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Definio:
a ausncia de menstruao por 12 meses em
mulher com idade acima de 45 anos na ausncia de
outras causas biolgicas, em conseqncia da falncia
ovariana fisiolgica.
A perimenopausa um perodo de transio
caracterizado pela irregularidade dos ciclos menstruais
e presena de sintomas da menopausa (flushes,
mudanas de humor, distrbios do sono,ressecamento
vaginal).
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Up to date Verso 19.1
Menopausa
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Up to date Verso 19.1
Menopausa
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* Stages most likely to be characterized by vasomotor symptoms,: elevated.
Adapted from Soules, MR et al. Fertil Steril 2001; 76:874.
Up to date Verso 19.1
Menopausa
Fisiologia
A produo ovariana sofre um progressivo declnio com a idade,
atingindo uma falncia completa na maioria das mulheres aos 50
anos.
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Fisiologia
O ovrio composto por trs compartimentos:
Teca- folicular: sntese estrognica;
Lteo: sntese estroprogestognica;
Estroma: sntese andrognica.
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Declnio dos folculos ovarianos com a idade
A comparison of the relationship between age and primordial follicle number in Block's study of 44 girls and
women aged 7 to 44 years with that of Gougeon's study of women aged 45 to 55 years. Follicle depletion appears to
accelerate in the decade preceding menopause.
Data from Block, E, Acta Anat 1952; 14:108 and Gougeon, A, Contraception Fertile Sexual 1984; 12:527.
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Up to date Verso 19.1
Menopausa
A
A
A
A
A
Mean daily levels of gonadotropins, sex steroids, and inhibins in older (ages 35-46 years; n=21),
shown in red, and younger women (ages 20-34 years; n=23), shown in blue.
Data from Welt, CK, McNicholl, DJ, Taylor, AE, Hall, JE. J Clin Endocrinol Metab 1999; 84:105.
Up To Date 19.1
Menopausa
Fisiologia
O alargamento do ciclo menstrual est ligado queda dos nveis de
inibina, que se inicia de 2 a 8 anos antes da menopausa.
Fisiologia
O declnio da funo folicular leva a perda do
feedback negativo na produo de
gonadotrofinas e caracteriza um hipogonadismo
hipergonadotrofico. H aumento de FSH e
queda do estradiol.
Idade da menopausa
Idade mdia aos 50 anos.
Manifestaes Clnicas
PRECOCES
Alteraes do padro de sangramento: oligomenorria; hipermenorria.
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Up to date Verso 19.1
Menopausa
Manifestaes Clnicas
MANIFESTAES TARDIAS
______________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Up to date Verso 19.1
Menopausa
Manifestaes Tardias
Efeitos no Osso: Diminuio da massa ssea pelo aumento da
remodelao. H diminuio de 2 a 5% ao ano nos primeiros 5 anos da
menopausa e de 0,5 a 1% ao ano, nos anos seguintes.
Diagnstico
Clinicamente: amenorria por 12 meses em mulher
acima de 45 anos.
____________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
____________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Tratamento
Avaliao individual dos riscos e benefcios, junto com a
paciente.
O objetivo a melhora da qualidade de vida.
Up To Date 19.1
Menopausa
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Vias de administrao
Progesterona orais:
Acetato de medoxiprogesterona (MPA)
Progesterona micronizada: escolha por ser natural e desprovida
de atividade andrognica.
Estudo Postmenopausal Estrogen/Prgestin Intervention Trial (PEPI) sugere
progesterona micronizada 200mg/dia pois mais benfica em relao aos
nveis de HDL.
Acetato de noretindrona (NETA)
Adesivos de progestgenos:
Acetato de noretindrona (125, 140, 170 ou 250mcg/dia);
Levonogestrel (20mcg/dia)
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Tratamento
Contra-indicaes da TRH
RELATIVAS
Histria de Ca de endomtrio;
Histria de Ca de mama;
Histria de tromboembolismo sem ser na vigncia de estrognio;
Doena heptica leve;
Enxaqueca.
ABSOLUTAS
Ca de endomtrio em atividade
Ca de mama em atividade
Tromboembolismo na vigncia de estrognio
Doena heptica grave.
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Tratamento
Efeitos colaterais:
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Tratamento
Segundo a FDA (Food and Drug Administration), as indicaes para
a TRH so:
Up To Date 19.1
Menopausa
Durao do Tratamento
Terapia por curto perodo para controle dos sintomas
deve ser por 2 a 3 anos, no mais do que 5 anos.
Up To Date 19.1
Menopausa
EFEITOS NO OSSO
Osteoporose e fraturas
Reifenstein and Albright documentaram h 60 anos a
associao entre o declnio do nveis de estrognio na
menopausa e a rpida perda ssea, osteoporose e associao
com maior risco de fraturas.
Muitos estudos documentaram que a reposio com Estrognio
ou E+P previne a perda ssea quando iniciados logo aps o
incio da menopausa.
O primeiro estudo a documentar reduo de fraturas com a TRH
foi o WHI incluindo fraturas vertebrais e do quadril.
O estudo HERS (2001) com mulheres no histerectomizadas
com doena coronariana falhou em demonstrar reduo
significativa na incidncia de fraturas com E+P.
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In Santen et al. Scientific Statement: Postmenopausal Hormone Therapy
JCEM, July 2010, 95 (Suppl 1):S7-S66
Menopausa
Am J Med. 2001 Apr 15;110(6):442-50.
Effects of hormone replacement therapy on clinical fractures and height loss:
The Heart and Estrogen/Progestin Replacement Study (HERS).
Cauley JA, Black DM, Barrett-Connor E, Harris F, Shields K, Applegate W, Cummings SR.
Source
Department of Epidemiology (JAC), University of Pittsburgh, Pennsylvania 15261, USA.
Abstract
PURPOSE:
To determine if estrogen plus progestin reduces the incidence of fractures or height loss in postmenopausal women with coronary
disease.
SUBJECTS AND METHODS:
We enrolled 2,763 postmenopausal women with coronary disease and with an intact uterus into the Heart Estrogen/progestin
Replacement Study, a randomized double-blind, placebo-controlled secondary prevention trial of cardiovascular disease.
Radiographically documented clinical fractures were a prespecified secondary endpoint. Height loss was used as a surrogate for
vertebral fractures. The average age of the women was 66.7 +/- 6.7 years, and fewer than 15% of the women had osteoporosis
based on their bone density. Women were randomly assigned to either 0.625 mg of conjugated equine estrogens plus 2.5 mg of
medroxyprogesterone acetate in 1 tablet daily (n = 1,380) or placebo (n = 1,383). Follow-up averaged 4.1 years; 82% of those
assigned to hormone treatment were taking it at the end of 1 year, and 64% at the end of the study.
RESULTS:
During 10,554 person years of follow-up, 286 women experienced a fracture: 138 in the treatment group (26.3 per 1,000 person years)
and 148 in the placebo group (28.0 per 1,000 person years); relative hazard, 0.94; 95% confidence interval 0.8 to 1.2, P = 0.61).
These included 58 wrist fractures (1.01; 0.6 to 1.7); 27 hip fractures (1.09; 0.5 to 2.3); 32 spine fractures (0.69; 0.3 to 1.4), and 192
other fractures (0.91; 0.7 to 1.2). There was no difference in average height loss between the treatment and placebo groups or in the
percent of women who lost more than 2 cm in height: 10.6% in the treatment group and 12.1% in the placebo group.
CONCLUSIONS:
There was no evidence of a reduction in the incidence of fractures or rate of height loss in older women not selected for osteoporosis.
Randomized studies are needed to clarify the effect of hormone replacement therapy on fracture risk among women with and without
osteoporosis.
Menopausa
EFEITOS CARDIOVASCULARES
Estudos epidemiolgicos sugerem reduo de DCV com a TRH.
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Tratamento
Womens Health Initiative (WHI) mudou o entendimento sobre os riscos e
benefcios da terapia hormonal. Estudou os efeitos da terapia combinada e do
estrognio sem oposio em mulheres na ps-menopausa entre 50 e 79 anos.
________________________________________________________________________________________________________________________
In Prentice et al.Am J Epidemiol 2009; 170: 12-23
Kaplan-Meier estimates of cumulative hazard rates of CHD
In the Women's Health Initiative, combined estrogen-progestin therapy was associated with a
significant increase in coronary events. CHD included nonfatal myocardial infarction and
death due to CHD. The overall hazard ratio for CHD was 1.24 (nominal 95 percent confidence
interval, 1.00 to 1.54).
Data from Manson, JE, Hsia, J, Johnson, KC, et al. Estrogen plus progestin and the risk of
coronary heart disease. N Engl J Med 2003; 349:523.
Kaplan-Meier estimates of cumulative hazard rates of stroke
In the Women's Health Initiative, combined estrogen-progestin therapy was associated with a significant increase
in stroke when compared with placebo. The intention-to-treat hazard ratio was 1.31, 95 percent CI 1.02 to 1.68.
Data from Wassertheil-Smoller, S, Hendrix, S, Limacher, M, et al. Effect of Estrogen Plus Progestin on Stroke in
Postmenopausal Women: The Women's Health Initiative: A Randomized Trial. JAMA 2003; 289:2673.
HRT increases invasive breast cancer
Data from Chlebowski, RT, Hendrix, SL, Langer, RD, et al. Risks and benefits of estrogen
and progestin in healthy postmenopausal women: principal results from the Women's
Health Initiative randomized controlled trial. JAMA 2003; 289:3243.
Estrogen-progestin therapy reduces hip fracture
In the Women's Health Initiative, combined estrogen-progestin replacement therapy was associated with
significant reduction in hip fracture (5 fewer hip fractures per 10,000 person-years, HR 0.7, unadjusted 95
percent CI 0.4 to 1.0).
Data from Risks and benefits of estrogen and progestin in healthy postmenopausal women: principal
results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321.
Menopausa
Menopausa
Tratamento
Menopausa
Primary Outcome Measures: rate of change of distal common carotid artery (CCA) far wall intima-media thickness
(IMT) [ Time Frame: Twice at baseline and then every 6 months on trial ] [ Designated as safety issue: No ]
Secondary Outcome Measures: neurocognitive function [ Time Frame: Baseline and at 3 years and end of
randomized treatment ] [ Designated as safety issue: No
cardiac computed tomography [ Time Frame: End of randomized treatment ] [ Designated as safety issue: No ]
measurement of coronary artery calcium and coronary artery lesions
Enrollment: 643
Study Start Date: July 2004
Estimated Study Completion Date: July 2013
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Menopausa
Menopausa
Timing hypothesis
Essa teoria props que o incio da TRH logo aps o incio da
menopausa seria cardioprotetor.
WHI mostrou menores taxas de DCV em mulheres que iniciaram
TRH at 10 anos da menopausa ou que tinham 50-59 anos no
inicio do estudo.
No brao E+P, mulheres com at 10 anos de menopausa tiveram
um HR para eventos cardiovasculares de 0,89, comparado com
1,70 naquelas com mais de 20 anos do inicio da menopausa.
No brao do CEE, aquelas com idade entre 50-59 a
tiveram HR de 0,56 comparado a HR de 1 para
as mulheres com idade mais avanada.
Menopausa
Timing hypothesis
Tromboembolismo: terapia oral leva ao aumento dos fatores
de coagulao e triglicerdeos apesar do benefcio sobre o aumento
do HDL e reduo do CT. O estudo KEEPS ir ajudar determinar
se estas mudanas contribuem para maior risco de aterosclerose
em mulheres recm-menopausadas.
Cancer
Mama: incio da TH aps 5 anos foi associado com reduo
do risco de ca de mama (RR 0,58) e comear imediatamente
no mostrou benefcios.
Menopausa
Timing hypothesis
Cancer
Endomtrio: TH com estrognios sem oposio leva a
hiperplasia endometrial e maior risco de cncer aps trs anos
de uso. E + P reduziu o risco em 76% observado em 3 a 5 anos
de uso.
Ovrio: estudos mostraram pequeno mas significante
aumento do risco de cncer ovariano epitelial em usurias
recentes de estrognios. O risco declina aps a cessao da
terapia.
Ca de clon: estudos observacionais
encontraram reduo no risco de cncer de
clon na TH com E +P.
Menopausa
Timing hypothesis
Cancer
Pulmo: houve aumento na incidncia de ca de pulmo em
mulheres em uso de E+P comparado ao placebo, ppte no
pequenas clulas. E o risco no diminuiu aps a interrupo do
tratamento.
Osso:
E2 com ou sem progesterona efetivo em prevenir perda ssea
na menopausa recente e aumentar a massa ssea na ps-
menopausa. Evidncia: A
SERMS Moduladores
Seletivos dos Receptores
de Estrognios.
Menopausa
Regimes Alternativos de Tratamento
________________________________________________________________________________________________________________________
In Bandeira F et al. Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Menopausa
Regimes Alternativos de Tratamento
No estudo KEEPS em andamento, um regime transdrmico est sendo
comparado com um regime oral para determinar se ambos tem a equivalncia
no efeito de progresso da aterosclerose.
preciso avaliar o uso de dose mais baixas de estrgenos com a mesma
eficcia.
Citalopran 30mg/dia
Venlaflaxina 75mg/dia
Fluoxetina 20mg/dia
Clonidina 0,1mg a 0,2mg/dia ou 1 patch semanal.
________________________________________________________________________________________________________________________
-Bandeira F, Graf H, Griz L, Faria M, Lazaretti-Castro M, editors.
Endocrinologia Bsica e Diabetes. 2nd Ed. Rio de Janeiro: Medbook Editora, 2009.
Concluses
A Terapia Hormonal na Menopausa deve ser usada para alvio dos
sintomas vasomotores e melhora da Qualidade de Vida, mas no para
a preveno de doenas crnicas.