti"e status at first neuropsyc iatric e"aluation, as a prelude to modeling cogniti"e impairment and its relations ip to any depressi"e2anxiety2alco ol disorder. As descri#ed in Ta#le A, cogniti"ely impaired !omen !ere significantly older $p 56.6661(, ! ite $p 56.6661(, and ad lo!er #ody mass index $p I 6.69(. TA-3F A TA-3F A @emograp ic, 3ifestyle, and Glinical Factors for Participants #y Gogniti"e *tatus at First 1europsyc iatric F"aluation T e results of modeling t e pro#a#ility of cogniti"e impairment for !omen !it or !it out any depressi"e2anxiety2alco ol disorder, #ased on multiple logistic regression, are presented in Ta#le ;. +e included co"ariates associated !it cogniti"e impairment status $!it p 56.26 in Ta#le /(, including age, education, race $! ite "ersus non2! ite(, smoking, dia#etes, #ody mass index, and #aseline 3M*F and year of first neuropsyc iatric e"aluation. Assignment to %T !as also included. After controlling for t e co"ariates, t e presence of any depressi"e2anxiety2alco ol disorder retained its association !it cogniti"e impairment status $p I 6.662(. T ose participants experiencing Yany depressi"e2anxiety2depressi"e disorderZ !ere more t an t!ice as likely to #e diagnosed !it cogniti"e impairment as t ose not experiencing any mor#idity $odds ratio I 2.6A, </= confidence inter"al I 1.3/J3.A6(. Clder !omen $p I 6.6661(, ! ites $p I 6.62(, and t ose !it dia#etes $p I 6.63( !ere also at ele"ated risk for cogniti"e impairment. TA-3F ; TA-3F ; 3ikeli ood of First @iagnosis of Gogniti"e .mpairment $Pro#a#le @ementia or Minor Gogniti"e .mpairment( as Associated +it *elected @emograp ic and Glinical Factors8 &esults of Multi"aria#le 3ogistic &egression Modeling, Gontrolling for Qear of First ... @.*GB**.C1 T is study continues to add to t e e"idence t at psyc iatric mor#idity, in particular depression, is significantly associated !it P@ and MG. in later life. Among +%.M* participants ! o screened positi"ely for suspicious cogniti"e impairment Yany psyc iatric2anxiety2alco ol disorderZ !as present in one of fi"e !omen, !it depression as t e most common disorder. +omen !it any depressi"e2anxiety2alco ol disorder !ere more likely to #e non2! ite, less likely to consume alco ol, and ad istories of dia#etes. T ese rates are alarming and ig lig t t e need for careful diagnosis and treatment of re"ersi#le mor#idities suc as depression and anxiety. Any depressi"e2anxiety2alco ol disorder, and in particular depression, !ere significantly associated !it #eing diagnosed !it P@ or MG.. T e fre)uency of any depressi"e2 anxiety2alco ol disorder and maEor depression in particular !ere a#out t!o times ig er in t e MG. group compared !it !omen !it no cogniti"e disorder and a#out 2/= greater t an !omen !it P@. Cur findings are consistent !it ot er population2#ased studies.16,36 %o!e"er, t ey are at "ariance !it t ose recently reported #y -ecker et al.12 from t e G%*2G. -ot studies used large community2#ased samples, and similar screening instruments, screening instrument cutpoints, and approac to diagnostic adEudication. Alt oug +%.M* used only !omen participants, G%*2G included #ot men and !omen, leading to t e ypot esis, are !omen ! o are depressed at greater risk for de"eloping cogniti"e impairment t an men !it depressionM

.n t is study, t ere !as a strong relations ip #et!een maEor depression and MG.. T ese findings are consistent from t ose originating from clinical populations. Apostol"a and Gummings31 a"e reported t at t e pre"alence of #e a"ioral symptoms associated !it MG., e.g., depression, anxiety, apat y, and irrita#ility ranged from 3/= to ;/=. T e classification of MG. as e"ol"ed a great deal since t is study !as #egun. +e defined MG. #ased on t e generally accepted model at t e time and did not su#classify su#Eects into amnestic, nonamnestic, or multiple domain types.32 Cf note, t e amnestic su#type as #een s o!n to #e associated !it a ig er num#er of neuropsyc iatric symptoms.33 Gould psyc iatric disorders suc as depression and anxiety contri#ute to t is con"ersionM T is )uestion re)uires furt er study, especially in lieu of a recent population2#ased study comparing G inese and B.K. su#Eects, ! ic found t at t e relations ip #et!een depression and dementia mig t #e temporal and only t e most se"ere depressi"e cases of depression are risk factors for dementia.39 T e multi"ariate analyses t at modeled cogniti"e impairment among +%.M* su#Eects !ere also interesting. T ose participants experiencing any depressi"e2anxiety2alco ol disorder !ere more t an t!ice as likely to #e diagnosed !it cogniti"e impairment t an t ose not experiencing any comor#idity. T is is not likely attri#uta#le to mistaking depressi"e symptoms for cogniti"e symptoms as our adEudication criteria made diagnosing eit er P@ or MG. more difficult if psyc iatric symptoms !ere present. .t !as t e strongest predictor of all demograp ic and clinical "aria#les and e"en ad a ig er odds ratio t an age. Cur data suggest t at a"ing a psyc iatric disorder, especially maEor depression, may #e a risk factor for t e de"elopment of a cogniti"e disorder. >i"en our concurrent assessment of cogniti"e and psyc iatric disorders, !e cannot confidently conclude causal direction. .t is also possi#le t at cogniti"e disorders are risk factors for psyc iatric disorders. T is finding furt er underscores t e long2standing diagnostic recommendation t at all patients ! o present !it cogniti"e impairment s ould #e screened for psyc iatric conditions, in particular depression. .nterestingly, in t ese analyses, %T did not predict cogniti"e impairment. *e"eral limitations of t is study must #e considered. First, it is important to note t at persons !it certain self2reported mental illness !ere excluded from t e +%.D t erefore, t e original co ort may not #e representati"e of t e population at large. *econd, it s ould #e noted t at t e 1o Psyc iatric @isorder group !as not a typical comparison condition in t at t ey pro#a#ly ad ele"ated rates of depression4anxiety gi"en t at t ey failed t e initial cogniti"e screen. T is may a"e attenuated t e differences #et!een groups. T ird, #ecause !omen only recei"ed a complete e"aluation if t ey registered a #elo! cutpoint score on t e 3M*F, our YnormalZ group may not #e a truly normal sample #ut rat er a group !it out clinically meaningful cogniti"e impairment. Fourt , MG. as a diagnostic category as #een continually refined since t e enrollment of su#Eects in t is study. +e defined MG. #ased on t e generally accepted model at t e time and did not su#classify su#Eects into amnestic, nonamnestic, or multiple domain types.32 Cf note, t e amnestic su#type as #een s o!n to #e associated !it a ig er num#er of neuropsyc iatric symptoms.33 Finally, t e small num#er of cases can affect t e "aria#ility of t e psyc iatric disorder pre"alence estimates. %o!e"er, for group comparisons, !e used small sample statistical met ods suc as t e Fis erSs exact test ! en appropriate. Furt ermore, for logistic regression analyses, !e presented confidence inter"als t at pro"ide information on t e sta#ility of t e estimates.

.n summary, study participants ! o s o!ed suspicious cogniti"e impairment and !ere carefully e"aluated and classified as a"ing a cogniti"e disorder $P@ and MG.(, or not, nearly one in fi"e ad any depressi"e2anxiety2alco ol disorders, most fre)uently maEor depression. %a"ing maEor depression !as significantly associated !it also recei"ing a diagnosis of P@ or MG. e"en after controlling demograp ic and medical conditions. T ese data clearly ig lig t t e importance of identifying psyc iatric illnesses among older !omen !it suspicious cogniti"e impairment e"en ! en detected #y simple cogniti"e screeners. Bnderdetection and undertreatment of psyc iatric mor#idities are costly to indi"iduals and to society. Article information Am J >eriatr Psyc iatry. Aut or manuscriptD a"aila#le in PMG 2616 *eptem#er 19. Pu#lis ed in final edited form as8 Am J >eriatr Psyc iatry. 2616 Fe#ruaryD 1:$2(8 1;;J1:A. doi8 16.16<;4J>P.6#613e31:1cA/:A9 PMG.@8 PMG2<3<691 1.%M*.@8 1.%M*22A199 G ristop er G. Golenda, M.@., M.P.%., Glaudine 3egault, P .@., *tep en &. &app, P .@., Margaret +. @e-on, P .@., Patricia %ogan, M.*, &o#ert +allace, M.@., M.*., 3inda %ers ey, M.@., P .@., Judit Cckene, P .@., &ac ael + itmer, P .@., 3a!rence *. P illips, M.@., and >loria F. *arto, M.@., P .@. From t e Texas ANM %ealt *cience Genter, TV $GGG(D @epartments of -iostatistics $G3, P%( and Psyc iatry and -e a"ioral Medicine $*&&(, +ake Forest Bni"ersity %ealt *ciences, +inston2*alem, 1GD @epartment of Pre"enti"e Medicine, Bni"ersity of Tennessee %ealt *cience Genter, Memp is, T1 $M+@(D @epartment of Fpidemiology, Bni"ersity of .o!a, .o!a Gity, .+ $&+allace(D @epartment of 1eurology, Bni"ersity of -uffalo Medical Genter, -uffalo, 1Q $3%(D @epartment of Pre"enti"e and -e a"ioral Medicine, Bni"ersity of Massac usetts, Am erst, MA $JC(D @i"ision of &esearc , Kaiser Permanente 1ort ern Galifornia, *an Francisco $&+ itmen(D @i"ision of Fndocrinology, Fmory Bni"ersity *c ool of Medicine, Atlanta, >A $3*P(D and Bni"ersity of +isconsin Genter for +omenSs %ealt &esearc , Madison, +. $>F*( *end correspondence and reprint re)uests to G ristop er Golenda, M.@., M.P.%., G ancellor for %ealt *ciences, +est 'irginia Bni"ersity, *uite 1666 %*G *out , PC -ox <666, Morganto!n, +' 2A/6A D Fmail8 ccolenda4at4 sc.!"u.edu Gopyrig t notice and @isclaimer T e pu#lis erKs final edited "ersion of t is article is a"aila#le at Am J >eriatr Psyc iatry T is article as #een corrected. *ee Am J >eriatr Psyc iatry. 2616 *eptem#er 2D 1:$/(8 9/A. *ee ot er articles in PMG t at cite t e pu#lis ed article. &eferences 1. Plassman -3, 3anga KM, Fis er >>, et al. Pre"alence of dementia in t e Bnited *tates8 t e aging, demograp ics, and memory study. 1euroepidemiology. 266;D2<812/J 132. OPMG free articleP OPu#MedP 2. >orelick P-. &isk factors for "ascular dementia and Al0 eimer disease. *troke. 2669D3/ suppl82A26J2A22. OPu#MedP 3. 3yketsos G>, 3ee %-. @epression and treatment of depression in Al0 eimerSs disease8 a practical update for t e clinician. @ement >eriatr Gogn @isord. 2669D1;8//J A9. OPu#MedP 9. 3yketsos G>, *tein#erg M, Tsc an0 JT, et al. Mental and #e a"ioral distur#ances in dementia8 findings from t e Gac e Gounty *tudy on Memory in Aging. Am J Psyc iatry. 2666D1/;8;6:J;19. OPu#MedP

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