Anxiety Dan Premenstrual

8/12/2019 Anxiety Dan Premenstrual

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Anxiety dan premenopause ganti menopause dg aspek psikiatrik

1.

ARTIGO ORIGINAL

Depressão e ansiedade em mulheres climatéricas:fatores associados

Depression and anxiety in menopausal omen: associatedfactors

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

IProfessores Adjuntos da disciplina de Ginecologia da Faculdade de Medicina daUniversidade Federal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasilII!outor, Professor Adjunto da disciplina de "#stetr$cia da Faculdade de Medicina da

Universidade Federal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasilIIIP%s-doutorado, Professor Adjunto do !eparta&ento de Fisiologia da UniversidadeFederal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasilI'P%s-graduando (!outorado) do entro de iologia da eprodu*+o da UniversidadeFederal de Juiz de Fora - UFJF - Juiz de Fora (MG), rasil'P%s-graduando (Mestrado) do entro de iologia da eprodu*+o da UniversidadeFederal 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

orrespondncia

R./1+O

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O2,.TI-O: deter&inar a prevalncia de depress+o e ansiedade e& &ulerescli&at.ricas e os prov/veis fatores respons/veis por sua ocorrncia0+3TODO/: e& estudo transversal, fora& selecionadas 12 &uleres 3uefre3uentara& u& a&#ulat%rio de cli&at.rio no per$odo de &aio de 4556 a agosto de45570 o&o crit.rio de inclus+o fora& consideradas &uleres na fai8a et/ria de 95 a6: 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 einjet/veis de dep%sito nos <lti&os seis &eses, endocrinopatias 3ue levasse& airregularidades &enstruais, epatopatias, coagulopatias, uso de drogas 3ueinterferisse& no ciclo &enstrual, ansiol$ticos e antidepressivos (pois o uso dessasdrogas era indicativo de diagn%stico pr.vio de altera*=es do u&or),isterecto&izadas, ooforecto&izadas, portadoras de c>ncer e de enfer&idadespsi3ui/tricas, pacientes 3ue tivesse& sido su#&etidas ? radioterapia ou3ui&ioterapia0 Fora& aplicados 3uatro 3uestion/rios durante a entrevista;Ana&nese, contendo dados sociode&ogr/ficos, cl$nicos e /#itos de vida@ ndiceMenopausal de latt-Bupper&an, co& o o#jetivo de diagnosticar as pacientesportadoras de s$ndro&e cli&at.rica@ a su#escala para Ansiedade, derivada da escalaCospitalar para Ansiedade e !epress+o (CA!D-A), co& a finalidade de diagnosticaros casos de Ansiedade e o Invent/rio de !epress+o de ecE, co& o intuito dediagnosticar as &uleres portadoras de depress+o0 Fora& realizadas as an/lisesdescritivas e de correla*+o entre as vari/veis@ o teste do χ 4 e de Cos&er-e&eso,usando o progra&a Doftare Dtatistica vers+o 60R./1LTADO/: a &.dia de prevalncia de depress+o entre as pacientes avaliadas foide 26,H en3uanto 3ue da ansiedade foi de :2,70 +o ouve diferen*asignificativa entre a prevalncia de depress+o e ansiedade e as trs fases docli&at.rio0 "#servou-se rela*+o significativa entre a presen*a de sinto&ascli&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& &uleres portadoras de ansiedade("9,4) e insNnia ("9,1) sendo a atividade re&unerada considerada fator deprote*+o ("5,4)0 "s fatores de risco relacionados ? ansiedade fora& a presen*ade depress+o ("6,L) e os antecedentes de tens+o pr.-&enstrual ("7,5)0

'ON'L1/4./: a prevalncia de depress+o e ansiedade . elevada no cli&at.rio,sendo poss$vel detectar fatores de risco relacionados ? sua ocorrncia0

$ala"ras5cha"e: MenopausaOpsicologia@ li&at.rioOpsicologia@ !epress+o@Ansiedade@ Prevalncia

A2/TRA'T

$1R$O/.: to deter&ine te prevalence of depression and an8iet in cli&acterico&en and te pro#a#le factors responsi#le for its occurrence0+.T6OD/: a transversal stud tat as selected 12 o&en attended at a

cli&acteric outpatient clinic, fro& Ma 4556 to August 45570 Inclusion criteria ere;o&en fro& 95 to 6: ears old o agreed it participating in te project0Q8clusion criteria; patients in or&onal terap, or&one-terap # i&plant, !IUsand depo injections in te preceding si8 &onts, endocrinopaties leading to&enstrual irregularities, epatopaties, tro&#opaties, use of drugs ic interferein te &enstrual ccle, an8ioltics and antidepressants (as teir use indicatesprevious diagnosis of &ood disorders), sterecto&, ooporecto&, cancer orpsciatric disease, and patients o ad #een su#&itted to radio or ce&oterap0!uring te intervie, four 3uestionnaires ere applied; Ana&nesis, containing socio-



de&ograpic, clinical and living a#its data@ latt-Bupper&anRs Menopausal Inde8 forcli&acteric sndro&e diagnosis@ An8iet su#-scale of te Cospital An8iet and!epression scale (CA!D-A) for an8iet diagnosis@ and ecERs !epression Inventorfor te diagnosis of depression0 !escriptive and correlation analsis a&ong tevaria#les, χ 4 and Cos&er-e&eso tests ere perfor&ed using te DtatisticaDoftare progra&, version 60

R./1LT/: te average depression prevalence a&ong te patients as 260H, iletat of an8iet as :2070 Sere as no significant difference #eteen teprevalence of depression and an8iet in te tree pases of cli&acteriu&0 Sere asa significant relationsip #eteen te presence of &oderate cli&acteric s&pto&sand te presence of &ood alterations (pK5055L)0 !epression as &ore fre3uent ino&en it an8iet ("904) and inso&nia ("901), aving a jo# #eing aprotection factor ("504)0 isE factors related to an8iet ere te presence ofdepression ("60L) and antecedents of pre-&enstrual tension ("705)0'ON'L1/ION/: te prevalence of depression and an8iet is ig in cli&acteriu&,#eing possi#le to detect risE factors related to teir occurrence0

7eyords: MenopauseOpscolog@ li&acteriu&Opscolog@ !epression@ An8iet@

Prevalence

Introdu8ão

" cli&at.rio representa u& pro#le&a de sa<de p<#lica, pela sua &agnitude e pelasrepercuss=es sociais produzidas, surgindo e& conse3uncia do au&ento dae8pectativa de vida ocorrida &undial&ente0 os pa$ses desenvolvidos, 25 dapopula*+o . representada por &uleres cli&at.ricas0 Degundo o Instituto rasileirode Geografia e Qstat$stica (IGQ), / cerca de 49 &il=es de &uleres co& &ais de95 anos, de acordo co& o censo realizado no ano de 45550 o rasil, sendo aperspectiva de vida e& torno dos 74,9 anos, u& ter*o da vida dessas &uleres ser/vivido no cli&at.rio, predo&inante&ente na fase de deficincia estrognicaL0

" cli&at.rio representa a transi*+o do per$odo reprodutivo para o n+o-reprodutivo0Inicia-se aos 95 anos e ter&ina aos 6: anos0 !entro desse espa*o de te&po, ocorrea &enopausa, 3ue corresponde ? <lti&a &enstrua*+o fisiol%gica da &uler,apro8i&ada&ente aos :5 anosL,40

o&o conse3uncia do ipoestrogenis&o 3ue se instala, surge& sinto&as

vaso&otores, atrofia vaginal, disfun*=es se8uais, sinto&as urin/rios, al.& doau&ento de risco para doen*a cardiovascular e osteoporose0 Fatores #iopsicossociaispode& deter&inar a ocorrncia de &anifesta*=es ps$3uicas, e8teriorizadas porirrita#ilidade, nervosis&o, depress+o e ansiedade20

Qsti&a-se 3ue u& ter*o das &uleres sofrer/, pelo &enos, u& epis%dio dedepress+o durante a vida, co& prevalncia de 1 no cli&at.rio0 essa .poca, algunsfatores favorece& o surgi&ento dessa condi*+o, co&o o &edo de envelecer,senti&ento de inutilidade, e carncia 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 conse3uncia a redu*+o da 3ualidade de vida9,:0

" estudo dos sinto&as depressivos e ansiosos no cli&at.rio . &uito antigo0Maudsle, na Inglaterra, e& LH76, descreveu u&a for&a de &elancolia 3ue ocorrerianessa 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$aco-depressiva por crit.rios evolutivos0 Qsse conceito foi &uito 3uestionado eele o refor&ulou, concluindo 3ue o surgi&ento desse 3uadro cl$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&anova condi*+o cl$nica60 Qssa afir&ativa . 3uestionada por v/rios pes3uisadores0 o&os diversos estudos realizados so#re os sinto&as depressivos e de ansiedade, n+o seencontrou #ase cient$fica para apoiar u& conceito <nico70 A associa*+o entre ocli&at.rio e instala*+o da depress+o e ansiedade continua sendo foco decontrov.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*=esor&onais 3ue ocorre& nessa fase de vida co&o respons/veis pelas altera*=es dou&orH0 esse conte8to, a peri&enopausa . u& per$odo de &aior vulnera#ilidadepara os transtornos ps$3uicos10 Alguns autores acredita& 3ue a peri&enopausaesteja forte&ente associada ao apareci&ento de sinto&as de ansiedade e depress+oe& &uleres se& ist%ria pr.via de doen*a &ental, 3uando presentes outros fatoresde risco, co&o elevado $ndice de &assa corp%rea, antecedentes de D$ndro&e detens+o pr.-&enstrual (SPM), ondas de calor, dist<r#ios do sono, dese&prego eestado &aritalL5,LL0 "utros autores valoriza& a presen*a de sinto&as vaso&otores(fogacos) 3ue, interferindo no sono da &uler, deter&inaria&, e& longo prazo, oapareci&ento dos 3uadros depressivos e ansiosos (Seoria !o&in%)L40 A partir de u&aperspectiva psicossocial, alguns pes3uisadores argu&enta& 3ue a depress+o e aansiedade 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$ndro&e do nino vazio, doen*a ou&orte de fa&iliares, di&inui*+o de rendaL20 Qstudos de&onstra& 3ue a pr/ticaregular de e8erc$cios f$sicos di&inui os n$veis de estresse, ansiedade e depress+o

durante o per$odo de &enopausa7

0 " custo econN&ico dos 3uadros de depress+o eansiedade para a sociedade . consider/vel, sendo co&par/vel ?3uele de outrasdoen*as, co&o as coronariopatiasL90 As repercuss=es sociais 3ue essas altera*=es dou&or deter&ina&, acrescidas do au&ento da &or#i&ortalidade, faze& co& 3ueseu estudo seja e8tre&a&ente i&portante e priorit/rio dentre as outras doen*as 3ueocorre& nesse per$odo de vida70 Pes3uisas de&onstrara& 3ue depress+o eansiedade s+o a 3uarta causa &undial de incapacita*+o social e o principal pro#le&ade sa<de p<#licaL20 !essa for&a, tendo e& vista ser este t%pico foco de &uitascontrov.rsias, n+o estando esta#elecidos, ao certo, os fatores direta&enterelacionados ao apareci&ento dessas altera*=es do u&or, al.& do custoconsider/vel e das repercuss=es sociais e fa&iliares deter&inadas pela depress+o eansiedade, decidi&os pela realiza*+o deste estudo, visando, ainda, a per&itir ainterven*+o do ginecologista na preven*+o e diagn%stico, au8iliando no trata&entodos 3uadros0 " principal o#jetivo do estudo foi descrever as ta8as de prevalncia e operfil cl$nico para depress+o e ansiedade e& &uleres atendidas e& u& a&#ulat%riode cli&at.rio de u& servi*o universit/rio0

+étodos



ealizou-se u& estudo cl$nico, prospectivo e transversal, sendo a popula*+oestudada constitu$da por 12 &uleres selecionadas dentre 255 &uleres atendidasno Dervi*o de li&at.rio do Cospital Universit/rio da Universidade Federal de Juiz deFora (CUOUFJF), no per$odo de &aio de 4556 a agosto de 4557, selecionadas deacordo co& os crit.rios de inclus+o e e8clus+o e ist%ria &enstrual de tal for&a 3uefosse poss$vel distri#u$-las e3uitativa&ente nas trs fases do cli&at.rio0

Fora& inclu$das no estudo &uleres na fai8a et/ria dos 95 aos 6: anos e 3ueconcordara& e& participar do projeto0 Fora& utilizados co&o crit.rios de e8clus+o;pacientes e& uso de terapia or&onal, or&onioterapia por i&plantes, !IU einjet/veis de dep%sito nos <lti&os seis &eses, endocrinopatias 3ue levasse& airregularidades &enstruais, epatopatias, coagulopatias, uso de drogas 3ueinterferisse& no ciclo &enstrual, ansiol$ticos e antidepressivos (pois o uso dessasdrogas era indicativo de diagn%stico pr.vio de altera*=es do u&or),isterecto&izadas, ooforecto&izadas, portadoras de c>ncer e de enfer&idadespsi3ui/tricas, pacientes 3ue tivesse& sido su#&etidas a radio ou 3ui&ioterapia0 "diagn%stico de cli&at.rio foi e&inente&ente cl$nico, #aseado na fai8a et/ria dapaciente@ j/ a &enopausa foi caracterizada pela ausncia de &enstrua*+o porper$odo &$ni&o de L4 &eses0

Utilizara&-se 3uatro instru&entos para esta pes3uisa; Ana&nese contendo dadossociode&ogr/ficos, infor&a*=es cl$nicas e /#itos de vida@ ndice Menopausal delatt-Bupper&an (IMB)@ Invent/rio de !epress+o de ecE (!I) e a Du#escalaCospitalar para Ansiedade, derivada da Qscala Cospitalar de Ansiedade e !epress+o(CA!D-A)0

a 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+op%s-parto, antecedente de depress+o, ist%ria de depress+o entre fa&iliares, &edode envelecer, separa*+o, &orte de fa&iliar, a#orreci&ento &arcante, s$ndro&e donino vazio, di&inui*+o da renda fa&iliar, atividade f$sica, art$stica, religiosa, /#ito

de fu&ar e de ingerir #e#ida alco%lica e relato de insNnia0 A ist%ria &enstrualdistri#uiu a popula*+o nas trs fases do cli&at.rio; pr.-&enopausa, peri&enopausae p%s-&enopausa, co& #ase na classifica*+o da Dociedade Internacional deMenopausa0 !e acordo co& essa classifica*+o, a pr.-&enopausa . iniciada aos 95anos e se caracteriza pela presen*a de regularidades &enstruais@ a peri&enopausase inicia co& o apareci&ento das irregularidades &enstruais (ciclos &enstruaiscurtos ou longos) e ter&ina u& ano ap%s a &enopausa@ a p%s-&enopausa te& co&ocaracter$stica a ausncia de &enstrua*+o, iniciando co& a &enopausa e ter&inandoaos 6: anos, fazendo li&ite co& a senilidade0

" ndice Menopausal de latt-Bupper&an (IMB) teve co&o o#jetivos diagnosticaras 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*+oo#tida na aplica*+o do 3uestion/rio40 Qsse instru&ento encontra-se adaptado evalidado para seu uso, sendo a&pla&ente utilizado tanto para prop%sitos depes3uisa co&o na pr/tica cl$nica, para &onitoriza*+o de efeitos dos diversostrata&entos institu$dos no cli&at.rio20 As respostas para cada sinto&a investigadosegue a seguinte escala de escores; 5 (ausncia de sinto&as)@ L (sinto&as leves)@ 4(sinto&as &oderados) e 2 (sinto&as intensos)0 Para o c/lculo do escore total, ossinto&as pes3uisados apresenta& pesos diferenciados, nos 3uais as ondas de calor(fogacos) 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 aintensidade do sinto&a pelo respectivo fator de convers+o e, e& seguida, fazendo aso&a dos resultados o#tidos, alcan*a-se u&a pontua*+o capaz de classificar as$ndro&e cli&at.rica e& leve, &oderada e intensa0 onsiderou-se s$ndro&ecli&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 deautoavalia*+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 decoro, irrita#ilidade, retra*+o social, indecis+o, distor*+o de i&age& corporal,ini#i*+o para o tra#alo, 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 evalidado para o portugus nu&a popula*+o de estudantes universit/rios e ve& sendoa&pla&ente aplicado e& &uitas pes3uisas co& a finalidade diagnosticar e classificaros 3uadros de depress+o0 Pacientes co& pontua*+o &aior 3ue L: fora&diagnosticadas co&o portadoras de depress+o0 onsiderou-se depress+o leve valoresentre 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 An8iet and !epression Dcale CA!D-A) foi utilizada paradiagnosticar os casos de ansiedade0 Se& co&o caracter$stica ser co&posta por duassu#escalas@ a su#escala de ansiedade e a su#escala de depress+o0 Qsta su#escalae8clui sinto&as &entais graves, detecta graus leves de transtornos afetivos e&a&#ientes n+o-psi3ui/tricos, e os 3uadros de ansiedade e depress+o, por.& n+o fazsua classifica*+o #aseada na intensidade dos sinto&as co& alta sensi#ilidade(12,7) e especificidade (74,6), tendo sido validada para o portugus L70 esteestudo, foi utilizada a su#escala de Ansiedade (CA!D-A), co& o o#jetivo dediagnosticar os 3uadros de s$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&opes3uisador0 U&a c%pia dos 3uestion/rios foi entregue ? entrevistada, para 3ue elaaco&panasse as 3uest=es, lidas e& voz alta, e as respostas assinaladas nosfor&ul/rios, pelo &es&o0 " projeto foi aprovado pelo o&it de Ttica e& Pes3uisada Universidade Federal de Juiz de Fora (QP-UFJF) so# o n0 5:504556 e& a#ril de45560 A coleta de dados ocorreu no per$odo de &aio de 4556 a agosto de 4557, noa&#ulat%rio de li&at.rio do CU-UFJF0

Sodas as &uleres 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 daprevalncia da depress+o e ansiedade nas trs fases do cli&at.rio0 Para esta#eleceras rela*=es entre fatores de risco e a sua ocorrncia, as vari/veis categ%ricas fora&e8pressas e& porcentage& () e suas &edidas de associa*+o fora& avaliadas peloteste do χ 40 'ari/veis nu&.ricas fora& e8pressas co&o &.dia desvio padr+o0este estudo, as vari/veis-resposta s+o ansiedade e depress+o0 Foi realizada u&aan/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*+osignificativa pelo teste do χ 40 A <nica vari/vel nu&.rica do estudo (idade) n+o foiinclu$da no &odelo de regress+o, u&a vez 3ue sua &.dia n+o foi significativa&entediferente e& rela*+o ao fator ansiedade (teste t; tL,29@ g1L@ p5,51) e ne& e&rela*+o ao fator depress+o (teste t; t5,41@ g1L@ p5,7H)0 " &odelo de regress+on+o-linear foi utilizado para avaliar o risco ("dds atio), co& os respectivos

intervalos de confian*a de 1: de cada vari/vel preditora inclu$da no &odelo 3uepudesse interferir no desfeco (ansiedade ou depress+o)0 " ajuste do &odelo foiverificado pelo teste de Cos&er-e&eso (pV5,L)0 Sodos os testes fora&#icaudais, respeitando-se todos os pressupostos estat$sticos0 Adotou-se co&osignificante u& n$vel de : para o erro alfa0 Sodas as an/lises fora& realizadasatrav.s do softare DtatisticaW vers+o 60 A ip%tese nula foi rejeitada 3uandopK5,5:0

Resultados

A popula*+o do estudo constou de 12 &uleres, distri#u$das nas trs fases docli&at.rio; pr.-&enopausa (2L pacientes), peri&enopausa (24 pacientes) e p%s-&enopausa (25 pacientes)0 A &.dia e o desvio padr+o de idade das &uleres napr.-&enopausa era& de 9:,:2,7 anos, na peri&enopausa de 9H,22,L e na p%s-&enopausa de :9,7:,5 anos0 " estudo foi co&posto de &uleres e& sua &aioria#ranca (74,5), 3ue &orava& co& o co&paneiro (66,6) e tina& atividadere&unerada (H5,6)0 !esse total, u&a era analfa#eta, 91 avia& co&pletado opri&eiro grau, 24 o segundo grau e LL o terceiro grau0 Do# o ponto de vista cl$nico,69,: relatou antecedentes de tens+o pr.-&enstrual, 2L,4 antecedentes dedepress+o e :6,1 u& a#orreci&ento &arcante nos <lti&os L4 &eses0 o& rela*+oaos /#itos de vida, 92,5 das &uleres afir&ara& ter 3uadro de insNnia pelo&enos trs vezes por se&ana (Sa#ela L)0

onsiderando-se a totalidade da a&ostra estudada, a prevalncia de depress+o foide 26,H, ao passo 3ue a prevalncia de ansiedade foi de :2,70 +o ouveassocia*=es significativas entre a ocorrncia de depress+o (p5,L4) e ansiedade(p5,HH) co& as trs fases do cli&at.rio consideradas, confor&e de&onstrada naSa#ela 40

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As vari/veis preditoras avaliadas na ana&nese das participantes do estudo e suacorrela*+o co& depress+o e ansiedade est+o listadas nas Sa#elas 2 e 90 o&o n+oouve associa*+o significativa entre a ocorrncia de depress+o (p5,L4) e ansiedade(p5,HH) co& as trs fases do cli&at.rio consideradas, n+o foi realizada a an/lisedas 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& riscoapro8i&ada&ente 3uatro vezes &aior e as pacientes co& insNnia, u& riscoapro8i&ada&ente cinco vezes &aior0 Por outro lado, o tra#alo re&unerado&ostrou-se u& fator de prote*+o, tendo essas pacientes u& risco cerca de cincovezes &enor de apresentar depress+o0

Xuanto ? ansiedade, as pacientes co& depress+o apresentara& riscoapro8i&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 deintensidade &oderada e a ocorrncia de depress+o e ansiedade (pK5,55L)0





Discussão

o rasil, sendo a perspectiva de vida e& torno dos 74,9 anos, u& ter*o da vida das&uleres ser/ vivido no cli&at.rio0 Qsti&a-se 3ue 22 das &uleres sofrer+o pelo&enos u& epis%dio de depress+o durante a vida, co& prevalncia de 1 nocli&at.rio:0 este estudo, o#servou-se u&a prevalncia significativa de depress+o eansiedade nas pacientes@ 26,H e :2,7, respectiva&ente, apesar do #o& n$veleducacional (apenas u&a . analfa#eta), de encontrare&-se ainda e& fase produtivae de a &aioria delas ter u&a atividade re&unerada0

o presente estudo, n+o ouve diferen*a na ocorrncia de depress+o e ansiedadenas trs fases do cli&at.rio, apesar de ser o#servada u&a elevada prevalncia0 "sresultados 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 prevalncia e& &uleres naperi&enopausaL1,450 A alta prevalncia dessas altera*=es do u&or, encontrada nessa

pes3uisa, pode ser resultado de v/rios fatores, co&o as altera*=es e flutua*=esor&onais 3ue ocorre& nessa fase da vida, os aspectos sociais e e&ocionais dessafai8a et/ria e a dificuldade 3ue t& essas &uleres de procurar atendi&entopsi3ui/trico para transtornos predo&inante&ente leves e &oderados, diante doestig&a 3ue a especialidade ainda carrega0 "utra e8plica*+o para esse acado seriao fato de as &uleres portadoras de depress+o ou ansiedade sere& &ais 3uei8osase tere& &enor toler>ncia e& rela*+o aos sinto&as do cli&at.rio #uscando &aisfre3uente&ente o atendi&ento ginecol%gico4L0 Sa&#.& foi o#servada u&a rela*+osignificativa entre a presen*a de sinto&as cli&at.ricos de intensidade &oderada e oapareci&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& outraspes3uisasLL,4L00 Ficou de&onstrado 3ue a insNnia . fator predisponente para aocorrncia 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 odesenvolvi&ento de sinto&as de depress+oLH,4L0 Sa&#.& co&provou-se, a3ui, 3ue aatividade re&unerada atua co&o fator de prote*+o0 A falta de u&a atividadere&unerada na fa&$lia . u& fator 3ue levaria a pro#le&as de autoesti&a, tendo-see& vista as d$vidas e outras dificuldades decorrentes do pro#le&a econN&ico 3ueestaria direta&ente relacionado ? presen*a de rea*=es depressivas0

Galliccio et al0: e oen et al04L relatara& 3ue as altera*=es or&onais 3ue ocorre&no cli&at.rio poderia&, e& &uleres predispostas, desencadear sinto&as ansiosos,atrav.s de &ecanis&o idntico ao da ocorrncia da s$ndro&e de tens+o pr.-&enstrual, no &enac&e0 Foi o 3ue se o#servou neste tra#alo0

Algu&as li&ita*=es &etodol%gicas deste estudo &erece& considera*=es; o desenotransversal do presente estudo avalia associa*=es entre depress+o e ansiedade nocli&at.rio co& fatores de risco, &as n+o per&ite interferncias so#re casualidade0 "



ta&ano 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 seau&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 &uler cli&at.rica atrav.s daidentifica*+o dos fatores relacionados ?s altera*=es do u&or0

onclui-se, co& este estudo, 3ue n+o ouve diferen*a significativa entre a ocorrnciade depress+o e ansiedade nas trs fases do cli&at.rio0 A depress+o foi &aisfre3uente e& &uleres portadoras de ansiedade e insNnia, sendo a atividadere&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&ascli&at.ricos de intensidade &oderada e o apareci&ento das altera*=es do u&or0

Refer9ncias

L0 Galv+o F, Farias MD, Azevedo PM, 'ilar MJP, Azevedo !G0 Prevalncia detranstornos &entais co&uns e avalia*+o da 3ualidade de vida no cli&at.rio0 evAssoc Med ras0 4557@:2(:);9L9-450 Y inEs Z

40 edraui P, Aguirre [, Cidalgo , Faad 0 Assessing &enopausal s&pto&sa&ong ealt &iddle aged o&en it te Menopause ating Dcale0 Maturitas04557@:7(2);47L-H0 Y inEs Z

20 Dilveira I, Petronilo PA, Douza M", Dilva S!, !uarte JMP, Maran+o SM", et

al0 Prevalncia de sinto&as do cli&at.rio e& &uleres dos &eios rural e ur#ano noio Grande do orte, rasil0 ev ras Ginecol "#stet0 4557@41(H);9L:-440

Y inEs Z

90 Duau GM, or&andia , odriguez , o&aguera J, Degarra 0 !epressives&pto&s and risE factors a&ong peri&enopausal o&en0 P Cealt Dci J0455:@49(2);457-L50 Y inEs Z

:0 Galliccio , Dcilling , Miller D, \acur C, Flas JA0 orrelates of depressives&pto&s a&ong o&en undergoing te &enopausal transition0 J Pscoso& es04557@62(2);462-H0 Y inEs Z

60 Appolin/rio J0 A depress+o na &enopausa; u&a entidade espec$fica] InfPsi3uiatr0 L111@LH(9);L57-L90 Y inEs Z

70 elson !, Da&&el M!, Free&an Q[, in C, Gracia , Dc&itz BC0 Qffect ofpsical activit on &enopausal s&pto&s a&ong ur#an o&en0 Med Dci DportsQ8erc0 455H@95(L);:5-H0 Y inEs Z

H0 [oods F, D&it-!ijulio B, Percival !, Sao Q^, Salor CJ, Mitcell QD0 D&pto&sduring te &enopausal transition and earl post&enopause and teir relation to



endocrine levels over ti&e; o#servations fro& te Deattle Midlife [o&enRs CealtDtud0 J [o&ens Cealt (arc&t)0 4557@L6(:);667-770 Y inEs Z

10 Sangen S, MEletun A0 !epression and an8iet troug te cli&acteric period; anepide&iological stud (CUS-II)0 J0 Pscoso& "#stet Gnaecol0 455H@41(4);L4:-2L0 Y inEs Z

L50 Free&an Q[, Da&&el M!, in C, Gracia , Bapoor D, Ferdousi S0 Se role ofan8iet and or&onal canges in &enopausal ot flases0 Menopause0455:@L4(2);4:H-660 Y inEs Z

LL0 Ale8ander J, !ennerstein , [oods F, McQen D, Cal#reic U, Botz B, et al0ole of stressful life events and &enopausal stage in ell#eing and ealt0 Q8pertev euroter0 4557@7(LL Duppl);D12-LL20 Y inEs Z

L40 Doares 0 !epression during te &enopausal transition; indo of vulnera#ilitor continuu& of risE] Menopause0 455H@L:(4);457-10 Y inEs Z

L20 i ^, ^u X, Ma , Dun \, ^ang _0 Prevalence of depression and an8iet s&pto&sand teir influence factors during &enopausal transition and post&enopause ineijing cit0 Maturitas0 455H@6L(2);42H-940 Y inEs Z

L90 Pae U, Mandelli , Bi& SD, Can , Masand PD, MarEs !M, et al0 Qffectiveness ofantidepressant treat&ents in pre-&enopausal versus post-&enopausal o&en; apilot stud on differential effects of se8 or&ones on antidepressant effects0 io&edPar&acoter0 In press@ 455H0 Y inEs Z

L:0 !e orenzi !D, !anelon , Daciloto , Padila J<nior I0 Fatores indicadores dasinto&atologia cli&at.rica0 ev ras Ginecol "#stet0 455:@47(L);L4-10 Y inEs Z

L60 Gorenstein , Andrade 0 'alidation of a Portuguese version of te ecE!epression Inventor and te Dtate-Srait An8iet Inventor in razilian su#jects0raz J Med iol es0 L116@41(9);9:2-70 Y inEs Z

L70 \ig&ond AD, Dnait P0 Se ospital an8iet and depression scale0 ActaPsciatr Dcand0 L1H2@67(6);26L-750 Y inEs Z

LH0 'eras A, assi A, 'alen*a AM, ardi AQ0 Prevalncia de transtornos depressivose ansiosos e& u&a a&ostra a&#ulatorial #rasileira de &uleres na &enopausa0 evPsi3uiatr io Gd Dul0 4556@4H(4);L25-90 Y inEs Z

L10 allegari , uttarelli M, ro&i A, !iurni M, Dalvaggio F, olis PF0 Fe&ale

pscopatologic profile during &enopausal transition; a preli&inar stud0Maturitas0 4557@:6(9);997-:L0 Y inEs Z

450 Parr 0 Dleep distur#ances at &enopause are related to sleep disorders andan8iet s&pto&s0 Menopause0 4557@L9(:);HL4-90 Y inEs Z

4L0 oen D, Doares , 'itonis AF, "tto M[, Carlo 0 isE for ne onset ofdepression during te &enopausal transition; te Carvard stud of &oods andccles0 Arc Gen Psciatr04556@62(9);2H:-150 Y inEs Z



2

Pdf

3

Korean Journal of Family MedicineKorean 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

Te study of te correlation of menopausal symptoms !it eart rate "aria#ility $%&'(as not #een ade)uate. Te aim of tis study !as to in"estigate te relationsip#et!een postmenopausal symptoms measured #y te menopause rating scale $M&*(and %&'.

Methods

+e assessed postmenopausal symptoms $using M&*( !it age, -M, educationalstatus, occupation, marital status, alcool and caffeine consumption, smoking istory,exercise, duration of sleep and amenorrea, degree of anxiety and depression,menarceal age, and eart rate "aria#ility. For e"aluation of %&', te record ofelectrocardiogram for / minutes in te resting state !as di"ided into temporal categoriesand fre)uency categories, and analy0ed.

Results

o significant differences in age, -M, duration of amenorrea, eart rate, systolic #loodpressure, diastolic #lood pressure, fasting #lood sugar, triglyceride, and igdensitylipoprotein !ere o#ser"ed #et!een t!o groups, !ic !ere di"ided according tomenopausal symptoms. o! fre)uency4ig fre)uency $F4%F( ratio !as significantlyiger in symptomatic !omen, compared !it asymptomatic !omen $P 5 6.6/(. osignificant differences of %&' index #y te se"erity of postmenopausal symptoms !ere

http://dx.doi.org/10.4082/kjfm.2011.32.5.299

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383141/#__ffn_sectitle

http://dx.doi.org/10.4082/kjfm.2011.32.5.299

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383141/#__ffn_sectitle



o#ser"ed. F4%F ratio of %&' parameters so!ed a significant increase in moderate orse"ere degree of 7ot flases7 and 7sleep pro#lem7 score $P 5 6.6/(. Anxiety scale insymptomatic !omen !as significantly iger tan in asymptomatic !omen $P 5 6.6/(.

Conclusion

Te a#o"e data suggest tat postmenopausal symptoms are associated !it alteredautonomic control of eart rate. n particular, ot flases and sleep pro#lems inmoderate or se"ere degree are related to increase of sympatetic 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 te postmenopausal state. %ealt management duringtis period could #e considered important #ecause it affects te entire )uality of life. 1( Menopause starts !en menstruation is terminated permanently due to loss of o"aryfunction, and its onset age is almost constant.2( n Korea, te mean age of menopauseis 9: years, and it occurs !itin /16 years around te age of 9: years. Te menopausalstate could #e #roadly di"ided into 3 stages8 premenopause, perimenopause, andpostmenopause. -ased on te last menstrual period, if te period of amenorrea islonger tan 12 monts, it is considered postmenopause. First 3 monts of amenorrea isconsidered premenopause. Perimenopause is amenorrea of 312 monts, and te"olume or fre)uency of menstruation #ecomes irregular due to estrogen deficiencyduring perimenopause.3( Many !omen present !it di"erse pysical as !ell aspsycological symptoms during perimenopause and postmenopause. Tey are referredto as climacteric symptoms or menopausal symptoms.According to te sur"ey conducted #y te Korean *ociety of Menopause, of ;6; !omen

!o under!ent natural menopause, :<= ans!ered tat tey experienced menopausalsymptoms or a"e symptoms currently.1( *uc menopausal symptoms include ot

flases, irregular eart #eats, insomnia, and fatigue, in addition to myalgia andartralgia, decreased desire, mood canges, 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 metods, suc as te>reene9( menopause index, Kupperman index, and te menopause rating scale $M&*(,etc. a"e #een used./( ?uestionnaire sur"ey metods a"e ad"antages in tat teycould #e simply and readily used for assessment of menopausal symptoms.Te #asic cause of menopausal symptoms is te complex relationsip of estrogenmeta#olism and te autonomic ner"ous system. Terefore, im#alance of te autonomicner"ous system may correlate !it menopausal symptoms. @isarmony of teautonomic ner"ous system could #e e"aluated #y measurement of eart rate "aria#ility

$%&'(.( %eart rate "aria#ility is cyclic inter"al canges of te eart rate.;( Tis is te"alue tat measures canges from one cardiac cycle to te next cycle or cange of te&& inter"al !it electrocardiogram. Te acti"ity le"el of te autonomic ner"ous systemcould #e )uantified #y analysis of eart rate "aria#ility using po!er spectral analysis$time and fre)uency domain analysis(.:(Bntil no!, study of te correlation of suc menopausal symptoms !it eart rate"aria#ility as not #een ade)uate. n tis study, te relationsip of menopausalsymptoms !it eart rate "aria#ility !as examined using a )uestionnaire sur"ey metod.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383141/#B1

























M%TH"#S

&' Study Sub(ects and )eriods

Among female patients !o under!ent pysical examination at an uni"ersity ospital or

"isited an outpatient clinic of te department of family from January 2616 to August2616, tis study !as conducted on /1 patients !ose amenorrea !as longer tan monts, #ut less tan 3 years. Cf tese, 1/ patients !ere excluded #ecause of follo!ingreasons8 past experience of medications tat may mediate an effect on %&-D ormonereplacement terapyD total ysterectomy or #ilateral ooprectomyD cases of tyroiddiseaseD cases in"ol"ing endocrine diseases suc as dia#etes, arrytmia,cardio"ascular diseaseD se"ere anemia !it emoglo#in lo!er tan 16 mg4dD and casesin"ol"ing a istory of psycological disease suc as insomnia, depression, orsci0oprenia. Te final num#er of study su#Eects !as 3.

*' Study Methods

&+ The scale o, menopausal symptoms

@ata !ere collected #y te su#Eects !o agreed to participate in te study and filled outte )uestionnaire #y temsel"es. *ocial and demograpic caracteristics of studysu#Eects, and diseases currently under treatment, past surgical istory, #ody massindex, education, profession, marital status, smoking, drinking, regular exercise, coffeedrinking, sleeping ours, age of menarce, and te amenorrea period !ere included intis )uestionnaire. n addition, for assessment of depression symptoms and anxietysymptoms, te ospital anxiety depression scale $%A@*( !as employedsimultaneously.<( Te M&* Korean "ersion, !as used to measure climactericsymptoms.16( Te M&* as #een used as an e"aluation tool for screening of

menopausal syndrome and treatments. Tis tool consists of items for total 11 symptoms,and pre"ious di"erse menopausal symptoms !ere di"ided into tree categories8psycological domain, somato"egetati"e domain, and urogenital domain.16( ac)uestion as a se"erity scale of symptoms as none $6 point(, sligt $1 point(, moderate$2 points(, se"ere $3 points(, or "ery se"ere $9 points(. Te total point is te sum of tepoints of eac )uestion, and it is distri#uted from a minimum of 6 to a maximum of 99points. %iger scores reflect se"ere le"els of symptoms. Te mean total score for Asiansis ;.2 points, psycological symptoms is 2.< points, pysical symptoms is 3.3 points, andurogenital symptoms is 1.6 point.16( n our study, / points of te M&* !as consideredas te cutoff point, and scores iger tan / points !ere classified into te group !itmenopausal symptoms. n addition, in regard to te se"erity of menopausal symptoms,69 points !ere classified as te group !it no4little symptoms, /: points as te mild

group, <1 points as te moderate group, and iger tan 1; points as te se"eregroup.16(

*+ Measurement o, HRV

To control te influence of circadian rytm, %&' !as measured in te fasting condition,after 16 minutes of sufficient rest, and #et!een : AM and 12 PM using te *A2666$Medicore, *eoul, Korea(.11( *u#Eects !ere instructed not to drink alcool on te day#efore measurement, and not to smoke on te day of measurement. For measurement,

















participants !ere seated on a cair, and an electrode !as attaced to te rigt !rist andte left ankleD measurement !as performed for / minutes in te resting state.For temporal analysis of te && inter"al cange during a period of / minutes, !emeasuered te standard de"iation of normal to normal inter"als in milliseconds $*@(,

!ic simultaneously reflects te cange caused #y te parasympatetic systemprimarily and te s)uare root of te mean s)uared differences of successi"e normal to

normal inter"als in milliseconds $&M**@(. As for te fre)uency category, te lo!fre)uency area $F, 6.696.1/ %0(, te ig fre)uency area $%F, 6.1/6.9 %0(, and teF4%F ratio !ere o#tained, and statistically analy0ed.

-+ Statistical analysis

For statistical analysis, te *P** "er. 12.6 $*P** nc., Gicago, , B*A( !as used.&egularity !as examined using te *apiro+ilk test, and, if it follo!ed te normaldistri#ution, te score difference among te groups !as analy0ed #y ttest. For casestat did not follo! te normal distri#ution, significance !as examined #y Mann+itneytest. For comparison of te symptom se"erity, te nonparametric test Kruskal+allistest !as applied. n eac analysis, a P"alue of 56.6/ !as considered statisticallysignificant.

R%S$.TS

&' Characteristics o, Study Sub(ects

Te final num#er of study su#Eects !as 3D ouse!i"es !ere most pre"alent, and all !ere married.Te Gron#ac H of M&* !as 6.:91. n te %A@*, internal consistency of anxiety scale

!as 6.<21, and internal consistency of depression scale !as 6.;6. According to testandard of M&* score, te group !it menopausal symptoms included 2 patients$;2.2=(, and te group !itout menopausal symptoms included 16 patients $2;.:=(.Te mean "alue of M&* index of te group !it menopausal symptoms and te group

!itout 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 %@ colesterol "alue did not differ significantly. n te group !itmenopausal symptoms, sleep ours !ere less and anxiety trait !as ele"ated incomparison !it te group !itout menopausal symptoms $P 5 6.6/( $Ta#le 1(.

Ta#le 1-aseline caracteristics of su#Eects.

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

Menopausal Symptoms and HRV

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383141/table/T1/?report=objectonly







Te F4%F ratio of te group !it menopausal symptoms !as found to #e significantlyiger tan tat of te group !itout menopausal symptoms $Ta#le 2(.

Ta#le 2%eart rate "aria#ility of asymptomatic !omen "s. symptomatic !omen.To examine te difference of %&' according to te le"el of climacteric symptoms, tey

!ere compared using te nonparametric Kruksal+allis test. %&' according to te le"elof climacteric symptoms did not so! 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 tose !it a lo!ertanmild le"el of ot flases,and te group !it a igertanmoderate le"el of ot flases. According to te resultscomparing differences of %&' index, te F4%F ratio !as found to #e ele"ated in tegroup !ose ot flases !ere iger tan moderate, and oter indexes of %&' #et!eente t!o groups did not differ $Ta#le 9(.

Ta#le 9

%eart rate "aria#ility according to se"erity of ot flases.

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!ertanmild le"el of sleep distur#ance, group and a igertanmoderate le"el of sleepdistur#ance group. According to te results comparing differences of %&' index, te


















F4%F ratio in a igertanmoderate le"el of sleep distur#ance group so!edstatistically significant ele"ation. Cter 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 te proprietary autonomy of te sinoatrial node and teautonomic ner"ous system. Te autonomic ner"ous system, !ic controls te sinoatrial

node, is constantly influenced #y di"erse canges of en"ironment, and te cyclic inter"alcange of eart rate tat appears at tat time is referred to as %&'. 12( Analysis of suc%&', !ic could #e used in assessing te acti"ity le"el of te autonomic ner"oussystem, could #e performed relati"ely inexpensi"elyD it is nonin"asi"e and )uantitati"eDtus, numerous studies a"e #een conducted. Gonse)uently, te task force of teuropean *ociety of Gardiology and te ort American *ociety of Pacing andlectropysiology standardi0ed te metod for measurement of %&' and itspysiological and clinical uses in 1<<.13( Glinical application of F is contro"ersialDnoneteless, F as #een used as te index of control of te sinoatrial node of te eart#y te sympatetic ner"e, and %F as te index of control of te sinoatrial #y te "agusner"e. And te F4%F ratio, !ic reflects acti"ity of sympatetic ner"es, as #een usedas te index of te #alance state of te autonomic ner"ous system.19( t as #een

reported tat te general caracteristic of %&' is so!n in general #y time domainanalysisD noneteless, fre)uency domain analysis #etter so!s te #alance state of tesympatetic ner"e and te parasympatetic ner"e.12(n tis study, te relationsip of menopausal symptoms and %&' !as examined. n temenopausal group, te F4%F ratio !as found to #e significantly ele"ated in comparison

!it te group !itout menopausal symptoms. Bntil no!, studies comparing te %&' ofyoung premenopausal !omen !it tat of postmenopausal !omen a"e reported tatte F4%F ratio !as ele"ated in postmenopausal !omen.19( %o!e"er, studiescomparing %&' of te group !it menopausal symptoms and te group !itoutmenopausal symptoms in perimenopausal and postmenopausal !oman, suc as ourresearc, a"e not #een conducted. &esults of tis study a"e so!n tat te group

!it menopausal symptoms so!ed a greater increase in sympatetic ner"e acti"ity.

o significant differences of %&' index !ere o#ser"ed according to se"erity ofpostmenopausal symptoms. &esults of tis study do not concur !it results of a studyreported #y An et al. in 266/,1/( !ic applied %&' as a standard of climactericsymptoms. Tey reported tat in te group !it se"ere menopausal symptoms, te*@ and te &M**@ !ere reduced. e"erteless, te study #y An et al.1/( as alimitation in tat te num#er of su#Eects !as small $n I 1(. Cur study also as a smallnum#er of su#EectsD tus, it is difficult to dra! a concrete conclusion in regard to teassociation of te le"el of menopausal symptoms !it %&'. *tudies !it larger num#erof su#Eects !ill #e re)uired in te future.























According to our results tat so! te association of te 11 su#categories of te M&*and te index of %&', te F4%F ratio !as found to increase in te group !ose le"elsof ot flases and sleep disorders !ere iger tan moderate. Te results concur !itresults reported #y %oikkala et al.1( in 266< tat so!ed te normali0ed F andnormali0ed %F "alue !ere different #y te le"el of ot flases. n addition, altougdirect comparison is difficult, te findings are similar to tose of te study #y &e#ecca et

al. in 266<, !ic !as on ot flases and control of te eart #y te "agus ner"e andso!ed tat %F decreased !en ot flases !ere se"ere. Cter studies and ours foundtat, according to ot flas symptoms, one of !ic is menopausal symptoms,im#alance of te autonomic ner"ous system suc as reduction of te acti"ity le"el of teparasympatetic ner"e may #e present. Te mecanism of postmenopausal sleepdisorders as not #een elucidated. %o!e"er, se"eral studies speculate tat ot flasesinduce !akefulness during sleep, resulting in cronic sleep depri"ation and fatigue.1;( Gonse)uently, deterioration of te sleep )uality lo!ers te le"el of acti"ity of teparasympatetic ner"es.12( +en te autonomic ner"ous system, !ic maintains teelectrical sta#ility of eart, is impaired, arrytmia or conse)uent deat may increase.12( Terefore, our study found tat te le"el of im#alance of te autonomic ner"ous system

!as different #y te se"erity of ot flases or sleep disorder symptoms.

Te group !it menopausal symptoms ad iger anxiety traits !it statisticalsignificance tat te group !itout menopausal symptoms. +en postmenopausalpysical symptoms manifest, anyone experiences negati"e selfesteem suc as urtpride, uselessness, lack of selfconfidence, etc.D tus, a state of emotional crisis, suc asanxiety, depression, etc. may #e induced.1:(Tis study as se"eral limitations. First, altoug /minute measurement of %&' as#een applied as a useful tool for e"aluation of te autonomic ner"ous system function,

!ic controls te eart, te area of "ery F, !ic directly so!s te le"el of acti"ity ofte sympatetic ner"ous system, could #e measured !it accuracy using 29ourmeasurement.13( *o, our study measured *@ and te F area amongmeasurements of /minute %&'D ten attempted indirect analysis. For more accuratestudies, measurement of 29our %&' is re)uired. *econd, te num#er of su#Eects !as

not sufficientD tus, te association of te le"el of menopausal symptoms !it %&' !asanaly0ed using a nonparametric testing metod. t is suggested tat studies on a largernum#er of su#Eects sould #e conducted.@espite suc limitations, our study o#ser"ed tat te presence or a#sence ofmenopausal symptoms !as associated !it %&'. Te %4%F ratio #ecame differentdepending on te se"erity of ot flases and sleep disorders, and te ele"ation ofanxiety trait and oter emotional disorders !ere o#ser"ed in te group !it menopausalsymptoms. Te association of menopausal symptoms !it cardio"ascular disease couldnot #e directly compared only #y %&'D noneteless, in cases experiencing a igertanmoderate le"el of ot flases and sleep disorders, #ased on te increase of teF4%F ratio, te increased le"el of acti"ity of te sympatetic ner"ous system could #econfirmed in our study.

Article in,ormation

Korean J Fam Med. 2611 JulyD 32$/(8 2<<36/.Pu#lised online 2611 July 2:. doi8 16.96:24kEfm.2611.32./.2<<PMG@8 PMG33:3191Jin C ee, *ung >oo Kang, *e %ong Kim, *eo Jin Park, and *ang +ook *ong









http://dx.doi.org/10.4082%2Fkjfm.2011.32.5.299

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lee%20JO%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Kang%20SG%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kim%20SH%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Park%20SJ%5Bauth%5D


http://www.ncbi.nlm.nih.gov/pubmed/?term=Song%20SW%5Bauth%5D








http://dx.doi.org/10.4082%2Fkjfm.2011.32.5.299


http://www.ncbi.nlm.nih.gov/pubmed/?term=Kang%20SG%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kim%20SH%5Bauth%5D





@epartment of Family Medicine, *t. 'incents %ospital, Te Gatolic Bni"ersity of Korea*cool of Medicine, *u!on, Korea.Gorresponding autor.

Gorresponding Autor8 *ang +ook *ong. Tel8 :23129<;:1, Fax8 :23129:;969,mail8 ss!koE4at4unitel.co.kr&ecei"ed August 36, 2616D Accepted July 12, 2611.

Gopyrigt L 2611 Te Korean Academy of Family MedicineTis is an Cpen Access article distri#uted under te terms of te Greati"e GommonsAttri#ution onGommercial icense $ttp844creati"ecommons.org4licenses4#ync43.6 (

!ic permits unrestricted noncommercial use, distri#ution, and reproduction in anymedium, pro"ided te original !ork is properly cited.Articles from Korean Journal of Family Medicine are pro"ided ere courtesy of KoreanAcademy of Family Medicine

Re,erences

1. Kim MJ, Kim J%. %o! long do menopausal ot fluses really last J Korean *oc

Menopause. 266<D1/8;3;:.2. *peroff , >lass &%, Kase >. Glinical gynecologic endocrinology and infertility. /ted. -altimore8 +illiams N +ilkinsD 1<<9.3. McKinlay *M, -ram#illa @J, Posner J>. Te normal menopause transition. Maturitas.1<<2D19816311/. OPu#Med9. >reene J>. A factor analytic study of climacteric symptoms. J Psycosom &es.1<;D26892/936. OPu#Med/. %einemann K, &ue#ig A, Pottoff P, *cneider %P, *trelo! F, %einemann A, et al.Te Menopause &ating *cale $M&*( scale8 a metodological re"ie!. %ealt ?ual ifeCutcomes. 2669D289/. OPMG free article OPu#Med. arnest GP, a"ie GJ, -lair *, Gurc T*. %eart rate "aria#ility caracteristics insedentary postmenopausal !omen follo!ing six monts of exercise training8 te @&+

study. Po* Cne. 266:D38e22::. OPMG free article OPu#Med;. ee QJ, Kim M*, Kim -T, K!ak T%, *im JQ, ee %&. %eart rate "aria#ility inmeta#olic syndrome. J Korean Acad Fam Med. 2662D2381932193<.:. Pomeran0 -, Macaulay &J, Gaudill MA, Kut0 , Adam @, >ordon @, et al. Assessmentof autonomic function in umans #y eart rate spectral analysis. Am J Pysiol.1<:/D29:8%1/1%1/3. OPu#Med<. %errmann G. nternational experiences !it te %ospital Anxiety and @epression*calea re"ie! of "alidation data and clinical results. J Psycosom &es. 1<<;D9281;91.OPu#Med16. -erlin Genter for pidemiology and %ealt &esearc. -erlin8 R> -erlinD Ocited 266<Jun 26. M&*te menopause rating scale Onternet A"aila#le from8ttp844!!!.menopauseratingscale.info .

11. Goi GJ, Goi +*, Kim K*. Te canges in eart rate "aria#ility #et!een morningand afternoon. J Korean Acad Fam Med. 266:D2<8/;</:9.12. *eo A&, Kang *>, *in J%, *ong *+. Te relationsip #et!een sleep )uality andeart rate "aria#ility in middleaged men. Korean J %ealt Promot @is Pre". 266<D<82:<2</.13. Task Force of te uropean *ociety of Gardiology and te ort American *ocietyof Pacing and lectropysiology. %eart rate "aria#ility. *tandards of measurement,pysiological interpretation, and clinical use. ur %eart J. 1<<D1;83/93:1. OPu#Med

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http://creativecommons.org/licenses/by-nc/3.0

http://www.ncbi.nlm.nih.gov/pubmed/1565019


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC516787/?report=reader







http://www.menopauserating-scale.info/



http://www.ncbi.nlm.nih.gov/pmc/about/copyright.html

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http://www.menopauserating-scale.info/




19. e"es 'F, *il"a de *a MF, >allo , Jr, Gatai AM, Martins , Grescencio JG, et al.Autonomic modulation of eart rate of young and postmenopausal !omen undergoingestrogen terapy. -ra0 J Med -iol &es. 266;D9689<19<<. OPu#Med1/. An *J, %!ang J%, Goi J, Go J%, Jang J-, ee K*. Practical use of %&' as#arometer of climacteric symptom. J Crient C#stet >ynecol. 266/D1:81<2262.1. %oikkala %, %aapalati P, 'iitasalo M, 'aananen %, *o"iEar"i A&, Qlikorkala C, et al.

Association #et!een "asomotor ot flases and eart rate "aria#ility in recentlypostmenopausal !omen. Menopause. 2616D1;831/326. OPu#Med1;. im +J. *leep in menopause. *leep Med Psycopysiol. 2662D<8<<<.1:. -eck GT. Te occurrence of depression in !omen and te effect of te !omensmo"ement. J Psyciatr urs Ment %ealt *er". 1<;<D1;8191. OPu#Med

•

9

-MG &esearc otes-ioMed Gentral

Te effect of ormone terapy on !omens )uality of life in te first year of te stonianPostmenopausal %ormone Terapy trial

Piret 'eerus, *irpaiisa %o"i, O..., and lina %emminki

Additional article informationA#stract-ackground

For postmenopausal !omen, te main reason to start ormone terapy $%T( is to reducemenopausal symptoms and to impro"e )uality of life $?C(. Te aim of tis study !as toanalyse te impact of %T on different aspects of symptom experience and ?C during a

randomised trial.

A total of 1:23 postmenopausal !omen !ere recruited into te stonianPostmenopausal %ormone Terapy $P%T( trial in 1<<<2661. +omen !ererandomised to #lind %T, openla#el %T, place#o or nontreatment arm. After one year inte trial, a )uestionnaire !as mailed and 13/< !omen $;/=( responded, : in te %Tarms and ;3 in te non%T arms. Mean age at filling in te )uestionnaire !as /<.:years. Te )uestionnaire included +omens %ealt ?uestionnaire $+%?( to assessmenopause specific ?C of middleaged !omen togeter !it a 1;item )uestionnaireon symptoms related to menopause, a )uestion a#out painful intercourse, and a)uestion a#out !omens selfrated ealt.&esults

After one year in te trial, fe!er !omen in te %T arms reported ot flases, trou#lesleeping, and s!eating on te symptom )uestionnaire. According to +%?, !omen in te%T arms ad fe!er "asomotor symptoms, sleep pro#lems, and pro#lems !it sexual#ea"iour, #ut more menstrual symptomsD %T ad no effect on depression, somaticsymptoms, memory, attracti"eness, or anxiety. A smaller proportion of !omen reportedpainful intercourse in te %T arms. Tere !ere no significant differences #et!een tetrial arms in !omenSs selfrated su#Eecti"e ealt.Gonclusions











Te results from te P%T trial confirm tat %T is not Eustified for treating symptoms,oter tan "asomotor symptoms, among postmenopausal !omen. +%? pro"ed to #e auseful and sensiti"e tool to assess ?C in tis age group of !omen.Key!ords8 &andomised controlled trial, Postmenopausal ormone terapy, ?uality of life-ackground

-ased on results from longterm randomised trials, te main indication for ormoneterapy $%T( among postmenopausal !omen is currently te treatment of menopausalsymptoms O1. At te same time, %T can a"e ad"erse outcomes, suc as "aginal#leeding and #reast tenderness O2, so its o"erall #enefit on su#Eecti"e !ell#eing can #eestimated #y comparing symptom experience as !ell as te )uality of life $?C( of

!omen using %T !it tose !o do not.

Te aim of te present study, !ic !as part of te stonian Postmenopausal %ormoneTerapy $P%T( trial, !as to determine !eter !omen recei"ing %T in a randomisedtrial experienced fe!er symptoms and #etter ?C after one year of use tan !omenrecei"ing a matced place#o or no drug. Menopause specific ?C, assessed using te

+omenSs %ealt ?uestionnaire $+%?( O3, !as defined as !omenSs perceptions of teirpysical and emotional !ell #eing. arlier, ?C as #een reported in te P%T trial atyear t!o using uro?o O3 !ic is a generic ealtrelated ?C measurement tool.

+omenSs ?C at te end of te first trial year !as assessed using a mailed)uestionnaire !ic included te +omenSs %ealt ?uestionnaire $+%?( O9, !ic as#een de"eloped to in"estigate psycological and somatic symptoms experienced #yperi and postmenopausal !omen and its psycometric properties a"e already #een

!ell documented O/,. n addition, information on selfrated ealt status, specificsymptoms related to menopause and painful intercourse !as compared among !omenin different trial arms.

n pre"ious studies, te effect of %T on ?C among postmenopausal !omen as #eenstudied in te +*@CM trial in te Bnited Kingdom and in te PP trial and te +%trial in te Bnited *tates O2,;<. All tese trials reported a positi"e effect of %T on"asomotor symptoms. Te participants in te P%T trial !ere younger tan te !omenparticipating in te +*@CM and +% trial, and te num#er of participants in te PPtrial !as relati"ely small. @espite te age differences te results from te P%T Trial areconsistent !it pre"ious findings from oter trials.Metods

+omen !ere recruited into te trial #y means of a )uestionnaire sent to all /69 yearold stonian speaking !omen in t!o areas $Tallinn and Tartu and teir surroundingcounties( in 1<<<2661 $n I 3<,;13( togeter !it an in"itation to participate in a

randomised pre"enti"e %T trial. Tey !ere sent an information leaflet containinginformation on %T a"aila#le at tat time and a detailed description of te trial, in"iting

!omen to participate in tis longterm trial studying te effects of %T on !omenSs ealt.Te names and addresses !ere o#tained from te stonian population registry. Adetailed description of te recruitment procedure, inclusion and exclusion criteria as#een pu#lised else!ere.O16 +omen !ere asked a#out teir education, li"ing area,marital status, ealt status, last menstrual period $MP(, "ie!s a#out menopause, and1; different symptoms tat a"e #een associated !it menopause. +omen !oresponded and !ere eligi#le according to te )uestionnaire data $n I 9,2</( !ere



randomised to one of te four trial arms8 eiter to #lind %T arm, place#o arm, non#lind%T arm or nontreatment arm $Figure 1(, and ten in"ited to te #aseline assessment.Figure 1Figure 1P%T trial flo! cart.

For te present analysis, !omen in te #lind and te non#lind %T arms !ere com#inedand tese arms !ere named %T arms, !ereas !omen participating in te place#o andte nontreatment arm !ere analysed togeter and tis group !as named non%T arms.From te 2,3:3 !omen !o came to see te trial pysician, 1,:23 !ere recruited aftersecondary assessment of eligi#ility $<1: to te %T arms and <6/ to te non%T arms(.

&egardless teir ysterectomy status $13= of !omen ad undergone su#totalysterectomy(, !omen in te %T arms recei"ed 6.2/ mg conEugated oestrogen $G(plus 2./ mg medroxyprogesterone acetate $MPA(, or 6.2/ mg G and / mg of MPA iftey !ere !itin 3 years from teir last period. +omen in te non%T arms recei"edeiter place#o or no treatment. At te end of te first trial year, nearly alf of te !omenin te %T arms reported to a"e used more tan :6= of teir trial medication, and

anoter 3;= !ere of medium aderence using 16;<= of allocated treatment. n tenon%T arms, "ery fe! !omen $2= used it for more tan :6= of trial duration( started%T, mainly due to menopausal symptoms O11.

After one year in te trial !omen recei"ed a postal )uestionnaire and 1,3/< $;9./=(responded, : in %T and ;3 in non%T arms. +omen !ere asked a#out symptomsrelated to menopause !it a 1;item symptom list $te same as at #aseline(, and a#outmenopause specific ?C using te +%?, te same "ersion as used in te BK in te+*@CMtrial O;. *elfrated ealt status !as to #e ranked as "ery good, good,moderate, satisfactory, poor, or "ery poor.

Te +%? is a 3 item scale de"eloped to measure emotional and pysical symptoms in

middleaged !omen and it contains nine su#scales. Te +%? !as translated intostonian #y t!o stonian researcers !it good nglis skills. Te feasi#ility of tetranslation !as tested #y a fe! stonian lay !omen aged /6/ years, and tey ad nodifficulties completing on te )uestionnaire. ater, te )uestionnaire !as #acktranslatedinto nglis #y a nati"e nglis speaking stonian translator. Te +%? su#scalesinclude8 depressed mood $; items(, anxiety4fears $9 items(, sleep pro#lems $3 items(,somatic symptoms $; items(, menstrual symptoms $9 items(, "asomotor symptoms $2items(, memory4concentration $3 items(, attracti"eness $2 items(, sexual #ea"iour $3items(. Te attracti"eness su#scale includes )uestions a#out selfesteem. Te)uestionnaire ans!ers a"e a 9point scale8 1 I yes, definitely, 2 I yes, sometimes, 3 Ino, not muc and 9 I no, not at all. According to te scale autorSs recommendation,item scores are transformed into a dicotomous scale8 if te response is 1 or 2, it is

scored 6. f te response is 3 or 9, it is scored 1. For eac su#scale te mean iscalculatedD 6 is interpreted as good and 1 as poor )uality of life. For certain items tescoring is re"ersed as some items are !orded positi"ely and some negati"ely O.

Te statistical significance of te differences #et!een te different arms !as determinedusing ttest, 2tests, +ilcoxon rank sum tests, and odds ratios !it </= confidenceinter"als. All analyses !ere done #y intentiontotreat principle. o adEustment !as usedduring te statistical analysis. Gorrelation #et!een sleeping pro#lems and "asomotor



symptoms !as assessed #y Pearson correlation coefficient. Te soft!are used !as*A* "ersion <.&esults

Te o"erall response rate to te first year )uestionnaire !as ;9./=. Tere !ere nodifferences #et!een te trial arms in response rate. n te #lind %T arm, 31/ !omen

$;/.<=(, in te place#o arm, 2;: !omen $;3.6=(, in te non#lind %T arm, 3;1 !omen$;3.:=(, and in te nontreatment arm, 3</ !omen $;/.9=( returned te mailed)uestionnaire.

Tere !ere no differences #et!een te respondents in different trial arms regarding teireducation $3/= ad a uni"ersity degree(, marital status $3= #eing married orcoa#iting( or years since menopause $a#out one tent of !omen !ere !itin 3 yearsfrom menopause( $Ta#le (Table1).1). The mean age of respondents in the HT arms wasstatistically significantly lo!er tan tat in te non%T arms $/<./ "ersus 6.1 years, *@9.6(, still te median age of respondents !as te same in %T and non%T arms andtere !as no difference #et!een te trial arms as regards time since menopause. Also,te mean age of all !omen participating in te %T arms of te trial !as a #it lo!er tan

tose in te non%T arms. @etailed #aseline caracteristics of trial participants arepresented else!ere O16.Ta#le 1Ta#le 1Gomparison of first year sur"ey respondentsS #ackground caracteristics in different trialarms, P%T Trial

Te means for te +%? scales !ere compared at te end of te first trial year indifferent arms $Ta#le (Table2).2). Women in HT arms had better scores for "asomotorsymptoms $p 5 6.6661(, sleep pro#lems $p I 6.66/( and sexual #ea"iour $p I 6.661(. Aseparate analysis so!ed tat !omen !it "asomotor symptoms tended to report sleeppro#lems $r I 6.2:, p 5 6.661(, in %T arms $r I6.2<, 56.661( as !ell as in non%T arms $r

I 6.2/, p 5 6.661(.Ta#le 2Ta#le 2?uality of life according to mean scales of +%? at te end of te first trial year, P%TTrial

Tere !as no difference in te mean +%? scales for depressed mood, somaticsymptoms, memory4concentration, anxiety4fears, and attracti"eness su#scales.%o!e"er, !omen in %T arms ad iger mean scales for menstrual symptoms $p I6.62(.

+en asking a#out specific symptoms !itin past t!o !eeks, fe!er !omen in te %T

arms reported s!eating $C& I 6.<D </=G8 6.//6.:(, trou#le sleeping $6.3D6.9<6.:6(, and ot flases $6.2:D6.216.3;( at te end of te first trial year, compared !it

!omen in te non%T arms $Ta#le (Table3).3). There were no differences in thereporting of other symptoms. In general the symptoms tat !ere most often reported #yrespondents !ere aces or stiffness in Eoints, lack of energy and #ackace.Ta#le 3Ta#le 3um#er and proportion of !omen reporting symptoms !itin past t!o !eeks at te endof te first trial year in different trial arms, P%T Trial



At te end of te first trial year, "ery fe! !omen complained a#out painful intercourseDtose in %T arms reported painful intercourse less fre)uently tan !omen in te non%Tarms $p 5 6.69(, !ile te num#er of !omen !o !ere not sexually acti"e $a#out one)uarter( !as nearly te same in all arms of te trial $Ta#le (Table44).Ta#le 9

Ta#le 9um#er and proportion of !omen reporting painful intercourse during te first trial yearin different trial arms, P%T Trial

Tere !ere no differences #et!een te trial arms in selfrated 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 theirhealth to be poor or "ery poor !as "ery small.Ta#le /Ta#le /+omenSs selfrated ealt status in different trial arms at te end of te first trial year,P%T Trial

@iscussion

+omen participating in te P%T Trial !ere generally younger tan tose in te +%and +*@CM trials O2,;,:,16. Te results from tese trials so! tat %T impro"esspecific symptoms of menopause. %o!e"er, no effect of %T on selfrated ealt statusor any oter psycological $anxiety, depressed mood, memory4concentration( or somaticsymptom !as o#ser"ed.

Te mean age at recruitment in te P%T trial !as /< years, !ereas in te +*@CMtrial it !as 9 years O;. Te response rate in te P%T trial !as ;/= compared to te/;= in te BK trial. Te same +%? )uestionnaire !as used #ot in te P%T trial andin te +*@CM trial to assess ealt related ?C. Gom#ined %T started after

menopause reduced "asomotor symptoms, sexual and sleep pro#lems #ot in te+*@CM trial and in te P%T trial after one year of use. *imilarly in #ot trials, nosignificant differences !ere found in oter menopausal symptoms, depression, or o"erall)uality of life O;.

Te mean age in te +% trial at recruitment !as 3 years. Te response rate todifferent )uestions ranged from :;= to <6= in te +% trial. ?C !as assessed !itte use of te &A@ 3item ealt sur"ey. n te +% trial, more !omen assigned tocom#ined %T and symptomatic at #aseline reported relief of ot flases, nigt s!eats,"aginal dryness at te end of te first trial year, #ut !omen in %T arms !ere more likelyto de"elop #reast tenderness, "aginal discarge, and eadaces O2. %T ad no effecton depression, somatic symptoms, memory, or anxiety O2. Te use of %T !as not

associated !it a meaningful #enefit in ?CD tere !as only a small #enefit in terms ofsleep distur#ance, pysical functioning, and #odily pain after one year in trial O:. 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 sleepdistur#ance, #ut not in oter )ualityoflife outcomes O:.

Te mean age of !omen participating in te PP Trial !as /.1 years at #aseline, and/2 symptoms !ere selfreported according to a cecklist at year one and tree. Te:;/ !omen participating in te trial !ere assigned to one of te fi"e trial arms, and



analysis !as restricted to aderent !omen only. o #aseline assessment of symptoms !as reported. Te results from te PP trial suggested a protecti"e effect ofpostmenopausal %T for "asomotor symptoms, an increase in #reast discomfort amongusers of progestincontaining regimens, and little influence on anxiety, cognition, oraffect O<.

Tus te results of te current study add to te findings of pre"ious researc and confirmte pattern of results tat appears to #e consistent for a range of ages of !omen starting%T. Te current P%T results are also similar to tose reported after te second trialyear of te P%T trial except for painful intercourse O12. At te end of te first trial year,painful intercourse !as impro"ed #y %T, !ereas at te end of te second trial year, teeffect !as re"ersed O12. A possi#le reason for tis could #e te decrease in aderencerates #et!een te first and second yearsD at te end te first trial year, te proportion of

!omen taking more tan :6= of allocated drugs in treatment arms !as 9= !ereas atte end of te second trial year it !as 32= O11. All analyses !ere done according tointentiontotreat principle.

Te +%? !as used in te stonian language for te first time, and it pro"ed to #e a

useful and sensiti"e tool to assess )uality of life in tis specific age group of !omen. ncontrast te uro?o )uestionnaire, !ic measures generic ealt related ?C, tat

!as used at te end of te second trial year of te P%T trial did not detect anydifferences #et!een te trial arms O12. ncluding #ot menopause specific and generic?C measures is recommended for )uality of life measurements in tis target group.

To examine te impact of #linding on recruitment, randomisation occurred #efore signingte informed consent. A large num#er of randomised !omen declined teir participationand did not enter te trial, #ut since tis appened #efore recruitment, it could a"e not#een related to teir treatment allocation. At recruitment, tere !ere no #aselinedifferences in te 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 te non#lind %T armtan in te nontreatment arm O12. Tere !ere no differences #et!een #ackgroundcaracteristics of te !omen in four trial arms O16,12. Cne of te limitations of tis studyis tat ?C !as not assessed at #aseline. +e presume tat tere !ere no significantdifferences #et!een te trial arms in tat aspect due to randomisation. o! aderencerates may a"e diluted to some extent te differences #et!een te trial arms.

Te differences in te results of te menstrual pro#lems $+%? su#scale( #et!een %Tand non%T groups at one year are likely to reflect "aginal #leeding, caused #y %T.Terefore, tey !ere not regarded irrele"ant for postmenopausal !omen and !ereincluded in te present analysis. Pre"ious analysis so!ed tat %T increased te risk of#leeding su#stantially O12. Cur )uestionnaire did not include )uestions on oter ad"erse

e"ents of %T, suc as #reast tenderness, #ut tese a"e #een te most often citedreasons for nonaderence to %T in earlier studies O11.Gonclusions

n te ligt of pre"ious researc in tis area, te results from te P%T trial confirm tat%T is not Eustified for treating symptoms oter tan "asomotor symptoms amongpostmenopausal !omen. Cur study so!s tat many symptoms tat are often attri#utedto menopause, suc as psycological and pysical symptoms, are not canged #y %T



and terefore %T sould not #e recommended as a treatment for tese symptoms !icare likely to a"e oter causes.

+%? allo!ed a detailed insigt on "arious aspects of life )uality of in tis target group. tcould #e used more !idely in e"aluations of medical and nonmedical inter"entionsamong peri and postmenopausal !omen.

A"aila#ility of supporting data

Ad"antages and disad"antages of postmenopausal ormone terapy8 a pre"enti"e trial te stonian Postmenopausal %ormone Terapy trial. ttp844!!!.controlledtrials.com4*&GT3/33:;/;43/33:;/;

%o"i *irpaiisa. Pre"enti"e Trial on Postmenopausal %ormone Terapy in stonia. Astudy of treatment preferences and trial process !itin a canging en"ironment.ttp844!!!.stakes.fi4"erkkoEulkaisut4muut4Tu1/;*takes266.pdf

'eerus Piret. Te impact of postmenopausal ormone terapy on ealt and use ofealt ser"ices8 experience from te stonian Postmenopausal %ormone Terapy

$P%T( trial. ttp844acta.uta.fi4pdf4<;:</199;139.pdfAutorsS contri#utions

P' accepts full responsi#ility for te !ork and for te conduct of te study, ad fullaccess to all data, and controlled te decision to pu#lis. P', *% and % areresponsi#le for te study concept and design, P' and *% for ac)uisition of data. T*,M%, P', *% and % contri#uted to te data analysis and interpretation of data, *%and P' drafted te manuscript and all autors read and appro"ed te final manuscript.Gompeting interests

All autors declare tat tey a"e no competing interests.@etails of tics Appro"al

Te trial design !as appro"ed #y Tallinn Medical &esearc tics Gommittee, stoniaon January 22, 1<<: $appro"al o 2(. All participants ga"e !ritten informed consent.Ackno!ledgements

+e sincerely tank eac and e"ery !oman for teir participation in te trial. +e alsotank te colla#orators from te clinical centres and from te ational nstitute for %ealt@e"elopment in stonia and from te ational nstitute for %ealt and +elfare inFinland.

Te trial !as funded #y te Academy of Finland $grants o <:3:, 2619<6(, *TAK*$ational &esearc and @e"elopment Gentre for +elfare and %ealt( in Finland, and te

stonian Ministry of ducation and &esearc $target funding no *F6<9662s6;(. Tefunding #odies ad no role in te study design, data collection, data analysis, datainterpretation, !riting of te report or in te decision to su#mit te paper for pu#lication.Article information-MG &es otes. 2612D /8 1;.Pu#lised online 2612 April 3. doi8 16.11:41;/6/66/1;PMG@8 PMG339<9/Piret 'eerus,corresponding autor1,2 *irpaiisa %o"i,3 Tiina *e"Un,9 Myra %unter,/and lina %emminki9,



1@epartment of epidemiology and #iostatistics, ational nstitute for %ealt@e"elopment, %iiu 92, 111<, Tallinn, stonia2%Eelt nstitute, Bni"ersity of %elsinki, PC -CV 96 $KytWsuontie 11(, F66619 Bni"ersityof %elsinki, %elsinki, Finland3ational nstitute for %ealt and +elfare $T%(4Finnis Cffice for %ealt TecnologyAssessment $Finota(, PC- 36 $intuladenkuEa 9(, F662;1, %elsinki, Finland

9ational nstitute for %ealt and +elfare $T%(, PC- 36 $intuladenkuEa 9(, F662;1,%elsinki, Finland/@ept Psycology, nstitute of Psyciatry $>uySs Gampus(, KingSs Gollege ondon, *1<&T, ondon, BKTampere *cool of Pu#lic %ealt, F33619, Bni"ersity of Tampere, Tampere, Finlandcorresponding autorGorresponding autor.Piret 'eerus8 piret."eerus4at4tai.eeD *irpaiisa %o"i8 sirpaliisa.o"i4at4tl.fiD Tiina *e"Un8tiina.se"on4at4otmail.comD Myra %unter8 myra.unter4at4kcl.ac.ukD lina %emminki8elina.emminki4at4tl.fi&ecei"ed August 29, 2611D Accepted April 3, 2612.Gopyrigt L2612 'eerus et al.D licensee -ioMed Gentral td.Tis is an Cpen Access article distri#uted under te terms of te Greati"e Gommons

Attri#ution icense $ttp844creati"ecommons.org4licenses4#y42.6(, !ic permitsunrestricted use, distri#ution, and reproduction in any medium, pro"ided te original

!ork is properly cited.Articles from -MG &esearc otes are pro"ided ere courtesy of -ioMed Gentral&eferences

*cenck>ustafsson K, -rincat M, rel GT, >am#acciani M, am#rinoudaki , MoenM%. et al. MA* position statement8 Managing te menopause in te context ofcoronary eart disease. Maturitas. 2611D:8<9;. OPu#Med -arna#ei 'M, Gocrane --, Aragaki AK, ygaard , +illiams &*, Mc>o"ern P>. etal. Menopausal symptoms and treatmentrelated effects of estrogen and progestin in te+omenSs %ealt nitiati"e. C#stet >ynecol. 266/D16/8163;3. OPu#Med

. ?/@. 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*. Te +omens %ealt ?uestionnaire8 a measure of midaged !omensperceptions of teir emotional and pysical ealt. Psycol %ealt. 1<<2D;89//9. %unter M*. Te !omens ealt )uestionnaire $+%?(8 te de"elopment,standardi0ation, and application of a measure of midaged !omens emotional andpysical ealt. ?ual ife &es. 2666D<8;33:. %unter M*. Te +omenSs %ealt ?uestionnaire $+%?(8 fre)uently asked )uestions$FA?( -MG %ealt ?ual ife Cutcomes. 2663D1891. OPMG free article OPu#Med +elton AJ, 'ickers M&, Kim J, Ford @, a!ton -A, Macennan A%. et al. %ealtrelated )uality of life after com#ined ormone replacement terapy8 randomisedcontrolled trial. -MJ. 266:D33;8a11<6. OPMG free article OPu#Med

%ays J, Cckene JK, -runner &, Kotcen JM, Manson J, Patterson &. et al. ffectsof strogen plus Progestin on %ealt&elated ?uality of ife. JM. 2663D39:81:3</9.OPu#Med >reendale >A, &e#oussin -A, %ogan P, -arna#ei 'M, *umaker *, Jonson *,-arrettGonnor . *ymptom relief and side effects of postmenopausal ormones8 resultsfrom te Postmenopausal strogen4Progestin nter"entions Trial. C#stet >ynecol.1<<:D<28<:2:. OPu#Med



'eerus P, %o"i *, Fiscer K, &au M, %akama M, %emminki . &esults from testonian Postmenopausal %ormone Terapy $P%T( Trial O*&GT3/33:;/;Maturitas. 266D//812;3. OPu#Med 'oro#Eo" *, %o"i *, 'eerus P, Pisare" %, &au M, %emminki . Treatmentaderence in te stonian postmenopausal ormone terapy trial O*&GT3/33:;/;Maturitas. 266/D/282:</. OPu#Med

'eerus P, Fiscer K, %o"i *, Karro %, &au M, %emminki . *ymptom reporting and)uality of life in te stonian Postmenopausal %ormone Terapy Trial. -MG +omenSs%ealt. 266:D:8/. OPMG free article OPu#Med

/

Arci"es of >ynecology and C#stetrics*pringerTe symptomatology of climacteric syndrome8 !eter associated !it te pysicalfactors or psycological disorder in perimenopausal4postmenopausal patients !itanxietydepression disorder

-orong Rou, Viaofang *un, O..., and JiaEia %u

Additional article informationA#stractPurpose

To explore !eter te symptoms of climacteric syndrome associated !it its pysicalfactors or psycological disorder in perimenopausal4postmenopausal patients !itanxietydepression disorder.Metods

+e recruited ;: climacteric patients !it anxietydepression disorder and ;2 control

participants in perimenopausal4postmenopausal !itout anxietydepression disorder fortis study. +e measured symptoms using te >reene Glimacteric *ymptom *cale in allcases. +e also collected demograpic data and tested sexual ormone, #lood pressure,#one density, cogniti"e, estrogen receptoralpa $&H( gene polymorpism aspysiological factors, using %A&*19 and G%@* assessed psycological disorderdegree.&esults

GMM* scores as !ell as stradiol and progesterone le"els in te anxietydepressiondisorder group !ere significantly lo!er compared to te control group $P 5 6.61(. naddition, te anxietydepression disorder group ad significantly iger >reeneGlimacteric *cale scores, as !ell as somatic symptoms compared to controls $P 5 6.61(.

Moreo"er, te anxiety, depression and somatic symptoms of te >reene Glimacteric*cale !ere positi"ely correlated !it %A&*19 and G%@* scores $P 5 6.661( andnegati"ely !it estrogen le"el and GMM* scores $P 5 6.6/( in te anxietydepressiondisorder group. >reene Glimacteric *cale *ymptoms !ere not significantly correlated

!it #lood pressure, #one density or oter factors $P X 6.6/(. Tere !as no significantcange in te allele fre)uency or te estrogen receptoralpa gene polymorpisms,#et!een te t!o groups $P X 6.6/(D o!e"er, te Pp genotype !as negati"elyassociated !it GMM* scores $r I appraises, P I 6.633(.imitations



Te sample si0e !as relati"ely small.Gonclusions

Te symptoms of somatic symptoms in patients !it climacteric syndrome and anxietydepression disorder are associated !it te emotional disorder #ut not !it a pysical

disease. Te Pp &H polymorpism P"u is associated !it a cogniti"e decrease.Key!ords8 Glimacteric, Anxietydepression, *omatic symptoms, Gogniti"e, Pysicaldiseasentroduction

+omen in perimenopausal or postmenopausal, !it te gradual degradation of o"arianfunction in te female ormone decreasing, can appear some pysiological andpsycological aspects of symptoms, main performance8 ot, s!eaty, tired, eadace,di00iness, num#, sore lim#s, attention poor, anxious and ner"ous, insomnia, moods!ings, and sorro! depression, clinical called Ymenopause syndromeZ or YclimactericsyndromeZ O1, 2. @epression or anxiety or depression com#ined anxiety $anxietydepression( is a common psycological disorder in menopausal !omen. n *+A 2616,

1:= of elderly !omen ad psycological disorders O3, and anxietydepression inaddition to a"e maEor depression, dropping interest, outside selfe"aluation, anxiety,ner"ousness, tendency to get angry, and also may #e associated !it fatigue, insomnia,inattention, memory loss, pain and so on menopause syndromelike symptoms. T!odiseases a"e common some syndromes caracteristic $especial somatic syndrome(easily confused in clinic, #ut also a"e difference risk for ealty. Altoug emotionaldisorders occur fre)uently in climacteric syndrome, climacteric syndrome tat se"erelycompromises life and !ork is rare. n contrast, anxietydepression disorder as seriousrisk for !omen O9. Cn te oter and, decline in te ealt of patients $e.g.,ypertension and osteoporosis( often accompanies mild cogniti"e dysfunctions O/, 1:,26. *ome patients are excessi"ely concerned a#out teir ealt and "isit clinicsfre)uently, !ic can lead to many misdiagnoses and !aste medical resources O, ;.

@o tese patients a"e multisystem symptoms resulted from somati0ed anxietydepression disorder or from truly organic diseases

&eports on syndromes caracteristic patients !it anxietydepression disorder inperimenopausal are limited. Are te multisystem symptoms of patients !it anxietydepression disorder in perimenopausal4postmenopausal as se"ere as teirpsycological ones Tis )uestion needs to #e in"estigated furter. strogen receptor$&( polymorpisms are associated !it many disorders including Al0eimerSs disease$A@(, osteoporosis and coronary eart disease O:11D o!e"er, little is kno!n a#out teassociation #et!een & polymorpisms and anxietydepression comor#id !itclimacteric syndrome. n tis study, !e analy0ed & polymorpisms, sex ormonele"els, psycological symptoms, cogniti"e function, #lood pressure, #one density,

menopausal transition $MT( stages and diseases course #ased on te >reeneGlimacteric *cale categories O12. Tis study !ould #e to recognise syndromescaracteristic and pro"ide te teoretical #ase for te early diagnosis of depression oranxiety in perimenopausal4postmenopausal.MetodsParticipants and sampling

-ased on our study aim and re)uirements for statistical analyses, #et!een 266; and2616, !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 te follo!ing definitions8 perimenopausal

!omen a"ing irregular menses, less tan 12 menses during te last 12 monts andpostmenopausal8 no more menses in te last 12 monts. All participants meet te*tages of &eproducti"e Aging +orksop $*T&A+( criteria for peri4postmenopause, MTscore of *T&A+ #e [1 to \2 O2, com#ined !it at least one symptom of climacteric

syndrome. Te age range of tis sample !as 966 years old. xclusion criteria of Allparticipants undergoing ormonal terapy, ormone terapy #y implant in te preceding monts, endocrinopaties leading to menstrual irregularities, epatopaties,trom#opaties, use of drugs !ic interfere in te menstrual cycle, anxiolytics andantidepressants $as teir use indicates pre"ious diagnosis of mood disorders(,ysterectomy, ooporectomy, cancer or psyciatric disease or oter se"erely organicdiseases. Tis study !as appro"ed #y te institutional re"ie! #oard of te TirdAffiliated %ospital of >uang0ou Medical Gollege $>uang0ou, Gina( and !ritteninformed consent !as o#tained from e"ery participant.

+e placed participants in te anxietydepression group using te anxiety anddepression diagnosis standard listed in G@16 O13. Te criteria include te follo!ing8 $1(

use of te %amilton Anxiety &ating *cale19 items $%A&*19( O19, 1/ and te Ginese"ersion of te 1;item %amilton @epression &ating *cale $G%@*( O1, all patients%A&*19 scores ]19 and or G%@* ]1;D $2( experience of maEor anxiety symptoms for atleast 3 monts or maEor depression symptoms for at least 2 !eeksD and $3( decline infunctioning at !ork and ome. Bsing tese standards, !e recruited ;: patients !itmaEor anxiety and or depression symptoms as anxietydepression group, of !om /:ad mixed anxiety and depression disease$MA@@, G@16 code F91.2(, 13 of !om adanxiety only $G@16 code F91.:( and ; of !om ad depression only $G@16 codeF32.6(.Te a"erage age of tese patients !as /2.19 ^ /.;9 years. Altougsomati0ation disorder is a somatoform disorder tat o"erlaps !it a num#er of functionalsomatic syndromes and as ig comor#idity !it maEor depression and anxietydisorders O1;. Te study anxietydepression patients !ere not coincided !it

somati0ation or somati0ation form disorder diagnosis criterion $G@16 code F9/.6,F9/.1(.Procedure

+e recorded patient demograpic information including age, education, disease courseand menopausal status. ducation le"el !as defined as time spent in scool. @iseasecourse !as defined as te duration of teir symptoms in yearsD a disease course of o"er monts !as considered to #e 1 year. Menopause !as defined as te cessation ofmenses for o"er 12 monts according to *&TA+ O2. Te early postmenopausal cases

!as 2 $33.33=( and 2: $3:.:<=( in anxietydepression group and control group. Tere !ere no difference #et!een tem $P 5 6.61(. +e used te %A&*19 and G%@* todetermine anxiety and depression le"els O191.

Te >reene Glimacteric *cale

+e analy0ed te caracteristics of climacteric syndrome #ased on te >reeneGlimacteric *cale. n 2616, te "alidation and relia#ility of >reene Glimacteric *cales$"alidation 6.:6.;, relia#ility 6.:36.:; in Ginese population( !as reported #y Renget al. in %ongKang. Te >reene Glimateric *cale measures a total of 21 symptoms$Ta#le 1( O12, 1:. ac symptom is rated #y te !oman erself according to its currentse"erity using a fourpoint rating scale8 notatall symptoms $6(D a little symptoms $1(D



)uite a #it symptoms $2(D extreme symptoms $3(. Te >reene Glimacteric *cale scoresinclude 21 items scores and an indi"idual score !itin fi"e symptom clusters8 $1( anxietysymptoms $symptoms 1(, $2( depression symptoms $symptoms ;11(, $3( somaticsymptoms $symptoms 121:(, $9( "asomotor symptoms $symptoms 1<26( and $/(sexual function $symptoms 21(. Te mean score for eac symptom is calculated #y tesum of all indi"idual scores di"ided #y te num#er of su#Eects. Te mean score of eac

symptom clusters are te mean scores of te symptoms !itin tat cluster.Ta#le 1Ta#le 1>reene Glimacteric *cale score comparisons #et!een te anxietydepression groupand te control group $x ^ s(

Te organic diseases diagnosis !as #ased on te 266; *%*G $uropean *ociety of%ypertensionuropean *ociety of Gardiology( Practice >uidelines O1<, te 266<Csteoporosis >uidelines O26, 21 and te standard for early detection of dementia,including mild cogniti"e impairment O22, #lood pressure, poor recognition a#ility and lo!#one density. Cur study used te Ginese Mini Mental *tate xamination $GMM*(O23, 29 to assess te patient recognition function and te Fan -eam Vray -one

@ensitometer to assess #one density. +e measured realtime #lood pressure o"er 29 to calculate patientsS a"erage systolic and diastolic measurements.

*exual ormone determination

+e measured estradiol $2(, progesterone and testosterone le"els using radioacti"eimmunoassays. Periperal "ein #lood !as collected #et!een ;866 and :866 am. -loodfrom nonmenopausal !omen !ere collected 3 days after teir menstrual cycles. Te"ariation of estradiol, progesterone and testosterone le"els !itin anyone group !as /.,;.2 and :.61=, respecti"ely. Te differences of estradiol, progesterone and testosteronele"els #et!een te groups !ere ./, ;.: and :./=, respecti"ely. Te sensiti"ity of eac*A assay !as 6.61, 6.661 and 6.6661 pg4ml, respecti"ely.

Te analysis of polymorpisms in &H genes, P"u and V#a primer design andsyntesis

Te se)uence for te estrogen receptors is as follo!s8 P18 /_GT>GGAGGGTATGT>TATGTTTTGGTATTGTGG3_D and P28 /_TGTTTGTGT>GGAGGGT>>G>TG>ATTATGT>A3_. n descending order, te @Amolecular !eigt $Mark *en0en, Qisengtang -iological nterprises td.( of tesereceptors are 2,666 #p41,66 #p41,266 #p4:66 #p466 #p4966 #p4266 #p.

Te metod for genotyping estrogen receptors uses tree steps. $1( +ole genomic@A !as extracted using te fast extraction metod. $2( A polymerase cain reaction

$PG&( !ere te total reaction estrogen receptor "olume !as /6 ` and comprised 39.3` sterile deioni0ed !ater, / ` 16 PG& #uffer, 266 bmol4 dTP 9 `, 96 pmolprimers, 166 ng @A template and 1 B Ta)@A polymerase. &eaction conditionsconsisted of a denature step at <9G for 3 min, follo!ed #y 3/ cycles of <9G for 36 s,1G for 96 s, ;2G for <6 s, and a final extension at ;2G for / min. Te extensionproduct si0e !as 1.3 k#. $3( Finally, a restricted en0ymatic reaction !as performed using B P"u and 16 B V#a for en0ymatic digestion, follo!ed #y a 1.2 agarose gel !itetidium #romide electroporesis for 96 min, !ic !as ten potograped.



T!o professional psycologists tested patientsS neurological and psycological statuses.Prior to tese tests, #ot psycologists !ere trained to adEust and unify teir standards.*tatistical analysis

All data !ere recorded as mean ^ standard de"iation $x ^ s(. +e used *P** 1;.6soft!are for all statistical analyses. $1( AC'A and AGC'A ranksum tests $i.e.,

"ariance arrytmias( analy0ed te demograpic and symptomatic differences #et!eente anxietydepression group and te control group. $2( PearsonSs correlation analy0edte relationsips #et!een symptoms, psycological scores and pysiological status. $3(Gis)uare tests analy0ed te fre)uency of estrogen receptoralpa polymorpisms. $9(Multifactorial logistic analyses analy0ed te relationsip #et!een te &H polymorpismand oter symptoms suc as sex ormone le"els, psycological scores $%A&*19 andG%@*( and cogniti"e functions. A P "alue of less tan 6.6/ !as considered significantlydifferent.&esults@ifferences in demograpic information, %A&*19, G%@*, GMM*, >reeneGlimacteric *cale scores and sexual ormone le"els #et!een groups

As so!n in Ta#le 1, tere !ere significant differences #et!een te anxietydepressiongroup and te control group $P 5 6.661( in all areas except difficulty in concentrating andsexual interest. Te "asomotor symptoms scores as !ell as te facial redness ande"ening s!eating scores for te anxietydepression group !ere significantly lo!er $P 56.6/( compared to te control groupD all oter anxietydepression group scores !ereiger tan te control group $P 5 6.61(. As so!n in Ta#le 2, te >reene climacteric*cale scores of anxiety, depression and somatic symptoms !ere significantly iger inte anxietydepression group $P 5 6.661( compared to control group, altoug te"asomotor symptoms scores !ere significantly lo!er $P 5 6.6/(. Te %A&*19 andG%@* scores of te anxietydepression group !ere significantly iger tan te controlgroup $P 5 6.661( !ereas te 2 and progesterone le"els !ere significantly lo!er $P 56.661(. Te cutoff score for te statistics in Ta#le 2 is 2; $mild cogniti"e difficulty O21.

An AGC'A rank sum test $"ariance arrytmias( so!ed tat te GMM* score inte anxietydepression group !as significantly lo!er tan te control group $P 5 6.61(.Tere !ere no significant differences in age, testosterone le"el, #one density, systolicand diastolic #lood pressure #et!een te t!o groups.Ta#le 2Ta#le 2Gomparison of >reene Glimacteric *cale, %A&*19, G%@*, and GMM* 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 generalcondition, psycological score, #one density, a"erage #lood pressure in anxietydepression disorder group

As so!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&*19 and G%@* scores $P 5 6.661( as !ell as negati"e correlations #et!een2 and progesterone le"els and GMM* scores $P 5 6.6/( !itin te anxietydepression group. Tere !as also a positi"e correlation #et!een education years in teanxietydepression group. Tere !as an additional correlation #et!een "asomotorsymptoms and %A&*19 scores, !ereas sexual factors !ere correlated !it G%@*scores $P 5 6.6/(. Tere !as no significant correlation #et!een >reene Glimacteric



*cale scores and #lood pressure, #one density, menopause, disease course or oterfactors $P X 6.6/(.Ta#le 3Ta#le 3Gorrelation analysis #et!een te >reene Glimacteric *cale symptoms !it generalcondition, psycological score, #one density and a"erage #lood pressure in anxiety

depression disorder groupPolymorpism analyses on te &H gene

+e used P, pV or x to indicate restriction en0ymes. o!ercase letters indicated tedigestion sites of te en0yme, !ereas capital letters indicated te a#sence of restricteden0yme sites. Te P"u restriction en0yme distinguises #et!een tree genotypes8 PP$1.3 k#(, Pp $1.3 k# \ :/6 #p \ 9/6 #p( and pp $:/6 #p \ 9/6 #p(. Te V#a restrictionen0yme distinguises #et!een tree genotypes8 VV $1.3 k#(, Vx $1.3 k# \ <16 #p \ 3<6#p(, and xx $<16 #p \ 3<6 #pD Fig. 1(.Fig. 1Fig. 1eft te endonuclease P"u distinguised tree genotypes8 PP $1.3 k#(, pp $:/6 #p \

9/6 #p( and Pp $1.3 k# \ :/6 #p \ 9/6 #p(. &igt te ndonuclease V#a ...& gene polymorpisms and te allele fre)uency distri#ution

Ta#le 9 so!s te allele fre)uency of te &H P"u and V#a polymorpisms. Te allelefre)uencies of te studied sample !ere consistent !it te %ardy+ein#erg >enetice)uations and representati"e populations. Te genotype distri#ution in te anxietydepression group !as PP1;.</=, Pp3<.;9=, pp92.31=, VV16.2=, Vx32./6= andxx/;.<=. Te allele fre)uency for P and V is 3;.:1 and 2.2:=, respecti"ely. -otgroups a"e a maEority of p and x gene sites. As so!n in Ta#le 9, tere !ere nosignificant differences #et!een te anxietydepression and control groups in tegenotypes of te &H P"u or V#a polymorpisms.Ta#le 9

Ta#le 9Te analysis of &H P"u genotypes and allele fre)uenciesTe correlation #et!een & gene polymorpisms and anxietydepression symptoms

Cne!ay factorial analyses indicated tat te Pp and pp genotypes !ere correlated !itanxiety, depression, and organic diseases, as !ell as G%@*, %A&*19 and GMM*scores. Te xx genotype !as correlated only !it organic disease and "asomotorsymptoms. +en !e introduced te ten factors a#o"e into a multifactorial logistic model,only te Pp genotype and GMM* scores !ere negati"ely correlated $y I 9./1 1.693[ 2.22, r I [6.16:, </= G 6.619 6.::3, P I 6.633(.@iscussion

Cur study so!s tat %A&*19, G%@* and >reene Glimacteric *cale scores of anxiety,depression and somatic symptoms !ere significantly iger inperimenopausal4postmenopausal patients !it anxietydepression disorder compared toa control group, !ereas 2 and Progesterone le"els !ere significantly lo!er $P 5 6.61(.Tese findings indicate tat, in addition to anxiety and depression disorders, somaticsymptoms are caracteristics of climacteric patients !it anxietydepression disorders.Tis finding is also consistent !it a pre"ious report using >reene Glimacteric *caleresults O2/, 2. Bsing a PearsonSs correlation analysis, !e found tat a decreased 2le"el is correlated !it anxiety, depression and somatic symptoms, !ic in turn migt



#e correlated !it te onset of anxietydepression disorder. Pre"ious !ork #y oterresearcer corro#orates tis finding O2;, 2:. Additionally, our study indicates tatanxiety, depression and somatic symptoms are correlated !it psycological scores #utnot !it #lood pressure, #one density, menopause or disease course. Tese findingsindicate te follo!ing8 $1( te >reene Glimacteric *cale is "alid for determiningclimacteric patients !it anxiety and depression disordersD and $2( te somatic

symptoms in climacteric patients !it anxietydepression disorders migt #e correlated !it emotional disorders only O2:, 2< and not !it organic diseases, suc asypertension and osteoporosis.

Te anxietydepression group so!ed a significant decrease in "asomotor symptoms, !ic is positi"ely correlated !it te %A&*19 score. Tis result is inconsistent !it ouroter findings. -ased on te symptoms of patients !it anxietydepression disorder, ourstudy so!s tat tere is correlation #et!een "asomotor symptoms and te occurrenceof anxiety disorders. Patients !it ligt anxiety may keep teir symptoms idden,

!ereas patients !it se"ere anxiety may so! "asomotor. %o!e"er, patients !itanxietydepression disorder so!ed a significant decrease in "asomotor symptoms,indicating tat tese symptoms may #e caracteristic of climacteric syndrome. *eritan

and oters a"e so!n tat "asomotor symptoms in patients !it climacteric syndromeare closely associated !it psycological status O2:, 36. Altoug !e sampled patients

!it climacteric syndrome and anxietydepression disorder, our results are consistent !it pre"ious findings. A recent report as so!n tat te somatic symptoms inclimacteric syndrome migt #e te accumulati"e effect of anxiety and facial redness,

!ic is also consistent !it our o#ser"ations O2<.

Cur study found a correlation #et!een education le"el and anxiety and depressionsymptoms, indicating tat people !it more education are more likely to #e anxiousduring menopause. Tis finding is inconsistent !it te study #y Kakkar et al. O1. +e didnot find a significant cange in sexual interest in te anxietydepression groupcompared to te control groupD tis finding is also not consistent !it te *+A report.

Asian attitudes to!ard sexrelated issues tend to #e conser"ati"e, !ic could explainour results. Tere seems to #e no cange in te sexual interest of patients !it anxietyand depression. Moreo"er, our study indicated tat sexual #ea"ior is negati"elycorrelated !it depression scores, !ic is consistent !it pre"ious findings O3, 31.

Te transcription factor of & is located in te cytosol and nucleus and includes t!oisoforms8 &H and &. %uman &H is located on te )292; gene O: and includeseigt exons and se"en introns, at a total lengt of 196 k#. n te first &H gene intron,

!e found a T to G mutation at 6.9 k# upstream of te second exon, and an A to >mutation /6 #p do!nstream of te locus, resulting in te restriction sites for P"u andV#a, respecti"ely, tus creating a restriction site polymorpism O:, <. Pre"ious studiesa"e so!n tat te &H gene polymorpism is correlated !it ot flases and "aginal

dryness #ut not !it emotional disorders in patients !it climacteric syndrome O32.

Cur study indicates tat te allele distri#ution of anxietydepression genotypes isPP1;.</=, Pp3<.;9=, pp92.31=, VV16.2=, Vx32./6= and xx/;.<=. Te alleledistri#ution fre)uency for te P and V alleles is 3;.:1 and 2.2:=, respecti"ely. TemaEority of alleles are p and x. *tatistical analysis re"ealed no significant differences inte genotypes of te &H P"u and V#a genes. Moreo"er, tere !as no correlation#et!een te &H allele and anxiety or depression symptoms. Tis finding is consistent

!it Malacara O32. -ased on a multifactorial logistic analysis, tere is a negati"e



relationsip #et!een te Pp genotype in te &H gene and te GMM* score in teanxietydepression group $r I [6.16:, P I 6.633(.

-randi et al. O: so!ed tat te PPVV genotype of &H !ere more fre)uent in patients !it Al0eimerSs disease $A@(, compared to a control group O:. strogen le"el decreaseis correlated to A@. strogen protects neurons. strogen terapy as positi"e effects on

anxietydepression disorder, cogniti"e malfunction and A@ in patients !it climactericsyndrome O33. @epression related to aging may #e a symptom of earlyonset A@ O:.Te *+A report found tat 1:= of older !omen a"e emotional disorders and tatdepression !as significantly correlated !it impaired cogniti"e function O/D o!e"er,tere !as no suc correlation #et!een emotional symptoms and cogniti"e malfunction inpatients !it climacteric syndrome O39. n our study, !e so!ed tat anxiety,depression and somatic symptoms !ere negati"ely correlated !it GMM* scores inte anxietydepression groupD o!e"er, tere !as no suc correlation in te controlgroup. Tus, tese findings are consistent !it *+A report !ic suggest cogniti"edecline correlation !it anxiety and or depression, #ut not climacteric syndrome. Tereis a negati"e correlation #et!een te Pp genotype in te &H gene and GMM*scores, !ic is inconsistent !it ClsenSs report. n ClsenSs study, te V#a genotype VV

!as negati"ely correlated !it impaired cogniti"e function in postmenopausal O3/.&ecently, Kim et al. O3 reported similar results. Te inconsistent results may #e relationto te difference of samples. s tere a correlation #et!een impaired cogniti"e function ofemotion disorder and te occurrence of mild cogniti"e impairment $e.g., MG or earlyonset A@( Are te &H polymorpism and decreased estrogen le"els common ordifferent mecanisms in patients !it climacteric syndrome as !ell as anxietydepression disorders and patients !it A@ Tese )uestions need to #e furterin"estigated in perimenopausal4postmenopausal patients !it anxietydepressiondisorders.Gonclusion

Te somatic symptoms in patients !it climacteric syndrome are correlated !it

emotional disorders #ut not !it organic diseases. Tere !as no correlation #et!een te&H allele polymorpism and anxiety or depression symptoms, !ereas te Ppgenotype of te &H P"u gene may #e related to impaired cogniti"e function inpatients !it anxiety or depression symptoms.Ackno!ledgments

Tis !ork !as supported #y te atural *cience Foundation of >uangdong Pro"ince, inGina $66223:/(.Gonflict of interest

Te autors declare tat tey a"e no conflict of interest.Cpen Access

Tis article is distri#uted under te terms of te Greati"e Gommons Attri#utiononcommercial icense !ic permits any noncommercial use, distri#ution, andreproduction in any medium, pro"ided te original autor$s( and source are credited.Article informationArc >ynecol C#stet. 2612 MayD 2:/$/(8 139/13/2.Pu#lised online 2611 o"em#er 2<. doi8 16.166;4s6696961121/10PMG@8 PMG332/91:



-orong Rou,corresponding autor1 Viaofang *un,2 Ming Rang,3 Qanua @eng,1 andJiaEia %u11@epartment of eurology, Te Tird Affiliated %ospital of >uang0ou Medical Gollege,>uang0ou, /161/6 Gina2&esearc nstitute of >ynecology and C#stetrics, Te Tird Affiliated %ospital of>uang0ou Medical Gollege, >uang0ou, /161/6 Gina

3@epartment of pidemics and %ealt *tatistics, >uangdong Parmacy Gollege,>uang0ou, /16296 Gina-orong Rou, Pone8 \:26:12<2161, Fax8 \:26:12<2<9<, mail8Rou#r:4at4yaoo.com.cn.corresponding autorGorresponding autor.&ecei"ed August /, 2611D Accepted o"em#er 1/, 2611.Gopyrigt L Te Autor$s( 2611Articles from *pringer Cpen Goice are pro"ided ere courtesy of *pringer&eferences1. Kakkar ', Kaur @, Gopra K, Kaur A, Kaur P. Assessment of te "ariation inmenopausal symptoms !it age, education and !orking4non!orking status in nortndian su# population using menopause rating scale $M&*( Maturitas. 266;D/;836319.

doi8 16.1614E.maturitas.266;.62.62. OPu#Med OGross &ef2. *oules M&, *erman *, Parrott , et al. xecuti"e summary8 *tages of &eproducti"eAging +orksop $*T&A+( Glimacteric. 2661D9$9(82;2;2. OPu#Med3. -rom#erger JT, Matte!s KA, *cott , -rock!ell *, A"is , Kra"it0 %M, et al.@epressi"e symptoms during te menopausal transition8 te *tudy of +omenSs %ealtAcross te ation $*+A( J Affect @isord. 266;D16382;2;2. doi816.1614E.Ead.266;.61.639. OPMG free article OPu#Med OGross &ef9. Glayton A%, inan PT $2616( @epression or menopause Presentation andmanagement of maEor depressi"e disorder in perimenopausal and postmenopausal

!omen. Prim Gare Gompanion J Glin Psyciatry. 12$1(8PGG.6:r66;9;. OPMG freearticle OPu#Med/. Golenda GG, egault G, &app *&, @e-on M+, %ogan P, +allace &, et al. Psyciatric

disorders and cogniti"e dysfunction among older, postmenopausal !omen8 results fromte +omenSs %ealt nitiati"e Memory *tudy. Am J >eriatr Psyciatry. 2616D1:$2(81;;1:. doi8 16.16<;4J>P.6#613e31:1c/:9. OPMG free article OPu#Med OGross &ef. @o!rick G, Katona G, Pe"eler &, loyd %. *omatic symptoms and depression8diagnostic confusion and clinical neglect. -r J >en Pract. 266/D//8:2<:36. OPMG freearticle OPu#Med;. &ief +, Me!es &, Martin A, >laesmer %, -raeler . Are psycological featuresuseful in classifying patients !it somatic symptoms Psycosom Med. 2616D;289://. doi8 16.16<;4P*Q.6#613e31:1d;3fce. OPu#Med OGross &ef:. -randi M, -ecerini , >ennari , &acci M, -iancetti A, acmias -, et al.Association of te estrogen receptor alpa gene polymorpisms !it sporadicAl0eimerSs disease. -iocem -iopys &es Gommun. 1<<<D2/833/33:. doi8

16.1664##rc.1<<<.1/. OPu#Med OGross &ef<. %errington @M, %o!ard T@, %a!kins >A, &e#oussin @M, Vu J, Reng *, et al.strogenreceptor polymorpisms and effects of estrogen replacement on igdensitylipoprotein colesterol in !omen !it coronary disease. ngl J Med. 2662D398<;<;9. doi8 16.16/4JMoa612</2. OPu#Med OGross &ef16. Ko#ayasi , FuEino T, *irogane T, Furuta , Ko#amatsu Q, Qaegasi M, et al.strogen receptor alpa polymorpism as a genetic marker for #one loss, "erte#ralfractures and suscepti#ility to estrogen. Maturitas. 2662D9181<3261. doi816.1614*63;:/122$61(662:;6. OPu#Med OGross &ef



11. oannidis JP, *ta"rou , Trikalinos TA, Rois G, -randi M, >ennari , et al.Association of polymorpisms of te estrogen receptor alpa gene !it #one mineraldensity and fracture risk in !omen8 a metaanalysis. J -one Miner &es. 2662D1;8269:266. doi8 16.13/<4E#mr.2662.1;.11.269:. OPu#Med OGross &ef12. >reene J>. Gonstructing a standard climacteric scale. Maturitas. 266:D18;::9.doi8 16.1614E.maturitas.266:.6<.611. OPu#Med OGross &ef

13. Gooper J. An o"er"ie! of te prospecti"e G@16 classification of mental disorders.-r J Psyciatry. 1<:<D1/9$*uppl 9(82123. OPu#Med19. Rang MQ $1<:9( Te *ymptom *cales re"ie!. *%A>%A J>*% QVB*angai Arc Psyciatry, pp 2129.1/. %amilton M. Te assessment of anxiety states #y rating. -r J Med Psycol.1</<D328/6//. doi8 16.11114E.2699:391.1</<.t#669;.x. OPu#Med OGross &ef1. Reng QP, Rao JP, Pillips M, et al. 'alidity and relia#ility of te Ginese %amilton@epression &ating *cale. -r J Psyciatry. 1<::D1/2869. doi816.11<24#Ep.1/2./.6. OPu#Med OGross &ef1;. *tein @J, Muller JG*. *pectr. Gogniti"eaffecti"e neuroscience of somati0ationdisorder and functional somatic syndromes8 reconceptuali0ing te triad of depressionanxietysomatic symptoms. 266:D13$/(83;<3:9. OPu#Med

1:. Gen &?, @a"is *&, +ong GM, am T%. 'alidity and cultural e)ui"alence of testandard >reene Glimacteric *cale in %ong Kong. Menopause. 2616D1;$3(8363/.OPu#Med1<. Mancia >, -acker >, @ominic0ak A, Gifko"a &, Fagard &, >ermano >, et al. 266;*%*G Practice >uidelines for te Management of Arterial %ypertension8 *%*GTask Force on te Management of Arterial %ypertension. J %ypertens. 266;D2/81;/11;2. doi8 16.16<;4%J%.6#613e32:2f6/:6f. OPu#Med OGross &ef26. Gooper A. Csteoporosis guideline. -r J >en Pract. 266<D/<89/1. doi816.33<<4#Egp6<V921636. OPMG free article OPu#Med OGross &ef21. Kim#er GM, >rimmer*omers KA. Multifaceted guideline implementation strategiesimpro"e early identification and management of osteoporosis. Aust %ealt &e".266<D338923933. doi8 16.16;14A%6<6923. OPu#Med OGross &ef

22. Petersen &G, *te"ens JG, >anguli M, Tangalos >, Gummings J, @eKosky *T.Practice parameter8 early detection of dementia8 mild cogniti"e impairment $an e"idence#ased re"ie!(. &eport of te ?uality *tandards *u#committee of te American Academyof eurology. eurology. 2661D/811331192. OPu#Med23. Rang RV, %ong V, i %, et al. Te MiniMental *tate xamination in populationaged // years and o"er in ur#an and rural areas of -eiEing. Rongua *en Jing >e RaRi. 1<<<D32819<1/3.29. Folstein MF, Folstein *, Mc%ug P&. YMinimental stateZ. A practical metod forgrading te cogniti"e state of patients for te clinician. J Psyciatr &es. 1<;/D1281:<1<:. doi8 16.161466223</$;/(<662. OPu#Med OGross &ef2/. *ierra -, %idalgo A, Gedraui PA. Measuring climacteric symptoms in ancuadorian population !it te >reene Glimacteric *cale. Maturitas. 266/D/182329/.

doi8 16.1614E.maturitas.2669.6:.663. OPu#Med OGross &ef2. Tra"ers G, CSeill *M, King &, -attistutta @, Koo *K. >reene Glimacteric *cale8norms in an Australian population in relation to age and menopausal status. Glimacteric.266/D:8/2. doi8 16.16:6413<;136966613993. OPu#Med OGross &ef2;. &yan J, -urger %>, *0oeke G, eert P, Ancelin M, %enderson '+, et al. Aprospecti"e study of te association #et!een endogenous ormones and depressi"esymptoms in postmenopausal !omen. Menopause. 266<D18/6</1;. doi816.16<;4gme.6#613e31:1:d3/f. OPMG free article OPu#Med OGross &ef



2:. *eritan A, osif AM, Park J%, et al. *elfreported anxiety, depressi"e, and"asomotor symptoms8 a study of perimenopausal !omen presenting to a speciali0edmidlife assessment center. Menopause. 2616D1;891691/. doi816.16<;4gme.6#613e31:1#f/a2. OPu#Med OGross &ef2<. ermer MA, Morra A, Moineddin &, Manson J, -lake J, Tierney MG. *omatic andaffecti"e anxiety symptoms and menopausal ot flases. Menopause. 2611D1:812<132.

OPu#Med36. >old -, Gol"in A, A"is , -rom#erger J, >reendale >A, Po!ell , et al.ongitudinal analysis of te association #et!een "asomotor symptoms andrace4etnicity across te menopausal transition8 study of !omenSs ealt across tenation. Am J Pu#lic %ealt. 266D<8122123/. doi8 16.216/4AJP%.266/.6<3. OPMGfree article OPu#Med OGross &ef31. Kat0-earnot *. Menopause, depression, and loss of sexual desire8 apsycodynamic contri#ution. J Am Acad Psycoanal @yn Psyciatry. 2616D3:8<<11.doi8 16.1/214Eaap.2616.3:.1.<<. OPu#Med OGross &ef32. Malacara JM, Pere0u)ue , Martine0>ar0a *, *ance0Marin FJ. Terelationsip of estrogen receptoralpa polymorpism !it symptoms and otercaracteristics in postmenopausal !omen. Maturitas. 2669D9<8131<. doi8

16.1614E.maturitas.2669.61.662. OPu#Med OGross &ef33. *er!in --, %enry JF. -rain aging modulates te neuroprotecti"e effects ofestrogen on selecti"e aspects of cognition in !omen8 a critical re"ie!. Fronteuroendocrinol. 266:D2<8::113. doi8 16.1614E.yfrne.266;.6:.662. OPu#Med OGross&ef39. >reendale >A, +igt &>, %uang M%, et al. Menopauseassociated symptoms andcogniti"e performance8 results from te study of !omenSs ealt across te nation. Am Jpidemiol. 2616D1;1812191229. doi8 16.16<34aEe4k!)6;. OPMG free article OPu#MedOGross &ef3/. Clsen , &asmussen %-, %ansen T, et al. strogen receptor alpa and risk forcogniti"e impairment in postmenopausal !omen. Psyciatr >enet. 266D18:/::. doi816.16<;461.ypg.66661<999/.2;///.;1. OPu#Med OGross &ef

3. Kim JJ, Pae GB, Kim M&, et al. Association #et!een strogen &eceptor >enePolymorpisms and @epression in PostMenopausal +omen8 A Preliminary *tudy.Psyciatry n"estig. 2616D;$3(822922;. doi8 16.9364pi.2616.;.3.229. OPMG free articleOPu#Med OGross &ef

Te nternational Journal of -ea"ioral utrition and Pysical Acti"ity-ioMed Gentral@ietary !eigt loss and exercise inter"entions effects on )uality of life ino"er!eigt4o#ese postmenopausal !omen8 a randomi0ed controlled trial

kuyo mayama, Gaterine M Alfano, O..., and Anne McTiernan

Additional article informationA#stract-ackground

Altoug lifestyle inter"entions targeting multiple lifestyle #ea"iors are more effecti"e inpre"enting unealty !eigt gain and cronic diseases tan inter"ening on a single#ea"ior, fe! studies a"e compared indi"idual and com#ined effects of diet and4or



exercise inter"entions on ealtrelated )uality of life $%&?C(. n addition, temecanisms of o! tese lifestyle inter"entions affect %&?C are unkno!n. Teprimary aim of tis study !as to examine te indi"idual and com#ined effects of dietary

!eigt loss and4or exercise inter"entions on %&?C and psycosocial factors$depression, anxiety, stress, social support(. Te secondary aim !as to in"estigatepredictors of canges in %&?C.

Metods

Tis study !as a randomi0ed controlled trial. C"er!eigt4o#ese postmenopausal !omen !ere randomly assigned to 12 monts of dietary !eigt loss $n I 11:(, moderateto"igorous aero#ic exercise $22/ minutes4!eek, n I 11;(, com#ined diet and exercise $n I11;(, or control $n I :;(. @emograpic, ealt and antropometric information, aero#icfitness, %&?C $*F3(, stress $Percei"ed *tress *cale(, depression O-rief *ymptomn"entory $-*(1:, anxiety $-*1:( and social support $Medical Cutcome *tudy *ocial*upport *ur"ey( !ere assessed at #aseline and 12 monts. Te 12mont canges in%&?C and psycosocial factors !ere compared using analysis of co"ariance,adEusting for #aseline scores. Multiple regression !as used to assess predictors ofcanges in %&?C.

&esults

T!el"emont canges in %&?C and psycosocial factors differed #y inter"entiongroup. Te com#ined diet \ exercise group impro"ed 9 aspects of %&?C $pysicalfunctioning, rolepysical, "itality, and mental ealt(, and stress $p 6.61 "s. controls(.Te diet group increased "itality score $p 5 6.61 "s. control(, !ile %&?C did notcange differently in te exercise group compared !it controls. %o!e"er, regardless ofinter"ention group, !eigt loss predicted increased pysical functioning, rolepysical,"itality, and mental ealt, !ile increased aero#ic fitness predicted impro"ed pysicalfunctioning. Positi"e canges in depression, stress, and social support !ereindependently associated !it increased %&?C, after adEusting for canges in !eigt

and aero#ic fitness.Gonclusions

A com#ined diet and exercise inter"ention as positi"e effects on %&?C andpsycological ealt, !ic may #e greater tan tat from exercise or diet alone.mpro"ements in !eigt, aero#ic fitness and psycosocial factors may mediateinter"ention effects on %&?C.Key!ords8 ealtrelated )uality of life, exercise, dietary !eigt loss, postmenopausal

!omen-ackground

early t!otirds of B* adults are o"er!eigt or o#ese O1. Tese indi"iduals are at

increased risk for a "ariety of cronic diseases including meta#olic disease, eartdisease, cancer, and psycosocial disorders O2, !ic may significantly reduce ealtrelated )uality of life $%&?C(. A re"ie! of : studies examining %&C? among !omenaged o"er // years old concluded tat postmenopausal !omen, especially tose !it-M greater tan 36 kg4m2, a"e lo!er %&?C in pysical functioning, energy, and"itality compared !it normal!eigt !omen O3.

ifestyle modification including dietary !eigt loss or pysical acti"ity as #een so!n toimpro"e %&?C O9. @espite te num#ers of studies reporting positi"e effects of



lifestyle modification on %&?C, limited studies a"e in"estigated possi#le mecanismsof cange in %&?C. Furter, te optimal lifestyle prescription for impro"ing %&?Cas not #een esta#lised O;.

ncreasing e"idence suggests tat te com#ination of diet and exercise may #e superiorto diet or exercise alone !it respect to reducing !eigt O:,<, impro"ing lipid profile

O16,11 and pre"enting type 2 dia#etes O12. %o!e"er, te fe! inter"ention studies tatcompared te effects of dietary !eigt loss and4or exercise inter"entions on %&?Ca"e so!n mixed results O131/. Among ; patients !it type 2 dia#etes,diet\exercise and dietonly inter"ention groups significantly impro"ed in a general )ualityof life measure O13. n 31 older adults !it osteoartritis, indi"iduals assigned to adiet\exercise inter"ention impro"ed %&?C $pysical functioning, general ealt, rolepysical, #ody pain, and social functioning( compared !it controls O19. Among 1/;ealty men, no differences in cange in %&?C !ere o#ser"ed among menrandomi0ed to diet\exercise, dietonly, exerciseonly, or control groups O1/.

@espite numerous exercise and dietary !eigt loss inter"entions reporting positi"ecanges in %&?C, te mecanisms #eind o! exercise and dietary !eigt loss

programs impro"e %&?C are not clear. +ile some inter"ention studies a"e so!ntat !eigt loss is associated !it impro"ed %&?C O1,1;, oters a"e so!n tatpeople impro"e %&?C !itout antropometric canges O1:,1<.

Te primary aim of tis study !as to examine te indi"idual and com#ined effects ofdietary !eigt loss and exercise inter"entions on %&?C. @efining te indi"idual andcom#ined effects of diet and exercise inter"entions on %&?C !ill elp informresearcers, practitioners and policy makers on optimal lifestyle prescriptions forimpro"ing %&?C. Te secondary aim !as to explore pysical and psycosocial factorsassociated !it canges in %&?C during te inter"ention. Te findings !ould pro"ideinformation to explain potential mecanisms of o! diet and exercise inter"entions affect%&?C.

Metods

Te utrition and xercise for +omen $+( trial !as a 12mont, randomi0edcontrolled trial conducted at te Fred %utcinson Gancer &esearc Genter, *eattle, +Afrom 266/ to 266<. Participants !ere recruited from te greater *eattle, +A area tougmass mailing and media placements from 266/ to 266:, and 93< !ere enrolled in testudy $Figure (%ig$re1).1). The st$dy incl$sion criteria included8 age /6;/ years oldD#ody mass index $-M( ] 2/.6 kg4m2 $if AsianAmerican ] 23.6 kg4m2(D 5 166 minutesper !eek of moderate or "igorous intensity pysical acti"ityD postmenopausalD not takingormone replacement terapy for te past 3 montsD no istory of #reast cancer, eartdisease, dia#etes mellitus, or oter serious medical conditionsD fasting glucose 5 12mg4dD currently not smokingD alcool intake of fe!er tan 2 drinks per dayD a#le to

attend diet4exercise sessions at te inter"ention siteD and normal exercise tolerance test.Figure 1Figure 1Flo! diagram of te trial.

+omen !ere randomi0ed to8 $1( dietary !eigt loss !it a goal of 16= !eigt reduction$ I 11:(, $2( moderateto"igorous intensity aero#ic exercise for 9/ minutes4day, /days4!eek $ I 11;(, $3( com#ined exercise and diet $ I 11;(, and control groups $ I:;(. *tudy staff performed randomi0ation troug a computer program de"eloped #y te



study statistician. &andomi0ation !as #locked on -M $5 36.6 kg4m2 or ] 36.6 kg4m2(and race4etnicity $+ite, -lack, and oters(. n addition, to acie"e a proportionallysmaller num#er of !omen assigned to te control group, a permuted #locksrandomi0ation !it #locks of 9 !as used, !ere in te control assignment !as randomlyeliminated from eac #lock !it a pro#a#ility of approximately 1 in 9. Te + trial !asdesigned to a"e sufficient po!er to detect a difference of 16= cange in serum

estrone, te primary study outcome, o"er a 12mont period making tree primarypair!ise comparisons8 diet \ exercise "s. exerciseD diet \ exercise "s. dietD and diet "s.exercise inter"ention groups. -ased on te num#er of participants !o completed te12mont assessments, !e estimate tat !e a"e <<.<= po!er to detect 16 pointscange in te pysical functioning scale $%&?C(.

All study procedures !ere re"ie!ed and appro"ed #y te Fred %utcinson Gancer&esearc Genter nstitutional &e"ie! -oard in *eattle, +A, and all participants pro"idedsigned nformed Gonsent.nter"entions

Te diet group recei"ed a reduced calorie !eigt loss inter"ention, a modification of te

@ia#etes Pre"ention Program $@PP( lifestyle O26 and ook A%A@ $Action for %ealt in@ia#etes( trial O21 inter"entions !it goals of8 total caloric intake of 1266 2666 kcal4day#ased on #aseline !eigt, 36= calories from fat, and 16= !eigt loss !itin te first29 !eeks !it maintenance for te rest of inter"ention period. Te diet inter"ention !asconducted #y dietitians !it training in #ea"ior modification. Participants ad indi"idualsessions !it te dietitians at least t!ice, ten met !eekly in small groups $a"erage /16

!omen( until !eek 29, and after!ard communicated !it te dietitians at least t!ice permont eiter "ia group sessions or "ia email4pone contact. Te diet inter"entionin"ol"ed sessions designed to de"elop strategies and skills to acie"e caloric and !eigtloss goals, !ic included selfmonitoring, goal setting, coping strategies, and pro#lemsol"ing.

Te exercise inter"ention !as 9/ minutes per day of moderateto"igorous intensityaero#ic exercise, / days per !eek including 3 exercise pysiologistsuper"ised sessionsper !eek at te facility. C"er te first : !eeks, participants gradually increased teintensity and duration of exercise training to ;6:/= of maximal eart rate $using Polareart rate monitors, ake *uccess, Q( for 9/ minutes per session and maintained tisle"el tereafter.

+omen in te diet\exercise group recei"ed #ot te reducedcalorie !eigt loss andexercise inter"entions. Te diet sessions !ere pro"ided separately for diet\exercise anddiet only groups. Altoug te diet and exercise group used te exercise facility !it

!omen assigned to te exerciseonly group, participants !ere instructed not to discusste diet inter"ention.

Gontrols !ere not gi"en an inter"ention during te trial, #ut !ere offered 9 group dietsessions and : !eeks of super"ised exercise sessions after 12 monts data collection.Measures

nformation on demograpics, medication use, antropometrics, aero#ic fitness, lifestyle#ea"iors, psycosocial factors, and %&?C !ere assessed at #aseline and 12 monts.*tudy staff in"ol"ed in tese assessments !ere #linded to randomi0ation. nformation onage, race4etnicity, education, marital status, and employment !ere collected using a



standardi0ed )uestionnaire. Participants !ere asked to #ring teir current prescriptionand o"ertecounter medications to te clinic, and information on drug name, dose,fre)uency, and duration of use !ere a#stracted. %eigt and !eigt !ere measured !ita stadiometer and digital scale, and -M !as calculated as kg4m2. Aero#ic fitness !asassessed !it a maximum grade treadmill test using te modified #rancing protocolO22,23. Pysical acti"ity !as measured using an inter"ie! adapted from te Minnesota

eisure Time Pysical Acti"ity ?uestionnaire O29. @ietary intake !as assessed using te+omens %ealt nitiati"e 126item food fre)uency )uestionnaire O2/.

Psycosocial factors examined included depression, anxiety, percei"ed stress, andsocial support. @epression and anxiety !ere assessed #y te -rief *ymptom n"entory1: O2. &a! scores !ere calculated and T scores !ere assigned according to tescoring manual O2; !it iger scores indicating more symptoms of depression andanxiety. Percei"ed stress !as assessed !it te Percei"ed *tress *cale O2:D scoresranged from 6 to 9 !it larger scores indicating greater percei"ed stress. C"erall socialsupport !as assessed #y te sort "ersion of te Medical Cutcomes *tudy $MC*(*ocial *upport *ur"ey O,2<. A mean of all item scores !as calculated and con"erted toa score ranging from 6 to 166. %iger social support scores suggest greater perception

of social support. %&?C !as assessed #y te MC* 3tem *ortForm %ealt *ur"ey$*F3( O36. igt su#scales $pysical functioning, rolepysical, #odily pain, "itality,general ealt, social functioning, roleemotional, and mental ealt( !ere calculated,per standard scoring protocol. *cores ranges from 6 to 166 !it iger scores indicatinga #etter state of %&?C. For te #odily pain su#scale, iger scores represent lesspain.*tatistical analyses

+e performed analyses using last o#ser"ation carried for!ard. For comparison, !e alsoperformed te analyses using a"aila#le data and using multiple imputation. Allrandomi0ed participants !ere included in te analyses follo!ing te intentiontotreatprinciple. Te #aseline caracteristics !ere compared across te 9 study arms using

analysis of "ariance $AC'A( and cis)uare tests, as appropriate. Ttests !ere used tocompare differences in #aseline %&?C and psycosocial factors $depression, anxiety,percei"ed stress, and social support( #y su#groups defined #y #aseline caracteristics8age $defined #y median split as 5 /; years "s. ] /; years(, etnicity $non%ispanic+ite, oters(, education $no college degree, college degree(, employment $employed,unemployed(, marital status $no partner, married or !it partner(, #aseline -M $2/ -M 5 36, ] 36 kg4m2(, and use of antidepressants or anxiolytics $no, yes(. -aselinecaracteristics tat significantly altered %&?C scores and psycosocial factors !ereincluded as co"ariates in te su#se)uent analyses. +e also tested models !itout teseco"ariates $unadEusted model(. Te 12mont canges in %&?C !ere comparedamong te 9 study arms using te analysis of co"ariance $AGC'A( adEusting for#aseline scores and co"ariates identified in te analysis gi"en a#o"e. +e used te

-onferroni correction to adEust for multiple comparisons $P"alue I 6.6/43 I 6.61; for 3comparisons(.

@ata for all participants !ere used in te follo!ing analyses. For %&?C su#scales !ic significantly differed across inter"ention groups, Pearsons correlation coefficients !ere calculated to assess te #i"ariate associations #et!een canges in %&?C andpysical and psycological factors $!eigt, aero#ic fitness, depression, percei"ed stressand social support(. Multiple regression analysis !as used to assess predictors of



%&?C cange. All analyses !ere performed !it *A* soft!are $"ersion <.1D *A*nstitute, Gary, G(.&esults

-aseline )uestionnaire data !as a"aila#le from 93: participants. Cf te 93< !omenrandomi0ed to te 9 study arms, 3<< completed pysical exams, 3;6 completed a

treadmill test, and 3:2 returned te )uestionnaire at 12 monts $Figure (%ig$re1).1).There were no differences in baseline %&?C score or psycosocial "aria#les$depression, anxiety, percei"ed stress, and social support( #et!een tose !ocompleted "s. did not complete te 12monts )uestionnaire $all p"alues X 6.6/(.-aseline caracteristics of study participants

Ta#le Table11 displays the baseline characteristics of the st$dy participants. &articipantswere a mean age of ' years mostly nonHispanic white ('*) and highly ed$cated(+* with college degree). There were no differences in baseline characteristics amongte 9 study arms $all p"alues X 6.6/(. Tere !ere no differences in psycosocial factorsand %&? #et!een te four study arms except te mental ealt score. Te exercisegroup ad iger mental ealt scores compared !it diet and control groups at

#aseline $p 5 6.6/(.Ta#le 1Ta#le 1-aseline caracteristics of study participants stratified #y trial armnter"ention effects on !eigt, aero#ic fitness and aderence

Te inter"ention effects on !eigt and aero#ic fitness and aderence !ere reportedelse!ere O31. n #rief, te diet, exercise, and diet\exercise groups decreased #ody

!eigt #y ;.2 kg o"er 12 monts $percent cange from #aseline #ody !eigt =@iet I:./=D p 5 6.61(, 2.6 kg $=xercise I 2.9=, p I 6.63(, and :.< kg $=@iet\xercise I16.:=, p 5 6.61(, respecti"ely compared !it controls. Approximately alf of teparticipants in te diet groups $diet 91./=D diet \ exercise groups /<./=( acie"ed te

goal of 16= !eigt reduction at 12 monts. Te exercise and diet \ exercise groups meta mean :6= and :/= of te goal of 22/ minutes per !eek of moderate intensity aero#icexercise, respecti"ely. Aero#ic fitness increased #y 6.1; 4min and 6.12 4min,respecti"ely in exercise and diet\exercise groups $all p 5 6.661, "s. control(.-aseline %&?C scores and psycosocial factors stratified #y su#groups

Ta#le Table22 displays mean H,-/ scores at baseline stratified by baselinecharacteristics. lder women (0 years) had lower rolephysical scores and percei"edstress# and higher "itality scores compared to younger !omen $5 /; yearsD p 5 6.6/(.one of te psycosocial factors and %&?C scores !ere different #et!een su#groupsdefined #y etnicity or education. mployed !omen ad lo!er social functioning tanunemployed !omen $p I 6.62(. +omen !o !ere married or !it partner reported

iger le"els of social support $p 5 6.6/D "s. no partner(. C#ese !omen ad lo!erpysical functioning and rolepysical scores $p 5 6.6/D "s. o"er!eigt(. +omen takingantidepressants or anxiolytics reported a iger le"el of #odily painD lo!er pysicalfunctioning, "itality, roleemotional, and mental ealt scoresD and iger le"els ofdepression and anxiety $all p 5 6.6/(.Ta#le 2Ta#le 2



-aseline scores of ealtrelated )uality of life $measured #y *F3( and psycosocialfactors $depression and anxiety measured #y -*1:, percei"ed stress measured #y tePercei"ed *tress *cale, social support measured #y MC* *ocial *upport *ur"ey(, ...nter"ention effects on : aspects of %&?C

C"erall, te 12monts canges in 9 su#scales of %&?C differed among te 9 groups8

pysical functioning $p 5 6.661(, rolepysical $p 5 6.661(, "itality $p 5 6.661(, and mentalealt $p I 6.6( $Ta#le (Table3).3). ompared with controls# the dieteercise gro$pincreased physical f$nctioning $p 5 6.661(, rolepysical $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(. Altoug #otte diet and diet\exercise groups increased "itality, te diet\exercise group so!ed alarger increase tan te diet only group $p I 6.69 comparing te t!o groups(. Te dietonly group increased "itality $p 5 6.661D "s. controls( and mental ealt $p I 6.6/D "s.controls(. Te exercise group did not impro"e any su#scales of %&?C compared !itcontrols.Ta#le 3Ta#le 3ndi"idual and com#ined effects of diet and4or exercise inter"ention on ealtrelated

)uality of life scores $measured #y *F3(nter"ention effects on psycosocial "aria#les

Te 12mont cange in percei"ed stress differed #y study arm $p I 6.69(. Tediet\exercise group significantly decreased percei"ed stress $6.// points( !ile tecontrol group increased teir stress le"els $6.32 points( $p I 6.66( $Ta#le (Table4).4).

5ltho$gh the o"erall and pairwise comparisons among 4 st$dy arms did not reacstatistical significance $due to te -onferroni correction for multiple comparisonD p6.61; !as considered statistically significant in te pair!ise comparision(, tediet\exercise group reduced depression $@iet\xercise I 1.; points, p I 6.63D "s.control Gontrol I 6.; points( and increased social support $@iet\xercise I 1.6 points,p I 6.6/D "s. control GontrolI 2.: points(.

Ta#le 9Ta#le 9ndi"idual and com#ined effects of diet and4or exercise inter"ention on psycosocialfactors $depression and anxiety measured #y -*1:, percei"ed stress measured #y tePercei"ed *tress *cale, social support measured #y MC* *ocial *upport *ur"ey(-i"ariate correlations #et!een canges in %&?C and pysical and psycosocialfactors

-i"ariate correlations !ere examined for 12mont canges in %&?C and factors tatsignificantly canged during te inter"ention using com#ined data of all 9 study groups$Ta#le (Table).). Weight loss was positi"ely associated with changes in physicalf$nctioning (r I 6.2:, p 5 6.661(, rolepysical $r I 6.1:, p 5 6.661(, "itality $r I 6.3, p 5

6.661( and mental ealt scores $r I 6.13, p I 6.66(. +eigt loss !as also associated !it an impro"ement in depression scores $r I 6.11, p I 6.62(. ncreased aero#ic fitness !as positi"ely associated !it pysical functioning scores $r I 6.1, p I 6.666;(.@ecreased depression and percei"ed stress, and impro"ed social support !ereassociated !it increases in pysical functioning, rolepysical, "itality and mental ealtscores $all p 5 6.661(. @ecreased depression !as associated !it increased pysicalfunctioning $r I 6.21, p 5 6.661(, rolepysical $r I 6.23, p 5 6.661(, "itality $r I 6.92, p5 6.661(, and mental ealt scores $r I 6.//, p 5 6.661(. ncreased stress !as in"erselyassociated !it pysical functioning $r I 6.22, p 5 6.661(, rolepysical $r I 6.26, p 5



6.661(, "itality $r I 6.32, p 5 6.661(, and mental ealt scores $r I 6./1, p 5 6.661(.ncreased social support !as associated !it impro"ed pysical functioning $r I 6.29, p5 6.661(, rolepysical $r I 6.22, p 5 6.661(, "itality $r I 6.22, p 5 6.661(, and mentalealt $r I 6.2/, p 5 6.661(.Ta#le /Ta#le /

-i"ariate correlations #et!een 12mont canges in ealtrelated )uality of life$measured #y *F3( and potential predictorsPredictors of 12mont canges in %&?C

Te 12mont canges in te four su#scales of %&?C tat significantly differed #yinter"ention arm $pysical functioning, rolepysical, "itality, and mental ealt( !erefurter examined to identify te predictors of %&?C cange $Ta#le (Table+).+). hangein aniety le"els did not differ by inter"ention arm therefore# it was not incl$ded in temodel O32. n multiple regression models, te 12mont canges in !eigt $ I 6./6, p5 6.661(, aero#ic fitness $ I 9.;, p I 6.61(, percei"ed stress $ I 6./:, p I 6.62(, andsocial support $ I 6.1;, p 5 6.661( predicted increased pysical functioning. &educed

!eigt $ I 6.;, p I 6.661( and depression $ I 6./6, p I 6.661( and impro"ed social

support $ I 6.29, p I 6.61( predicted increased rolepysical score. &educed !eigt $I 6.;9, p 5 6.661(, depression $ I 6.92, p 5 6.661( and percei"ed stress $ I 6.;<, pI 6.669( !ere associated !it impro"ed "itality. +eigt loss $ I 6.1/, p I 6.69( anddecreases in depression $ I 6.93, p 5 6.661( and percei"ed stress $ I 1.2:, p 56.661( predicted positi"e canges in mental ealt.Ta#le Ta#le Predictors of 12mont canges in ealtrelated )uality of life $measured #y *F3(

+e also performed te analyses using a"aila#le data and using multiple imputation.Tere !ere no su#stantial differences #et!een te results on tese analyses except forte relationsip #et!een canges in aero#ic fitness and te pysical functioning scale.

Te correlation coefficient #et!een 12mont canges in aero#ic fitness and tepysical functioning scale !as significant in te lasto#ser"ation carried for!ard andcomplete case analyses $p 5 6.61(, !ile it !as nonsignificant in te multiple imputationanalyses $p I 6.6<, data are a"aila#le on re)uest(. Terefore, !e presented te resultsof last o#ser"ation carried for!ard analyses in tis paper. Te analysis results did notdiffer su#stantially !en te co"ariates !ere remo"ed from te model $unadEustedmodel, supplementary ta#les are a"aila#le on re)uest(.@iscussion

Tis study examined te indi"idual and com#ined effects of dietary !eigt loss and4oraero#ic exercise inter"entions on %&?C among sedentary, o"er!eigt4o#esepostmenopausal !omen. To our kno!ledge, tis trial is te first to compare indi"idual

and com#ined effects of dietary !eigt loss and exercise inter"ention on %&?C ino"er!eigt4o#ese, postmenopausal !omen !itout maEor medical conditions. +e foundtat te com#ined dietary !eigt loss and exercise group impro"ed more aspects of%&?C and psycosocial factors $depression, stress and social support( !it largerincrements compared !it diet or exercise alone. +e also found significant associations#et!een !eigt loss, increased aero#ic fitness, and impro"ements in %&?C andpsycological factors, suggesting tat tese factors may explain, at least in part, teimpro"ed %&?C o#ser"ed in te diet and exercise inter"entions.



Te com#ined dietary !eigt loss and exercise group impro"ed more aspects of %&?Cand !it larger increments compared !it diet or exercise alone. Cur findings !ereconsistent !it pre"ious trials in clinical populations, among tose !it type 2 dia#etesO13 or osteoartritis O19. Te latter trial reported up to a 1./ point increase in allsu#scales of *F3 !it a 1:mont diet\exercise inter"ention O19, !ic !as greatertan te o#ser"ed canges in our sample $/11 points(. Tis may #e caused #y

differences in te study sample, as te o#ser"ed increase in %&?C scores among ourcom#ined diet\exercise group !as consistent !it pre"ious !eigt loss trials in generalpopulations O9,1;. n a mont !eigt loss trial $lo! calorie diet and aero#ic exercise(among 2<: o#ese !omen $age /6;/(, !omen lost <.9= of #aseline !eigt andincreased pysical functioning and "itality scores #y and : points, respecti"ely O1;.Anoter mont !eigt loss trial in 199 o"er!eigt4o#ese adults reported a mean

!eigt loss of /. kg and 2 to 11point impro"ements in : su#scales of *F3 O9.

n contrast to a num#er of studies reporting positi"e effects of exercise on %&?C, !edid not find significant impro"ements in any aspects of %&?C in !omen randomi0ed tote exerciseonly group. t is possi#le tat our participants ad ig #aseline %&?C

!ic could a"e caused a ceiling effect. Preference for type of exercise could also a"e

affected te results. Gourneya et al. found tat participants !o preferred resistanttraining so!ed greater increase in %&?C !en assigned to resistant training groupcompared !it tose assigned to aero#ic exercise or control groups O33. Curparticipants migt a"e preferred to #e assigned to a group oter tan te exerciseonlygroup, !ic could a"e resulted in minimal canges in %&?C.

Te com#ined diet\exercise inter"ention also impro"ed psycosocial factors$depression, stress, and social support(, !ile tere !ere no effects on tese factors inte diet or exercise alone groups. Altoug !e are not a!are of studies comparing tesepsycological outcomes in indi"idual "s. com#ined diet and exercise inter"entions,lifestyle modification programs in"ol"ing diet and exercise a"e #een so!n to impro"epsycological ealt. A 12mont intensi"e lifestyle inter"ention program of te ook

A%A@ $Action for %ealt in @ia#etes( Trial, mediated troug !eigt loss $mean :.: kg !eigt loss among inter"ention group( and aero#ic fitness, impro"ed depression in 9223o"er!eigt adults !it type 2 dia#etes O1:. A cardiac rea#ilitation program reducedstress, !ic !as associated !it !eigt loss and impro"ed aero#ic fitness O39. Curfinding tat te com#ined diet\exercise group impro"ed psycological factors isconsistent !it tese studies, #ut te reasons for te impro"ements are not clear. +edid not find any significant correlations #et!een !eigt loss or aero#ic fitness !it tesepsycosocial factors except for a correlation #et!een !eigt loss and reduceddepression. Future studies are recommended to in"estigate mecanisms #y !iclifestyle inter"entions may impro"e psycological ealt.

Positi"e canges in depression and stress !ere significantly associated !it 9 su#scales

of %&?C, !ic remained significant after adEusting for canges in !eigt and aero#icfitness. *tudies a"e so!n tat psycological disorders affect "arious aspects of%&?C. An analysis of 11,292 outpatients in te B.*. so!ed tat indi"iduals !o aredepressed a"e lo!er pysical functioning, rolepysical and social functioningcompared !it nondepressed indi"iduals O3/. Anoter study as so!n tat increaseddepressi"e symptoms !ere associated !it decline in all : aspects of *F3 amongfemale patients !it remitted maEor depression disorder O3. Cur study confirmed tatpsycological conditions a"e a significant impact on %&?C and tat a lifestyle



#ea"ioral cange of a diet and exercise in com#ination, is a potential metod toimpro"e psycological ealt.

mpro"ed aero#ic fitness !as an independent predictor of 12mont canges in pysicalfunctioning. Gonsistent !it our findings, &oss et al. found tat canges in -M andaero#ic fitness independently explained a cange in pysical functioning score, and tat

impro"ed aero#ic fitness ad independent effects #eyond -M cange only in pysicalfunctioning scale among : su#scales of *F3 in a mont lifestyle inter"ention amongo#ese !omen O1;. An analysis from te ook A%A@ trial found tat #ot !eigt lossand increased aero#ic fitness mediated te inter"ention effects on pysical compositescores O1:. n our pre"ious 12mont exercise trial in 1;3 postmenopausal !omen, !efound tat a cange in aero#ic fitness !as associated !it a cange in pysicalfunctioning #ut not !it canges in eiter mental ealt or general ealt O.

+eigt loss in te present study !as associated !it impro"ements in #ot pysical andmental aspects of %&?C. A 12mont follo!up of a mont lifestyle inter"entionfound tat indi"iduals !o continued to lose !eigt during te follo!up period so!edimpro"ed "itality and general ealt of *F3 and tat !eigt loss !as associated !it

impro"ements in tese aspects of *F3 among /6: postmenopausal !omen O3;. Curfindings confirmed tat o#esity is a risk factor for reduced %&?C and tat !eigt losscan impro"e #ot pysical and mental aspects of %&?C.

Pre"ious studies a"e so!n an important role of psycosocial factors on explainingo! exercise impacts )uality of life O3:91. n multiple sclerosis patients, depression,social support, selfefficacy and fatigue mediated effects of exercise on )uality of lifeO91. >reater social support !as associated !it stronger exercise selfefficacy in olderadults in anoter study O92. xercise selfefficacy mediated te exercise effect onmental and pysical aspects of %&?C in older !omen O96. %iger exercise selfefficacy !as associated !it greater pysical po!er score, a com#ined score of aero#icfitness and fi"e items from te *enior Fitness Test O93 among older adults O99. t is

possi#le tat te o#ser"ed associations of !eigt loss and impro"ed aero#ic fitness !it%&?C in our study could #e mediated troug increase in exercise selfefficacy. Futurestudies may #enefit from testing psycosocial predictors of )uality of life including selfefficacy to furter determine te mecanism of o! inter"entions affect %&?C.

Te strengts of tis trial include its large sample si0eD randomi0ed controlled designDtree inter"ention arms allo!ing direct comparisons of indi"idual and com#ined exerciseand diet groups to eac oter and controlsD excellent aderence to inter"entionprescriptionD lo! rate of dropouts $<=(D and use of "alidated measures of %&?C andpsycosocial factors. n particular, direct comparison #et!een com#ined diet\exerciseand diet or exercise alone allo!ed us to understand te indi"idual and com#inedcontri#ution of tese lifestyle #ea"iors on %&?C.

Tis study is limited #y some factors tat sould #e kept in mind !en interpreting teresults. Cur sample consisted primarily of non%ispanic +ite !omen !it a igeducation le"el on a"erage. %ence, our findings may not #e generali0a#le to men, or

!omen in oter etnic groups or !it different education le"els. Anoter limitation is terelati"ely ig %&?C scores among our sample. "en toug !e found significanteffects on se"eral aspects of %&?C, te analysis may a"e suffered from a ceilingeffect. -ased on tese limitations, future studies are needed to test te effects of tese



dietary !eigt loss and exercise inter"entions in oter populations suc as !omen ofoter race4etnicity groups or in men.Gonclusions

Cur findings suggest tat te com#ination of dietary !eigt loss and exercise may a"ea larger #eneficial effect on %&?C compared !it dietary !eigt loss or exercise

alone. +eigt loss and impro"ements in aero#ic fitness and psycosocial factors$depression, stress, and social support( !ere predictors of increased %&?C,suggesting tat tese factors could mediate te inter"ention effects on %&?C.A##re"iations

AGC'A8 analysis of co"arianceD AC'A8 analysis of "arianceD -M8 #ody mass indexD-*8 -rief *ymptom n"entoryD @PP8 @ia#etes Pre"ention ProgramD %&?C8 ealtrelated )uality of lifeD ook A%A@8 Action for ealt in @ia#etesD MC*8 MedicalCutcome *tudy *ocial *upport *ur"eyD *F38 Medical Cutcomes *tudy 3tem *ortForm %ealt *ur"ey.Gompeting interests

Te autors declare tat tey a"e no competing interests.Autors contri#utions

conducted data analyses, interpreted te results and drafted te manuscript. GMAinterpreted te results and drafted te manuscript. AK and G- ac)uired te data. Vperformed analysis. >- designed te study. AM designed te study, ac)uired te data,interpreted te results, and drafted te manuscript. All autors a"e re"ised andappro"ed te manuscript.Ackno!ledgements

Te utrition and xercise for +omen $+( trial !as supported #y &61 GA16/26961A1 from te ational Gancer nstitute $G(. +ile !orking on te trial, GMA !as

employed at te Cio *tate Bni"ersity, and located to G follo!ing completion of ereffort on te + trial. AK !as supported #y G &2/GA6<9::6 at te time of tis studyand is currently supported #y G 2&2/GA6/;<<. KF is supported #y/K2&&62/61/63 from ational Genter for &esearc &esources $G&&(, acomponent of te ational nstitute of %ealt $%( and % &oadmap for Medical&esearc.Article informationnt J -ea" utr Pys Act. 2611D :8 11:.Pu#lised online 2611 Ccto#er 2/. doi8 16.11:419;</:::11:PMG@8 PMG321//kuyo mayama,1 Gaterine M Alfano,2 Angela Kong,3 Karen Foster*cu#ert,9Garolyn -ain,1 iren Viao,1 Gaterine @uggan,1 GingQun +ang,1,/ Kristin

Gamp#ell, >eorge -lack#urn,; and Anne McTiernancorresponding autor1,9,:1Pu#lic %ealt *ciences @i"ision, Fred %utcison Gancer &esearc Genter, *eattle,+A, B*A2Cffice of Gancer *ur"i"orsip, ational Gancer nstitute, ational nstitutes of %ealt,-etesda, M@, B*A3Gancer ducation and Gareer @e"elopment Program, Bni"ersity of llinois at Gicago,Gicago, , B*A9@epartment of Medicine, *cool of Medicine, Bni"ersity of +asington, *eattle, +A,B*A



/@epartment of -iostatistics, *cool of Pu#lic %ealt, Bni"ersity of +asington, *eattle,+A, B*A@epartment of Pysical Terapy, Bni"ersity of -ritis Golum#ia, 'ancou"er, -G,Ganada;@epartment of *urgery, -et srael @eaconess Medical Genter, %ar"ard Medical*cool, -oston, MA, B*A

:@epartment of pidemiology, *cool of Pu#lic %ealt, Bni"ersity of +asington,*eattle, +A, B*Acorresponding autorGorresponding autor.kuyo mayama8 iimayama4at4fcrc.orgD Gaterine M Alfano8 alfanoc4at4mail.ni.go"DAngela Kong8 akong4at4uic.eduD Karen Foster*cu#ert8 kfoster4at4u.!asington.eduDGarolyn -ain8 ce#ain4at4fcrc.orgD iren Viao8 lxiao4at4fcrc.orgD Gaterine @uggan8cduggan4at4fcrc.orgD GingQun +ang8 cy!ang4at4fcrc.orgD Kristin Gamp#ell8kristin.camp#ell4at4u#c.caD >eorge -lack#urn8 g#lack#u4at4#idmc.ar"ard.eduD AnneMcTiernan8 amctiern4at4fcrc.org&ecei"ed January 11, 2611D Accepted Ccto#er 2/, 2611.Gopyrigt L2611 mayama et alD licensee -ioMed Gentral td.Tis is an Cpen Access article distri#uted under te terms of te Greati"e Gommons

Attri#ution icense $ttp844creati"ecommons.org4licenses4#y42.6(, !ic permitsunrestricted use, distri#ution, and reproduction in any medium, pro"ided te original

!ork is properly cited.Tis article as #een cited #y oter articles in PMG.Articles from Te nternational Journal of -ea"ioral utrition and Pysical Acti"ity arepro"ided ere courtesy of -ioMed Gentral&eferences

Flegal KM, Garroll M@, Cgden G, Gurtin &. Pre"alence and trends in o#esity amongB* adults, 1<<<266:. JAMA. 2616D363$3(823/291. doi8 16.16614Eama.266<.2619.OPu#Med OGross &ef A"enell A, -room J, -ro!n TJ, Poo#alan A, Aucott , *tearns *G, *mit +G, Jung

&T, Gamp#ell MK, >rant AM. *ystematic re"ie! of te longterm effects and economicconse)uences of treatments for o#esity and implications for ealt impro"ement. %ealtTecnol Assess. 2669D:$21(811:2. iiii". OPu#Med Jones >, *utton A. ?uality of life in o#ese postmenopausal !omen. Menopause nt.266:D19$1(8232. doi8 16.12/:4mi.266;.66;639. OPu#Med OGross &ef -lissmer -, &ie#e @, @ye >, &uggiero , >reene >, Gald!ell M. %ealtrelated)uality of life follo!ing a clinical !eigt loss inter"ention among o"er!eigt and o#eseadults8 inter"ention and 29 mont follo!up effects. %ealt ?ual ife Cutcomes.266D9893. doi8 16.11:419;;;/2/993. OPMG free article OPu#Med OGross &ef Kaukua J, Pekkarinen T, *ane T, MustaEoki P. %ealtrelated )uality of life in o#eseoutpatients losing !eigt !it "erylo!energy diet and #ea"iour modificationa 2yfollo!up study. nt J C#es &elat Meta# @isord. 2663D2;$16(812331291. doi8

16.163:4sE.iEo.6:623;<. OPu#Med OGross &ef -o!en @J, Fesinmeyer M@, Qasui Q, T!oroger *, Blric GM, r!in M, &udolp &,aGroix K, *c!art0 &&, McTiernan A. &andomi0ed trial of exercise in sedentarymiddle aged !omen8 effects on )uality of life. nt J -ea" utr Pys Act. 266D3839. doi816.11:419;</::339. OPMG free article OPu#Med OGross &ef Fontaine K&, -arofsky . C#esity and ealtrelated )uality of life. C#es &e".2661D2$3(81;31:2. doi8 16.1694E.19;;:<x.2661.66632.x. OPu#Med OGross &ef orris *, Rang V, A"enell A, >regg , -o!man -, *erdula M, -ro!n TJ, *cmidG%, au J. ongterm effecti"eness of lifestyle and #ea"ioral !eigt loss inter"entions



in adults !it type 2 dia#etes8 a metaanalysis. Am J Med. 2669D11;$16(8;2;;9. doi816.1614E.amEmed.2669.6/.629. OPu#Med OGross &ef +ing &&. Pysical acti"ity in te treatment of te adultood o"er!eigt and o#esity8current e"idence and researc issues. Med *ci *ports xerc. 1<<<D31$11 *uppl(8*/9;//2. OPu#Med *tefanick M, Mackey *, *eean M, lls!ort , %askell +, +ood P@. ffects of

diet and exercise in men and postmenopausal !omen !it lo! le"els of %@ colesteroland ig le"els of @ colesterol. ngl J Med. 1<<:D33<$1(81226. doi816.16/4JM1<<:6;6233<6163. OPu#Med OGross &ef +ood P@, *tefanick M, +illiams PT, %askell +. Te effects on plasma lipoproteinsof a prudent !eigtreducing diet, !it or !itout exercise, in o"er!eigt men and

!omen. ngl J Med. 1<<1D32/$;(8919. doi8 16.16/4JM1<<16:1/32/6;63.OPu#Med OGross &ef Cro0co J, -ucleitner AM, >imene0Pere0 >, &o)ue FM, &icter -, Mauricio @.xercise or exercise and diet for pre"enting type 2 dia#etes mellitus. Gocrane@ata#ase *yst &e". 266:. p. G@6636/9. OPu#Med Kaplan &M, %art!ell *, +ilson @K, +allace JP. ffects of diet and exerciseinter"entions on control and )uality of life in noninsulindependent dia#etes mellitus. J

>en ntern Med. 1<:;D2$9(822622:. doi8 16.166;4-F62/<993. OPu#Med OGross &ef &eEeski +J, Foct -G, Messier *P, Morgan T, Paor M, Penninx -. C#ese, olderadults !it knee osteoartritis8 !eigt loss, exercise, and )uality of life. %ealt Psycol.2662D21$/(891<92. OPu#Med %ellenius M, @alof G, A#erg %, Krakau , de Faire B. ?uality of life is not negati"elyaffected #y diet and exercise inter"ention in ealty men !it cardio"ascular risk factors.?ual ife &es. 1<</D9$1(81326. doi8 16.166;4-F669393;:. OPu#Med OGross &ef Palmeira A, Markland @A, *il"a M, -ranco T, Martins *G, Minderico G*, 'ieiraP, -arata JT, *erpa *C, *ardina -. et al. &eciprocal effects among canges in

!eigt, #ody image, and oter psycological factors during #ea"ioral o#esity treatment8a mediation analysis. nt J -ea" utr Pys Act. 266<D8<. doi8 16.11:419;</::<.OPMG free article OPu#Med OGross &ef

&oss KM, Milsom 'A, &ickel KA, @e#ragan0a , >i##ons M, Mura!ski M, PerriM>. Te contri#utions of !eigt loss and increased pysical fitness to impro"ements inealtrelated )uality of life. at -ea". 266<D16$2(8:9::. doi816.1614E.eat#e.266:.12.662. OPMG free article OPu#Med OGross &ef +illiamson @A, &eEeski J, ang +, 'an @orsten -, Fa#ricatore A, Toledo K. mpactof a !eigt management program on ealtrelated )uality of life in o"er!eigt adults

!it type 2 dia#etes. Arc ntern Med. 266<D1<$2(8131;1. doi816.16614arcinternmed.266:./99. OPMG free article OPu#Med OGross &ef *egal &J, &eid &@, Gourneya K*, Malone *G, Parliament M-, *cott G>, 'enner PM,?uinney %A, Jones +, @Angelo M. et al. &esistance exercise in men recei"ingandrogen depri"ation terapy for prostate cancer. J Glin Cncol. 2663D21$<(81/31/<.doi8 16.12664JGC.2663.6<./39. OPu#Med OGross &ef

Kno!ler +G, -arrettGonnor , Fo!ler *, %amman &F, acin JM, +alker A,atan @M. &eduction in te incidence of type 2 dia#etes !it lifestyle inter"ention ormetformin. ngl J Med. 2662D39$(83<3963. OPMG free article OPu#Med &yan @%, speland MA, Foster >@, %affner *M, %u##ard '*, Jonson KG, Kan *,Kno!ler +G, Qano"ski *R. ook A%A@ $Action for %ealt in @ia#etes(8 design andmetods for a clinical trial of !eigt loss for te pre"ention of cardio"ascular disease intype 2 dia#etes. Gontrol Glin Trials. 2663D29$/(8162:. doi8 16.1614*61<;29/$63(66693. OPu#Med OGross &ef



Pate &&, -lair *, @urstine J, ddy @, %anson P, Painter P, *mit K, +olfe A.>uidelines for xercise Testing and Prescription. 9. Piladelpia, PA8 ea N Fe#igerD1<<1. *cauer J, %anson P. Bsefulness of a #rancing treadmill protocol for e"aluation ofcardiac functional capacity. Am J Gardiol. 1<:;D6$1(813;313;;. doi8 16.16146662<19<$:;(<622<. OPu#Med OGross &ef

Taylor %, Jaco#s @&, *cucker -, Knudsen J, eon A*, @e#acker >. A)uestionnaire for te assessment of leisure time pysical acti"ities. Journal of cronicdiseases. 1<;:D31$12(8;91;//. doi8 16.16146621<:1$;:(<66/:<. OPu#Med OGross&ef Patterson &, Kristal A&, Tinker F, Garter &A, -olton MP, AgursGollins T.Measurement caracteristics of te +omens %ealt nitiati"e food fre)uency)uestionnaire. Annals of epidemiology. 1<<<D<$3(81;:1:;. doi8 16.1614*169;2;<;$<:(666//. OPu#Med OGross &ef @erogatis &, Melisaratos . Te -rief *ymptom n"entory8 an introductory report.Psycol Med. 1<:3D13$3(8/</6/. doi8 16.161;4*66332<1;6669:61;. OPu#Med OGross&ef @erogatis &. -rief *ymptom n"entory 1:8 Administration, scoring, and procedures

manual. Minneapolis8 G* Pearson, ncD 2661. Goen *, Kamarck T, Mermelstein &. A glo#al measure of percei"ed stress. J %ealt*oc -ea". 1<:3D29$9(83:/3<. doi8 16.236;4213969. OPu#Med OGross &ef *er#ourne G@, *te!art A. Te MC* social support sur"ey. *ocial science Nmedicine $1<:2( 1<<1D32$(8;6/;19. doi8 16.161462;;</3$<1(<61/6-. OPu#MedOGross &ef +are J. *F 3 ealt sur"ey8 manual and interpretation guide. -oston, MA8 Te%ealt nstitute e! ngland Medical GenterD 1<<3. Foster*cu#ert K, Alfano GM, @uggan G&, Viao , Gamp#ell K, Kong A, -ain G,+ang GQ, -lack#urn >, McTiernan A. ffect of @iet and xercise, Alone or Gom#ined,on +eigt and -ody Gomposition in C"er!eigttoC#ese Postmenopausal +omen.C#esity $*il"er *pring( 2611. OPMG free article OPu#Med

MacKinnon @P, ock!ood GM, %offman JM, +est *>, *eets '. A comparison ofmetods to test mediation and oter inter"ening "aria#le effects. Psycol Metods.2662D;$1(8:3169. OPMG free article OPu#Med Gourneya K*, McKen0ie @G, Mackey J&, >elmon K, &eid &@, Friedenreic GM,ada A-, Proulx G, 'allance JK, ane K. et al. Moderators of te effects of exercisetraining in #reast cancer patients recei"ing cemoterapy8 a randomi0ed controlled trial.Gancer. 266:D112$:(81:9/1:/3. doi8 16.16624cncr.233;<. OPu#Med OGross &ef @au#enmier JJ, +eidner >, *umner M@, Mendell , Merritt+orden T, *tudley J,Crnis @. Te contri#ution of canges in diet, exercise, and stress management tocanges in coronary risk in !omen and men in te multisite cardiac lifestyle inter"entionprogram. Ann -ea" Med. 266;D33$1(8/;:. doi8 16.126;4s1/329;<a#m3361h;.OPu#Med OGross &ef

+ells K-, *te!art A, %ays &@, -urnam MA, &ogers +, @aniels M, -erry *,>reenfield *, +are J. Te functioning and !ell#eing of depressed patients. &esultsfrom te Medical Cutcomes *tudy. Jama. 1<:<D22$;(8<19<1<. doi816.16614Eama.22.;.<19. OPu#Med OGross &ef ten @oesscate MG, Koeter M+, -ockting G, *cene A%. %ealt related )uality oflife in recurrent depression8 a comparison !it a general population sample. J Affect@isord. pp. 12132. OPu#Med



Qankura @J, Gonroy M-, %ess &, Pettee KK, Kuller %, Kriska AM. +eigt regain andealtrelated )uality of life in postmenopausal !omen. C#esity $*il"er *pring(266:D1$16(822/<22/. doi8 16.163:4o#y.266:.39/. OPu#Med OGross &ef +ite *M, +oEcicki T&, McAuley . Pysical acti"ity and )uality of life in communityd!elling older adults. %ealt ?ual ife Cutcomes. 266<D;816. doi8 16.11:419;;;/2/;16. OPMG free article OPu#Med OGross &ef

McAuley , Konopack JF, Motl &+, Morris K*, @oerksen *, &osengren K&.Pysical acti"ity and )uality of life in older adults8 influence of ealt status and selfefficacy. Ann -ea" Med. 266D31$1(8<<163. doi8 16.126;4s1/329;<a#m3161h19.OPu#Med OGross &ef McAuley , @oerksen *, Morris K*, Motl &+, %u , +oEcicki T&, +ite *M,&osengren K&. Pat!ays from pysical acti"ity to )uality of life in older !omen. Ann-ea" Med. 266:D3$1(81326. doi8 16.166;4s121666:<63<. OPMG free articleOPu#Med OGross &ef Motl &+, McAuley , *nook M, >liottoni &G. Pysical acti"ity and )uality of life inmultiple sclerosis8 intermediary roles of disa#ility, fatigue, mood, pain, selfefficacy andsocial support. Psycol %ealt Med. 266<D19$1(8111129. doi816.16:6413/9:/66:62291<62. OPMG free article OPu#Med OGross &ef

McAuley , Jerome >J, Mar)ue0 @V, la"sky *, -lissmer -. xercise selfefficacy inolder adults8 social, affecti"e, and #ea"ioral influences. Ann -ea" Med. 2663D2/$1(81;. doi8 16.126;4*1/329;<A-M2/61h61. OPu#Med OGross &ef &ikli &, Jones GJ. *enior fitness test manual. Gampaign, 8 %uman KineticsD 2661. Konopack JF, Mar)ue0 @V, %u , la"sky *, McAuley , Kramer AF. Gorrelates offunctional fitness in older adults. nt J -ea" Med. 266:D1/$9(831131:. doi816.16:6416;6//66:623///;. OPMG free article OPu#Med OGross &ef

;

Glinics%ospital das Glinicas da Faculdade de Medicina da Bni"ersidade de *ao Paulo

ffect of massage in postmenopausal !omen !it insomnia A pilot study

@enise Cli"eira, %elena %acul, O..., and ia -ittencourt

Additional article informationT&C@BGTC

early :6= of !omen going troug menopause experience some kind of clinicalsymptom and in 96= of cases te symptoms are sufficiently intense to lead te patientto seek medical assistance.1 Te most common symptoms are "asomotor insta#ility,ner"ousness, anxiety, irrita#ility, depression and insomnia, all significantly detrimental to

!ell#eing. nsomnia is igly pre"alent and affects #et!een 2:= and 3= of

postmenopausal !omen.2 Te searc for complementary terapies is increasing,massage terapy #eing among tese.

Te effects of massage on te acti"ation of arterial and "enous #lood flo!, te lympaticsystem, in addition to impacting oedema, te conEuncti"e tissue and muscles,3 are !ellkno!n. Troug acting on te somatic, autonomic and central ner"ous system, massagepromotes impro"ed "isceral functioning and reesta#lises omeostasis.9



Troug cutaneomuscle stimulation on te surface of te #ody, te receptors of touc,pressure, eat, "i#ration and pain are acti"ated and tese stimuli are transported to teautonomous and central ner"ous systems, unleasing neurocemical reactions./ Arecent study so!ed tat !omen !it complaints of insomnia principally cose corporalterapies, !ereas anoter one concluded tat massage promotes relaxation andsleep and is identified as an agreea#le inter"ention #y te elderly.;

Altoug te #enefits of massage !ere descri#ed in a study, no o#Eecti"e parameters ofsleep !ere e"aluated.: Furtermore, tere are tus far no studies !ic e"aluate teeffects of massage specifically on postmenopausal !omen. Cter studies o#ser"ed tatyoga impro"ed climacteric symptons in !omen in periand postmenopause.<16

Te o#Eecti"e of tis pilot study !as to e"aluate te effect of terapeutic massage oninsomnia, depression, and anxiety troug su#Eecti"e and o#Eecti"e parameters inpostmenopausal patients !it insomnia.MAT&A* A@ MT%C@**u#Eects

n tis study, !e selected se"en postmenopausal !omen !it insomnia8 difficulty infalling sleep or insomnia symptoms for at least tree times a !eek $mean age ^ *@8/.2: ^ 1.<;$*@(, range /6 to / years, mean #odymass index $-M( 5 36 kg4m2(. Testudy !as appro"ed #y te tical Gommittee of te Federal Bni"ersity of *ao Paulo$GP696:46;(. nclusion criteria re)uired tat indi"iduals #e in postmenopause $at least1 year of amenorrea #efore enrollment and an F*% le"el a#o"e 36 mlB4m(, !it nopre"ious exposure to exogenous ormones.

xclusion criteria !ere serious ealt pro#lems and use of antidepressants or sleepinducing aids. +e also excluded !omen !it sleep apnea $apnea ipopnea index inpolysomnograpy iger tan 1/4our(.Protocol design

*tudy su#Eects accordingly under!ent te follo!ing8 a screening inter"ie! tat includeda complete medical istory, anamnesis, and Kupperman index11, as !ell as completegynecological and ematological examinations.Terapeutic massage

Tese "olunteers !ere su#mitted to sixteen oneour sessions of massage t!ice !eeklyand e"aluated on psycological and pysiological parameters.?uestionnaires

?uestionnaires !ere applied #efore and after inter"ention. Te n"entories of *elfe"aluation $*piel#erger *tate Trait Anxiety n"entory *TA and ,12 and -eck

@epression n"entory13(, !ic e"aluate te degree of anxiety and depression of te"olunteers, !ere applied in te pretrial, 9t, :t, 12t and 1t sessions. Te *leep@iary $Morin, G. "ersion( e"aluates sleeping a#its, as !ell as te caracteristics and)uality of sleepD19 tis )uestionnaire !as responded to on a daily #asis #y te"olunteers.

Te *tate Trait Anxiety n"entory $*TA( is made up of 96 affirmations !ic relate to tefeelings of te indi"idual and is di"ided into t!o partsD *TA and *TA eac is



composed of 26 affirmations to !ic a score of one to four must #e gi"en. Te first parte"aluates stateanxietyD te second e"aluates anxioustrait.

Te -eck @epression n"entory is made up of 21 )uestions te iger te scoreattri#uted to eac )uestion, te more depressed is te indi"idual.

Te *leep @iary is an easily completed )uestionnaire !ic sould prefera#ly #eresponded to soon after te patient !akes up and carried out for a minimum period oft!o !eeks. Tis )uestionnaire contains information suc as te time of going to #ed, tetime taken to fall asleep, o! many times te patient a!akens during te nigt, te timeof !aking up, of getting out of #ed, te num#er of sleep ours, te )uality of sleep andte consumption of alcool and4or coffee, tus descri#ing te caracteristics of sleep inte period analysed.1/Polysomnograpy $P*>(

P*> !as performed !it a computeri0ed system consisting of surface electrodes forelectroencepalograpy, electromyograpy, electrooculograpy, electrocardiograpy,impedance pneumograpy to record a#dominal4cest mo"ement, termal sensors and

nasal cannula to measure nasal and oral air flo!, a sensor to detect #ody position, a !rist infrared oximeter attaced to te patients distal palange to gauge oxyemoglo#in,and a snoring sensor.

After te exam, a pysician trained in P*> analy0ed te sleep stage according to tecriteria set fort #y &ectscaffen and Kales.1 &espiratory e"ents !ere analy0ed #ycriteria esta#lised #y te Gommittee of te American Academy of *leep Medicine, as

!ere arousals and periodic leg mo"ements.1;

Te oter sleep parameters !ere8 sleep latency, &M sleep latency, sleep efficiency,stages 3 and 9, &M sleep.*tatistical analysis

n te statistical analysis of te data, nonparametric tests !ere utili0ed due to te"aria#ility of te "aria#les studied. For te analysis of te in"entories, te Friedman Test

!as utili0ed and for te analysis of te polysomnograpia te +ilcoxon Test !asused.1:&*BT**leep and clinical complaints

a( *u#Eecti"e )uestionnaires

Tere !as a significant $p56.6/( impro"ement in te symptoms of anxiety anddepression.

Figure 1 *TA Figure 1Figure 1Anxiety scores of "olunteers as e"aluated #y *TA* )uestionary during sessions !itterapeutic massage.

Figure 2 *TA Figure 2



Figure 2Anxiety scores of "olunteers as e"aluated #y *TAT )uestionary during sessions !itterapeutic massage.

Figure 3 -@Figure 3

Figure 3@epression scores of "olunteers as e"aluated #y -@ )uestionary during sessions !itterapeutic massage.

Te *leep @iary so!ed tat all of te participants fell asleep more rapidly, presented agradual impro"ement in )uality of sleep and a!oke feeling #etter.

#( Polysomnograpy $P*>(

For sleep arcitecture "aria#les, o#Eecti"e measure #y P*> indicated tat tere !as asignificant difference in &M latencyD sleep stage 1D sleep stage 3 and 9.

Ta#le 1 Follo!upTa#le 1Ta#le 1Polysomnograpy results #efore and after terapeutic massage $TM(.

Te "olunteers !ere ree"aluated after a period of one year. Tey did not undergo anyoter terapy during tis time. Tey !ere asked a#out teir sleep complaints8 t!o

!omen stated altoug tey ad impro"ed sleep during massage treatment, no! teyare suffering from insomnia. T!o !omen stated tat tey !ere sleeping #etter and treestated tat tey ad no pro#lems at all !it teir current sleep patterns.@*GB**C

Te present study so!ed tat terapeutic massage decreased te se"erity ofsu#Eecti"e sleep distur#ance related to menopause. First, tere !as a decrease ininsomnia and anxietydepressi"e symptomsD te treatment also suppressed otermenopausal symptoms. *econd, P*> findings re"ealed a decrease in &M latency andincreased stages tree and four.

n ligt of te large num#er of !omen suffering from climacteric syndrome, tere is asurprisingly skeletal literature on alternati"e treatments to sleep difficulties inpostmenopausal !omen. Altoug menopausal !omen a"e #een te su#Eect ofendocrinological researc, less attention as #een gi"en to treatment #y e"aluatingsleep $su#Eecti"e and o#Eecti"e(. A recent study so!ed tat a large num#er ofpostmenopusal !omen seek complementary and alternati"e terapies. n tis researc,

/3 !omen !ere inter"ie!ed and 13.;= preferred te use of massage. Among tese !omen, :1.:= stated impro"ement in climacteric symptons after terapeuticmassage.1<

Terapeutic massage reduced stress in "arious clinical situations suc as tat ofdepression, pain syndromes and autoimmune diseases.26 Tese parameters !ereassayed !it te measurement of su#stances like cortisol, serotonin and dopamine. n astudy !it elderly su#Eects, it !as o#ser"ed tat foot massage $reflexoterapy( impro"ed)uality of sleep, reduced depression and increased te le"el of serotonin.21 +it te



same tecni)ue, a significant difference !as also o#ser"ed in climacteric symptoms, infatigue, in total colesterol and in te le"el of cortisol.22

n a multicentric controlled study, massage !as done to treat insomnia and tePitts#urg *leep ?uality ndex and te *leepless Anxiety *cale *leepless @epression*cale !ere used to e"aluate patient symptoms. Tey concluded tat tere !as a

significant impro"ement in <= of te cases, similar to te trend o#ser"ed in tis study.:

n te post+omens %ealt nitiati"e era,23 considera#le de#ate as #een directed atte risks of %T. Tis leads !omen in menopause to seek #eneficial ealt ad"ice andmake positi"e lifestyle canges. n our study, 1 terapeutic massage sessions so!eda significant impro"ement $p56.6/( in te symptoms of anxiety and depression. +itregard to te @iary, tere !as an impro"ement in )uality of sleep, since all participantsfell asleep more rapidly, presented a gradual impro"ement in )uality of sleep andreferenced impro"ed !ell#eing upon a!akening. Polysomnograpy re"ealed asignificant difference in &M latency in te first sleep stage and in sleep stages treeand four.

Cne limitation of te present study is te limited num#er of !omen as !ell as tea#sence of a control group. e"erteless, tese preliminary results indicate tatmassage can #e an alternati"e in treating postmenopausal !omen !it insomnia.

-ased on te present results, !e suggest tat terapeutic massage is #eneficial forimpro"ing su#Eecti"e sleep )uality in postmenopausal !omen, as !ell as for alle"iatingsymptoms of depression and anxiety. *ince sleep complaints are common duringmenopause, future studies sould include a control group to assess te potential ofmassage as treatment or complementary treatment for insomnia in postmenopausal

!omen.AGKC+@>MT*

Tis !ork !as supported #y grants from Associajo Fundo de ncenti"o Psicofarmacologia $AFP(, GP) and FAP*P $GP@ <:4193633 to *.T.(.Article informationGlinics $*ao Paulo(. 2611 Fe#ruaryD $2(8 39339.doi8 16.1/<64*1:6;/<32261166626662PMG@8 PMG36/<:;/@enise Cli"eira, %elena %acul,, *ergio Tufik, and ia -ittencourtBni"ersidade Federal de *o Paulo, @epto de Psico#iologia, *o Paulo, *P, -ra0ilBni"ersidade Federal de *o Paulo, @epto de >inecologia, *o Paulo, *P, -ra0ilmail8 elenaacul4at4psico#io.epm.#r Tel.8 Pone8 // 11 219<61//Gopyrigt L 2611 %ospital das Glnicas da FMB*PTis is an Cpen Access article distri#uted under te terms of te Greati"e Gommons

Attri#ution onGommercial icense $ttp844creati"ecommons.org4licenses4#ync43.64( !ic permits unrestricted noncommercial use, distri#ution, and reproduction in anymedium, pro"ided te original !ork is properly cited.Tis article as #een cited #y oter articles in PMG.Articles from Glinics are pro"ided ere courtesy of %ospital das Glinicas da Faculdadede Medicina da Bni"ersidade de *ao Paulo&F&G*



1. %arrison. Medicina interna. n8 Garr - &, -radsa! K @, editors. @istr#ios do o"rioe do trato reproduti"o feminino 19t ed. &io de Janeiro8 Mc>ra!%ill nteramericana do-rasil tdaD 1<<:. p. 13:6.2. Gampos %%, -ittencourt &A, %aidar MA, Tufik *, -aracat G. Pre"alncia dedistr#ios do sono na pUs menopausa. &e" -ras >inec C#stet. 266/D2;8;31.3. >oats >G. Massage te scientific #asis of an ancient art8 part 2. Pisiological and

terapeutic effects. -r J *p Med. 1<<9D2:81/3. 16.1134#Esm.2:.3.1/3 OPMG freearticle OPu#Med9. Mantle F. *leepless and unsettled. ursing times. 1<<D<289;. OPu#Med/. >uimares GM, Pinge MGM, Qamamura Q, Mello AM. ffects of acupuncture on#ea"ioral, cardio"ascular and ormonal responses in restraintstressed +istar rats.-ra0 J Med &es. 1<<;836. OPu#Med. e!ton KM, -uist @*M, Keenan , Anderson A, aGroix AR. Bse of alternati"eterapies for menopause symptoms8 &esults of a population#ased sur"ey. C#stet>ynecol. 2662D16681:2/. 16.1614*662<;:99$62(6266/; OPu#Med;. *ciff A. iterature re"ie! of #ack massage and similar tecni)ues to promote sleepin elderly people. Pflege. 266D1<813;3. 16.162941612/362.1<.3.13 OPu#Med:. Rou QF, +ei Q, Rang P, >ao *, ing >, Rang R?, et al. Multicentral

controlled study on treepart massage terapy for treatment of insomnia of deficiency of#ot te eart and spleen. Rongguo Ren Jiu. 266D283:/:. OPu#Med<. -ootaForce G, Turston &G, Taylor M&. A pilot study of a %ata yoga treatmentfor menopausal symptoms. Maturitas. 266;D/;82:</. 16.1614E.maturitas.266;.61.612OPu#Med16. Goen -, Kanaya AM, Macer J, *en %, Gang AA, >rady @. Feasi#ility andaccepta#ility of restorati"e yoga for treatment of ot fluses8 A pilot trial. Maturitas.266;D/81<:269. 16.1614E.maturitas.266.6:.663 OPu#Med11. Kupperman %*, +etcler --, -latt M%>. Gontemporary terapy of te menopausalsyndrome. JAMA. 1</<D1;1812;3;. OPu#Med12. *piel#erger G@, >orsuc &, usene &. Galifornia8 GonsultingPsycologistsPressD 1<;6. Manual for te statetrait anxiety in"entory $Yselfe"aluating )uestionnaire(

13. -eck AT. Filadelfia8 Genter for Gogniti"e TerapyD 1<;:. @epression in"entory.19. Morin G, spie GA. e! Qork8 *pringerD 2669. nsomnia A Glinical guide toassessment and treatment.1/. 2663. Gonsenso -rasileiro de nsqnia. %ypnos &e"ista do *ono.1. &ectscaffen A, Kales A, editors. os Angeles8 -rain nformation *er"ice, -rain&esearc nstituteD 1<:. A manual of standardi0ed tecnology tecni)ues and scoringsystems for sleep stages of uman su#Eects.1;. #er G, Ancolisrael *, Gesson A, Jr, ?uan *. +estcester8 American Academy of*leep MedicineD 266;. Te AA*M Manual for te *coring of *leep and Associated"ents8 &ules, Terminology and Tecnical *pecifications, First dition.1:. *iegel *, Gastellan J., Jr Porto Alegre8 ArtmedD 266. statstica no paramtricapara cincias do comportamento. 2t ed. p.99:.

1<. @aley A, MacArtur G, McManis &, *tokesampard %, +ilson *, &oalfe A, et al.Factors associated !it te use of complementary medicine and nonparmacologicalinter"ention in symptomatic menopausal !omen. Glimacteric. 266D<8339.16.16:6413<;13666:96;9 OPu#Med26. Field T, &eif M%, @iego M, *cangerg *, Kun G. Gortisol decreases and serotoninand dopamine increase follo!ing massage terapy. nt J eurosci. 266/D11/813<;913.16.16:646626;9/6/<6</9/< OPu#Med



21. *ong &%, Kim @%. Te effects of foot reflexion massage on sleep distur#ance,depression disorder and te pysiological index of te elderly. Taean Kano %akoeGi. 266D381/29. OPu#Med22. ee QM. ffects of foot reflexology massage on climacteric symptom, fatigue andpysiologic parameters of middle aged !omen. J Korean Acad Adult urs.266D1:82:9<2.

23. +omenSs %ealt nitiati"e. +riting >roup for te +omenSs %ealt nitiati"ein"estigators. &isks and #enefits of estrogen plus progestogin in ealtypostmenopausal !omen8 principal results from te +omenSs %ealt nitiati"erandomi0ed controlled trial. JAMA. 2662D2::832133. 16.16614Eama.2::.3.321 OPu#Med

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*eminars in reproducti"e medicineAutor Manuscript% Pu#lic Access"aluation and Management of *leep @istur#ance @uring te Menopause Transition

%adine Joffe, M.@., M.*c., Anda Massler, M.@., M.*c., and Katerine M. *arkey, M.@.,P.@.

Additional article informationA#stract

*leep distur#ances in midlife !omen are common and a"e #een associated !it temenopause transition itself, symptoms of ot flases, anxiety and depressi"e disorders,aging, primary sleep disorders $i.e., o#structi"e sleep apnea, periodic lim# mo"ementdisorder(, comor#id medical conditions and medications, as !ell as !it psycosocialand #ea"ioral factors. -ecause tere are se"eral common sources of sleep pro#lems in

midlife !omen, te cause of an indi"idual !omans sleep distur#ance may #emultifactorial. ffecti"e #ea"ioral and parmacological terapies are a"aila#le to treatsleep distur#ances of different etiologies. Tis re"ie! pro"ides an o"er"ie! of differenttypes of sleep distur#ance occurring in midlife !omen and presents data supporting teuse of ormone terapy, ypnotic agents, and #ea"ioral strategies to treat sleeppro#lems in tis population. Te re"ie! aims to e)uip clinicians e"aluating menopauseage !omen !it te kno!ledge and e"aluation tools to diagnose, engage sleep experts

!ere appropriate, and treat sleep distur#ance in tis population. *leep disorders inmidlife !omen sould #e treated #ecause su#stantial impro"ements in )uality of life andealt outcomes are acie"a#le.ntroduction

*leep complaints increase dramatically in !omen during midlife,O1 suggesting apotential association #et!een sleep distur#ance and te menopause transition. n te266/ ational nstitutes of %ealt *tateofte*cience Gonference panel report onmenopauserelated symptoms,O2 sleep distur#ance !as identified as a key symptom ofte menopause transition. octurnal ot flases a"e #een ypotesi0ed to #e a primarysource of menopauseassociated sleep distur#ance. %o!e"er, oter contri#utors tosleep disruption must also #e considered in midlife !omen !o report sleepingpro#lems. Gommon etiologies of persistent sleep distur#ance in tis population includeot flases, agerelated factors, primary sleep disorders, and psyciatric illness.O3



Additional nonpatological causes of sleep disruption may result from psycosocial,#ea"ioral, and stressrelated factors.

Tis re"ie! pro"ides an o"er"ie! of different types of sleep distur#ance occurring inmidlife !omen. *leeprelated 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 tese common sources of sleepdistur#ance during te menopause transition, as !ell as oter nonpatologicalcontri#utors, are re"ie!ed. Trougout te article, differences #et!een percei"ed ando#Eecti"ely measured sleep are discussed. Te re"ie! aims to e)uip clinicianse"aluating menopauseage !omen !it te kno!ledge and e"aluation tools to diagnose,engage sleep experts !ere appropriate, and treat sleep distur#ance in midlife !omen.Terminology and @efinitions

Te term sleep distur#ance descri#es su#Eecti"ely percei"ed sleep pro#lems tat do notnecessarily meet criteria for a clinical disorder #ut are #otersome to te indi"idual. ncontrast, insomnia is a clinically defined disorder tat is diagnosed !en an indi"idualreports a constellation of symptoms tat meets criteria for an insomnia syndrome.O9 Te

insomnia diagnosis re)uires a report of difficulty initiating sleep, maintaining sleep, orexperiencing nonrestorati"e sleep, despite ade)uate opportunity for sleep. @aytimefunctional impairments resulting from nocturnal sleep distur#ance must also #e reported.O9 nsomniacs commonly descri#e excessi"e daytime sleepiness and4or fatigue tat cooccurs !it teir diminised a#ility to sleep at nigt. A diagnosis of insomnia does notre)uire tat sleep distur#ance #e documented o#Eecti"ely.O/ n fact, !enpolysomnograpy $P*>( is conducted, a#normalities may or may not #e detected and,e"en if documented, may not correspond to te clinical complaints.O/ Tus P*> is notrecommended routinely to diagnose insomnia.O e"erteless, P*> can sometimes #euseful in insomnia patientsespecially tose !o fail to respond to treatment#ecauseit as te potential to re"eal an occult sleep disorder tat !as not suspected #ased onistory and pysical examination !en te initial diagnosis of insomnia !as made.O;

Anoter common sleep disorder tat does not re)uire a P*> for diagnosis is restlesslegs syndrome $&*(. &* is a sleep disorder caracteri0ed #y an urge to mo"e te legsduring periods of rest or inacti"ity.O9 -y definition, &* symptoms a"e a circadianpattern !it increasing se"erity at nigt. &* is considered a sleep disorder #ecausedeli#erate lim# mo"ements initiated to pro"ide relief from &* discomfort delay te onsetof sleep. ndi"iduals !it &* fre)uently report sleeponset insomnia and su#se)uentdaytime sleepiness and fatigue.

n contrast to insomnia and &*, oter primary sleep disorders $e.g., sleep apnea andperiodic lim# mo"ement disorder OPM@( are diagnosed using o#Eecti"e measurementsof sleep. Gon"entional P*> detects sleep stages $rapid eye mo"ement O&M, non&M

ligt Ostage 1 and 2, also called 1 and 2, and non&M deep sleep Ostage 3 and 9,also called 3( #y measuring #rain acti"ity using electroencepalograpy $>(com#ined !it electrooculograpy and electromyograpy to measure eye mo"ementsand muscle acti"ity, respecti"ely.O:,< &espiratory effort and airflo! indicators and pulseoximetry are used concurrently to diagnose sleepdisordered #reating, most commonlyo#structi"e sleep apnea $C*A(, !ic is defined #y repetiti"e episodes of complete$apnea( or partial $ypopnea( air!ay o#struction tat are associated !it transientoxygen desaturations and sort arousals from sleep. Multiple arousals related to air!ayo#struction trougout te nigt lead to snoring and sleep fragmentation, !ic can



result in sleepiness, letargy, and mood distur#ances during te daytime.O9 A P*>e"aluation for C*A sould #e considered !en indi"iduals report snoring togeter !ita!akenings from sleep, unrefresing sleep, and4or daytime sleepiness.

A diagnosis of PM@ sould #e considered !en an indi"idual reports a!akenings andkicking during te nigt, restless sleeping, and daytime fatigue. PM@ is diagnosed

#ased on repetiti"e, stereotyped lim# mo"ements $PMs( tat last up to se"eral secondsand lead to fragmentation of and repeated a!akenings from sleep, !ic results indaytime sleepiness and fatigue. %o!e"er, PMs are considered patological only if teyoccur fre)uently at nigt and produce arousals from sleep. Te patopysiology ofPM@ is unkno!n, #ut it fre)uently cooccurs !it &*, &M #ea"ior disorder, ornarcolepsy. Bp to :6= of patients !it &* also a"e PM@, and 36= of indi"iduals

!it PM@ also a"e &*.O16 *econdary, re"ersi#le causes of PMs, includingantidepressant medication use and C*A, also exist. n contrast to &*, PM@ is adisorder associated !it a!akenings after sleep is initiated, and PM@ re)uires a P*>to esta#lis te diagnosis.

Actigrapy is an alternate tecnology to P*> tat is used to document rest and acti"ity

states. Te de"ice is !orn like a !rist!atc and measures acti"ity counts !it anaccelerometer. *leep and !akefulness are estimated from te acti"ity counts usingalgoritms tat !ere de"eloped #y correlating patterns of mo"ement !it >#aseddetermination of sleep. Actigrapy pro"ides an estimate of sleep time, sleep onset, sleepoffset, and sleep efficiency and also detects sleep distur#ance associated !it increasedmo"ement. t does not measure sleep arcitecture, o!e"er, and te accrued data arenot fully concordant !it tose procured #y P*>.O11 1 Altoug actigrapy cannot #eused to make a diagnosis of sleep apnea or PM@, it offers ad"antages o"er P*> formeasuring sleep distur#ance and insomnia, including te capacity to monitor sleep#ea"ior o"er multiple nigts and te a#ility to measure sleep in an indi"iduals usualsleeping en"ironment.Association #et!een *leep @istur#ance and te Menopause Transition

n contrast to men, sleep complaints increase dramatically during midlife in !omen, !itte pre"alence increasing from 12 to 96= in !omen during te late 96s and early /6s,O1 consistent !it te typical age of te menopause transition. pidemiological studiesindicate tat !omen are more likely to report sleeping pro#lems as tey transition fromlate reproducti"e age into te perimenopause.O1;21 n epidemiological studiesdocumenting te presence of an insomnia syndrome, peri and early postmenopausal

!omen are more likely to meet criteria for an insomnia disorder tan older reproducti"eage !omen $2= "ersus 13=(.O22 Tese results igligt te "ulnera#ility to percei"edsleep distur#ance and insomnia during te menopause transition.

%o!e"er, in contrast to te percei"ed sleep distur#ance associated !it te menopause

transition, studies examining differences in o#Eecti"ely measured sleep patterns usingP*> a"e not found clear e"idence tat peri and postmenopausal !omen a"e !orsemeasured sleep tan premenopausal !omen.O1:,23,29 n one large epidemiologicalstudy tat found compara#le P*> sleep among !omen in different menopause statusgroups,O1: postmenopausal !omen o#tained an a"erage of 19 minutes more sleep pernigt tan premenopausal !omen and ad sligtly more deep sleep $1= "ersus 13=(.O1: Tese differences are consistent !it #etter P*> sleep in te postmenopausalgroup, #ut, in ligt of te iger rate of su#Eecti"e sleep complaints in tis sample of



postmenopausal !omen, tese P*> findings may represent a compensatory responseto oter unmeasured sleep differences.

Altoug te a#sence of a#normalities in P*>measured sleep in perimenopausal !omen migt appear inconsistent !it te percei"ed sleep distur#ance reported duringte menopause transition, it is nota#le tat 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/ or in indi"iduals !it sleep disorders suc asC*A.O2 ndi"iduals reporting insomnia fre)uently do not a"e a#normalities on P*>,O/and, in older adults, significant sleep a#normalities can #e seen on P*> amongindi"iduals !o do not identify temsel"es as a"ing a sleep pro#lem.O2;

Ganging le"els of sex ormones across te menstrual cycle and troug temenopause transition a"e #een associated !it differences in percei"ed sleep )ualityand o#Eecti"ely measured sleep patterns.O26,2:31 lists findings from studies reportingassociations #et!een reproducti"e ormone le"els and sleep in !omen during temenopause transition. Taken togeter, results of tese studies suggest tat decreasesin estradiol and increases in folliclestimulating ormone, progesterone, and testosterone

may ad"ersely modulate sleep!ake #ea"iors and contri#ute to te eigtened risk forsleep distur#ance and insomnia in !omen undergoing te menopause transition.Factors Associated !it Percei"ed and Measured *leep @istur#ance in +omen duringte Menopause Transition

*e"eral clinical caracteristics a"e #een associated !it sleep complaints in peri andpostmenopausal !omen $(. *tudies in"estigating sources of percei"ed and P*>measured sleep distur#ance in midlife !omen !o report sleep pro#lems a"e found a"ariety of associated factors.O3,21,32,33 Te specific conditions associated !it sleepdistur#ance "ary depending on te particular sleep parameter in"estigated.Psycological symptoms and ot flases are associated most strongly !it percei"edsleep distur#ance, !ereas C*A and PM@ are associated !it o#Eecti"e a#normalities

in P*>measured sleep. *uc studies suggest tat midlife !omen !it sleep pro#lemsare a eterogeneous group. >i"en te !ide range of potential sleep pro#lems, it isexpected tat sleep distur#ance during midlife is multifactorial and tat se"eral sleepdisrupting causes may cooccur e"en !itin an indi"idual !oman. Te callenge ofmaking attri#utions of sleep distur#ance to specific ealt conditions is made e"en morecomplicated #y agerelated increases in sleep tat can #e difficult to disentangle.*leep @istur#ance and %ot Flases

igttime ot flases, or nigt s!eats, are almost uni"ersal in !omen !it daytime otflases. +en ot flases persist during te nigt, tey fre)uently, #ut not uni"ersally,a!aken a !oman from sleep, altoug not e"ery nocturnal ot flas is associated !itan a!akening. +omen !it ot flases may also experience nocturnal a!akenings tat

are unrelated to a "asomotor e"ent. %ot flases occur in 6 to :6= of !omen during temenopause transitionO39 and persist for 9 to / years on a"erage.O3/,3 -ecause ofteir pre"alence, nocturnal ot flases are tougt to #e a common source of sleepdistur#ance in midlife !omen.

Multiple large epidemiological studies a"e concluded tat, altoug ot flases areassociated !it reduced sleep )uality, including unrefresing sleep and repeated #riefa!akenings from sleep, tey are unlikely contri#utors to pro#lems !it falling asleep atte #eginning of te nigt.O3,1:26,2<,31,33,3;,3: %ot flases4nigt s!eats correlate



!it te se"erity of insomnia symptomsO3< and are associated !it a greater likelioodof an insomnia diagnosis $2:./= "ersus 16./=(.O22 For !omen !it se"ere ot flases,:1.3= report poor sleep )uality, and 93.:= meet criteria for cronic insomnia.O22

@espite te strong association #et!een ot flases and insomnia, only limited andcontradictory e"idence supports an association #et!een ot flases and o#Eecti"ely

measured sleep distur#ance.O1:,23,29,3;92 Altoug percei"ed ot flases correlate !it poor percei"ed sleep )uality, studies measuring ot flases o#Eecti"ely a"e notlinked ot flases to percei"ed sleep distur#ance.O93 *imilarly, percei"ed ot flases

!ere not associated !it differences in P*> parameters of sleep in a largeepidemiological study,O1: and a smaller study found reduced sleep efficiency and longer&M latency in !omen reporting ot flases.O29 %o!e"er, !en sleep !as measuredusing actigrapy, ot flases !ere associated !it selected components of sleepdisruption $i.e., greater nigttime !akefulness and more !ake episodes(.O3<

+en ot flases are measured o#Eecti"ely, data #earing on te relationsip too#Eecti"ely measured sleep are conflicting $ (.O3;,92,999 Tese studies comparedcrosssectional P*>measured sleep parameters in symptomatic midlife !omen !it

tose o#ser"ed in !omen !itout o#Eecti"ely measured ot flases. &esults from tesestudies are inconsistent, !it four identifying a deleterious effectO3;,9692 and oneso!ing no effect of ot flases on sleep.O3: Te contradictory results of tese studiesmay result from small sample si0es, crosssectional designs, and "arying eligi#ilitycriteria and analytic approaces. Four studies of postmenopausal !omen did not re)uiresleep complaints for eligi#ility,O3:,9692 and anoter study of #reast cancer patients

!it insomnia did not re)uire ot flases for eligi#ility.O3; Additional studies are clearlyneeded to #etter elucidate and isolate te impact of ot flases on o#Eecti"e parametersof sleep.

Altoug te a#sence of a clearcut association #et!een ot flases and o#Eecti"elymeasured sleep appears to contradict te strong association #et!een percei"ed ot

flases and su#Eecti"e sleep distur#ance, tese sleep parameters measure differentcomponents of sleep tat may not necessarily #e o"erlapping. n addition, altoug P*>is te gold standard for screening and )uantifying sleep distur#ance, P*> is typicallyconducted in te la#oratory for 1 to 3 nigts, potentially pro"iding insufficient sampling toade)uately capture sleep distur#ance related to ot flases. *upporting tis notion is teo#ser"ation of nigttonigt "aria#ility in te se"erity of oter disorders tat disrupt sleepsuc as C*AO9; and insomnia.O9:,9< Future in"estigations may inform !iccomponent of o#Eecti"ely measured sleep predicts te perception of poor sleep )uality in

!omen !it ot flases.

@ata on te mecanism #y !ic ot flases may disrupt sleep are limited andcontro"ersial.O2 %ot flases can #e documented o#Eecti"ely during te nigttime e"en in

te a#sence of an a!akening, indicating tat not all ot flases are e)ually disrupti"e tonocturnal sleep.O96 Te likeliood of !aking up in association !it a ot flas may "aryin part !it te sleep stage in !ic te ot flas occurs, !it a greater likeliood ofa!akening during sleep periods composed of less &M sleep.O9/

Ganges in core #ody temperature $TG( produced #y ot flases may #e anotermecanism troug !ic ot flases produce sleep disruption. Termoregulation istigtly coupled to sleep, and some a"e ypotesi0ed tat an ina#ility to dissipate eatat nigt reflects a yperaroused state tat may lead to insomnia.O/6 %ot flases are



commonly preceded #y a transient increase in TG.O/1 At ot flas onset, sternals!eating occurs, !ic dissipates eat and results in a decline in TG, sometimestransiently #elo! #aseline TG le"els. Altoug it as #een ypotesi0ed tat fluctuationsin TG precipitate an a!akening, data indicating tat a!akenings are e)ually likely toprecede or follo! a nocturnal ot flas suggest tat te TG increase fre)uentlypreceding a flas may not necessary #e responsi#le for inducing an a!akening.O3:

%o!e"er, it is plausi#le tat te central ner"ous system canges tat likely precede #otte fluctuation in TG and te perception of a ot flas may #e responsi#le forprecipitating an a!akening.

C"erall, TG is lo!er among !omen !it ot flases trougout te day and nigt,O/1suggesting a disruption of te typical circadian temperature rytm. &esults of tesepreliminary studies are at odds !it oter in"estigations indicating tat iger TG duringsleep is associated !it !orse P*>measured sleep.O/2,/3 A potential link #et!eentermoregulation, ot flases, and sleep disruption !arrants furter in"estigation todetermine te precise mecanism underlying tese interrelated pysiological processes.*leep @istur#ance, Anxiety, and @epressi"e *ymptoms

n addition to ot flases, iger le"els of depressi"eO26,21,2<,33 and anxietyO3,21,2<symptoms a"e #een associated !it a perception of !orse sleep )uality in midlife

!omen. *uc studies a"e not specifically distinguised !eter !omen !itdepressi"e and4or anxiety symptoms meet criteria for a psyciatric disorder. Cterstudies confirm tat e"en mild psycological distress is linked to !orse sleep )uality.O2

Psyciatric disorders including maEor depression, dystymia, generali0ed anxietydisorder, panic disorder, and oter mood and anxiety disorders all a"e sleep disruption$percei"ed and o#Eecti"ely measured( as a common symptom component.O/9,//-ecause !omen are at increased risk for experiencing a maEor depressi"e episodeduring te perimenopause,O/,/; sleep distur#ance during midlife may #e a marker of aclinically significant mood disorder tat !arrants furter e"aluation. Moreo"er, #ecause

ot flases are strongly associated !it depression symptomsO/:,/< and !omen !itot flases are more likely to de"elop a maEor depressi"e episode,O/ sleep pro#lemsmay result from #ot ot flases and depression in !omen !o a"e multiple concurrentsymptoms. Midlife !omen !o a"e depression in addition to ot flases and sleepdisruption report !orse sleep )uality and o#Eecti"ely measured sleep tan tose !itoutdepression,O6 suggesting tat depression and ot flases may a"e an additi"e effecton sleep distur#ance.

To confound matters, !omen !it a prior istory of depression are more likely to reportot flasesO1 and may de"elop sleep distur#ance #ecause of ot flases !en teyare not depressed. Anoter potential temporal pattern is tat sleep distur#ance resultingfrom ot flases may also increase te risk of su#se)uent depression.O2,3 ndeed,

disrupted sleep as #een so!n to precede te onsetO9 and recurrenceO/ ofdepression in oter populations.

ike depression, anxiety correlates strongly !it insomnia. Tis link as #eenesta#lised for specific anxiety disorders, including panic disorder,O generali0edanxiety disorder,O; social po#ia,O: and posttraumatic stress disorder.O< n addition,trou#le sleeping is associated !it mild anxiety symptoms, presenting as iger le"els ofstress, tension, and selfconsciousness.O21 Moreo"er, like depressi"e symptoms,anxiety also correlates !it and commonly precedes te onset of ot flases during te



menopause transition,O;6,;1 raising te possi#ility tat sleep distur#ance may resultfrom anxiety, ot flases, or #ot. -ecause anxiety and depressi"e symptomscommonly, #ut not uniformly, cooccur, it can #e difficult to disentangle te indi"idualcontri#utions of tese psycological symptoms. Tus, in e"aluating !omen !o reportsleep distur#ance during te menopause transition, anxiety disorders, depressi"edisorders, and ot flases sould all #e considered as potential contri#uting factors tat

may act independently or Eointly to disrupt sleep.Primary *leep @isorders

Primary sleep disorders suc as C*A, &*, and PM@ are common in midlife !omenand contri#ute to complaints of distur#ed sleep in tis population.

Te o"erall pre"alence of C*A is estimated at <= in !omen, #ut tis pre"alenceincreases as !omen transition into midlife, !it te pre"alence increasing from ./= to:.;= to 1= in !omen in teir 36s, 96s, and /6s, respecti"ely.O;2 *e"eral pysiologicalcanges tat occur in midlife !omen con"erge to increase C*A in tis population. Forinstance, C*A risk rises #ot !it age and !it increasing #ody mass index $-M(.O;3*tudies tat a"e examined C*A specifically in midlife !omen suggest tat #ody !eigt

is a stronger predictor of C*A tan is menopausal status per se,O;9;; and tus !omen !o experience excessi"e !eigt gain in midlife may experience more disruptedsleep and sleepdisordered #reating.O;: oneteless, !en controlling for age and-M, C*A is more common among postmenopausal !omen tan premenopausal

!omen, suggesting tat te menopause transition is also a factor in te de"elopment ofC*A.O;2;<

"idence suggests tat sleepdisordered #reating is underdiagnosed in !omen,O;2,:6,:1 peraps due to gender #iasO:1 or differing symptom presentations #et!eenmen and !omen.O:2,:3 Gompared !it men !it C*A, !omen !it C*A are morelikely to a"e an initial complaint of insomnia or depression.O:3 t is incum#ent onclinicians treating sleep distur#ances in midlife !omen not to o"erlook symptoms

suggesti"e of sleepdisordered #reating and to refer suc patients for P*> gi"en temedical risks associated !it C*A including coronary artery disease,O:9 ypertension,O:/ stroke,O: depression,O:;and deat.O::

&* is anoter common sleep disorder tat disrupts sleep in midlife !omen. Altoug&* affects 16= of te population, te disorder is t!ice as common in !omen as men,O:< and te risk of &* in !omen increases !it age and parity.O<6 @uring midlife, &*occurs more fre)uently in !omen !it "asomotor symptoms, #ut tis disorder as not#een linked !it menopausal status or ormone terapy.O<1 Te patopysiologyin"ol"es iron meta#olism and dopaminergic neurotransmission primarily,O<2,<3 #utsecondary causes $e.g., tyroid disease, antidepressant medication use( also exist. Apossi#le etiologic role of reproducti"e ormones in &* is suggested #y an association

#et!een &* and increased endogenous estradiol le"els in pregnant !omen.O<9-ecause &* increases !it aging and secondary causes tat are common in midlife

!omen, a clinical istory for &* symptoms sould #e o#tained !en pro#lems initiatingsleep are reported.

PM@ is anoter primary sleep disorder tat increases in pre"alence !it age and iscommon among menopausal !omen.O</ -ecause PMs may result from te use ofantidepressant medications and sleepdisordered #reating, #ot of !ic are common



in midlife !omen, secondary causes of PMs sould #e considered #ecause tey mayplay a role in te ig pre"alence of PM@ in tis population.

Altoug a role for estrogen in te etiology of PM@ as #een suggested #y increasedPMs during pregnancy,O< te role of sex ormones in PM@ as not #een !elldefined in !omen undergoing te menopausal transition. T!o small randomi0ed

controlled trials of ormone terapy in postmenopausal !omen so!ed tat estrogenplus progesterone,O<; #ut not estrogen alone,O</ decreased PMs. Te link #et!eenreproducti"e ormones and PM@ is unclear, and furter study of te roles of estrogenand progesterone in te etiology and treatment of PMs is needed.Agerelated *leep Ganges and Medical Gonditions

Altoug percei"ed sleep distur#ance in midlife !omen is associated !it temenopausal transition, sleep complaints in tis population also correlate !it agerelatedsleep canges and !it medical conditions tat increase during midlife.O<: Gommonconditions tat may affect sleep tat increase !it age include o#esity,O<< cancer,O166gastroesopageal reflux,O161 urinary incontinence and nocturnal micturition,O;;,162169 tyroid dysfunction,O16/ cronic pain syndromes,O16 and fi#romyalgia.O16; As

!omen age, increased use of neuroacti"e medications may also contri#ute to sleepdifficulties.-ea"ioral and Psycosocial Factors

Cter common causes of sleep distur#ances in midlife !omen tat may contri#ute tosignificant sleep disruption include poor sleep ygiene $i.e., irregular sleep!akescedule, excessi"e napping, insufficient sleep(, decreased sleep due to "olitionalfactors $i.e., staying up late or rising early #y coice or to meet !ork or socialo#ligations(, and en"ironmental distur#ances $e.g., snoring #ed partner, sleeping !itligts, tele"ision, cell pone on(.

Psycosocial factors may also contri#ute to sleep distur#ances. @istur#ed sleep in

midlife !omen as #een linked to marital dissatisfaction,O16: and !omen in midlife areoften sand!iced #et!een te timeconsuming demands of caring for teir cildren andteir aging parents. Terefore, altoug ot flases, medical conditions, psyciatricillness, sleep disorders, and medications may #e etiological in sleep distur#ance,#ea"ioral and psycosocial factors are important in te differential diagnoses for temidlife !oman reporting nonrestorati"e sleep, sleep disruption, and4or daytime fatigue.O;;Management *trategies for *leep @istur#ances during te Menopause Transition

&andomi0ed place#ocontrolled trials a"e demonstrated te efficacy of ormoneterapy $%T( and ypnotic agents for treatment of sleep distur#ance occurring in !omenduring te perimenopause and early postmenopause. n tis section, !e summari0e

results of randomi0ed controlled trials $&GT*( comparing %T and ypnotic terapies toplace#o in te management of sleep disorders in perimenopausal and postmenopausal

!omen. Also discussed #riefly are nonparmacological #ea"ioral inter"entions tata"e #een studied !idely for te management of insomnia $i.e., cogniti"e #ea"ioralterapy, sleep ygiene(, al#eit not specifically in te context of reproducti"e aging.

-eyond te scope of tis re"ie! is a discussion of oter commonly used sleeping aidsfor sleep disruption, including #en0odia0epines, tra0odone, melatonin, melatoninagonists, dipenydramine, and oter o"ertecounter treatments. Many of tese are



effecti"e ypnotics, #ut none a"e #een studied specifically in !omen !it sleepdistur#ances related to te menopause transition.strogen and Progestin Terapy

Te effect of %T on sleep as #een studied !idely in postmenopausal !omen $and(. Te"ast maEority of &GTs comparing %T to place#o a"e found tat %T impro"es percei"ed

sleep )uality and selfreported sleeping pro#lems more tan place#o,O<;,16<122altoug se"eral oters did not find an ad"antage of %T o"er place#o $(.O123,129

&esults of studies using P*> to measure %T effects on sleep parameters o#Eecti"elya"e #een mixed $(, !it some reporting impro"ement in selected components ofsleepO<;,11;,11:,121,122,12/,12 and oters descri#ing eiter no effectO;,</,122 ore"en deleterious effects of inter"entions on isolated components of P*>measuredsleep.O122,12; C"erall, most of te studies in"ol"ing P*> measures so!ed small #utfa"ora#le effects of %T on sleep. Te most consistent findings are less fragmentation ofsleep, !it a reduction in !akefulness and arousals. Tese decreases in P*>measuredsleep fragmentation are consistent !it su#Eecti"e reports of impro"ed sleep )uality !it%T. %o!e"er, te positi"e effects of %T on sleep as measured #y P*> !ere small in

some studies, !ic may limit te clinical significance of tese findings. nconsistencies#et!een study results relating to selected P*>measured sleep parameters are difficultto interpret in part #ecause of small sample si0es and due to "aria#ility in measurementapproaces and outcome "aria#les. Additional studies are tus needed to gain a #etterunderstanding of te effects of %T on P*>measured sleep in !omen during and afterte menopause transition.

Analyses of te effects of %T on sleep a"e commonly #een conducted as part of largerin"estigations of multiple )ualityoflife domains and primarily in !omen !o do not a"ea specific sleep complaint, altoug someO112,11/,11<,126,12: re)uired ot flases foreligi#ility. Altoug no sleep complaint !as re)uired, it is nota#le tat impro"ed sleep

!as reported and4or measured #y P*> among study populations of predominantly

asymptomatic !omen. %o!e"er, some studies found tat te #eneficial effects !eresmall and potentially not clinically meaningful. Finally, se"eral &GTs reported tat %Tad a more marked effect on sleep eiter among !omen !it ot flases or for tose

!it sleep distur#ances associated !it ot flases,O112119 suggesting tat sleepingpro#lems cooccurring !it nocturnal ot flases are most amena#le to treatment !it%T.O11

Most studies administered com#ined estrogen and progestin terapy, making it difficultto distinguis te #eneficial effects of estrogen from tat of te coadministered progestin.O<;,16<,116,11211/,11;121,129,12/,12; %o!e"er, #eneficial effects on sleep !erealso seen in studies using estrogen aloneO</,111,122,12,12<,136 or progestin alone,O121,12: suggesting tat estrogen and progestins may a"e independent terapeutic

effects on sleep. >reater #enefit of natural progesterone o"er medroxyprogesterone onpercei"ed sleep )uality and on selected P*>#ased sleep parameters as #een so!nin preliminary studies comparing %T preparations composed of different progestins.O11;,11<

@ata are limited on te effect of %T on sleeping pro#lems among !omen !it primarysleep disorders $(. *tudies in postmenopausal !omen !o a"e a clinical diagnosis ofinsomnia so! #etter percei"ed sleep )uality and a trend to!ard impro"ement of P*>measured sleep parameters !it %T.O11:,12/ &esults of a fe! studies in"estigating te



effects of ormone terapy in postmenopausal !omen suggest tat %T may ameliorateapnea symptoms in !omen !itout a formal diagnosis of C*A.O<;,11:,12/,136 *tudiesexamining effects of %T on PMs in !omen !itout a PM@ disorder a"e not so!n

!orsening of PMs,O</,<; !ic is important in ligt of te suggested deleterious role ofestrogen in younger !omen !it [email protected]<

Te mecanisms troug !ic estrogen and progestin terapies may impro"e sleepare not kno!n. strogen itself may a"e a direct sleep effect #y increasing omeostaticdri"e for sleepDO131 o!e"er te specific mecanisms troug !ic tese effects mayoccur a"e not #een descri#ed in umans. *tudies in rodents suggest tat te effect ofestradiol on sleep4!ake cycles may #e explained #y a reduction in prostaglandinsyntesis in te "entrolateral preoptic nucleus of te ypotalamus.O132 Alternati"ely,for !omen !it cooccurring ot flases, estrogen terapy may impro"e sleepdistur#ance as an indirect conse)uence of its salutary effects on nocturnal ot flases.O11

Progestins are kno!n to exert a direct sleep induction or ypnotic effect mediatedtroug gammaamino#utyric acidacti"e meta#olites.O133 Progestins are also a potent

respiratory stimulant tat decrease te num#er of apnea episodes in men,O139 #ut littleis kno!n a#out effects of progestins in !omen !it C*A.on#en0odia0epine *edati"eypnotics

Te non#en0odia0epines 0olpidem and es0opiclone a"e #een so!n to #e moreeffecti"e tan place#o in te treatment of insomnia in peri and early postmenopausal

!omen.O13/13; *tudies so! tat tese ypnotic agents impro"e sleep in !omen !o a"e difficulty initiating O13/,13 and4or maintaining sleep.O13,13; Participants intese studies typically ad ot flases tat cooccurred !it teir sleep distur#ance andde"eloped in concert !it te onset of ot flases. n addition to treating insomniasymptoms, use of es0opiclone reduced te num#er of percei"ed ot flases occurring atnigt, #ut not during te daytime, suggesting tat !omen sleep troug teir nocturnal

"asomotor symptoms, rater tan te agent a"ing a direct effect on ot flases.O13*leep %ygiene and Gogniti"e -ea"ioral Terapy for nsomnia

nsomnia and milder forms of sleep distur#ance may respond !ell tononparmacological treatment suc as sleep ygiene approaces and cogniti"e#ea"ioral terapy for insomnia. *leep ygiene in"ol"es targeted #ea"ioral modificationapproaces tat can #e taugt in te office, re"ie!ed on multiple online resources sucas !!!.sleepfoundation.org, and implemented at ome. *leep ygiene addressescommonsense ealt practices suc as exercise, diet, cigarette smoking, alcool use,as !ell as en"ironmental factors including ligt, noise, and temperature exposure tatmay interfere !it sleep.O13: Cter components of good sleep ygiene includerituali0ed #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 #ea"ioral terapy for insomnia $G-T( is a structured sorttermpsycoterapy inter"ention conducted #y a licensed psycologist or #ea"ioral medicinepractitioner. G-T identifies te psycological and #ea"ioral factors tat play a role inan indi"iduals insomnia. Gomponents include stimulus control, sleep ygiene, sleeprestriction, paradoxical intention, relaxation training, and reframing of negati"e4false#eliefs a#out sleep and insomnia. G-T !orks #y modifying faulty #eliefs, expectations,and attri#utions a#out sleep and insomnia. &GTs of G-T so! #enefit in ;6 to :6= of



indi"iduals !it primary insomnia.O13: Multiple !ellcontrolled trials a"e documentedte sustained efficacy of G-T up to monts after a course of treatment is completed.O13<191 *ome studies suggest tat G-T is more efficacious tan ypnoticmedications,O191 !ereas oters report superior outcomes !en G-T is com#ined

!it a ypnotic medication.O13< Altoug G-T as #een so!n to #e igly effecti"e fortreating 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 specificallyassociated !it te menopause transition, !it !orse percei"ed sleep )uality reported#y peri and early postmenopausal !omen tan #y similarly aged premenopausal

!omen. Altoug ot flases are linked to percei"ed sleep pro#lems, teir association toP*>measured sleep remains unclear, and oter common medical conditions, mentalealt pro#lems, agerelated factors, and primary sleep disorders also correlate strongly

!it sleep pro#lems in tis population. "aluation of midlife !omen !it sleepcomplaints sould in"ol"e consideration of tese potential causes of sleep disruption,including te possi#ility tat different sleep pro#lems may cooccur. Persistent sleep

distur#ance and insomnia may arise from a com#ination of predisposing, precipitating,and perpetuating factors.O192 Terefore, !omen !o report sleep pro#lems during temenopause transition may #e predisposed to de"elop ne!onset sleep distur#ance fromot flases and oter sleepdisrupting factors.O193

Treatment considerations for !omen !it menopauseassociated sleep distur#anceinclude use of ormone terapy, ypnotic agents, and #ea"ioral inter"entions. naddition, concurrent terapy may #e re)uired to target cooccurring symptoms of otflases, depression, and anxiety, !ere present. n some indi"iduals, te constellation ofcooccurring symptoms may #e te primary determinant for treatment. For example,

!omen !it prominent ot flases may #e treated optimally !it %T, !ic is likely tosuppress #ot sleep and "asomotor symptoms.O11 Tose !it concurrent ot flases

!o are una#le to take %T can #e treated !it a com#ination of terapies targeting #otsleep distur#ance and ot flases. Alternati"ely, ypnotic treatments can #e used alone,especially if "asomotor symptoms are not particularly #otersome or if ot flases areprimarily nocturnal, in !ic case treatments targeting sleep can #e used to elp !omensleep troug ot flases, rater tan directly suppress ot flases.O13 +idely usednonormonal parmacological treatments for ot flases include serotonergicantidepressants $i.e., selecti"e serotonin reuptake ini#itor O**&, selecti"enoradrenergic reuptake ini#itor O*&( and selected antidepressants $i.e., ga#apentin,prega#alin(.O199,19/ n some cases, use of te **&4*& to treat ot flases may alsoimpro"e sleep distur#ance, tere#y eliminating te need for ypnotic treatments.O19%o!e"er, oter studies suggest tat augmentation of *&4**& !it te ypnotic agent0olpidem impro"es sleep and )ualityoflife relati"e to use of te *&4**& alone in

!omen !it ot flases and associated sleep distur#ance.O19; n tis common scenarioof cooccurring ot flases and sleep distur#ance, te need to prioriti0e targetinginsomnia symptoms !it a specific ypnotic terapy likely "aries according to te degreeof sleep impairment resulting from ot flases. %o!e"er, com#ined treatments sould #econsidered #ecause concurrent terapy may #e re)uired to optimi0e !ell#eing.

Analogous to te approac used to target cooccurring ot flases in !omen !it sleepdistur#ance, com#ined treatments may also #e re)uired for !omen !o a"e sleeppro#lems concurrent !it depression and anxiety disorders. +omen !it persistent



sleep disruption sould #e e"aluated for suc psyciatric illnesses and referred fortreatment !ere appropriate. *imilarly, !omen !ose sleep pro#lems are part of aprimary sleep disorder, suc as C*A, &*, or PM@, sould #e referred for specificterapies targeting treatments for tese disorders.Gonclusions

n summary, sleep difficulties in midlife !omen are common and a"e #een associated !it te menopause transition itself, symptoms of ot flases, anxiety and depressi"edisorders, aging, primary sleep disorders, comor#id medical conditions and medications,as !ell as !it psycosocial and #ea"ioral factors. Glinicians sould #e a!are of tepre"alence of sleep distur#ance and sleep disorders in tis population and refer !omenfor e"aluation if a sleep disorder is suspected, particularly in ligt of te mor#idity andmortality associated !it sleep apnea. ffecti"e #ea"ioral and parmacologicalterapies are a"aila#le to treat sleep distur#ances of different etiologies, and once aspecific diagnosis is made, affected !omen sould #e treated #ecause su#stantialimpro"ements in )uality of life and ealt outcomes are acie"a#le. Tere are se"eralcommon sources of sleep pro#lems in midlife !omen, and an indi"idual !omans sleepdistur#ance may #e multifactorial. Gareful e"aluation of te nature of te sleep

distur#ance !ill elp identify te underlying causes and determine priorities fore"aluation and treatment.

Ta#le 1Ta#le 1Association #et!een &eproducti"e %ormones and *leep ?uality and Patterns in Midlife+omenTa#le 2Ta#le 2Factors Associated !it *leep Gomplaints during and after te Menopause TransitionTa#le 3Ta#le 3

ffect of C#Eecti"ely Measured %ot Flases on C#Eecti"ely Measured *leepTa#le 9Ta#le 9@ou#le-lind &andomi0ed Place#oGontrolled Trials *o!ing ffect of strogen and4orProgestin Terapy on Percei"ed *leep ?ualityTa#le /Ta#le /@ou#le-lind &andomi0ed Trials *o!ing ffect of strogen and4or Progestin Terapyon *leep Parameters Measured C#Eecti"ely !it Polysomnograpy and Percei"ed *leep?ualityAckno!ledgments

Tis researc !as supported in part #y 1&61M%6:2<22 $%J(. Te autors tankli0a#et . emon, M.A., and *tepanie Gonnors, -.A., for teir administrati"e support.Article information*emin &eprod Med. Autor manuscriptD a"aila#le in PMG 2613 August ;.Pu#lised in final edited form as8*emin &eprod Med. 2616 *eptem#erD 2:$/(8 969921.Pu#lised online 2616 *eptem#er 1/. doi8 16.16//4s6636122<66PMG@8 PMG3;3:3;%M*@8 %M*/66/6



%adine Joffe, M.@., M.*c., Anda Massler, M.@., M.*c., and Katerine M. *arkey, M.@.,[email protected] notice and @isclaimerTe pu#lisers final edited "ersion of tis article is a"aila#le at *emin &eprod Med*ee oter articles in PMG tat cite te pu#lised article.&eferences

1. Girignotta F, Mondini *, Rucconi M, en0i P, ugaresi . nsomnia8 anepidemiological sur"ey. Glin europarmacol. 1<:/D:$*uppl 1(8*9<*/9. OPu#Med2. ational nstitutes of %ealt *tateofte*cience Gonference statement Managementof menopauserelated symptoms. Ann ntern Med. 266/D192$12 Pt 1(816631613.OPu#Med3. Freedman &&, &oers TA. *leep distur#ance in menopause. Menopause.266;D19$/(8:2:2<. OPu#Med9. American Academy of *leep Medicine *econd dition $G*@2(8 @iagnostic andGoding Manual. 2nd ed American Academy of *leep MedicineD +estcester, 8 266/.Te nternational Glassification of *leep @isorders./. -uysse @J, Ancolisrael *, dinger J@, icstein K, Morin GM. &ecommendationsfor a standard researc assessment of insomnia. *leep. 266D2<$<(811//11;3.

OPu#Med. ittner M, %irsko!it0 M, Kramer M, et al. American Academy of *leep Medicine.*tandards of Practice Gommitte Practice parameters for using polysomnograpy toe"aluate insomnia8 an update. *leep. 2663D2$(8;/9;6. OPu#Med;. Jaco#s A, &eynolds GF, Kupfer @J, o"in PA, renpreis A-. Te role ofpolysomnograpy in te differential diagnosis of cronic insomnia. Am J Psyciatry.1<::D19/$3(83939<. OPu#Med:. &acelefsky >, Flynt J, ##in A. Possi#le teratogenicity of tricyclic antidepressants.ancet. 1<;2D1$;;//(8:3:3<. OPu#Med<. &ectscaffen A, Kales A, editors. A Manual of *tandardi0ed Terminology,Tecni)ues, and *coring *ystem for *leep *tages of %uman *u#Eects. B.*.>o"ernment Printing CfficeD +asington, @G8 1<:. OPu#Med

16. Montplaisir J, -oucer *, Poirier >, a"igne >, apierre C, esprance P. Glinical,polysomnograpic, and genetic caracteristics of restless legs syndrome8 a study of 133patients diagnosed !it ne! standard criteria. Mo" @isord. 1<<;D12$1(81/. OPu#Med11. *ade A, %auri PJ, Kripke @F, a"ie P. Te role of actigrapy in te e"aluation ofsleep disorders. *leep. 1<</D1:$9(82::362. OPu#Med12. Jeanouis >, "on >i0ycki %, Ri0i F, *pielman A, %auri P, Tau# %. Te actigrapdata analysis soft!are8 . A no"el approac to scoring and interpreting sleep!akeacti"ity. Percept Mot *kills. 1<<;D:/$1(821<22. OPu#Med13. Jeanouis >, "on >i0ycki %, Ri0i F, *pielman A, %auri P, Tau# %. Te actigrapdata analysis soft!are8 . A no"el approac to scoring and interpreting sleep!akeacti"ity. Percept Mot *kills. 1<<;D:/$1(826;21. OPu#Med19. Jeanouis >, Ri0i F, "on >i0ycki %, %auri P. Actigrapic assessment of sleep in

insomnia8 application of te Actigrap @ata Analysis *oft!are $A@A*( Pysiol -ea".1<<<D/$9/(8/<3. OPu#Med1/. Kusida GA, Gang A, >adkary G, >uilleminault G, Garrillo C, @ement +G.Gomparison of actigrapic, polysomnograpic, and su#Eecti"e assessment of sleepparameters in sleepdisordered patients. *leep Med. 2661D2$/(83:<3<. OPu#Med1. -lood M, *ack &, Percy @G, Pen JG. A comparison of sleep detection #y !ristactigrapy, #ea"ioral response, and polysomnograpy. *leep. 1<<;D26$(83::3</.OPu#Med



1;. Kra"it0 %M, >an0 PA, -rom#erger J, Po!ell %, *uttonTyrrell K, Meyer PM. *leepdifficulty in !omen at midlife8 a community sur"ey of sleep and te menopausaltransition. Menopause. 2663D16$1(81<2:. OPu#Med1:. Qoung T, &a#ago @, Rgierska A, Austin @, aurel F. C#Eecti"e and su#Eecti"e sleep)uality in premenopausal, perimenopausal, and postmenopausal !omen in te+isconsin *leep Goort *tudy. *leep. 2663D2$(8;;2. OPu#Med

1<. @ennerstein , @udley G, %opper J, >utrie J&, -urger %>. A prospecti"epopulation#ased study of menopausal symptoms. C#stet >ynecol. 2666D<$3(83/13/:. OPu#Med26. Kra"it0 %M, Janssen , *antoro , et al. &elationsip of daytoday reproducti"eormone le"els to sleep in midlife !omen. Arc ntern Med. 266/D1/$26(823;623;.OPu#Med21. C!ens JF, Matte!s KA. *leep distur#ance in ealty middleaged !omen.Maturitas. 1<<:D36$1(891/6. OPu#Med22. Cayon MM. *e"ere ot flases are associated !it cronic insomnia. Arc nternMed. 266D1$12(81222:. OPu#Med23. *arkey KM, -earpark %M, Ace#o G, Millman &P, Ga"allo A, Garskadon MA. ffectsof menopausal status on sleep in midlife !omen. -ea" *leep Med. 2663D1$2(8<:6.

OPu#Med29. *a"er J, >i#lin , ent0 M, ee K. *leep patterns and sta#ility in perimenopausal

!omen. *leep. 1<::D11$(8///1. OPu#Med2/. &egestein ?&, Frie#ely J, *ifren J, et al. *elfreported sleep in postmenopausal

!omen. Menopause. 2669D11$2(81<:26;. OPu#Med2. -uysse @J, %all M, *trollo PJ, et al. &elationsips #et!een te Pitts#urg *leep?uality ndex $P*?(, p!ort *leepiness *cale $**(, and clinical4polysomnograpicmeasures in a community sample. J Glin *leep Med. 266:D9$(8/3/;1. OPMG freearticle OPu#Med2;. 'itiello M', arsen %, Moe K. Agerelated sleep cange8 gender and estrogeneffects on te su#Eecti"eo#Eecti"e sleep )uality relationsips of ealty, noncomplainingolder men and !omen. J Psycosom &es. 2669D/$/(8/63/16. OPu#Med

2:. Glark AJ, Flo!ers J, -oots , *ettar *. *leep distur#ance in midlife !omen. J Ad"urs. 1<</D22$3(8/2/:. OPu#Med2<. %ollander , Freeman +, *ammel M@, -erlin JA, >risso JA, -attistini M. *leep)uality, estradiol le"els, and #ea"ioral factors in late reproducti"e age !omen. C#stet>ynecol. 2661D<:$3(83<13<;. OPu#Med36. *o!ers MF, Reng %, Kra"it0 %M, et al. *ex steroid ormone profiles are related tosleep measures from polysomnograpy and te Pitts#urg *leep ?uality ndex. *leep.266:D31$16(8133<139<. OPMG free article OPu#Med31. Kra"it0 %M, Rao V, -rom#erger JT, et al. *leep distur#ance during te menopausaltransition in a multietnic community sample of !omen. *leep. 266:D31$;(8<;<<<6.OPMG free article OPu#Med32. -ro!n JP, >alliccio , Fla!s JA, Tracy JK. &elations among menopausal

symptoms, sleep distur#ance and depressi"e symptoms in midlife. Maturitas.266<D2$2(81:91:<. OPMG free article OPu#Med33. Pien >+, *ammel M@, Freeman +, in %, @e-lasis T. Predictors of sleep )ualityin !omen in te menopausal transition. *leep. 266:D31$;(8<<1<<<. OPMG free articleOPu#Med39. >old -, *ternfeld -, Kelsey J, et al. &elation of demograpic and lifestyle factorsto symptoms in a multiracial4etnic population of !omen 96// years of age. Am Jpidemiol. 2666D1/2$/(8939;3. OPu#Med



3/. Politi MG, *cleinit0 M@, Gol F. &e"isiting te duration of "asomotor symptoms ofmenopause8 a metaanalysis. J >en ntern Med. 266:D23$<(81/6;1/13. OPMG freearticle OPu#Med3. Gol F, >utrie J&, Politi M, @ennerstein . @uration of "asomotor symptoms inmiddleaged !omen8 a longitudinal study. Menopause. 266<D1$3(89/39/;. OPu#Med3;. *a"ard J, @a"idson J&, "ers %, et al. Te association #et!een nocturnal ot flases

and sleep in #reast cancer sur"i"ors. J Pain *ymptom Manage. 2669D2;$(8/13/22.OPu#Med3:. Freedman &&, &oers TA. ack of sleep distur#ance from menopausal ot flases.Fertil *teril. 2669D:2$1(813:199. OPu#Med3<. nsrud K, *tone K, -lack!ell T, et al. Fre)uency and se"erity of ot flases andsleep distur#ance in postmenopausal !omen !it ot flases. Menopause.266<D1$2(82:2<2. OPu#Med96. rlik Q, Tataryn ', Meldrum @&, omax P, -aEorek J>, Judd %. Association of

!aking episodes !it menopausal ot fluses. JAMA. 1<:1D29/$1;(81;911;99.OPu#Med91. Freedman &&, -enton M@, >enik &J, >raydon FV. Gortical acti"ation duringmenopausal ot flases. Fertil *teril. 266D:/$3(8;9;:. OPu#Med

92. +ood!ard *, Freedman &&. Te termoregulatory effects of menopausal otflases on sleep. *leep. 1<<9D1;$(89<;/61. OPu#Med93. Turston &G, -lumental JA, -a#yak MA, *er!ood A. Association #et!een otflases, sleep complaints, and psycological functioning among ealty menopausal

!omen. nt J -ea" Med. 266D13$2(8131;2. OPu#Med99. rlik Q, Tataryn ', Meldrum @&, omax P, -aEorek J>, Judd %. Association of

!aking episodes !it menopausal ot fluses. JAMA. 1<:1D29/$1;(81;911;99.OPu#Med9/. Freedman &&, &oers TA. ffects of &M sleep and am#ient temperature on otflasinduced sleep distur#ance. Menopause. 266D13$9(8/;/:3. OPu#Med9. Freedman &&, &oers TA. ack of sleep distur#ance from menopausal ot flases.Fertil *teril. 2669D:2$1(813:199. OPu#Med

9;. Amadi , *apiro >K, Gung *A, *apiro GM. Glinical diagnosis of sleep apnea#ased on single nigt of polysomnograpy "s. t!o nigts of polysomnograpy. *leep-reat. 266<D13$3(822122. OPu#Med9:. -uysse @J, Geng Q, >ermain A, et al. igttonigt sleep "aria#ility in older adults

!it and !itout cronic insomnia. *leep Med. 2616D11$1(8/9. OPMG free articleOPu#Med9<. dinger J@, Mars >&, McGall +', r!in G+, ininger A+. *leep "aria#ility acrossconsecuti"e nigts of ome monitoring in older mixed @M* patients. *leep.1<<1D19$1(8131;. OPu#Med/6. ack G, >radisar M, 'an *omeren J, +rigt %&, usington K. Te relationsip#et!een insomnia and #ody temperatures. *leep Med &e". 266:D12$9(836;31;.OPu#Med

/1. Freedman &&, orton @, +ood!ard *, Gornlissen >. Gore #ody temperature andcircadian rytm of ot flases in menopausal !omen. J Glin ndocrinol Meta#.1<</D:6$:(823/923/:. OPu#Med/2. >radisar M, ack , +rigt %, %arris J, -rooks A. @o cronic primary insomniacsa"e impaired eat loss !en attempting sleep Am J Pysiol &egul ntegr GompPysiol. 266D2<6$9(8&111/&1121. OPu#Med/3. Murpy PJ, Gamp#ell **. *ex ormones, sleep, and core #ody temperature in olderpostmenopausal !omen. *leep. 266;D36$12(81;::1;<9. OPMG free article OPu#Med



/9. &iemann @, -erger M, 'oderol0er B. *leep and depressionresults frompsyco#iological studies8 an o"er"ie!. -iol Psycol. 2661D/;$13(8;163. OPu#Med//. Bde T+, Gortese -M, 'edeniapin A. Anxiety and sleep pro#lems8 emergingconcepts and teoretical treatment implications. Gurr Psyciatry &ep. 266<D11$9(82<2;. OPu#Med/. Goen *, *oares G, 'itonis AF, Ctto M+, %arlo! -. &isk for ne! onset of

depression during te menopausal transition8 te %ar"ard study of moods and cycles.Arc >en Psyciatry. 266D3$9(83:/3<6. OPu#Med/;. Freeman +, *ammel M@, in %, elson @-. Associations of ormones andmenopausal status !it depressed mood in !omen !it no istory of depression. Arc>en Psyciatry. 266D3$9(83;/3:2. OPu#Med/:. A"is , -ram#illa @, McKinlay *M, 'ass K. A longitudinal analysis of teassociation #et!een menopause and depression. &esults from te Massacusetts+omens %ealt *tudy. Ann pidemiol. 1<<9D9$3(8219226. OPu#Med/<. Joffe %, %all J, *oares G, et al. 'asomotor symptoms are associated !itdepression in perimenopausal !omen seeking primary care. Menopause.2662D<$(83<23<:. OPu#Med6. Joffe %, *oares G, Turston &G, +ite @P, Goen *, %all J. @epression is

associated !it !orse o#Eecti"ely and su#Eecti"ely measured sleep, #ut not morefre)uent a!akenings, in !omen !it "asomotor symptoms. Menopause.266<D1$9(8;1;<. OPMG free article OPu#Med1. Freeman +, *ammel M@, in %. Temporal associations of ot flases anddepression in te transition to menopause. Menopause. 266<D1$9(8;2:;39. OPMG freearticle OPu#Med2. &iemann @, 'oderol0er B. Primary insomnia8 a risk factor to de"elop depression JAffect @isord. 2663D;$13(82//2/<. OPu#Med3. -reslau , &ot T, &osental , Andreski P. *leep distur#ance and psyciatricdisorders8 a longitudinal epidemiological study of young adults. -iol Psyciatry.1<<D3<$(891191:. OPu#Med9. Ford @, Kamero! @-. pidemiologic study of sleep distur#ances and psyciatric

disorders. An opportunity for pre"ention JAMA. 1<:<D22$11(819;<19:9. OPu#Med/. Perlis M, >iles @, -uysse @J, Tu V, Kupfer @J. *elfreported sleep distur#ance asa prodromal symptom in recurrent depression. J Affect @isord. 1<<;D92$23(826<212.OPu#Med. *tein M-, Gartier M, +alker J&. *leep in nondepressed patients !it panicdisorder8 . *ystematic assessment of su#Eecti"e sleep )uality and sleep distur#ance.*leep. 1<<3D1$:(8;29;2. OPu#Med;. -langer , Morin GM, anglois F, adouceur &. nsomnia and generali0ed anxietydisorder8 effects of cogniti"e #ea"ior terapy for >A@ on insomnia symptoms. J Anxiety@isord. 2669D1:$9(8/1/;1. OPu#Med:. *tein M-, Kroft G@, +alker J&. *leep impairment in patients !it social po#ia.Psyciatry &es. 1<<3D9<$3(82/12/. OPu#Med

<. Cayon MM, *apiro GM. *leep distur#ances and psyciatric disorders associated !it posttraumatic stress disorder in te general population. Gompr Psyciatry.2666D91$(89<9;:. OPu#Med;6. Freeman +, *ammel M@, in %, >racia G&, Kapoor *, Ferdousi T. Te role ofanxiety and ormonal canges in menopausal ot flases. Menopause. 266/D12$3(82/:2. OPu#Med;1. >old -, Gol"in A, A"is , et al. ongitudinal analysis of te association #et!een"asomotor symptoms and race4etnicity across te menopausal transition8 study of



!omens ealt across te nation. Am J Pu#lic %ealt. 266D<$;(8122123/. OPMGfree article OPu#Med;2. Qoung T, Palta M, @empsey J, *katrud J, +e#er *, -adr *. Te occurrence ofsleepdisordered #reating among middleaged adults. ngl J Med.1<<3D32:$1;(81236123/. OPu#Med;3. Qoung T, *katrud J, Peppard P. &isk factors for o#structi"e sleep apnea in adults.

JAMA. 2669D2<1$1(82613261. OPu#Med;9. Garskadon MA, -earpark %M, *arkey KM, et al. ffects of menopause and nasalocclusion on #reating during sleep. Am J &espir Grit Gare Med. 1<<;D1//$1(826/216.OPu#Med;/. Kopelman P>, Apps MG, Gope T, mpey @+. Te influence of menstrual status,#ody !eigt and ypotalamic function on nocturnal respiration in !omen. J & GollPysicians ond. 1<:/D1<$9(829329;. OPu#Med;. -lock AJ, +ynne J+, -oysen P>. *leepdisordered #reating and nocturnal oxygendesaturation in postmenopausal !omen. Am J Med. 1<:6D<$1(8;/;<. OPu#Med;;. Alexander J, eylan T, Kot0 K, @ennerstein , &icardson >, &osen#aum &.Assessment and treatment for insomnia and fatigue in te symptomatic menopausal

!oman !it psyciatric comor#idity. xpert &e" euroter. 266;D;$11, *uppl(8*13<

*1//. OPu#Med;:. Andersen M, -ittencourt &, Antunes -, Tufik *. ffects of progesterone on sleep8a possi#le parmacological treatment for sleep#reating disorders Gurr Med Gem.266D13$2<(83/;/3/:2. OPu#Med;<. -ixler C, 'gont0as A, in %M, et al. Pre"alence of sleepdisordered #reating in

!omen8 effects of gender. Am J &espir Grit Gare Med. 2661D13$3 Pt 1(86:13.OPu#Med:6. &edline *, Kump K, Tisler P', -ro!ner , Ferrette '. >ender differences in sleepdisordered #reating in a community#ased sample. Am J &espir Grit Gare Med.1<<9D19<$3 Pt 1(8;22;2. OPu#Med:1. Qoung T, %utton &, Finn , -adr *, Palta M. Te gender #ias in sleep apneadiagnosis. Are !omen missed #ecause tey a"e different symptoms Arc ntern Med.

1<<D1/$21(8299/29/1. OPu#Med:2. @ursunoglu , C0kurt *, *arikaya *. s te clinical presentation different #et!eenmen and !omen admitting to te sleep la#oratory *leep -reat. 266<D13$3(82</2<:.OPu#Med:3. *epertycky M&, -anno K, Kryger M%. @ifferences #et!een men and !omen in teclinical presentation of patients diagnosed !it o#structi"e sleep apnea syndrome.*leep. 266/D2:$3(836<319. OPu#Med:9. Peker Q, Garlson J, %edner J. ncreased incidence of coronary artery disease insleep apnoea8 a longterm follo!up. ur &espir J. 266D2:$3(8/<62. OPu#Med:/. Peppard P, Qoung T, Palta M, *katrud J. Prospecti"e study of te association#et!een sleepdisordered #reating and ypertension. ngl J Med.2666D392$1<(813;:13:9. OPu#Med

:. Ar0t M, Qoung T, Finn , *katrud J-, -radley T@. Association of sleepdisordered#reating and te occurrence of stroke. Am J &espir Grit Gare Med. 266/D1;2$11(8199;19/1. OPMG free article OPu#Med:;. Peppard P, *0kloGoxe M, %la KM, Qoung T. ongitudinal association of sleeprelated #reating disorder and depression. Arc ntern Med. 266D1$1(81;6<1;1/.OPu#Med::. Qoung T, Finn , Peppard P, et al. *leep disordered #reating and mortality8eigteenyear follo!up of te +isconsin sleep coort. *leep. 266:D31$:(816;116;:.OPMG free article OPu#Med



:<. Pillips M, adouceur G@, @re"ets +G. A neural model of "oluntary and automaticemotion regulation8 implications for understanding te patopysiology andneurode"elopment of #ipolar disorder. Mol Psyciatry. 266:D13$<(8:2<, :33:/;. OPMGfree article OPu#Med<6. -erger K, uedemann J, Trenk!alder G, Jon B, Kessler G. *ex and te risk ofrestless legs syndrome in te general population. Arc ntern Med. 2669D19$2(81<

262. OPu#Med<1. +esstrom J, ilsson *, *undstromPoromaa , Blf#erg J. &estless legs syndromeamong !omen8 pre"alence, comor#idity and possi#le relationsip to menopause.Glimacteric. 266:D11$/(892292:. OPu#Med<2. Allen &. @opamine and iron in te patopysiology of restless legs syndrome $&*(*leep Med. 2669D/$9(83:/3<1. OPu#Med<3. Allen &P. &ace, iron status and restless legs syndrome. *leep Med. 2662D3$(89;9:. OPu#Med<9. @0aEa A, +erle &, ancel M, Pollmcer T. le"ated estradiol plasma le"els in

!omen !it restless legs during pregnancy. *leep. 266<D32$2(81<1;9. OPMG freearticle OPu#Med</. PoloKantola P, &auala , rkkola &, rEala K, Polo C. strogen replacement

terapy and nocturnal periodic lim mo"ements8 a randomi0ed controlled trial. C#stet>ynecol. 2661D<;$9(8/9://9. OPu#Med<. ikkola , k#lad B, kolm , Mikola %, Polo C. *leep in multiple pregnancy8#reating patterns, oxygenation, and periodic leg mo"ements. Am J C#stet >ynecol.1<<D1;9$/(812212/. OPu#Med<;. %acul %, -ittencourt &, Andersen M, %aidar MA, -aracat G, Tufik *. ffects oformone terapy !it estrogen and4or progesterone on sleep pattern in postmenopausal

!omen. nt J >ynaecol C#stet. 266:D163$3(826;212. OPu#Med<:. -erecki>isolf J, -egum , @o#son AJ. *ymptoms reported #y !omen in midlife8menopausal transition or aging Menopause. 266<D1$/(81621162<. OPu#Med<<. Patel *&, -lack!ell T, &edline *, et al. Csteoporotic Fractures in Men &esearc>roup. *tudy of Csteoporotic Fractures &esearc >roup Te association #et!een sleep

duration and o#esity in older adults. nt J C#es $ond( 266:D32$12(81:2/1:39. OPMGfree article OPu#Med166. *tepanski J, +alker M*, *c!art0#erg *, -lakely J, Cng JG, %outs AG. Terelation of trou#le sleeping, depressed mood, pain, and fatigue in patients !it cancer. JGlin *leep Med. 266<D/$2(813213. OPMG free article OPu#Med161. Mody &, -olge *G, Kannan %, Fass &. ffects of gastroesopageal reflux diseaseon sleep and outcomes. Glin >astroenterol %epatol. 266<D;$<(8</3</<. OPu#Med162. Asplund &, A#erg %. octurnal micturition, sleep and !ell#eing in !omen of ages969 years. Maturitas. 1<<D29$12(8;3:1. OPu#Med163. Asplund &, A#erg %. @aytime sleepiness in 969 yearold !omen in relation tosomatic ealt and medical treatment. *cand J Prim %ealt Gare. 1<<:D1$2(811211.OPu#Med

169. Asplund &, A#erg %. octuria and ealt in !omen aged 969 years. Maturitas.2666D3/$2(819319:. OPu#Med16/. +inkelman J+, >oldman %, Piscatelli , ukas *, @orsey GM, Gunningam *.Are tyroid function tests necessary in patients !it suspected sleep apnea *leep.1<<D1<$16(8;<6;<3. OPu#Med16. Fis#ain @A, Gole -, e!is J, >ao J. +at is te e"idence for cronic pain #eingetiologically associated !it te @*M' category of sleep disorder due to a generalmedical condition A structured e"idence#ased re"ie!. Pain Med. 2616D11$2(81/:1;<.OPu#Med



16;. Ger"in &@, Teodorescu M, Kus!aa &, et al. C#Eecti"e measures of disorderedsleep in fi#romyalgia. J &eumatol. 266<D3$<(8266<261. OPMG free article OPu#Med16:. Troxel +M, -uysse @J, %all M, Matte!s KA. Marital appiness and sleepdistur#ances in a multietnic sample of middleaged !omen. -ea" *leep Med.266<D;$1(821<. OPMG free article OPu#Med16<. +elton AJ, 'ickers M&, Kim J, et al. +*@CM team %ealt related )uality of life

after com#ined ormone replacement terapy8 randomised controlled trial. -MJ.266:D33;8a11<6. OPMG free article OPu#Med116. ielsen TF, &a"n P, Pitkin J, Gristiansen G. Pulsed estrogen terapy impro"espostmenopausal )uality of life8 a 2year place#ocontrolled study. Maturitas.266D/3$2(81:91<6. OPu#Med111. -runner &, >ass M, Aragaki A, et al. +omens %ealt nitiati"e n"estigatorsffects of conEugated e)uine estrogen on ealtrelated )uality of life in postmenopausal

!omen !it ysterectomy8 results from te +omens %ealt nitiati"e &andomi0edGlinical Trial. Arc ntern Med. 266/D1/$1;(81<;1<:. OPu#Med112. *crmann &, %oller T, -enda . stradiol and drospirenone for climactericsymptoms in postmenopausal !omen8 a dou#le#lind, randomi0ed, place#ocontrolledstudy of te safety and efficacy of tree dose regimens. Glimacteric. 2669D;$2(81:<1<.

OPu#Med113. 'estergaard P, %ermann AP, *tilgren , et al. ffects of / years of ormonalreplacement terapy on menopausal symptoms and #lood pressurea randomisedcontrolled study. Maturitas. 2663D9$2(8123132. OPu#Med119. %ays J, Cckene JK, -runner &, et al. +omens %ealt nitiati"e n"estigatorsffects of estrogen plus progestin on ealtrelated )uality of life. ngl J Med.2663D39:$1<(81:3<1:/9. OPu#Med11/. >am#acciani M, Giaponi M, Gappagli -, et al. ffects of lo!dose, continuouscom#ined estradiol and noretisterone acetate on menopausal )uality of life in earlypostmenopausal !omen. Maturitas. 2663D99$2(81/;13. OPu#Med11. PoloKantola P, rkkola &, %elenius %, rEala K, Polo C. +en does estrogenreplacement terapy impro"e sleep )uality Am J C#stet >ynecol. 1<<:D1;:$/(81662

166<. OPu#Med11;. Montplaisir J, orrain J, @enesle &, Petit @. *leep in menopause8 differential effectsof t!o forms of ormone replacement terapy. Menopause. 2661D:$1(8161. OPu#Med11:. *aletu -. *leep, "igilance and cognition in postmenopausal !omen8 place#ocontrolled studies !it 2 mg estradiol "alerate, !it and !itout 3 mg dienogest.Glimacteric. 2663D$*uppl 2(83;9/. OPu#Med11<. >am#acciani M, Giaponi M, Gappagli -, et al. ffects of lo!dose, continuouscom#ined ormone replacement terapy on sleep in symptomatic postmenopausal

!omen. Maturitas. 266/D/6$2(8<1<;. OPu#Med126. e"ine @+, @ailey M, &ockill -, Tipping @, augton MJ, *umaker *A.'alidation of te +omens %ealt nitiati"e nsomnia &ating *cale in a multicentercontrolled clinical trial. Psycosom Med. 266/D;$1(8<:169. OPu#Med

121. *cssler P, Kluge M, Qassouridis A, et al. Progesterone reduces !akefulness insleep > and as no effect on cognition in ealty postmenopausal !omen.Psyconeuroendocrinology. 266:D33$:(811291131. OPu#Med122. PoloKantola P, rkkola &, rEala K, Pullinen *, 'irtanen , Polo C. ffect of sortterm transdermal estrogen replacement terapy on sleep8 a randomi0ed, dou#le#lindcrosso"er trial in postmenopausal !omen. Fertil *teril. 1<<<D;1$/(8:;3::6. OPu#Med123. @iem *, >rady @, ?uan J, et al. ffects of ultralo!dose transdermal estradiol onpostmenopausal symptoms in !omen aged 6 to :6 years. Menopause.266D13$1(813613:. OPu#Med



129. %einric A-, +olf CT. n"estigating te effects of estradiol orestradiol4progesterone treatment on mood, depressi"e symptoms, menopausalsymptoms and su#Eecti"e sleep )uality in older ealty ysterectomi0ed !omen8 a)uestionnaire study. europsyco#iology. 266/D/2$1(81;23. OPu#Med12/. *aletuRylar0 >, Anderer P, >ru#er >, et al. nsomnia related to postmenopausalsyndrome and ormone replacement terapy8 sleep la#oratory studies on #aseline

differences #et!een patients and controls and dou#le#lind, place#ocontrolledin"estigations on te effects of a no"el estrogenprogestogen com#ination $Glimodien,afamme( "ersus estrogen alone. J *leep &es. 2663D12$3(823<2/9. OPu#Med12. AntoniEe"ic A, *talla >K, *teiger A. Modulation of te sleep electroencepalogram#y estrogen replacement in postmenopausal !omen. Am J C#stet >ynecol.2666D1:2$2(82;;2:2. OPu#Med12;. Kalleinen , Polo C, %imanen *, Joutsen A, PoloKantola P. Te effect ofestrogen plus progestin treatment on sleep8 a randomi0ed, place#ocontrolled, dou#le#lind trial in premenopausal and late postmenopausal !omen. Glimacteric.266:D11$3(8233293. OPu#Med12:. -lock AJ, +ynne J+, -oysen P>, indsey *, Martin G, Gantor -. Menopause,medroxyprogesterone and #reating during sleep. Am J Med. 1<:1D;6$3(8/6/16.

OPu#Med12<. PoloKantola P, Portin &, Polo C, %elenius %, rEala K, rkkola &. Te effect ofsortterm estrogen replacement terapy on cognition8 a randomi0ed, dou#le#lind,crosso"er trial in postmenopausal !omen. C#stet >ynecol. 1<<:D<1$3(89/<9.OPu#Med136. PoloKantola P, &auala , %elenius %, rkkola &, rEala K, Polo C. -reatingduring sleep in menopause8 a randomi0ed, controlled, crosso"er trial !it estrogenterapy. C#stet >ynecol. 2663D162$1(8:;/. OPu#Med131. Paul K, Turek F+, Kryger M%. nfluence of sex on sleep regulatory mecanisms.J +omens %ealt $arcmt( 266:D1;$;(81261126:. OPu#Med132. Mong JA, @e"id0e , >ood!illie A, Pfaff @+. &eduction of lipocalintypeprostaglandin@syntase in te preoptic area of female mice mimics estradiol effects on

arousal and sex #ea"ior. Proc atl Acad *ci B * A. 2663D166$2/(81/261/211. OPMGfree article OPu#Med133. Friess , Tagaya %, Tracsel , %ols#oer F, &upprect &. Progesteroneinducedcanges in sleep in male su#Eects. Am J Pysiol. 1<<;D2;2$/ Pt 1(8::/:<1.OPu#Med139. *trol KP, %ensley MJ, *aunders A, *carf *M, -ro!n &, ngram &%., JrProgesterone administration and progressi"e sleep apneas. JAMA. 1<:1D29/$12(812361232. OPu#Med13/. *oares G, Joffe %, &u#ens &, Garon J, &ot T, Goen . s0opiclone in patients

!it insomnia during perimenopause and early postmenopause8 a randomi0edcontrolled trial. C#stet >ynecol. 266D16:$(819621916. OPu#Med13. Joffe %, Petrillo , 'iguera A, et al. s0opiclone impro"es insomnia and depressi"e

and anxious symptoms in perimenopausal and postmenopausal !omen !it ot flases8a randomi0ed, dou#le#linded, place#ocontrolled crosso"er trial. Am J C#stet >ynecol.2616D262$2(81;1, e1e1;1, e11. OPu#Med13;. @orsey GM, ee KA, *carf M-. ffect of 0olpidem on sleep in !omen !itperimenopausal and postmenopausal insomnia8 a 9!eek, randomi0ed, multicenter,dou#le#lind, place#ocontrolled study. Glin Ter. 2669D2$16(81/;:1/:. OPu#Med13:. Morin G. Gontri#utions of cogniti"e#ea"ioral approaces to te clinicalmanagement of insomnia. Prim Gare Gompanion J Glin Psyciatry. 2662D98212.



13<. Morin GM, 'allievres A, >uay -, et al. Gogniti"e #ea"ioral terapy, singly andcom#ined !it medication, for persistent insomnia8 a randomi0ed controlled trial. JAMA.266<D361$1<(8266/261/. OPMG free article OPu#Med196. *i"ertsen -, Cm"ik *, Pallesen *, et al. Gogniti"e #ea"ioral terapy "s 0opiclonefor treatment of cronic primary insomnia in older adults8 a randomi0ed controlled trial.JAMA. 266D2</$29(82:/12:/:. OPu#Med

191. dinger J@, +olgemut +K, &adtke &A, Mars >&, ?uillian &. Gogniti"e#ea"ioral terapy for treatment of cronic primary insomnia8 a randomi0ed controlledtrial. JAMA. 2661D2:/$19(81:/1:9. OPu#Med192. *pielman A. Assessment of insomnia. Glin Psycol &e". 1<:D8112/.193. @rake G, &icardson >, &oers T, *cofield %, &ot T. 'ulnera#ility to stressrelated sleep distur#ance and yperarousal. *leep. 2669D2;$2(82:/2<1. OPu#Med199. oprin0i G, ?in &, -alcue"a P, et al. Pase , randomi0ed, dou#le#lind,place#ocontrolled e"aluation of prega#alin for alle"iating ot flases, 6;G1. J GlinCncol. 2616D2:$9(8919;. OPMG free article OPu#Med19/. oprin0i G, *loan J, *tearns ', et al. e!er antidepressants and ga#apentin forot flases8 an indi"idual patient pooled analysis. J Glin Cncol. 266<D2;$1;(82:312:3;.OPMG free article OPu#Med

19. *u"antouukkonen , Koi"unen &, *undstrWm %, et al. Gitalopram and fluoxetinein te treatment of postmenopausal symptoms8 a prospecti"e, randomi0ed, <mont,place#ocontrolled, dou#le#lind study. Menopause. 266/D12$1(81:2. OPu#Med19;. Joffe %, Partridge A, >io##ie%urder A, et al. Augmentation of "enlafaxine andselecti"e serotonin reuptake ini#itors !it 0olpidem impro"es sleep and )ualityoflife in#reast cancer patients !it ot flases8 a randomi0ed dou#le#lind, place#ocontrolledtrial. Menopause. 2616 Jun 29D pu# aead of print. OPu#Med

<

Menopause $e! Qork, .Q.(Autor Manuscript

% Pu#lic Accessstrogen Treatment mpairs Gogniti"e Performance follo!ing Psycosocial *tress andMonoamine @epletion in Postmenopausal +omen

Paul A. e!ouse, M.@., Julie @umas, P.@., O..., and *imon . Qoung, P.@.

Additional article informationA#stractC#Eecti"e

&ecent studies a"e so!n !omen experience an acceleration of cogniti"e pro#lemsafter menopause, and tat 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"iouslyso!n tat te negati"e emotional effects of psycosocial stress are magnified in normalpostmenopausal !omen after estrogen treatment. Tis study examined !eterestradiol administration can modify cogniti"e performance after exposure topsycological stress and monoamine depletion.Metods

Participants consisted of 22 postmenopausal !omen placed on eiter oral place#o or1;estradiol $2( $1 mg4day for 1 mont, ten 2 mg4day for 2 monts(. At te end of te



3 mont treatment pase, participants under!ent tree depletion callenges in !ictey ingested one of tree amino acid mixtures8 deficient in tryptopan, deficient inpenylalanine4tyrosine, or #alanced. Fi"e ours later, participants performed te Trier*ocial *tress Test $T**T(, follo!ed #y mood and anxiety ratings and cogniti"e testing.Gogniti"e measures included tests of attention, psycomotor function, and "er#alepisodic memory.

&esults

2treated compared to place#otreated participants exi#ited significant !orsening ofcogniti"e performance on tasks measuring attentional performance and psycomotorspeed. *imilar trends for impairment !ere seen in measures of longterm episodicmemory compared to place#otreated postmenopausal !omen. 2treated participantsalso so!ed a significant increase in negati"e mood and anxiety compared to place#otreated !omen after #ut not #efore te T**T, toug te !orsening of #ot cogniti"eand #ea"ioral functioning !ere not correlated. Tese effects !ere independent oftryptopan or tyrosine4penylalanine depletion and !ere not manifest #efore te T**Tor at #aseline.Gonclusions

Tese data suggest tat te relationsip #et!een estrogen administration andcogniti"e4#ea"ioral performance in postmenopausal !omen may #e more complex taninitially appreciated and tat effects of psycosocial stress may influence !eterormone effects are #eneficial.Key!ords8 estrogen, menopause, monoamines, stress, cognitionT&C@BGTC

*tudies of te cogniti"e effects of estrogen or of !omen follo!ing menopause a"estrongly suggested tat estrogen le"els are directly rele"ant to cogniti"e function.xperimental studies of postmenopausal estrogen or estrogen treatment a"e in generaltended to so! positi"e effects on cogniti"e functioning1. -eneficial effects of ormone

terapy on cognition after menopause a"e #een confirmed in a num#er of studiesso!ing tat administration of estrogen to ealty postmenopausal !omen $PM+(impro"ed "isuospatial a#ilities, memory, and frontal lo#e function 2; :16, altoug notall studies a"e not so!n positi"e effects 111/ and studies examining estrogenterapy specifically in older postmenopausal !omen a"e not so!n significant #enefit,including te large +omens %ealt nitiati"e $+%( study 126. Metaanalyses21, 22demonstrated tat ormone terapy so!s cogniti"e #enefit in younger !omen #ut older

!omen so! less e"idence of #enefit or small negati"e effects.

C"erall, studies support te ypotesis tat estrogen elps to maintain aspects ofattention, "er#al and "isual memory232/, and may a"e positi"e effects on tasksmediated #y te prefrontal cortex2 and ippocampus2; especially in younger PM+,

altoug in te recent *+A study, perimenopausal !omen did not so! te expectedimpro"ement !it estradiol treatment2:. Gertain estrogen receptor polymorpismsappear to #e associated !it te risk of de"eloping cogniti"e impairment2< and estrogenreduces neuronal generation of amyloid peptides !ic may #e rele"ant to te onsetof Al0eimers disease $A@(36. PM+ appear to #e at iger risk for A@, particularly iftey carry te APC9 allele31, and tere is considera#le epidemiologic e"idence from#ot prospecti"e and casecontrol studies tat 2 use in PM+ may decrease te risk ofte de"elopment and4or expression of A@323, !it an o"erall odds ratio of 6.29. nmemory clinics, ormone users so!ed lo!er rates of dementia diagnoses "ersus mild



cogniti"e impairment tan nonusers, !o deteriorated more rapidly tan ormoneusers3;.

n contrast to cogniti"e functioning, te increased "ulnera#ility for depression seen inreproducti"eage !omen in !omen declines after te menopause3:, 3< altoug teperimenopause may #e associated !it increased "ulnera#ility for #ot depressi"e

symptoms and a diagnosis of ne! onset depression96, 91. +ile some studies a"esupported positi"e mood effects of estrogen or ormonal terapy in postmenopausal

!omen929/, oters a"e not99:.

%o!e"er, tere are fe! studies regarding te interaction #et!een mood effects andcogniti"e performance in postmenopausal !omen. A strong candidate for explaining tecogniti"e and mood alterations after menopause is te influence of declining le"els ofgonadal steroids on neurotransmitter systems and mood regulatory systems3<, perapsinteracting !it genetic "ulnera#ility and life stress9<. A potential ypotesis for o!estrogen or its loss after menopause exerts effects on cognition and mood is trouginteractions !it modulatory neurotransmitter systems. For example, significant !orkas #een done on examining o! estrogen interacts !it colinergic system acti"ity to

alter cogniti"e functioning in #ot animal models and umans $see >i##s/6 and @umaset al,/1 for re"ie!(. &ecently, tis la#oratory as so!n tat estradiol $2( appears toimpro"e cogniti"e performance related to colinergic function as measured #y increasedcogniti"e resistance to anticolinergic #lockade in normal PM+/2. Tis impro"ementmay #e dose and domain specific, i.e. lo!er doses impro"es primarily attentionalfunctioning, iger doses may influence episodic memory/3. ffects of 2 on colinergicfunction related to episodic memory may #e agespecific !it younger !omen so!ing#enefit #ut older !omen so!ing no #enefit or impairment $pro"iding direct experimentalsupport for te 7critical period ypotesis7/3 of estrogen #enefit after menopause(.%o!e"er, oter monoamine neurotransmitters appear to a"e su#stantial modulatoryroles on mood, anxiety, and on cogniti"e performance and #ea"ior. For example,estrogen so!s effects on modulation of serotonin and dopamine receptor density/9,

dopamine release//, and potentiation of serotonin function//<. Postmenopausal !omen respond more #riskly to serotoninergic antidepressants if taking estrogens63.

Gatecolamine and indolamine systems can #e in"estigated in umans utili0ingconceptually similar treatmentcallenge models to tose tat a"e #een utili0ed toin"estigate colinergic systemormone interactions. +e a"e pre"iously reported teeffects of estrogen and monoamine depletion on mood follo!ing psycosocial stress9.As an extension of tis study !e no! report te effects of te same manipulation oncogniti"e functioning. Te primary goal of te o"erall proEect !as to test !eter sortterm administration of 2 to normal PM+ !ould alter mood reacti"ity and cogniti"eperformance to experimental psycosocial stress and )uantitati"ely cange te#ea"ioral responses to G* catecolamine and4or serotonin depletion,

parmacological callenges tat directly interact !it central monoamine systems.

strogen le"els "ary #ot !itin indi"iduals and compared to premenopausal le"elsduring te perimenopause and postmenopause and tis "aria#ility is associated !itpysical and #ea"ioral symptomatology/, . +e reasoned tat fluctuations inestrogen le"els may lead to alterations in le"els of monoamine neurotransmitters, !icmay influence mood reacti"ity and cogniti"e performance to external e"ents. Tus, topro#e te interaction of estrogen and monoamine neurotransmitters on cognition andmood, !e used te tecni)ue of monoamine depletion and experimentallyinduced



psycosocial stress. Acute tryptopan depletion $AT@( is a !ellesta#lised tecni)uefor examining te role of serotonin systems in mood ;, :. Acutepenylalanine4tyrosine depletion $APT@( is a ne!er tecni)ue designed to examine teeffects of reduced catecolamine syntesis and transmission on #ea"ior andperformance <. Tryptopan depletion can, in some circumstances, produce ad"erseeffects on mood and #ea"ior tat are considered rele"ant to understanding te causes

of affecti"e illness :, ;6. Furter, central catecolamine depletion as #een examinedin normal premenopausal !omen and as #een found to produce negati"e effects onmood under stress <.

n tis study, !omen !o !ere postmenopausal $X /6 years( took a fixed dose of 1;estradiol $2( or place#o for tree monts and ten participated in tree callengesusing monoamine depletion to #riefly cange te relati"e amounts of monoamineneurotransmitters in te #rain $serotonin, dopamine, and norepineprine(. Participantsten participated in a psycosocial stress paradigm to potentiate negati"e mood $Trier*ocial *tress Test, T**T(;1 tat in"ol"es pu#lic speaking and as #een so!npre"iously to relia#ly produce mildmoderate psycosocial stress. +e a"e reportedpre"iously on te mood effects of tis manipulation9, in !ic !e so!ed significant

enancement of negati"e mood effects after te psycosocial stress maneu"er in te2treated participants. %ere !e report on te cogniti"e results from tat study !itadditional participants.

+e ypotesi0ed tat te psycosocial stress manipulation $T**T( !ould enance anynegati"e mood and cogniti"e effects of monoamine depletion and tat estrogenadministration !ould #lunt or #uffer potential negati"e effects produced #y tecom#ination of te monoamine depletion and te stress test in a measura#le and)uantifia#le !ay. *ince estrogen as #een noted to interact !it #ot serotonergic andcatecolaminergic systems, it !as ypotesi0ed tat depletion of eiter monoaminesystem !ould interact !it estrogen treatment to alter cogniti"e performance.MT%C@*

Te #asic design consisted of a dou#le#lind parallel group design $eac su#Eect !asrandomly assigned to recei"e eiter 3 monts of 2 or place#o( !it eac treatmentgroup ten undergoing acute depletion and social stress callenges. All participantssigned fully informed consent after an explanation of all procedures, risks, and #enefits.Participants recei"ed w166 as compensation for teir time and a small gift pack aftereac study session. Te study !as appro"ed #y te Bni"ersity of 'ermont Gommitteefor %uman &esearc in te Medical *ciences $&-(.Participants

Participants !ere recruited troug ne!spaper ad"ertisement and ealt ne!sletterspu#lised #y our Medical Genter, pu#lic information sessions, ne!spaper

ad"ertisements, and random mailings. *tudy participants !ere first screened #y ponefor eligi#ility. Participants consisted of 22 normal PM+ ages /2:3 $MI9.3, *@I16.(.*u#Eect demograpics are descri#ed in Ta#le 1.Ta#le 1Ta#le 1*u#Eect @emograpic @ata $nI22(Medical *creening



Participants !ere !itout menses for at least 1 year, ad an F*% le"el greater tan 36mB4ml, nonsmokers, ad a normal mammogram !itin te last year, and !ere !itoutsurgicallyinduced menopause $#ilateral ooporectomy(. Tey !ere not taking %T, ororal contracepti"es, and !ere at least one year !itout suc treatment. Participants

!ere pysically ealty, ad a #ody mass index 39 kg4m2, and ad no cardio"asculardisease oter tan mild ypertension. Participants !it maEor concomitant illnesses !ere

excluded on te #asis of istory, pysical exam, and la#oratory tests assessingematopoietic, renal, epatic and ormonal function. $G-G, Gem 26, T*%, B4A, G>(.Participants !ere pysically examined #y a gynecologic nursepractitioner to esta#lisgeneral pysical ealt and for specific pysical contraindications for 2 terapy $e.g.adnexal mass, large uterine fi#roids, etc.(

Participants !ere excluded if tey ad specific contraindications for 2 treatment, orcurrent or any past Axis psyciatric disorders. *pecific criteria for exclusion for te 2treatment included contraindications for ormone replacement including istory of #reastcancer or 2dependent neoplasiaD #lood pressure X 164166 $untreated(D istory ofdeep "ein trom#osis or oter trom#oem#olic diseaseD epatomaD se"ere migraines orstroke on oral contracepti"esD concurrent use of #ar#iturates, rifampin, insulin,

car#ame0epine, oral ypoglycemics, antidepressants, or lipidlo!ering drugsD kno!nintolerance to conEugated 2sD dia#etesD untreated tyroid diseaseD clinical osteoporosisDse"ere menopausal symptoms. All participants !ere taking no centrally acti"e drugs. oparticipants !ere taking selecti"e estrogen receptor modulators $*&Ms( or er#almenopause preparations. A minimum of 19 days elapsed #et!een discontinuingcentrally acti"e or psycoacti"e agents and participation in tis study.Gogniti"e4-ea"ioral *creening

All participants !ere cogniti"ely and #ea"iorally assessed using standard testsdesigned to exclude participants !it cogniti"e or #ea"ioral impairment. Participants

!ere e"aluated using te Mini Mental *tate xam $MM*(;2, -rief Gogniti"e &ating*cale;3, te Mattis @ementia &ating *cale;9, to esta#lis a >lo#al @eterioration *cale

score $>@*( !ic rates te degree of cogniti"e impairment;/. Participants !erere)uired to a"e a >@* score of 12 and a MM* score of greater tan or e)ual to 2;.Participants !ere excluded if tey scored #elo! 123 on te @ementia &ating *cale;9scale and !ere matced across te t!o groups in terms of educational #ackground.

-ea"ioral screening consisted of a partial *tructured Glinical nter"ie! for @*M'T&$*G@(; to esta#lis te presence4a#sence of present or past Axis maEor psyciatricdisorders, particularly any present or past istory of mood disorders. n addition,participants completed te -eck @epression &ating *cale;; and a menopause symptomcecklist modified from *er!in;: to detect su#clinical depressi"e symptoms. Anexclusion cut off score of 16 !as used for te -eck @epression &ating *cale.strogen4Place#o Treatment

After screening and acceptance into te study, eac su#Eect !as placed randomly and#lindly on eiter oral place#o or 1; estradiol $2( $using identical pink capsules( for 3monts. Tere !ere 11 !omen in te 2 group and 11 !omen in te place#o group.+omen !ere initially placed on 2 1 mg per day for 36 days, and ten !ere increased to2 mg per day. Tis !as done #ecause early pilot trials re"ealed tat estrogenrelatedside effects $e.g. #reast tenderness or spotting( tended to #e noticed #y participants ifte participant !as #egun on 2 mg of 2 from te #eginning. Bsing 1 mg of 2 for tefirst 36 days elped to protect te #lind.. At te end of te 3 mont treatment period,



participants participated in a series of callenge studies designed to examine differencesin sensiti"ity to acute transmitter depletion and psycosocial stress. 2 or place#otreatment continued trougout te callenge4stress studies. T!el"e days ofmedroxyprogesterone acetate $MPA( $Pro"era( !as gi"en at te end of te study toproduce sedding of te endometrial lining.Acute @epletion Gallenges

All studies took place on te Bni"ersity of 'ermont >eneral Glinical &esearc Genter$>G&G(. ac participant under!ent tree test days, at least se"en days apart, in !ictey recei"ed te eac of te t!o amino acid depletion mixtures and te nutritionally#alanced control mixture. Te depletion se)uence !as determined #y a random orderprocedure.

Te procedure for te administration of te amino acid mixtures !as te same as !ea"e used pre"iously<. Participants !ere placed on a lo!protein diet for te e"eningmeal prior to eac study day. Follo!ing an o"ernigt fast, te study #egan at 6:66 !it#aseline testing and e"aluation. Participants ten ingested one of tree amino acid $AA(mixtures8 $1( a nutritionally #alanced AA mixture, $2( a mixture deficient in tryptopan

$AT@(, or $3( a mixture deficient in penylalanine and tyrosine $APT@(. Te compositionof te AA mixtures !as tat used in prior studies, adEusted for te generally lo!er !eigtof !omen. Mixtures consisted of amino acid suspended and !ater, !it te !orst tastingamino acids $ metionine, cysteine and arginine( in capsules. Te li)uidsuspensions !ere fla"ored !it noncaloric, noprotein fla"oring of orange, grapefruit,lemon, cocolate, or cran#errylemon $su#EectSs coice( to disguise te unpleasant taste.+e a"e pre"iously demonstrated te feasi#ility of administering 3 AA mixtures tofemale participants !it accepta#le tolera#ility;<. Testing concluded !it a ig proteinsnack for repletion of amino acid le"els.*ocial *tress Test

Fi"e ours after amino acid ingestion, participants performed a mildly stressful

psycological task, te Trier *ocial *tress Test $T**T(;1. Te T**T consisted of treeparts, a #rief nstruction Period, a 16min Anticipation Period, and a 16min Test Period.For te #rief nstruction Period, participants !ere taken to te T**T room !ere 3persons !ere already sitting at a ta#le and a "isi#le "ideo camera !as set up. Tesu#Eect !as asked to stand on an YVZ on te floor in front of te panel of people. Tenstructor presented te su#Eect !it one of tree scenarios and asked te su#Eect toprepare a /min speec a#out te topic. Participants !ere told tat te panel !asspecially trained to monitor non"er#al #ea"ior and tat a "oicefre)uency analysis ofte speec !ould #e performed. Follo!ing te instructions, te su#Eect returned to erroom.

@uring te Anticipation Period, participants !ere asked to prepare te /min speec.

Tey !ere gi"en 16 minutes to prepare and take notes in a separate room, #ut !ere notallo!ed to use tem during teir speec. Participants presented teir /min speecfollo!ed #y / minutes of aritmetic pro#lems. Te T**T !as originally designed to #econducted one time per su#Eect, utili0ing only te first speec scenario and aritmeticpro#lem. n order to repeatedly confront te su#Eect !it te T**T on eac of te treestudy "isit days, te t!o additional scenarios and aritmetic pro#lems !ere created. Foreac of te tree scenarios, te su#Eect !as asked to take on a role !itin a gi"encontext and ad to con"ince a panel to grant er a specific re)uest8 1( &ole of a Eo#applicant for te position of manager at a #anking firm. 2( &ole of te director of a



rea#ilitation program for prisoners re)uesting a donation of a large sum of money tosupport te program. 3( &ole of a #uilding de"eloper re)uesting a #uilding permit to #uilda strip mall in a rural e! ngland to!n. For te aritmetic pro#lem portion of te TestPeriod, te pro#lems consisted of serial su#tractions of a t!o digit num#er from a fourdigit num#er, and upon e"ery mistake, te su#Eect !as asked to #egin again at te firstnum#er. &epeated exposure to te T**T as #een so!n to induce an e)ual

pysiologic stress response :6, :1. Gonsultation !it te creators of te T**T and teirre"ie! of our scenarios produced general agreement tat te repeated use of te T**T

!it our scenarios ad precedent and !ould produce repeated e)ui"alent stress$*commer, personal communication(.

Participants !ere #riefed #efore te study #egan a#out te general nature of te T**Tand !at !as expected of tem. Tis !as done so as to e)uali0e te anticipation of teT**T across te tree study days. t sould #e noted tat te actual performance of tesu#Eect during te T**T !as not e"aluated. Te psycological stress induced !as aproduct of te actual e"ent of standing in front of a panel of strangers and deli"ering aspeecD tus, te topic of te speec !as less important. &egardless, te speecscenarios and aritmetic pro#lems !ere Eudged to #e e)ual in difficulty and e)ui"alently

contro"ersial topics for te population #eing studied. Furter, te order of scenarios !asrandomi0ed across participants, decreasing te possi#ility tat differences in scenarios

!ould produce different stress outcomes. Participants !ere de#riefed at te end of testudy regarding te mild deception in te stress test $i.e., no actual monitoring of testperformance(.CBTGCM MA*B&*GC>T'

A cogniti"e testing #attery !as constructed to e"aluate a num#er of cogniti"e domainspotentially sensiti"e to monoamine depletion and psycosocial stress as !ell as affected#y loss of and su#se)uent treatment !it estrogen. Tese cogniti"e domains includedtests of simple attention, complex attention and "er#al episodic memory. ac task is

descri#ed #elo!. Te cogniti"e #attery !as performed once eac study day, after tepsycosocial stress maneu"er. Participants !ere pretrained on te entire cogniti"e#attery prior to study initiation to ensure sta#le asymptotic performance to ensuree)ui"alent cogniti"e performance at #aseline #et!een te groups.

*imple Attention

Te Gritical Flicker Fusion $GFF( task:2 and te Goice &eaction Time $G&T( task:3from te Milford Test -attery !ere used as te measures of simple attention and !ereperformed using te eeds Psycomotor @e"ice. @uring te GFF task tere !ere t!odifferent types of trials. n an ascending trial, te participant pressed a #utton tatindicated !en te fre)uency of flasing ligts ad increased to te point tat te ligts

appear to #e no longer flasing #ut rater appear continuously on $YfusedZ(. Te ligts#egan flasing at a rate of 12 %0 and te fre)uency !as increased to /6 %0. n adescending trial, te participant pressed a #utton !en te fre)uency of apparentlyfused ligts !as decreased suc tat ligts #egan to appear to #e flasing. Te ligts#egan flasing at /6 %0 and decreased to 12 %0. Te participant needed to respond#efore te fre)uency it te upper or lo!er limit in eac trial. Te participant !aspresented !it tree of eac trial type. @ependent measures for tis task !ere temedian detection fre)uency across all trials, as !ell as te median detection fre)uency



on te ascending and descending trials separately. o!er fre)uency "alues aregenerally understood to reflect impaired attention and4or arousal.

Te G&T task !as a reaction time task in !ic participants kept teir index finger on aYomeZ ligt sensiti"e diode $*@( until one of six G@ ligts arrayed in a semicircle,approximately 2/ cm from te YomeZ key, !as lit on te response #ox. Te su#Eect lifted

er index finger and mo"ed it to co"er te *@ corresponding to te illuminated G@.*e ten returned er finger to te YomeZ *@. Tree performance measures !ereo#tained from te G&T. Te first !as te median total reaction time $&T( per trial. Tesecond !as te median recognition &T, te amount of time it took te su#Eect to lift erfinger off of te ome *@ once te signal to respond appeared. Te tird measure !aste median motor &T, te time it took te participant to mo"e er finger and to co"er te*@ corresponding to te illuminated G@.

Gomplex Attention

Te measures of complex attention !ere te @igit *ym#ol *u#stitution Test $@**T:9(,and te Gonnors Gontinuous Performance Test $GPT:/(. n te @**T, participants !ere

presented !it nine num#ers tat corresponded to nine sym#ols. Cn te ans!er formte participant !as instructed to !rite te sym#ol tat corresponded to eac num#er andto complete as many as possi#le in <6 seconds. Te dependent measure !as te totalcorrect completions.

n te computeri0ed GPT task, indi"idual letters appeared on te computer screen for366 ms !it a response period of t!o seconds for 126 trials. Participants !ere instructedto press a #utton !en tey sa! an A follo!ed #y an V. Te dependent measures !ereits, errors of omission and commission, and it reaction time.

'er#al pisodic Memory

Te -uscke *electi"e &eminding Task $*&TD -uscke, 1<;3( and te 'er#al PairedAssociates Test $'PAD +ecsler Memory *cale ( !ere used as measures of "er#alepisodic memory. n te *&T, participants !ere read a list of 19 !ords, follo!ed #y animmediate recall trial. Te experimenter ten reminded te participant of any !ords sedid not recall and se !as instructed to recall all 19 !ords again. Tis process !asrepeated for eigt trials. Tree measures !ere o#tained from tis task8 te total num#erof !ords recalled across all lists, te recall consistency from one trial to te next, and terecall failure from one trial to te next.

n te 'PA, participants !ere read a list of eigt pairs of !ords. Ten tey !ere read tefirst !ord in eac pair and asked te recall te associate. Te list !as read and recalleda maximum of times. f te participant recalled all !ords on te list !itin te first tree

trials, te tests !as discontinued after tree trials. Four of te !ord pairs !ere strongassociates $easy pairs( !ile te oter four !ere !eak associates $ard pairs(.@ependent measures !ere num#er correct for te strong and !eak associates aftertree and six trials.

Te final test of "er#al memory !as a Paragrap &ecall test:. Participants !ere read asort paragrap and ten asked to retell te story from memory. Te dependentmeasure !as te num#er of information units correctly recalled from memory.



Gogniti"e task !ere performed in te follo!ing order8 GFF, *&T, G&T, 'PA, GPT,@**T, Paragrap &ecall. Tis administration order !as te same for all participants onall study days. A minimum of 16 e)ui"alent "ersions of te testing forms !ere created sotat a ne! "ersion of eac test !as a"aila#le for eac of te testing days. Tese forms

!ere counter#alanced across study days for all participants.

-ea"ior

Te primary mood and anxiety measure !as te su#Eectcompleted Profile of Mood*tates $PCM*(:;. Tis scale is a / item adEecti"e cecklist tat generates #ipolarfactoranalytically deri"ed factors, $elateddepressed, composedanxious, energetictired, agreea#leostile, confidentunsure, and cleareadedconfused( or 12 unipolarfactors, plus total score. Tis scale as #een used extensi"ely in callenge studyparadigms and is sensiti"e to te effects of psycotropic drugs and G* statemanipulations. t !as administered 3 times during te experimental session8 predepletion, postdepletion prior to T**T, and post T**T. Participants completed a -eck@epression ndex $-@( ;; t!ice during te day8 predepletion and postdepletion #utprior to te T**T.

euroendocrine4pysiologic

Measures of estradiol and F*% !ere collected to assess compliance and teeffecti"eness of 2 terapy. stradiol and F*% !ere measured !it an A@'A Gentaurcemiluminescence competiti"e immunoassay $estradiol( and an A@'A Gentaur t!osite sand!ic immunoassay $F*%( #ot utili0ing a la#eled acridinium ester. *amples

!ere collected at screening and on te first day of eac callenge se)uence. -lood !ascollected on eac study day for measures of plasma total tryptopan, penylalanine, andtyrosine to assess te ade)uacy of depletion. *amples !ere collected predepletion$[9/S( and end of session $\966S(. Plasma penylalanine and tyrosine concentrations

!ere determined using a -eckman *ystem >old amino acid analy0er using gradient

%PG !it precolumn deri"ati0ation and fluorometric detection. Tryptopan !asmeasured #y isocratic %PG !it fluorometric detection. Gortisol !as measured #yradioimmunoassay $@iagnostic Products Gorporation(.

'ital signs !ere recorded predepletion at [9/S, preT**T at \366S, and postT**T at\966S@ATA AAQ**

Te general approac !as tat of mixed model repeated measures analysis of "ariance$AC'A( utili0ing *A* P&CG MV@. nitial analysis of cogniti"e measures !as a 23treatmentD 2 $2 "s PG( depletion 3 $AT@, ATP@, Mock( mixed model AC'A as ano"erall test of te effect of estradiol treatment and monoamine depletion effects on

cognition follo!ing psycosocial stress. Treatment $2 "s. place#o( !as te #et!eenparticipants factor and depletion $AT@, APT@, and mock( !ere te !itinsu#Eect factors.For te mood measures only, time !as an additional factor as tere !as a predepletion,prestress maneu"er mood assessment. Gogniti"e testing !as performed once on eacof te tree experimental days and tus eac su#Eect performed cogniti"e testing undereac monoamine depletionpsycosocial stress condition. As te primary effect ofinterest in tis study !as te impact of 2 treatment on cogniti"e performance follo!ingmonoamine depletion and psycosocial stress, if no treatment#ydepletion effect !asfound, results !ere collapsed across depletions and te analyses !ere redone as an



independent samples ttest. +en tere !as a significant interaction $e.g. treatment depletion(, nonortogonal apriori contrasts !ere used to test for differences #et!eentreatment across depletions. Gorrelations #et!een cogniti"e and mood measures !ereperformed using Pearson productmoment correlations adEusted for multiplecomparisons. Te alpa le"el for reEection of te null ypotesis !as set at p5.6/.&*BT*

Participants

Participants !ere matced for age, education, !eigt, and years since menopause$Ta#le 1(. Te mean age of participants !as 9.3^ 16.. -M a"eraged 2.23 ^ 9.9;kg4m2 and participants !ere an a"erage of 19.3 ^ 16./ years post menopause. Tis !asa igly educated group !it an a"erage of 19.< years of education. Fifteen participantsad ad pre"ious experience !it ormone replacement terapy $X1 year pre"iously(and ; did not. For tose !omen !o ad pre"iously used ormone terapy, te a"erageduration of ormone use !as 3.< ^ 9.< years.F*%, stradiol and Gortisol e"els

Pretreatment F*% so!ed a mean le"el of /.;3 mB4ml $menopausal le"el is

considered a#o"e 363/ mB4ml( and !as not significantly different #et!een treatmentgroups $t$1:( I.<:, p X .39. After tree monts of treatment, te 2treated participantsso!ed a significantly reduced mean F*% le"el of 2<. compared to te place#otreatedparticipants !o ad a mean le"el of <.6 $t$1;(I/.3<, p 5 .661(. Mean plasma estradiolle"els after tree monts of treatment !ere significantly ele"ated at 13/.3 pg4ml for te2treated group compared to 1:.3 pg4ml for te place#otreated group $t$1<(I/.19,p5.661(. Te le"els of estradiol seen in te 2treated !omen are compara#le to latefollicular pase le"els in premenopausal !omen, !ereas te le"el seen in te place#otreated !omen is compara#le to te early follicular pase. Gortisol le"els !ere measuredat #aseline and \926 minutes $postT**T(. -aseline le"els $predepletion, preT**T(

!ere iger, $p5 .61( in te 2treated participants #ut declined similarly across teexperimental day in #ot treatment groups.

Amino Acid e"els

Plasma concentrations of total tryptopan, penylalanine, and tyrosine !ere measuredat #aseline $predepletion( and at \966 minutes $postdepletion( $Ta#le 2(. Aftertryptopan depletion, plasma tryptopan le"els declined ;=. Aftertyrosine4penylalanine depletion, #ot tyrosine and penylalanine le"els declined #y6= suggesting tat an ade)uate depletion !as acie"ed <, ::.Ta#le 2Ta#le 2Amino Acid e"els $nI22(Glinical Assessment of Mood across Treatment Pase

A comparison of te clinical depression ratings $-@( from screening to te end of tetreatment pase for eac su#Eect re"ealed no significant time#ytreatment interaction$F$1,1:(I./:, p X .9/(. Furtermore, a comparison of te end of treatment -@ scores$te #aseline -@ score on te first depletion callenge day( #et!een treatment groupsso!ed a small numerical difference $PG8 2.<1 ^ 3.D 28 9.// ^ 2.<( tat !as notsignificantly different #et!een treatments $t$26(I1.1<, p X. 2/(. Tese data demonstratetat te treatment alone $2 or place#o( did not produce significant or clinically manifestnegati"e canges in mood across te treemont treatment pase nor did te groupsdiffer prior to #eginning te monoamine depletion callenges.



Gogniti"e Performance

Gogniti"e testing results are presented in Ta#le 3. Gogniti"e testing !as only performedafter te T**T. n general, significant impairment !as seen across many cogniti"emeasures in te 2 treated group, particularly on attention and psycomotor measures.Ta#le 3

Ta#le 3Gogniti"e performance scores #y treatment and depletion condition $n I 22D Place#o I11D 2 I 11(.Attention4Psycomotor

Gritical Flicker Fusion $GFF(

Attentional performance as measured #y te median fre)uency of all trials so!ed asignificant main effect of treatment $F$1,26( I :., p I .66:( !it 2treated participantsso!ing a reduced fre)uency compared to place#otreated participants $Figure 1(,suggesting impaired attention. Tere !as a strong trend for a treatment#ycallengeinteraction $F$2,26( I 3.1;, p X .6( !it te tyrosine4penylalanine depletion condition

so!ing a sligtly poorer performance compared to tryptopan depletion and mockdepletion after 2 treatment. Falling trials so!ed a significant $F$1,26( I 11.1, p I .663( main effect of 2 treatment as !ell, producing a median fre)uency reduction, #utrising trials did not $p X .11(.Figure 1Figure 1Gogniti"e performance measures follo!ing te Trier *ocial *tress Test. @ata arepresented for estradiol $2( and place#o $PG( treatment groups for eacmonoaminergic depletion8 Acute Tryptopan @epletion $AT@(, AcuteTyrosine4Penylalanine @epletion ...

Goice &eaction Time $G&T(

For te G&T, total median &T so!ed no treatment#ycallenge interaction. Gollapsingte data across callenge conditions demonstrated a significant $t$26( I 2.:, p 5 .6/(effect of 2 treatment !it te pattern of means so!ing tat estrogen treatedparticipants performed slo!er across all depletion conditions tan place#o treatedparticipants $Figure 1(. Te recognition component of te G&T so!ed a significanteffect of callenge, F$2,3;( I 16.69, p I .6663, on median recognition &T !it tetyrosine4penylalanine depletion so!ing a slo!er &T ten eiter te mock ortryptopan depletion conditions. %o!e"er tere !as no significant treatment orcallenge#ytreatment effects. Analyses collapsed across callenge conditions re"ealeda significant effect of 2 treatment $t$26( I 2.2/, p 5 .6/( !it &T significantly greater$slo!er( for 2treated participants. For te motor component of G&T, tere !ere no

significant treatment#ycallenge interaction effects on median &T, #ut as !it te otercomponents, collapsing across callenge conditions re"ealed a significant $t$26( I 2.:,p 5 .6/( slo!ing effect of 2 treatment.

Gontinuous Performance Task $GPT(

As tere !ere no significant callenge#ytreatment interactions, !e examined treatmenteffects #y looking at te data collapsed across callenge conditions. Te proportion ofits so!ed a significant $t$26( I 2./, p 5 .6/( negati"e effect of estrogen treatment,



!it 2 treated participants demonstrating a reduced proportion of its across allconditions. A similar significant pattern $t$26( I 2./, p 5 .6/( !as seen in errors ofomission !it errors so!ing increases under all conditions for te 2 treatedparticipants. Tere !ere no significant or trendle"el effects on commission errors, #utte proportion of commission errors !as "ery lo!.

-y contrast, tere !as a significant F$1,26( I .1;, p I .62 positi"e main effect of 2treatment on it &T !it 2 treated participants so!ing a faster &T $#et!een 6 and166 ms( across all depletion conditions. Te contrast in tese results suggests tepossi#ility tat 2 treated participants demonstrated a speedaccuracy tradeoff,#ecoming faster, #ut less accurate. o oter parameters so!ed significant effects.

@igit *ym#ol *u#stitution Task $@**T(

Tere !as a significant, F $1,26( I 9.3, p I .69, main effect of treatment on te num#erof items correctly completed !it 2treated participants so!ing a significantly $p I .661( reduced num#er of items correctly completed compared to te place#otreatedparticipants $Figure 1(. n addition, tere !as a significant callenge#ytreatment

interaction, F$2, 3:( I 3.::, p I .63, !it 2treated participants so!ing significantlyt$26( I 2./, p 5 .6/( fe!er correct completions after tyrosine4penylalanine depletion.Memory

*electi"e &eminding Task $*&T(

Tere !ere no effects at 2 treatment on tis task. Tere !as a trend $p I .12( for :trialrecall to #e reduced under #ot tryptopan and tyrosine4penylalanine depletionconditions. n addition, recall consistency so!ed a significant main effect of depletioncallenge, F$2, 3;( I 9.<3, p I .61(, !it consistency #eing significantly reduced under#ot tryptopan and tyrosine4 penylalanine depletion conditions. Tere !as nointeraction !it 2 treatment on tis parameter. &ecall Failure so!ed a pattern of

increased failure scores under 2 treatment, #ut te effect of treatment !as notsignificant.

'er#al Paired Associate Task $'PA(

+ile tere !as no significant callenge#ytreatment interactions, collapsing acrosscallenge conditions, tere !as a significant $t$26( I 2.1/, p 5 .6/( effect of 2 suc tat2treated participants so!ed a reduced recall of ard !ord pairs across all depletionconditions $Figure 1(. Tere !as a similar trend $p I.1( for 2treated participants toso! a similarly reduced recall for easy pairs of !ords.

Paragrap &ecall

Tere !ere no significant or a trendle"el treatment, callenge, or interaction effects ontis measure.Mood ffects

Te effects of te ormonemonoamine depletions4psycosocial stress manipulation onmood !ere pre"iously presented in detail in e!ouse et al. 9. +e #riefly re"ie! andupdate tose findings ere, focusing on te PCM* results.



An examination of te entire model for te PCM* total score and su#scales re"ealed nosignificant treatment#ydepletion callenge interactions. Tus te analyses !ere redonecollapsing across callenge conditions to examine ormone treatment effects. TotalMood @istur#ance score so!ed a significant interaction of ormone treatment #y time,F$2, 26( I <.96, p I .661, !it 2 su#Eect so!ing a significant increase in Total Mood@istur#ance scores follo!ing te stress4monoamine depletion manipulation. xamining

te su#scale scores from te PCM* re"ealed similar ormone treatment#ytimeinteractions for @epression $F$2,26( I 9./6, p I.62(, Gonfusion $F I 3.<3. p I .69(, and'igor $F I .;, p I .663(, !it 2 participants so!ing significant score cangesindicating !orsening selfratings follo!ing te stress4monoamine depletion manipulationcompared to place#o treatment. n addition, on te Tension su#scale, tere !as a maineffect of ormone treatment, F $1, 26( I .:9, p I .62(, !it 2treated participantsso!ing iger scores across time. Te Anger4%ostility su#scale so!ed only tri"ialsignificant effects of time and did not so! any treatment or ormone treatmentstressmanipulation effects.Gorrelation !it Mood ffects of Psycosocial *tress and Monoamine @epletion

+e examined !eter group differences in cogniti"e performance correlated !it

canges in selfrated mood follo!ing te psycosocial stress manipulation andmonoamine depletion. +e compared te PCM* total score and su#scale scores at tepostdepletion rating in relationsip to te performance measures tat !ere o#tained atte same time. Te relationsips !ere inconsistent, !it some mood measurescorrelating !it performance under place#o on some tasks and under estrogen onoters.

Tere !ere small correlations #et!een te Tension su#scale of te PCM* and impairedperformance on te *electi"e &eminding Task, te G&T, and te @**T, o!e"er tepattern of treatment correlations !as inconsistent as te Tension su#scale correlated

!it performance on place#o on some tasks and estrogen on oters. A similar pattern !as seen for te @epression, Fatigue, and Gonfusion su#scales. Furtermore, none of

tese correlations sur"i"ed correction for multiple comparisons. Tus it does not appeartat te magnitude of te mood canges alone explained te estrogen treatmentrelatednegati"e effects on cogniti"e performance.

+e also ad pre"iously9 examined effects of age, T**T scenario, and te effect ofrepeated administration of te T**T on mood dependent "aria#les. eiter age, day,nor T**T scenario interacted !it ormone treatment or depletion callenge. Moreo"er,tere !as no significant effect of repeated administration of te T**T and no significantinteraction !it ormone treatment or depletion callenge !as found.'ital *igns

Cnly minor effects of ormone treatment and amino acid depletion !ere seen on "ital

signs. Tere !as a trend for a treatment#ycallenge interaction on diastolic #loodpressure $p X .6;( !it diastolic #lood pressure so!ing a sligt increase after tyrosinepenylalanine depletion. o effects !ere seen on systolic #lood pressure. Pulse so!edsignificant main effects of callenge $F$2,33( I 3.;;, p 5 .6/( and time $F$2,3:( I :.96, p5 .661(, #ut no interactions !it ormone treatment !as found. Te pattern of meansso!ed tat te mock depletion !as not associated !it an increase in pulse across tepsycosocial stress maneu"er compared to te AT@ or ATP@ depletions tat !ereassociated !it a relia#le increase in pulse. Temperature so!ed a small significantF$1,1< I 6.:1, p 5 .661( timerelated cange as expected #ut did not so! any



significant 2 treatmentrelated effects or any systematic results of monoaminedepletion. o clinically rele"ant canges occurred.@*GB**C

Postmenopausal !omen !o !ere administered estradiol $2( at a dose of 1 mg of oral1;estradiol per day for 1 mont, ten 2 mg per day for 3 monts generally exi#ited

poorer cogniti"e performance follo!ing a psycologically stressful e"ent compared toplace#otreated !omen. Tis response !as independent of te effects of monoaminedepletion, !ic appeared to a"e only a small o"erall effect on te cogniti"e andemotional responses and did not interact !it te effects of 2. Tese effects did notappear to #e secondary to #aseline mood differences prior to depletion or te T**T, asparticipantsS end of treatment depression scores $-eck(, and predepletion mood scores$PCM*( and depression scales !ere not significantly different #et!een treatmentgroups. +e expected tat monoamine depletion and psycosocial stress togeter !ouldproduce negati"e cogniti"e and mood canges, as !as seen #y eyton et al.< #ut tatmigt #e modified #y te presence of 2. Monoamine depletion produced only minornegati"e cogniti"e canges compared to mock depletion. -y comparison, te effects of2 treatment on cogniti"e performance follo!ing social stress !ere larger and appeared

to #e largely independent of te monoamine depletion maneu"ers.

Te 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 so!n to #e impro"ed #y 23, :<. Te current study relia#ly so!ed tat estradioltreatment after psycosocial stress lengtened reaction time and decreased perceptualdiscrimination a#ility. @umas et al/2 so!ed tat tese measures !ere impro"ed #yestradiol treatment after colinergic callenge. %o!e"er, estradiol ad te oppositeeffect on tese measures after psycosocial stress. Additionally, tere !as also partialimpairment on some "er#al episodic memory measures for te estradiol group relati"e tote place#o group. Tese data contrast !it prior data #y Maki and colleagues and*er!in and colleagues<, <6 !o so!ed tat 2 impro"ed "er#al episodic memory

performance, altoug tese studies !ere not done !it a psycosocial stress or neurocemical stress maneu"er. Tus, te psycosocial stress manipulation in tis studyappeared to interact !it te estradiol treatment to generally impair cogniti"eperformance, !ic !as te opposite of !at !e originally ypotesi0ed. -elo! !ediscuss furter te implications for suc an interaction.

Te one exception to tese findings !as te it &T measure during te GPT task, !icimpro"ed in 2treated participants after te psycosocial stress4amino acid depletionmaneu"er, in contrast to te &T for oter tasks suc as te G&T, !ic so!edsignificant slo!ing. Cn te GPT task participants displayed a speedaccuracy trade offtat interacted !it te effects of estrogen treatment. Te 2 treated participants madefe!er its #ut ad faster it &Ts compared to te place#o treated group. Additionally,

differences in task specifics may explain tese results. Te G&T task is a sensorydetection and motor task. -y contrast, te GPT test re)uires a deeper le"el of stimulusprocessing to make an appropriate decision on !eter to respond to particular stimuli,and tus as greater test demands tan te simpler G&T task. Furter studies souldin"estigate !eter task complexity or dept of processing canges te effect of stressor ormonerelated alterations on cogniti"e performance.

Tese results differ from prior pu#lised findings from our la#oratory so!ing tat treemonts of 2 administration to PM+ enances cogniti"e performance follo!ing



colinergic #lockade/2, /3, o!e"er, tere !ere significant differences #et!een tepresent study and our prior pu#lised !ork on 2 and cogniti"e performance. Altougte pattern of 2 administration and te su#Eect population !as "ery similar to our priorstudies so!ing cogniti"e enancement, no psycosocial stress manipulation !as usedin our prior studies, rater partial colinergic #lockade pro"ided te pro"ocati"e stimulus.Tese prior studies so!ed tat 2 treatment reduced te sensiti"ity to colinergic

#lockade and reduced te cogniti"e impairment associated !it tat #lockade. Tus, 2appears to so! e"idence of enancing colinergicsystem related cogniti"e function. -ycontrast, no colinergic manipulation !as used in te present study, rater te focus

!as on emotional stress and monoamine neurotransmitter manipulations. Te impact ofemotional or psycosocial stress on te a#ility of te 2 to enance colinergicrelatedcogniti"e performance remains to #e examined.%o! @oes Psycosocial or motional *tress or *tress %ormones Affect Gognit"ePerformance

A series of studies a"e so!n tat psycosocial stress can induce certain cogniti"edeficits #ot !orking memory and retrie"al deficits<1.<2, <3. Gronic stress appears toa"e longterm negati"e effects on memory functioning and #rain structure<9. %o!e"er,

emotional arousal can result in enancing as !ell as impairing effects on long termmemory. Te directionality of tis effect may depend on te #aseline state of arousal,te type of emotion present, and te pase of te cogniti"e or memory process tat isexposed to emotional arousal or stress. *ignificant gender differences exist in teneuronal circuitry in"ol"ed in emotioncognition interactions suggesting te possi#ilitytat sex steroids may play a role in tis process</. Kim and @iamond< a"e suggestedtat excess amygdala input and increased glucocorticoid secretion act to impairippocampal plasticity and su#se)uent learning. *ince estrogen le"els can modulate%PA axis acti"ity in response to psycosocial stress<; as !ell as te acti"ity of lim#icstructures suc as te amygdala response to negati"e emotional information<:, <<, it islikely tat 2 may directly affect te #rain circuitry in"ol"ed in an acute stress responseand su#se)uent emotional learning.

*tudies of te effects of 2 on emotional perception are also fe!. Pearson ande!is166 a"e so!n tat recognition of emotional expressions is relia#ly alteredacross te menstrual cycle !it te recognition of fear impro"ing !en 2 le"els !ereig. Protopopescu and colleagues<< a"e so!n tat specific su#regions of or#italfrontal cortex $CFG( canged teir pattern of acti"ity in reaction to negati"e emotionalstimuli across te menstrual cycle. Te autors interpreted tis data as premenstrualenancement of topdo!n modulation of lim#ic acti"ity, !it te accompanyingsuppression of sensory e"aluati"e function. n a some!at differently designedmenstrual cycle study, >oldstein and colleagues<: so!ed tat #rain areas associated

!it negati"e emotional responses including te amygdala, anterior cingulate gyrus, andCFG so!ed lo!er acti"ity during midlate follicular pase $!en estradiol le"els could

#e expected to #e ig( tan during early follicular pase $!en estradiol le"els !ould#e lo!er(. o suc studies a"e examined te #rain acti"ity associated !it emotionalstimuli or emotional cognition in postmenopausal !omen or !it %T. Alterations incortical acti"ity produced #y differing circulating le"els of ormones suc as 2 may tusplay a role in regulating o! te amygdala and oter emotionrelated structures respondto emotional stimuli and4or stressful e"ents<:, <<, 161. %o! te processing of emotionalstimuli canges after menopause is at tis point unkno!n. Tus, it may #e tat testeady administration of 2 to postmenopausal !omen at a plasma le"el consistent !it



late follicular pase, as in tis study, may a"e produced alterations in te cortical orsu#cortical processing of stressful or emotional experiences.

n t!o recent re"ie!s, Pelps162, 163 as noted tat te amygdala is responsi#le forte emotional contri#ution to declarati"e memory. *pecifically, se suggests tat teamygdala can modulate #ot te encoding and storage of ippocampaldependent

memories and tat #idirectionally te ippocampus, #y forming episodic representationsof emotional significance, can influence te amygdala response !en emotional stimuliare encountered162. -ased on our data and neuroimaging studies of premenopausal

!omen, it is not unreasona#le to suggest tat sex ormone status may a"e significantimpact on cogniti"e processes after emotional stress in PM+. Cur data suggests tatexogenously manipulated 2 le"els may a"e significant impact on #ot emotionalreacti"ity and cogniti"e performance. t is terefore important in future studies toexamine o! menopause and postmenopausal %T may affect emotional reacti"ity andemotional memory.

Postmenopausal !omen appear to so! greater sensiti"ity tan premenopausal !omenin teir pysiologic response to cogniti"e and speec tasks !it te difference #eing

ascri#ed to #ot age and ormonal status169. Pre"ious studies of te effects oformones on experimental stressors a"e found tat te "arious forms of estrogenappear to reduce some of te pysiologic effects of mild la#oratoryinduced stress $e.g.sol"ing aritmetic pro#lems(16/, 16. indeim and colleagues16; so!ed tat tegreater #iopysical response of PM+ follo!ing stress !as reduced after six !eeks oftransdermal estradiol treatment. strogen treatment as #een so!n to enanceparasympatetic responsi"eness to experimental stress, suggesting reducedsympatetic acti"ation16: altoug in one study te T**T !as not found to pro"oke adifferential effect on pysiological measures in estrogen treated !omen<;. KaEantie andPillips16< conclude tat tere is an increase in sympatoadrenal responsi"eness aftermenopause !ic is attenuated during oral ormone terapy.

Te lack of interaction of te 2induced effect on cogniti"e impairment follo!ingpsycosocial stress !it monoamine depletion suggests tat oter neurotransmittersystems may #e in"ol"ed in mediating tese effects. +ile te exact neurocemicalmecanisms responsi#le for te negati"e cogniti"e and emotional responses seen erecannot #e ascertained from tis particular study, te lack of concomitant progesteroneadministration suggests tat te impact of stressrelated symptoms tat !ould normally#enefit from progesteronederi"ed neurosteroid>A-AA receptor interactions may a"e#een ad impact on te effects seen in tis study.imitations

+ile te effects of estrogen on cognition after psycosocial stress in tis study !erelarge, caution is indicated in interpreting tese results. Goncerns regarding te

repeata#ility of te T**T as !ell as te dose of 2 are similar to our prior study9. TeT**T !as not originally designed for repeated administration and repeated presentationmay diminis te stressful response to te test. +e examined tis possi#ility in detail inour prior pu#lised !ork9, and !ile !ere small effects of te day and scenario, temagnitude !as small suggesting little a#ituation or sensiti0ation in te current study. naddition, te negati"e effect of estradiol treatment remained across all depletioncallenges. +e also ad to use a #et!eensu#Eects design !it regard to estradioltreatment #ecause of limitations regarding o! often participants can perform tedepletion callenges and T**T. Te cogniti"e #attery !as only performed after te



psycosocial stress maneu"er, #ecause te primary comparison of interest !as #et!eentreatments, rater tan !itinsu#Eects. Additionally, te lengt and difficulty of te entireexperimental procedure !as suc tat adding predepletion cogniti"e testing !as felt to#e too #urdensome for participants. Tus !e do not a"e information a#out o! teparticipants !ould a"e performed prior to te monoamine depletion and psycosocialstress. %o!e"er, participants !ere extensi"ely cogniti"ely screened at #aseline and

trained on te cogniti"e #attery prior to initiation of te o"erall study and tus !e areconfident tat cogniti"e performance !as essentially e)ui"alent #et!een te t!o groupsprior to estrogen or place#o treatment and amino acid4psycosocial stress callenge.Additionally, te te 2 dose used in tis study !as some!at iger tan a"erageclinical doses, altoug not #eyond te normal clinical range. stradiol #lood le"els !erenot iger tan is typically seen during te late follicular pase of a normal menstrualcycle. +e a"e so!n pre"iously tat 2 le"els in tis range are #eneficial in acolinergic callenge model/2 o!e"er te interaction !it psycosocial stress in tecurrent study so!ed te opposite effects. Additional cortisol sampling #eyond te t!osamples tat !e o#tained !ould a"e #een elpful to furter caracteri0e te magnitudeof te stress response, #ut !e !ere una#le to do so in tis study design. Finally,altoug tis !as te #linded study, !e recogni0e tat te su#Eecti"e effects of estradiol

may a"e #een difficult to fully #lind.GCGB*C

T!enty t!o postmenopausal !omen !o !ere administered 2 for 3 monts exi#itedmarked !orsening of cogniti"e performance after a social stress test compared toplace#otreated PM+. Tese effects !ere generally independent of Tryptopan orTyrosine4Penylalanine depletion and !ere not significantly correlated !it negati"emood canges. Tese data imply tat te effect of 2 on cogniti"e performance aftermenopause is not straigtfor!ard and may interact significantly !it psycological stressor especially stressful e"ents. ffects of te ormonestress interaction on cogniti"eperformance did not appear to #e significantly modified "ia catecolamine orindoleamine mecanisms. Furter researc !ill #e necessary to confirm and clarify

tese findings as !ell as explore underlying mecanisms. &eplication !itout tedepletion maneu"er, te examination of te effects of different doses of 2, com#ined2 and progestin terapy, and te examination of !omen during different pases of temenstrual cycle !ill elp clarify tese findings.Ackno!ledgements

Tis !ork !as supported #y an ndependent n"estigator a!ard from A&*A@ and &61A>6219; to P.., G%& grant MCP1/66/1 to *..Q, and >G&G M616616<.

Te autors !is to tank te staff of te Bni"ersity of 'ermont >eneral Glinical&esearc Genter for teir efforts in te support of tis proEect and our researc"olunteers for teir dedication to clinical researc.

Footnotes

Gonflicts of nterest4@isclosures8 one. n addition, none of te sponsors ad any role inte design or conduct of te study, management, analysis, and interpretation of te data,or preparation, re"ie!, or appro"al of te manuscript.

A partial "ersion of tis !ork !as pre"iously presented as a poster at te *ociety foreuroscience Annual Meeting, +asington, @G, o"em#er 1<, 266:



Article informationMenopause. Autor manuscriptD a"aila#le in PMG 2611 July 1.Pu#lised in final edited form as8Menopause. 2616 JulyD 1;$9(8 :6:;3.doi8 16.16<;4gme.6#613e31:1e1/df9PMG@8 PMG2<9323:

%M*@8 %M*22/;Paul A. e!ouse, M.@.,1 Julie @umas, P.@.,1 %eater +ilkins, -.A.,1 mily Goderre,-.A.,1 Gyntia K. *ites, M.@.,2 Magdalena aylor, M.@., P.@.,1 Ga!ki -enkelfat,M.@.,3 and *imon . Qoung, [email protected] euroscience &esearc Bnit, @epartment of Psyciatry, Bni"ersity of 'ermontGollege of Medicine2@i"ision of &eproducti"e Medicine, -aystate Medical Genter, Tufts Bni"ersity *cool ofMedicine3@epartment of Psyciatry, Mc>ill Bni"ersity *cool of MedicineAddress for Gorrespondence $P(8 Glinical euroscience &esearc Bnit, @epartment ofPsyciatry, Bni"ersity of 'ermont Gollege of Medicine, 1 *out Prospect *t., -urlington,'T 6/961, 'oice8$:62( :9;9/6, Fax8 $:62( :9;;::<, Mo#ile8 $:62( 3;39:92, mail8

Paul.e!ouse4at4u"m.edu, %ome Page8 !!!.u"m.edu4cnruGopyrigt notice and @isclaimerTe pu#lisers final edited "ersion of tis article is a"aila#le at Menopause*ee oter articles in PMG tat cite te pu#lised article.&eference ist1. *er!in --. strogen and Gogniti"e Functioning in +omen. ndocrine &e"ie!s.2663D29$2(81331/1. OPu#Med2. &esnick *M, Metter J, Ronderman A-. strogen replacement terapy andlongitudinal decline in "isual memory8 a possi#le protecti"e effect. eurology.1<<;D9<819<119<;. OPu#Med3. *mit Q&, >iordani -, aEinessCeill &, Ru#ieta J. ongterm estrogen replacementis associated !it impro"ed non"er#al memory and attentional measures in

postmenopausal !omen. Fertility and *terility. 2661D;$(81161116;. OPu#Med9. Jaco#s @M, Tang MV, *tern Q, et al. Gogniti"e function in nondemented older !omen

!o took estrogen after menopause. eurology. 1<<:D/683:3;3. OPu#Med/. *ay!it0 *, aftolin F, Relterman @, et al. -etter oral reading and sorttermmemory inmidlife, postmenopausal !omen taking estrogen. Menopause.2663D16$/(892692. OPu#Med. Krug &, -orn J, &asc -. A 3day estrogen treatment impro"es prerontal cortexdependent cogniti"e function in postmenopausal !omen. Psyconeuroendocrinology.266D318</<;/. OPu#Med;. *te"ens Glark, Prest!ood o!dose estradiol alters #rain acti"ity. Psyciatry&esearc8 euroimaging. 266/D13<$3(81<<21;. OPu#Med:. @uka T, Tasker &, Mc>o!an JF. Te effects of 3!eek estrogen ormone

replacement on cognition in elderly ealty females. Psycoparmacology.2666D19<812<13<. OPu#Med<. *er!in --. strogenic effects on memory in !omen. Annals of te e! QorkAcademy of *ciences. 1<<3D;938213236. OPu#Med16. Kimura @. strogen replacement terapy may protect against intellectual decline inpostmenopausal !omen. %ormones and -ea"ior. 1<</D2<8312321. OPu#Med11. @itkoff G, Grary +>, Gristo M, o#o &A. strogen impro"es psycological functionin asymptomatic postmenopausal !omen. C#stetrics and >ynecology. 1<<1D;:8<<1<</. OPu#Med



12. -arrettGonnor , Krit0*il"erstein @. strogen replacement terapy and cogniti"efunction in older !omen. Journal of te American Medical Association.1<<3D2<$26(823;291. OPu#Med13. -inder F, *cectman K-, -irge *J, +illiams @-, Kort +M. ffects of ormonereplacement terapy on cogniti"e performance in elderly !omen. Maturitas.2661D3:813;19. OPu#Med

19. PoloKantola P, Portin &, Polo C, %elenius %, rEala K, rkkola &. Te effect of sortterm estrogen replacement terapy on cognition8 a randomi0ed, dou#le#lind, crosso"ertrial in postmenopausal !omen. C#stetrics N >ynecology. 1<<:D<1$3(89/<9.OPu#Med1/. Alola P, PoloKantola P, rkkola &, Portin &. strogen terapy and cognition8 A year single#lind follo!up study in postmenopausal !omen. eurology. 266;D;8;6;6<. OPu#Med1. -uck!alter J>, Grooks 'G, &o#ins *-, Petitti @-. %ormone Bse and Gogniti"ePerformance in +omen of Ad"anced Age. Journal of te American >eriatric *ociety.2669D/281:21:. OPu#Med1;. speland MA, &app *&, *umaker *, et al. GonEugated e)uine estrogen and glo#alcogniti"e function in postmenopausal !omen. Journal of te American Medical

Assocation. 2669D2<1$29(82</<2<;. OPu#Med1:. Almeida CP, autensclager T, 'asikaran *, eedman P, >ela"is A, Flicker . A26!eek randomi0ed controlled trial of estradiol replacement terapy for !omen aged ;6years and older8 effect on mood, cognition, and )uality of life. euro#iology of Aging.266D2;$1(819119<. OPu#Med1<. &esnick *M, Goker %, Maki PM, &app P&, speland MA, *umaker *A. Te+omens %ealt nitiati"e *tudy of Gogniti"e Aging $+%*GA(8 a randomi0ed clinical trialof te effects of ormone terapy on ageassociated cogniti"e decline. Glinical Trials.2669D1$/(89969/6. OPu#Med26. *umaker *A, egault G, Kuller , et al. GonEugated e)uine estrogens and incidenceof pro#a#le dementia and mild cogniti"e impairment in postmenopausal !omen. Journalof te Americam Medical Association. 2669D2<1$29(82<9;2</;. OPu#Med

21. Maki PM. A *ystematic &e"ie! of Glinical Trials of %ormone Terapy on Gogniti"eFunction8 ffects of Age at nitiation and Progestin Bse. Annals of te e! QorkAcademy of *cience. 266/D16/281:21<;. OPu#Med22. %oger"orst , +illiams J, -udge M, &iedel +, Jolles J. Te nature of te effect offemale gonadal ormone replacement terapy on cognition function in postmenopausal

!omen8 a metaanalysis. euroscience. 2666D161$3(89://12. OPu#Med23. *er!in --. %ormones, mood, and cogniti"e functioning in postmenopausal !omen.C#stetrics and >ynecology. 1<<3D:;$2 $supplement((826*2*. OPu#Med29. e-lanc *, Jano!sky J, Gan -K*, elson %@. %ormone replacement terapy andcognition8 systematic re"ie! and metaanalysis. Journal of te American MedicalAssociation. 2661D2:/$11(819:<19<<. OPu#Med2/. *er!in --. strogen and cogniti"e aging in !omen. euroscience.

266D13:81621162. OPu#Med2. Keenan PA, 00at +%, >ins#urg K, Moore >J. Prefrontal cortex as te site ofestrogens affect on cognition. Psyconeuroendocrinology. 2661D28/;;/<6. OPu#Med2;. Maki PM. strogen effects on te ippocampus and frontal lo#es. nternationalJournal of Fertility and +omens Medicine. 266/D/6$2(8;;1. OPu#Med2:. >reendale >A, %uang M%, +igt &>, et al. ffects of te menopause transition andormone use on cogniti"e performance in midlife !omen. eurology. 266<D;281:/61:/;. OPMG free article OPu#Med



2<. Qaffe K, ui , >rady @, Massa *, *tone K, Morin P. strogen receptor 1polymorpisms and risk of cogniti"e impairment in older !omen. -iological Psyciatry.2662D/18;;:2. OPu#Med36. Vu %, >ouras >K, >reenfield JP, et al. strogen reduces neuronal generation ofAl0eimer #amyloid peptides. ature Medicine. 1<<:D9$9(899;9/1. OPu#Med31. -retsky PM, -uck!alter J>, *eeman T, et al. "idence for an interaction #et!een

apolipoprotein genotype, gender, and Al0eimer disease. Al0eimer @isease NAssociated @isorders. 1<<<D13$9(821221. OPu#Med32. Paganini%ill A, %enderson '+. strogen deficiency and risk of Al0eimers diseasein !omen. American Journal of pidemiology. 1<<9D196$3(82/21. OPu#Med33. Tang MV, Jaco#s @, *tern Q, et al. ffect of estrogen during menopause on risk andage at onset of Al0eimers disease. ancet. 1<<D39:$<62/(892<932. OPu#Med39. Panidis @K, Matalliotakis M, &ousso @%, Kourtis A, Koumantakis . Te role ofestrogen replacement terapy in Al0eimers disease. uropean Journal of C#stetrics N>ynecology and &eproducti"e -iology. 2661D</8:<1. OPu#Med3/. Ka!as G, &esnick *, Morrison A, et al. A prospecti"e study of estrogen replacementterapy and te risk of de"eloping Al0eimerSs disease. eurology. 1<<;D9:81/1;1/21.OPu#Med

3. Randi PP, Garlson MG, Plassman -, et al. %ormone replacement terapy andincidence of Al0eimer disease in older !omen. Journal of te American MedicalAssociation. 2662D2::$1;(82123212<. OPu#Med3;. Gosta MM, &eus ', +olko!it0 CM, Manfredi F, ie#erman M. strogen&eplacement Terapy and Gogniti"e @ecline in Memorympaired PostMenopausal+omen. -iological Psyciatry. 1<<<D981:21::. OPu#Med3:. *oares G, Poitras J&, Prouty J. ffect of reproducti"e ormones and selecti"eestrogen receptor modulators on mood during menopause. @rugs N Aging.2663D26$2(8:/166. OPu#Med3<. *teiner M, @unn , -orn . %ormones and mood8 from menarce to menopause and#eyond. Journal of Affecti"e @isorders. 2663D;9$1(8;:3. OPu#Med96. Goen *, *oares G, 'itonis AF, Ctto M+, %arlo! -. &isk for ne! onset of

depression during te menopausal transition8 Te %ar"ard study of moods and cycles.Arc >en Psyciatry. 266D3$9(83:/3<6. OPu#Med91. Freeman +, *ammel M@, in %, elson @-. Associations of ormones andmenopausal status +it depressed mood in !omen !it no istory of depression. Arc>en Psyciatry. 266D3$9(83;/3:2. OPu#Med92. +ooley MA, >rady @, Gauley JA. Postmenopausal estrogen terapy anddepressi"e symptoms in older !omen. Journal of >eneral nternal Medicine.2666D1/8/3//91. OPMG free article OPu#Med93. Palinkas A, -arrettGonnor . strogen use and depressi"e symptoms inpostmenopausal !omen. C#stet >ynecol. 1<<2D:6$1(8363. OPu#Med99. R!eifel J, C-rien +%. A metaanalysis of te effect of ormone replacementterapy upon depressed mood. Psyconeuroendocrinology. 1<<;D22$3(81:<212.

OPu#Med9/. *cmidt PJ, ieman , @anaceau MA, et al. strogen replacement inperimenopauserelated depression8 A preliminary report. American Journal of C#stetricsand >ynecology. 2666D1:3$2(8919926. OPu#Med9. %latky MA, -ootroyd @, 'ittingoff , *arp P, +ooley MA.for te %&>?ualityoflife and depressi"e symptoms in postmenopausal !omen After recei"ing ormoneterapy8 results from te %eart and strogen4Progestin &eplacement *tudy $%&*( trialJAMA 2662. 2:;//<1/<;./<;. OPu#Med



9;. %ays J, Cckene JK, -runner &, et al. ffects of estrogen plus progestin on ealtrelated )uality of life. Te e! ngland Journal of Medicine. 2663D39:$1<(81:3<1:/9.OPu#Med9:. &esnick *M, Maki PM, &app *&, et al. ffects of com#ination estrogen plusprogestin ormone treatment on cognition and affect. Journal of Glinical ndocrinologyand Meta#olism. 266D<181:621:16. OPu#Med

9<. Gaspi A, *ugden K, Moffitt T, et al. nfluence of life stress on depression8moderation #y a polymorpism in te /%TT gene. *cience. 2663D36183:3:<.OPu#Med/6. >i##s &-. strogen Terapy and Gognition8 A &e"ie! of te Golinergic %ypotesis.ndocr &e". 266< er.266<663. OPMG free article OPu#Med/1. @umas J, dgren G, e!ouse PA. strogen replacement after menopause8 role innormal cognition and Al0eimers disease. Aging %ealt. 266D28<//<./2. @umas JA, %ancur-ucci G, aylor M, *ites G, e!ouse PA. strogen treatmenteffects on anticolinergicinduced cogniti"e dysfunction in normal postmenopausal

!omen. europsycoparmacology. 266D31826/26;:. OPu#Med/3. @umas JA, %ancur-ucci G, aylor M, *ites G, e!ouse P. strogen interacts !itte colinergic system to affect te "er#al memory in postmenopausal !omen8 e"idence

for te critical period ypotesis. %ormones and -ea"ior. 266:D/381/<1<. OPMG freearticle OPu#Med/9. Fink >, *umner -%, &osie &, >race C, ?uinn JP. strogen control of centralneurotransmission8 effect on mood, mental state, and memory. Gellular and Moleculareuro#iology. 1<<D1$3(832/399. OPu#Med//. Mc@ermott J, Kreut0#erg J@, iu -, @lu0en @. ffects of estrogen treatment onsensorimotor task performance and #rain dopamine concentrations in gonadectomi0edmale and female G@1 mice. %ormones and -ea"ior. 1<<9D2:$1(812:. OPu#Med/. &u#ino! @, *cmidt P, &oca G. strogenserotonin interactions8 implications foraffecti"e regulation. -iological Psyciatry. 1<<3D998:3<:/6. OPu#Med/;. Mc!en -. strogen actions trougout te #rain. &ecent Progress in %ormone&esearc. 2662D/;$1(83/;3:9. OPu#Med

/:. -etea G, Mirkes *J, u R, *treicer JM, Gameron J. @ifferences in centralserotonergic acti"ity in stresssensiti"e "ersus stressresilient monkeys8 tryptopanydroxylase $TP%(, serotonin reuptake transporter $*&T( and serotonin 1Aautoreceptor $/%T1A( m&A expression. Paper presented at8 Te *ociety of -iologicalPsyciatry 2663 Annual MeetingD 2663D 2663D *an Francisco, GA./<. *cmidt PJ. Mood, depression and reproducti"e ormones in te menopausaltransition. Te American Journal of Medicine. 266/D11:$12-(8/9*/:*. OPu#Med6. *cneider *, *mall >+, %amilton *%, -ystritsky A, emeroff G-, Meyers -*.strogen replacement and response to fluoxetine in a multicenter geriatric depressiontrial. American Journal of te >eriatric Psyciatry. 1<<3D/8<;16. OPu#Med1. agata %, o0aki M, akano %. *ortterm com#inational terapy of lo!doseestrogen !it selecti"e serotonin reuptake ini#itor $flu"oxamine( for ooporectomi0ed

!omen !it ot flases and depressi"e tendencies. Journal of C#stetrics N>ynaecology &esearc. 266/D31$2(816;119. OPu#Med2. *oares G, Poitras J&, Prouty J, Alexander A-, *ifren J, Goen *. fficacy ofcitalopram as a monoterapy or as an adEuncti"e treatment to estrogen terapy forperimenopausal and postmenopausal !omen !it depression and "asomotorsymptoms. Journal of Glinical Psyciatry. 2663D9$9(89;39;<. OPu#Med3. &asgon , @unkin J, Fair#anks , et al. strogen and response to sertraline inpostmenopausal !omen !it maEor depressi"e disorder8 A pilot study. Journal ofPsyciatric &esearc. 266;D91$39(833:393. OPu#Med



9. e!ouse PA, @umas J, %ancur-ucci G, et al. strogen Administration egati"elyAlters Mood Follo!ing Monoaminergic @epletion and Psycosocial *tress inPostmenopausal +omen. europsycoparmacology. 266:D33$;(81/191/2;.OPu#Med/. Prior JG. Perimenopause8 te complex endocrinology of te menopausal transition.ndocr &e". 1<<:D1<$9(83<;92:. OPu#Med

. Maki PM. Menopause and anxiety8 immediate and longterm effects. Menopause.266:D1/$(81633163/. 1616.16<;4gme.1636#1613e31:1:d31::23. OPu#Med;. Qoung *, *mit *, Pil &C, r"in F&. Tryptopan depletion causes a rapidlo!ering of mood in normal males. Psycoparmacology. 1<<3D:;81;31;;. OPu#Med:. @elgado P. Monoamine depletion studies8 mplications for antidepressantdiscontinuation syndrome. Journal of Glinical Psyciatry. 266D; *upplement 98222.$*upplement 9( OPu#Med<. eyton M, Qoung *, Pil &C, et al. ffects on mood of acute penylalanine4tyrosinedepletion in ealty !omen. europsycoparmacology. 1<<<D22$1(8/23. OPu#Med;6. Qoung *, eyton M. Te role of serotonin in uman mood and social interaction8insigt from altered tryptopan le"els. Parmacology -iocemistry and -ea"ior.1<<3D;18:/;:/. OPu#Med

;1. Kirsc#aum G, Pirke KM, %ellammer @%. Te Trier *ocial *tress Testa tool forin"estigating psyco#iological stress responses in a la#oratory setting.europsyco#iology. 1<<3D2:$12(8;:1. OPu#Med;2. Folstein MF, Folstein *, Mc%ug P&. 7Minimental state78 a practical metod forgrading te cogniti"e state of patients for te clinician. Journal of Psyciatric &esearc.1<;/D12$3(81:<1<:. OPu#Med;3. &eis#erg -, *cenk M, Ferris *, *c!art0 >, deeon M. Te -rief Gogniti"e &ating*cale $-G&*(8 Findings in primary degenerati"e dementia $P@@( Psycoparmacology-ulletin. 1<<3D$1<(89;/6.;9. Jurica PJ, eitten G, Mattis *. @ementia &ating *cale2. ut0, F8 PsycologicalAssessment &esources nc.D 2661.;/. &eis#erg -, Ferris *%, de eon MJ, Grook T. Te >lo#al @eterioration *cale for

assessment of primary degenerati"e dementia. American Journal of Psyciatry.1<<3D13<$<(8113113<. OPu#Med;. First M-&*, >i##on M, +illiams J-+. *tructured Glinical nter"ie! for @*M'T&Axis @isordersPatient dition. *G@4P, 242661 ed. +asington, @.G.8 AmericanPsyciatric Press nc.D 2661.;;. -eck AT, +ard G%, Mendelson M, Mock J, r#aug J. An in"entory for measuringdepression. Arci"es of >eneral Psyciatry. 1<1D98/33. OPu#Med;:. *er!in --. Te impact of different doses of estrogen and progestin on mood andsexual #ea"ior in postmenopausal !omen. Journal of Glinical ndocrinology andMeta#olism. 1<<1D;2$2(833393. OPu#Med;<. llen#ogen MA, Qoung *, @ean P, Palmour &M, -enkelfat G. Mood response toacute tryptopan depletion in ealty "olunteers8 sex differences and temporal sta#ility.

europsycoparmacology. 1<<D1/$/(89/9;9. OPu#Med:6. Kirsc#aum G, Pruessner JG, *tone AA, et al. Persistent ig cortisol responses torepeated psycological stress in a su#population of ealty men. PsycosomaticMedicine. 1<</D/;$/(89:9;9. OPu#Med:1. &oleder , *commer G, %ellammer @%, ngel &, Kirsc#aum G. *exdifferences in glucocorticoid sensiti"ity of proinflammatory cytokine production afterpsycosocial stress. Psycosomatic Medicine. 2661D3$(8<<;2. OPu#Med



:2. Kupke T, e!is &. &elati"e influence of su#Eect "aria#les and neurologicalparameters on neuropsycological performance of adult sei0ure patients. Arci"e ofGlinical europsycology. 1<:<D983/133. OPu#Med:3. %indmarc . Psycological performance models as indicators of te effects ofypnotic drugs on sleep. Psycoparmacology. 1<:9D*18/::. OPu#Med:9. +ecsler @. +ecsler Adult ntelligence *cale&e"ised. *an Antonio8 Te

Psycological GorporationD 1<:1.:/. Te Gontinuous Performance Test Ocomputer program. 'ersion 3.6. Toronto8 Multi%ealt *ystemsD 1<</.:. e0ak M@. europsycological Assessment. 2nd ed 1<</.:;. Mcair @M, orr M, @roppleman F. Profile of Mood *tates. *an @iego, GA8ducational and ndustrial Testing *er"iceD 1<;1.::. >oligtly K, loyd JA, %o#son J, >allager P, Mercer >, Qoung A%. Acutetryptopan depletion in sci0oprenia. Psycological Medicine. 2661D318;/:9.OPu#Med:<. -aker @, Golerton -, >leason G, et al. strogen fa"ora#ly affects selecti"eattention for ealty postmenopausal !omen. *ociety for euroscience, 2662. 2662<6. Maki P, Ronderman A, &esnick *. nanced "er#al memory in nondemented elderly

!omen recei"ing ormonereplacement terapy. American Journal of Psyciatry.2661D1/:$2(822;233. OPu#Med<1. -artolic i, -asso M&, *cefft -K, >lauser T, Titanic*cefft M. ffects ofexperimentallyinduced emotional states on frontal lo#e cogniti"e task performance.europsycologia. 1<<<D3;$(8;;:3. OPu#Med<2. *coofs @, Preu @, +olf CT. Psycosocial stress induces !orking memoryimpairments in an n#ack paradigm. Psyconeuroendocrinology. 266:D33$/(893/3.OPu#Med<3. Kulmann *, Piel M, +olf CT. mpaired memory retrie"al after psycosocial stress inealty young men. te Journal of euroscience. 266/82<;;2<:2. OPu#Med<9. upien *J, Fiocco A, +an , et al. *tress ormones and uman memory functionacross te lifespan. Psyconeuroendocrinology. 266/D36$3(822/292. OPu#Med

</. Koc K, Pauly K, Kellermann T, et al. >ender differences in te cogniti"e control ofemotion8 An fM& study. europsycologia. 266;D9/$12(82;992;/9. OPu#Med<. Kim JJ, @iamond @M. Te stressed ippocampus, synaptic plasticity and lostmemories. at &e" eurosci. 2662D3$(89/392. OPu#Med<;. Kudielka -M, *cmidt&ein!ald AK, %ellammer @%, Kirsc#aum G. Psycologicaland endocrine responses to psycosocial stress and dexametasone4corticotropinreleasing ormone in ealty postmenopausal !omen and young controls8 te impact ofage and a t!o!eek estradiol treatment. euroendocrinology. 1<<<D;6$(8922936.OPu#Med<:. >oldstein JM, Jerram M, Poldrack &, et al. %ormonal cycle modulates arousalcircuitry in !omen using functional magnetic resonance imaging. Te Journal ofeuroscience. 266/D2/8<36<<31. OPu#Med

<<. Protopopescu V, Pan %, Altemus M, et al. Cr#itofrontal cortex acti"ity related toemotional processing canges across te menstrual cycle. PA*. 266/D162$99(816616/. OPMG free article OPu#Med166. Pearson &, e!is M-. Fear recognition across te menstrual cycle. %ormones and-ea"ior. 266/82;2;1. OPu#Med161. Amin R, pperson G, Gonsta#le &T, Ganli T. ffects of estrogen "ariation onneural correlates of emotional response ini#ition. euromage. 266D32$1(89/;99.OPu#Med



162. Pelps A. %uman emotion and memory8 nteractions of te amygdala andippocampal complex. Gurrent Cpinion in euro#iology. 2669D1981<:262. OPu#Med163. Pelps A. motion and cognition8 insigts from studies of te uman amygdala.Annual &e"ie! of Psycology. 26682;/3. OPu#Med169. *aa# P>, Matte!s KA, *toney GM, Mc@onald &%. Premenopausal andpostmenopausal !omen differ in teir cardio"ascular and neuroendocrine responses to

#ea"ioral stressors. Psycopysiology. 1<:<D2$3(82;62:6. OPu#Med16/. Geresini >, Freddi M, Morganti *, et al. Te effects of transdermal estradiol on teresponse to mental stress in postmenopausal !omen8 a randomi0ed trial. AmericanJournal of Medicine. 2666D16<$(8939:. OPu#Med16. Komesaroff PA, sler M@, *udir K. strogen supplementation attenuatesglucocorticoid and catecolamine responses to mental stress in perimenopausal !omen.J Glin ndocrinol Meta#. 1<<<D:9$2(8616. OPu#Med16;. indeim *&, egro &*, -ernstein , et al. -ea"ioral stress responses inpremenopausal and postmenopausal !omen and te effects of estrogen. AmericanJournal of C#stetrics and >ynecology. 1<<2D1;81:311:3. OPu#Med16:. -urleson M%, Malarkey +-, Gacioppo JT, et al. Postmenopausal ormonereplacement8 effects on autonomic, neuroendocrine, and immune reacti"ity to #rief

psycological stressors. Psycosomatic Medicine. 1<<:D681;2/. OPu#Med16<. KaEantie , Pillips @+. Te effects of sex and ormonal status on tepysiological response to acute psycosocial stress. Psyconeuroendocrinology.266D31$2(81/1. OPu#Med

16

Te American Eournal of geriatric psyciatry 8 official Eournal of te American Associationfor >eriatric PsyciatryAutor Manuscript% Pu#lic Access

Tis article as #een corrected. *ee Am J >eriatr Psyciatry. 2616 *eptem#er 2D 1:$/(89/.Psyciatric @isorders and Gogniti"e @ysfunction Among Clder, Postmenopausal+omen8 &esults From te +omenSs %ealt nitiati"e Memory *tudy

Gristoper G. Golenda, M.@., M.P.%., Glaudine egault, P.@., O..., and >loria . *arto,M.@., P.@.

Additional article informationA#stractC#Eecti"e

To estimate te fre)uency of depressi"e symptoms and selected psyciatric disorders inte +omenSs %ealt nitiati"e Memory *tudy $+%M*( coort and related tem tocogniti"e syndromes.@esign

+%M* !as a randomi0ed, dou#le#linded, place#ocontrolled pre"ention clinical trialexamining !eter opposed and unopposed ormone terapy reduced te risk ofdementia in ealty postmenopausal !omen. Participants scoring #elo! a designatedcutpoint on a cogniti"e screener recei"ed a compreensi"e neuropsyciatric !orkup and



adEudicated outcome of no cogniti"e impairment, mild cogniti"e impairment, or pro#a#ledementia.Participants

*e"en tousand four undred se"entynine +%M* participants #et!een age / and ;<years and free of dementia at te time of enrollment in +%M*. Fi"e undred t!entyone

uni)ue participants contri#uted complete data re)uired for tese analyses.Measures

@epressi"e symptoms !ere measured !it te 1/item >eriatric @epression *cale andte presence of selected psyciatric disorders $maEor depression, generali0ed anxiety,and panic and alcool a#use( !as made using te P&MM@.&esults

Te 1:= of !omen ad at least one psyciatric disorder !it depression #eing te mostcommon $1=( follo!ed #y general anxiety or panic $=( and alcool a#use $1=(.@epression and te presence of a psyciatric disorder !ere associated !it impairedcogniti"e status. Participants a"ing a psyciatric disorder !ere more tan t!ice as likely

to #e diagnosed !it cogniti"e impairment as tose !it no psyciatric disorder $oddsratio I 2.6, </= confidence inter"al I 1.1;3.6(. Clder age, !ite race, and dia#etes

!ere also associated !it cogniti"e impairment.Gonclusion

Te fre)uency of a psyciatric disorder is associated !it poorer cogniti"e functioningamong older !omen enrolled in +%M*. Tat approximately one in fi"e !omen ad apro#a#le psyciatric disorder, most typically depression, igligts te need for greaterdetection and treatment efforts in tis population.Key!ords8 Psyciatric disorders, cognition, MG, risk of dementia, comor#idity

Approximately one of e"ery se"en Americans older tan ;6 years suffers from some

form of dementia.1 Moreo"er, te pre"alence of dementia increases significantly !itage. *ome form of dementia is present in approximately 1./= adults at te age of /years2 and rises to nearly 3:= in tose aged <6 years and older.1 @iscrete psyciatricdisorders suc as depression or oter affecti"e and anxiety disorders may cooccur !itdementia.3 Te pre"alence of clinically significant depression in patients !it Al0eimerdisease is #et!een 26= and 2/=.9,/

Te occurrence of psyciatric comor#idities !it mild cogniti"e impairment $MG( or earlydementia is an area of increasing interest, especially te relationsip #et!eendepression and dementia. pidemiologic studies a"e #een inconsistent, o!e"er.arly studies from France and te Bnited *tates so!ed opposite findings. Te Frencstudy failed to find an association !it depressi"e symptoms and cogniti"e deterioration

o"er a 3year period,; !ereas te B.*. study found a t!ofold risk of incident dementiain persons !it preexisting depression.: Anoter study found tat depressi"e symptomspredicted future cogniti"e losses in elderly persons !it preexisting moderate cogniti"eimpairment #ut did not find an association #et!een depressi"e symptoms and onset orrate of decline for cogniti"ely intact elderly.< n contrast, te Monongaela 'alleyndependent lders *ur"ey demonstrated tat depressi"e symptoms !ere crosssectionally related to cogniti"e function #ut not associated !it decline, and for tose

!o de"eloped dementia o"er time, #aseline depressi"e symptoms did not exert muceffect on decline.16 More recently, Godos et al.11 noted tat from #aseline to ;year



follo!up, iger le"els of #aseline depressi"e symptoms !ere associated !it greaterdecline in cogniti"e performance among older adults aged ;6;< years at #aseline.Finally, -ecker et al.12 found no consistent relationsip #et!een mood state and tede"elopment of dementia in su#Eects participating in te community#ased coort study,te Gardio"ascular %ealt *tudyGognition $G%*G(.

Te relationsip #et!een depression and te de"elopment of dementia is muc strongerin clinical studies !ere patient diagnoses a"e #een esta#lised, and it as #eeno#ser"ed tat patients !it Yre"ersi#le dementiaZ often fail to acie"e a completecogniti"e reco"ery after remission of depression and during follo!up. @uring follo!up,an a"erage of 11=23= of patients !it an initially re"ersi#le dementia #ecomeirre"ersi#ly demented e"ery year.131;

Te +omenSs %ealt nitiati"e Memory *tudy $+%M*(,1: a large, randomi0ed, dou#le#linded, place#ocontrolled pre"ention clinical trial, examined !eter postmenopausalormone terapy $%T( reduces te risk of allcause dementia in ealty nondemented

!omen aged /;< years at #aseline. Tis study pro"ides an opportunity to examine teassociation #et!een depression and se"eral psyciatric disorders and pro#a#le

dementia $P@( and MG. t is predicted tat depression !ill #e associated !it diagnosedP@ and MG. t is also predicted tat nondepressi"e disorders $anxiety, panic, andalcool a#use( !ill also #e associated !it incident dementia and MG, #ut teassociation !ill not #e as strong as !it depression. n addition, !e !ill examine !eter+%M* treatment assignment or demograpic or ealt "aria#les are related topsyciatric mor#idity.MT%C@**ample

Participants for +%M* !ere recruited during +% %T trial from te estrogen plusprogestin arm. 'isits occurred annually for ; years $1<</2662(.1; Te ;,9;< +%M*participants !ere /;< years of age at #aseline and free of P@ as ascertained #y te

+%M* protocol. Potential +%M* participants !ere asked !eter tere !ere anyreasons, suc as serious emotional pro#lems, mental illness, or too muc stress, tat

!ould make it ard for tem to #e in a researc study. xclusion from te study #asedon tese screening )uestions !as tus strictly selfreport. Furtermore, at te finaleligi#ility assessment, te clinic staffs !ere asked to use teir o!n Eudgment todetermine !eter te !oman !as ineligi#le #ased on depression. o oterinclusion4exclusion criteria !ere re)uired.

A detailed description of te +%M* protocol for determining P@ and MG as #eenpu#lised.1; -riefly, in Pase 1 of te +%M* protocol, te participants recei"ed acogniti"e screening !it te Modified MiniMental *tate xamination $3M*( at #aselineand annually tereafter. +omen ad"anced to Pase 2 of te protocol if tey scored

#elo! an educationadEusted cutpoint on te 3M*.1<,26 Tere !ere /21 !omen !oad"anced once or more to Pase 2.

Criginally, te cut scores !ere ;2 for tose !it : years of formal education and ;for tose !it ]< years of education. %o!e"er, to increase sensiti"ity, after 1 montsne! cutpoints of :6 for tose !it : years of education and :: for tose !it ]<years of education !ere implemented. Tis resulted in an increase of 1 su#Eects tat

!ere included in te coort of /21.



n Pase 2, !omen under!ent a compreensi"e neuropsyciatric examination tatincluded te Gonsortium to sta#lis a &egistry for Al0eimerSs @isease #attery ofneuropsycological tests and standardi0ed inter"ie!s of te participant and a proxy toassess ac)uired cogniti"e and #ea"ioral impairments.21,22 Pase 3 consisted of aclinical e"aluation #y a #oardcertified pysicianspecialist. Te pysicianspecialistclassified te +%M* participant as a"ing no cogniti"e impairment $G(, MG, or P@,

#ased on @iagnostic and *tatistical Manual of Mental @isorders, Fourt dition,criteria.23 All clinical and test data !ere ten transmitted to te +%M* GGG for re"ie!and central adEudication #y a committee consisting of tree #oardcertified specialists$t!o neurologists and one geriatric psyciatrist( !it extensi"e experience in dementia.Measures

@epressi"e *e"erity

@epressi"e symptom se"erity !ere assessed !it te 1/item >eriatric @epression*cale $>@*(.29 Participants reporting ]/ symptoms and ]16 symptoms on te >@*

!ere classified as depressed, and tose !it fe!er symptoms !ere considered notdepressed.

Psyciatric @iagnoses

Te P&MM@ psyciatric diagnostic inter"ie!2/ !as administered #y a trained andcertified examiner and re"ie!ed #y te clinician to identify te follo!ing disorders8 maEordepression, generali0ed anxiety, and panic and alcool a#use. YAny depressi"eanxietyalcool disorderZ !as a composite category created if !omen !ere classified as a"ingat least one of te four psyciatric diagnoses. Te P&MM@ as #een used !it teelderly including tose !it cogniti"e impairment.22: *creening instruments for#ipolar disorders, tougt disorders, personality disorders, or oter su#stance a#usedisorders !ere not used.

Panic @isorder

Te panic symptoms list from te P&MM@ includes 13 symptoms, so in addition to acategorical classification $panic disorder "ersus no panic disorder( a total symptomse"erity score !ic is te sum of te symptoms reported during te Ylast really #adtimeZ an anxiety attack occurred during te past mont.

Anxiety @isorder

Te generali0ed anxiety scale includes six symptoms tat a"e #otered te participantmore tan alf te days during te last mont. Te score for te symptoms ranges from6 to . A score 52 represents no anxiety. f te score is ]2, te participant is ten asked

!eter 1( te pro#lems make it ard to do er !ork, take care of tings at ome, or getalong !it oter people, 2( se as !orried a great deal a#out different tings, and 3(se as ad all tese pro#lems for as long as monts. A positi"e ans!er to all tree)uestions reflects pro#a#le generali0ed anxiety disorder. Cne of te tree ans!ers #eingnegati"e reflects anxiety, not oter!ise specified.

Alcool A#use @isorder



Alcool a#use !as determined !it te participant ans!ering a series of fi"e )uestionson alcool use. f any !as ans!ered positi"ely, anoter series of fi"e )uestions !ereasked a#out doctorSs suggestion of a drinking pro#lem, or drinking !ile !orking ortaking care of oters, or missing or #eing late at !ork #ecause of drinking, or pro#lemsgetting along !it oters !ile drinking, or dri"ing a car after se"eral drinks. f any of te)uestions from te second series !as ans!ered positi"ely, te participant !as identified

!it pro#a#le alcool a#use4dependence. Cter!ise, no alcool pro#lem is registered.Analysis

All analyses !ere conducted at te +ake Forest Bni"ersity +%M* GoordinatingGenter. @ata !ere a#stracted from te first #elo! te cutpoint 3M* score. YCntrialZ datafrom all /21 participants !o recei"ed te full e"aluation at least once after scoring#elo! te cutpoint on te 3M* !ere analy0ed. Pre"alence rates !ere compared#et!een comparison groups using 2 or FiserSs exact tests. To furter in"estigate tepresence or a#sence of a disorder, logistic regression models !ere used to find te #estfitting and most parsimonious model.2< Te response "aria#le, a disorder, is adicotomous outcome $yes or no(. AdEustments for year of first #elo! te cutpoint 3M*score, age, and #aseline 3M* scores !ere included in models for te t!o main

outcomes, i.e., any depressi"eanxietyalcool disorder and maEor depression. Amulti"aria#le logistic regression model !as fitted to determine associations #et!eenpsyciatric outcomes and cogniti"e outcomes and selected demograpic and clinicalfactors. Parameters for te logistic models !ere estimated using standard maximumlikeliood metods. Te assessment of goodness of fit included computation ande"aluation of o"erall measures #ased on residuals, e.g., te Pearson residual and tede"iance residual.&*BT*

@uring te course of te +%M* clinical trial $ I ;,9;<(, in total <;1 neuropsyciatrice"aluations !ere completed. Cf tese, <36 yielded a final diagnosis of G, MG, or [email protected] tese :<1 e"aluations, representing /21 uni)ue participants, contri#uted complete

data re)uired for tese analyses.

Ta#le 1 includes te num#er of follo!up assessments at eac annual "isit. Missing dataresulted from incomplete cogniti"e assessments #ecause of "arious reasons includingrefusals, transportation issues, and oter ealt pro#lems. T!el"e $2=( of te firsta#normal 3M* scores occurred at #aseline and none resulted in a P@ diagnosis. Tefollo!ing percents of first a#normal 3M* scores occurred at su#se)uent "isits8 23=,36=, 1=, 13=, <=, /=, and 1= at years 1;, respecti"ely.TA- 1TA- 1Follo!Bp Assessments of +omen ntered into te +%M* Goort

Te pre"alence of psyciatric mor#idities at first a#normal 3M* score is presented inTa#le 2. Te most common disorder !as maEor depression affecting :9 $1=(participants. >eneral anxiety or panic !as diagnosed in = of te sample, !ereasalcool a#use !as only found in 1=. Any depressi"eanxietyalcool disorder !aspresent in <3 $1:=( !omen at first #elo! te 3M* cutpoint score. one of tesemor#idities differed #y treatment assignment to %T $data not so!n(.TA- 2TA- 2



Fre)uency of Psyciatric Gomor#idities at First Pase 2 europsyciatric "aluation $I /21(

Te relationsip #et!een +% #aseline demograpic, life style, and clinicalcaracteristics and psyciatric mor#idity status !as examined $Ta#le 3(. Te presenceof any depressi"eanxietyalcool disorder !as associated !it race $p 56.61( !it

!ites less likely to #e affected tan non!ites. Alcool use !as lo! o"erall and lesscommon among tose !it any depressi"eanxietyalcool disorder $2:= "ersus 96=, pI 6.62(. Tose !it any depressi"eanxietyalcool disorder !ere more tan t!ice aslikely to a"e reported a istory of dia#etes $2:= "ersus 13=, p 56.661(. Tere !ere nodifferences in tese #aseline caracteristics #y treatment assignment $data not so!n(.TA- 3TA- 3@emograpic, ifestyle, and Glinical Factors for Participants #y Any @epressi"eAnxietyAlcool @isordera at First Pase 2 europsyciatric "aluation

A total of 23< $9=( participants !ere classified as G, 21/ $91=( as MG and ;$13=( as P@. Te cogniti"e groups !ere significantly different in relation to some

psyciatric outcomes. %a"ing any depressi"eanxietyalcool disorder $p 56.61( anda"ing maEor depression $p I 6.62( !ere significantly associated !it cogniti"e status.Te MG group !as more likely to a"e maEor depression or any depressi"eanxietyalcool disorder tan te G group, significantly more likely to a"e maEor depression orany psyciatric mor#idity tan !it te P@ or G groups $Ta#le 9(. Te num#er of

!omen !it depressi"e se"erity scores a#o"e te >@* cutpoint of 16 !as greateramong !omen Eudged to #e cogniti"ely impaired $MG and P@( tan !omen !it G $pI 6.63(, #ut te difference failed to reac statistical significance !it con"entionalcutpoint of >@* I / $p I 6.21(. *imilar results !ere o#tained after controlling for year offirst a#normal 3M* score, age, and #aseline 3M* scores for te presence of anydepressi"eanxietyalcool disorder and maEor depression.TA- 9

TA- 9Psyciatric Gomor#idities at First Pase 2 europsyciatric "aluation #y Gogniti"e*tatus

As so!n earlier, tere !ere 2:2 participants classified !it cogniti"e impairment $P@ orMG( at te time of teir first a#normal 3M* score and neuropsyciatric e"aluation. naddition, 3: oter participants !ere su#se)uently classified !it impairment at a laterannual assessment. Terefore, !e compared psyciatric comor#idities, at te time offirst diagnosis, for tose cogniti"ely impaired "ersus tose !o remained nonimpaired,at te time of teir last ad"ancement to te neuropsyciatric e"aluation $Ta#le /(. Tefindings !ere similar to Ta#le 9 e"en after adEusting for year of first 3M* score #elo!cutpoint, age, and #aseline 3M* scores. Te cogniti"ely impaired group experienced

iger le"els of depression, #ased on >@* cutpoints ]/ and ]16, and maEor depression$p 6.69(. Any depressi"eanxietyalcool disorder also so!ed te same pattern $p56.61(.TA- /TA- /Psyciatric Gomor#idities for Participants at First Gogniti"e mpairment 'ersus Tose+itout mpairment at ast europsyciatric "aluation



+e determined te demograpic, life style, and clinical factors associated !it cogniti"estatus at first neuropsyciatric e"aluation, as a prelude to modeling cogniti"e impairmentand its relationsip to any depressi"eanxietyalcool disorder. As descri#ed in Ta#le ,cogniti"ely impaired !omen !ere significantly older $p 56.6661(, !ite $p 56.6661(, andad lo!er #ody mass index $p I 6.69(.TA-

TA- @emograpic, ifestyle, and Glinical Factors for Participants #y Gogniti"e *tatus at Firsteuropsyciatric "aluation

Te results of modeling te pro#a#ility of cogniti"e impairment for !omen !it or !itoutany depressi"eanxietyalcool disorder, #ased on multiple logistic regression, arepresented in Ta#le ;. +e included co"ariates associated !it cogniti"e impairmentstatus $!it p 56.26 in Ta#le /(, including age, education, race $!ite "ersus non!ite(,smoking, dia#etes, #ody mass index, and #aseline 3M* and year of firstneuropsyciatric e"aluation. Assignment to %T !as also included. After controlling forte co"ariates, te presence of any depressi"eanxietyalcool disorder retained itsassociation !it cogniti"e impairment status $p I 6.662(. Tose participants experiencing

Yany depressi"eanxietydepressi"e disorderZ !ere more tan t!ice as likely to #ediagnosed !it cogniti"e impairment as tose not experiencing any mor#idity $odds ratioI 2.6, </= confidence inter"al I 1.3/3.6(. Clder !omen $p I 6.6661(, !ites $p I6.62(, and tose !it dia#etes $p I 6.63( !ere also at ele"ated risk for cogniti"eimpairment.TA- ;TA- ;ikeliood of First @iagnosis of Gogniti"e mpairment $Pro#a#le @ementia or MinorGogniti"e mpairment( as Associated +it *elected @emograpic and Glinical Factors8&esults of Multi"aria#le ogistic &egression Modeling, Gontrolling for Qear of First ...@*GB**C

Tis study continues to add to te e"idence tat psyciatric mor#idity, in particulardepression, is significantly associated !it P@ and MG in later life. Among +%M*participants !o screened positi"ely for suspicious cogniti"e impairment Yanypsyciatricanxietyalcool disorderZ !as present in one of fi"e !omen, !it depressionas te most common disorder. +omen !it any depressi"eanxietyalcool disorder

!ere more likely to #e non!ite, less likely to consume alcool, and ad istories ofdia#etes. Tese rates are alarming and igligt te need for careful diagnosis andtreatment of re"ersi#le mor#idities suc as depression and anxiety.

Any depressi"eanxietyalcool disorder, and in particular depression, !ere significantlyassociated !it #eing diagnosed !it P@ or MG. Te fre)uency of any depressi"eanxietyalcool disorder and maEor depression in particular !ere a#out t!o times iger

in te MG group compared !it !omen !it no cogniti"e disorder and a#out 2/=greater tan !omen !it P@. Cur findings are consistent !it oter population#asedstudies.16,36 %o!e"er, tey are at "ariance !it tose recently reported #y -ecker etal.12 from te G%*G. -ot studies used large community#ased samples, and similarscreening instruments, screening instrument cutpoints, and approac to diagnosticadEudication. Altoug +%M* used only !omen participants, G%*G included #ot menand !omen, leading to te ypotesis, are !omen !o are depressed at greater risk forde"eloping cogniti"e impairment tan men !it depression



n tis study, tere !as a strong relationsip #et!een maEor depression and MG. Tesefindings are consistent from tose originating from clinical populations. Apostol"a andGummings31 a"e reported tat te pre"alence of #ea"ioral symptoms associated !itMG, e.g., depression, anxiety, apaty, and irrita#ility ranged from 3/= to ;/=. Teclassification of MG as e"ol"ed a great deal since tis study !as #egun. +e definedMG #ased on te generally accepted model at te time and did not su#classify su#Eects

into amnestic, nonamnestic, or multiple domain types.32 Cf note, te amnestic su#typeas #een so!n to #e associated !it a iger num#er of neuropsyciatricsymptoms.33 Gould psyciatric disorders suc as depression and anxiety contri#ute totis con"ersion Tis )uestion re)uires furter study, especially in lieu of a recentpopulation#ased study comparing Ginese and B.K. su#Eects, !ic found tat terelationsip #et!een depression and dementia migt #e temporal and only te mostse"ere depressi"e cases of depression are risk factors for dementia.39

Te multi"ariate analyses tat modeled cogniti"e impairment among +%M* su#Eects !ere also interesting. Tose participants experiencing any depressi"eanxietyalcooldisorder !ere more tan t!ice as likely to #e diagnosed !it cogniti"e impairment tantose not experiencing any comor#idity. Tis is not likely attri#uta#le to mistaking

depressi"e symptoms for cogniti"e symptoms as our adEudication criteria madediagnosing eiter P@ or MG more difficult if psyciatric symptoms !ere present. t !aste strongest predictor of all demograpic and clinical "aria#les and e"en ad a igerodds ratio tan age. Cur data suggest tat a"ing a psyciatric disorder, especiallymaEor depression, may #e a risk factor for te de"elopment of a cogniti"e disorder.>i"en our concurrent assessment of cogniti"e and psyciatric disorders, !e cannotconfidently conclude causal direction. t is also possi#le tat cogniti"e disorders are riskfactors for psyciatric disorders. Tis finding furter underscores te longstandingdiagnostic recommendation tat all patients !o present !it cogniti"e impairmentsould #e screened for psyciatric conditions, in particular depression. nterestingly, intese analyses, %T did not predict cogniti"e impairment.

*e"eral limitations of tis study must #e considered. First, it is important to note tatpersons !it certain selfreported mental illness !ere excluded from te +%D terefore,te original coort may not #e representati"e of te population at large. *econd, itsould #e noted tat te o Psyciatric @isorder group !as not a typical comparisoncondition in tat tey pro#a#ly ad ele"ated rates of depression4anxiety gi"en tat teyfailed te initial cogniti"e screen. Tis may a"e attenuated te differences #et!eengroups. Tird, #ecause !omen only recei"ed a complete e"aluation if tey registered a#elo! cutpoint score on te 3M*, our YnormalZ group may not #e a truly normal sample#ut rater a group !itout clinically meaningful cogniti"e impairment.

Fourt, MG as a diagnostic category as #een continually refined since te enrollmentof su#Eects in tis study. +e defined MG #ased on te generally accepted model at te

time and did not su#classify su#Eects into amnestic, nonamnestic, or multiple domaintypes.32 Cf note, te amnestic su#type as #een so!n to #e associated !it a igernum#er of neuropsyciatric symptoms.33 Finally, te small num#er of cases can affectte "aria#ility of te psyciatric disorder pre"alence estimates. %o!e"er, for groupcomparisons, !e used small sample statistical metods suc as te FiserSs exact test

!en appropriate. Furtermore, for logistic regression analyses, !e presentedconfidence inter"als tat pro"ide information on te sta#ility of te estimates.



n summary, study participants !o so!ed suspicious cogniti"e impairment and !erecarefully e"aluated and classified as a"ing a cogniti"e disorder $P@ and MG(, or not,nearly one in fi"e ad any depressi"eanxietyalcool disorders, most fre)uently maEordepression. %a"ing maEor depression !as significantly associated !it also recei"ing adiagnosis of P@ or MG e"en after controlling demograpic and medical conditions.Tese data clearly igligt te importance of identifying psyciatric illnesses among

older !omen !it suspicious cogniti"e impairment e"en !en detected #y simplecogniti"e screeners. Bnderdetection and undertreatment of psyciatric mor#idities arecostly to indi"iduals and to society.Article informationAm J >eriatr Psyciatry. Autor manuscriptD a"aila#le in PMG 2616 *eptem#er 19.Pu#lised in final edited form as8Am J >eriatr Psyciatry. 2616 Fe#ruaryD 1:$2(8 1;;1:.doi8 16.16<;4J>P.6#613e31:1c/:9PMG@8 PMG2<3<691%M*@8 %M*22199Gristoper G. Golenda, M.@., M.P.%., Glaudine egault, P.@., *tepen &. &app,P.@., Margaret +. @e-on, P.@., Patricia %ogan, M.*, &o#ert +allace, M.@., M.*.,

inda %ersey, M.@., P.@., Judit Cckene, P.@., &acael +itmer, P.@., a!rence*. Pillips, M.@., and >loria . *arto, M.@., [email protected] te Texas ANM %ealt *cience Genter, TV $GGG(D @epartments of -iostatistics$G, P%( and Psyciatry and -ea"ioral Medicine $*&&(, +ake Forest Bni"ersity %ealt*ciences, +inston*alem, GD @epartment of Pre"enti"e Medicine, Bni"ersity ofTennessee %ealt *cience Genter, Mempis, T $M+@(D @epartment of pidemiology,Bni"ersity of o!a, o!a Gity, + $&+allace(D @epartment of eurology, Bni"ersity of-uffalo Medical Genter, -uffalo, Q $%(D @epartment of Pre"enti"e and -ea"ioralMedicine, Bni"ersity of Massacusetts, Amerst, MA $JC(D @i"ision of &esearc, KaiserPermanente ortern Galifornia, *an Francisco $&+itmen(D @i"ision of ndocrinology,mory Bni"ersity *cool of Medicine, Atlanta, >A $*P(D and Bni"ersity of +isconsinGenter for +omenSs %ealt &esearc, Madison, + $>*(

*end correspondence and reprint re)uests to Gristoper Golenda, M.@., M.P.%.,Gancellor for %ealt *ciences, +est 'irginia Bni"ersity, *uite 1666 %*G *out, PC-ox <666, Morganto!n, +' 2/6 D mail8 ccolenda4at4sc.!"u.eduGopyrigt notice and @isclaimerTe pu#lisers final edited "ersion of tis article is a"aila#le at Am J >eriatr PsyciatryTis article as #een corrected. *ee Am J >eriatr Psyciatry. 2616 *eptem#er 2D 1:$/(89/.*ee oter articles in PMG tat cite te pu#lised article.&eferences1. Plassman -, anga KM, Fiser >>, et al. Pre"alence of dementia in te Bnited*tates8 te aging, demograpics, and memory study. euroepidemiology. 266;D2<812/132. OPMG free article OPu#Med

2. >orelick P-. &isk factors for "ascular dementia and Al0eimer disease. *troke.2669D3/ suppl8226222. OPu#Med3. yketsos G>, ee %-. @epression and treatment of depression in Al0eimerSsdisease8 a practical update for te clinician. @ement >eriatr Gogn @isord. 2669D1;8//9. OPu#Med9. yketsos G>, *tein#erg M, Tscan0 JT, et al. Mental and #ea"ioral distur#ances indementia8 findings from te Gace Gounty *tudy on Memory in Aging. Am J Psyciatry.2666D1/;8;6:;19. OPu#Med



/. Payne J, yketsos G>, *teele G, et al. &elationsip of cogniti"e and functionalimpairment to depressi"e features in Al0eimerSs disease and oter dementias. Jeuropsyciatry Glin eurosci. 1<<:D16899699;. OPu#Med. &eis#erg -, Ferris *%, Kluger A, et al. Mild cogniti"e impairment $MG(8 a istoricalperspecti"e. nt Psycogeriatr. 266:D2681:31. OPu#Med;. @ufouil G, Furer &, @artigues JF, et al. ongitudinal analysis of te association

#et!een depressi"e symptomatology and cogniti"e deterioration. Am J pidemiol.1<<D19983991. OPu#Med:. @e"anand @P, *ano M, Tang MV, et al. @epressed mood and te incidence ofAl0eimerSs disease in te elderly li"ing in te community. Arc >en Psyciatry.1<<D/381;/1:2. OPu#Med<. -assuk **, -erkman F, +ypiE @. @epressi"e symptomatology and incident cogniti"edecline in an elderly community sample. Arc >en Psyciatry. 1<<:D//816;316:1.OPu#Med16. >anguli M, @u Q, @odge %%, et al. @epressi"e symptoms and cogniti"e decline inlate life. Arc >en Psyciatry. 266D381/316. OPu#Med11. Godos J, Kado @M, *eeman T, et al. @epressi"e symptoms as a predictor ofcogniti"e decline8 MacArtur studies of successful aging. Am J >eriatr Psyciatry.

266;D1/89691/. OPu#Med12. -ecker JT, QueFang G, ope0 C, et al. @epressed mood is not a reisk factor forincident dementia in a community#ased coort. Am J >eriatr Psyciatry. 266<D1;833. OPMG free article OPu#Med13. &eding M, %aycox J, -lass J. @epression in patients referred to a dementia clinic.Arc eurol. 1<:/D928:<9:<. OPu#Med19. Kral ', mery C. ong term follo!up of depressi"e pseudodementia. Gan JPsyciatry. 1<:<D39899/99;. OPu#Med1/. &eynolds GF, Kupfer @J, %oc GG, et al. T!oyear follo!up of elderly patients !itmixed depression and dementia. Glinical and electroencepalograpic sleep findings. JAm >eriatr *oc. 1<:D398;<3;<<. OPu#Med1. Gopeland J&, @a"idson A, @e!ey M, et al. Al0eimerSs disease, oter dementias,

depression and pseudodementia8 pre"alance, incidence and tree year outcome ini"erpool. -r J Psyciatry. 1<<2D11823623<. OPu#Med1;. Alexopoulos >*, Meyers -*, Qoung &G, et al. Te course of geriatric depression

!it Yre"ersi#le dementiaZ8 a controlled study. Am J Psyciatry. 1<<3D1/681<31<<.OPu#Med1:. *umaker *A, egault G, Kuller , et al. +omenSs %ealt nitiati"e Memory *tudy8GonEugated e)uine estrogens and incidence of pro#a#le dementia and mild cogniti"eimpairment in postmenopausal !omen8 +omenSs %ealt nitiati"e Memory *tudy. JAMA.2669D2<182<9;2</:. OPu#Med1<. Teng , Gui %G. Te modified minimental state $3M*( examination. J GlinPsyciatry. 1<:;D9:831931:. OPu#Med26. Tom#aug T, Mc@o!ell , KristEansson -, et al. Minimental state examination

$MM*( and te modified MM* $3M*(8 a psycometric comparison and normati"edata. Psycol Assess. 1<<D:89:/<.21. Tariot P. G&A@ #ea"ior rating scale for dementia. nt. Psycogeriatr. 1<<D:suppl 3831;326. OPu#Med22. Morris JG, %eyman A, Mos &G, et al. Te Gonsortium to sta#lis a &egistry forAl0eimerSs @isease $G&A@(. Part . Glinical and neuropsycological assessment ofAl0eimerSs disease eurology. 1<:<D3<811/<11/. OPu#Med23. American Psyciatric Association. @iagnostic and *tatistical Manual of Mental@isorders. 9t ed. +asington, @G8 American Psyciatric Association PressD 1<<9.



29. -urke +J, &occaforte +%, +engel *P. Te sort form of te >eriatric @epression*cale8 a comparison !it te 36item form. J >eriatr Psyciatry eurol. 1<<1D981;31;:.OPu#Med2/. *pit0er &, +illiams J-, Kroenke K, et al. Btility of a ne! procedure for diagnosingmental disorders in primary care. Te P&MM@ 1666 study. JAMA. 1<<9D2;281;9<1;/. OPu#Med

2. Fiser KM, Gopena"er '. Assessing te mental ealt of rural older adults in pu#licousing facilities8 a comparison of screening tools. J >enontol ursing. 266D328233.OPu#Med2;. Pre"ille M, Gote >, -oyer &, et al. @etection of depression and anxiety disorders #yome care nurses. Aging Ment %ealt. 2669D:8966966<. OPu#Med2:. 'alenstein %, Kales %, Mello! A, et al. Psyciatric diagnosis and inter"ention inolder and ounger patients in primary care clinic8 effect of a screening and diagnosticinstrument. J Am >ertr *oc. 1<<:D9819<<1/6/. OPu#Med2<. %osmer @+, emeso! *. Applied ogistic &egression. e! Qork8 +ileyD 1<:<.36. *tepaniuk J, &itcie , Tuokko %A. europsyciatric impairments as predictors ofmild cogniti"e impairment, dementia, and Al0eimerSs disease. Am J Al0eimers @isCter @ementia. 266:D23832333. OPu#Med

31. Apostol"a >, Gummings J. europsyciatric manifestations in mild cogniti"eimpairment8 a systematic re"ie! of te literature. @ement >eriatr Gogn @isord.266:D2/811/12. OPu#Med32. Matte!s F, *tepan -G, McKeit >, et al. Medical &esearc Gouncil Gogniti"eFunction and Ageing *tudy. T!oyear progression from mild cogniti"e impariement todementia8 to !at extent do different definitions agree. J Am >eriatr *oc. 266:D/819291933. OPu#Med33. d!ards &, *pira AP, -arnes @, et al. europsyciatric symptoms in mildcogniti"e impairment8 differences #y su#type and progression to dementia. nt J >eriatrPsyciatry. 266<D298;1;22. OPMG free article OPu#Med39. Gen &, %u *, +ei , et al. *e"erity of depression and risk for su#se)uent dementia8coort studies in Gina and BK. -r J Psyciatry. 266:D1<383;33;;. OPu#Med

Anxiety Dan Premenstrual

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