Braga

A PRIMAVERA

VEM AÍ…

Aproveitem melhores tempos !

estamos hoje expostos aestamos hoje expostos a

vulcõesvulcões de

estudos explosivosestudos explosivos

que derramam as cinzasque derramam as cinzas

das das notícias erradasnotícias erradas

sobre todo o Mundo…sobre todo o Mundo…

como a conferência de como a conferência de imprensa sobre o imprensa sobre o WHIWHI::

com notícias muitíssimo com notícias muitíssimo quentes…quentes…

e…, só mais tarde… a primeira e…, só mais tarde… a primeira publicação do publicação do WHIWHI (JAMA)… (JAMA)…

Os manifestos panfletários…

Os seus manifestos panfletários não foram transmitidos em primeira mão aos responsáveis pela saúde das mulheres. Ao contrário, comunicaram-nos à Imprensa que os aceitou erróneamente como verdadeiros e os publicou em títulos de caixa alta !

Assim conseguiram gerar o pânico nas populações, e a confusão de riscos relativos com riscos absolutos!

WHI and breast cancer

Once again, it is apparent that the alarmist

reports that spread world-wide when the first results of the WHI study were published in 2002 were unjustified based on the more recent further analyses, particularly in peri- and early postmenopausal women.

Press statement of IMS. April 11, 2006.

As encíclicas…

“O que é especialmente preocupante acerca das declarações e encíclicas das prescrições é a aceitação cega da infalibilidade do WHI e do MWS”

Sturdee D and MacLennan A –(Editorial) Should epidemiology, the media and quangos determine clinical practice? Climacteric 2004;7:1-2

“Baseado no grupo de estudo do WHIWHI, a implementação dos resultadosimplementação dos resultadospara a para a clínica tem pouca base clínica tem pouca base científica, se é que tem alguma…científica, se é que tem alguma…””

Adam Ostrzenski and Katarzyna M Ostrzenska. Am J Obst Gynecol 2005;193:1599-604

The women enrolled in WHI and HERS initiated EPT more than a decade after menopause on average, and the majority of events that produced this pattern occurred in older women.

March 2007 position statement of The North American Menopause Society.Menopause 2007;14(2):1-17

Data from large studies such as the WHI and HERS should not be extrapolated to symptomatic postmenopausal women younger than 50 years of age who initiate HT at that time as these women were notstudied in those trials


It is not possible to extrapolate conclusions from the study of one compound, dose, and route of administration directly to another.


The WHI study was not designed, and therefore was not powered, to investigate the consequences of hormone therapy (HT) in women below 60 years of age.

Press statement of IMS. February 13, 2006.

e ….

os investigadores do WHI

não sabem interpretar os seus resultados…não sabem interpretar os seus resultados…

a pesar de os apresentarem

como a verdade…a verdade…

“O Estudo da Saúde das Enfermeiras (NHS) e outros semelhantes podem estar correctos e o WHI estar equivocado, ou vice-versa”

Rossouw J, 2003

”Pode suceder também que cada um deles esteja equivocado.

Talvez o estrogénio das pastilhas não seja a molécula em que nos devamos concentrar”

Rossouw J, 2003

“ Se os dois estudos estiverem certos então pode ter sucedido que as mulheres estudadas em ambos fossem diferentes nalgum aspecto que os investigadores não decifraram”.

Rossouw J, 2003

WHIWHI(Women´s Health Initiative)(Women´s Health Initiative)

O que é que mudou?O que é que mudou?porpor

Manuel Neves-e-CastroManuel Neves-e-CastroXII Jornadas Minhotas de GinecologiaXII Jornadas Minhotas de Ginecologia

Março 2007Março 2007

e-mail: [email protected]

NADA !NADA !

NADA!NADA!

e por quê?...

porque só agora é que a comunidade científica percebeu

o que é o WHIe

o que não é o WHI…

desde há 4 anos…a SPM soube e sabe ler o a SPM soube e sabe ler o WHI WHI !!

e por isso se pode verificar que sempre estivemos na vanguarda da leitura correcta (que agora se confirma), nos concensos e artigos publicados !

http://www.spmenopausa.pt

http://www.spmenopausa.pt/

O que é que o WHI é ?e

O que é que o WHI não é ?

O O WHIWHI não foi desenhadonão foi desenhado para para estudar o efeito da THMestudar o efeito da THM

• em mulheres menopáusicas sintomáticas

• durante os primeiros 10 anos após a menopausa

WHIWHI

• O WHI foi um estudo desenhado apenas para se verificar se a THM tinha efeitos protectores das doenças cardiovasculares:

- em mulheres sem os sintomas frequentes da pós-menopausa (afrontamentos, suores nocturnos, etc)

- com mais de 10 anos após a menopausa (a média de idades foi de 63 anos)

- submetidas a uma única terapêutica hormonal contínua (0,625mg de estrogéneos equinos conjugados e 2,5 mg de acetato de medroxiprogesterona) que não era ajustada em função da idade (até 80 anos!...) nem dos seus efeitos secundários !

Por que motivo se fez o estudo Por que motivo se fez o estudo WHIWHI??

Para determinar o efeito a longo prazo dos tratamentos hormonais na:

prevenção dedoenças cardíacas e

fracturas do colo do fémur, e

possíveis aumentos de risco para cancro da mama e

cancro do cólon.

Mensagem do Presidente do Estudo WHIMensagem do Presidente do Estudo WHIwww.hormone.org

Press Statement IMSIMS

The The WHI WHI study study was not designedwas not designed, and

therefore was not powered, to investigate theto investigate the

consequences of hormone therapy (HT) in consequences of hormone therapy (HT) in

women below 60 years of agewomen below 60 years of age. Therefore,

any attempt to present the results of the study any attempt to present the results of the study

as indicating that HT may inflict damage to theas indicating that HT may inflict damage to the

heart in generalheart in general – – a message that was accepteda message that was accepted

by many medical societies and regulatory Authoritiesby many medical societies and regulatory Authorities

is simply wrong and must be amendedis simply wrong and must be amended.

WHIWHI

Que vantagens trouxe?

Uma Uma chamada de atençãochamada de atenção para para em termos gerais de THMem termos gerais de THM

- se estudarem doses mais baixas do E e P

- se estudar o benefício/risco

a) das vias de administração

b) das moléculas de P e E usadas

c) da duração das THM

- se determinar qual a idade pós-menopáusica segura para se iniciar uma THM

A forma como se interpretaram A forma como se interpretaram os resultados em termos de:os resultados em termos de:

- Risco Absoluto (RA ou AR)

- Risco Relativo (RR ou RR)

- Risco Atribuível (RAt ou AtR)

- Número Necessário para Causar Dano (NNCD ou NNH)

A MENOPAUSA FOI ATACADA A MENOPAUSA FOI ATACADA

POR UMPOR UM

TERRORISTA HORMONALTERRORISTA HORMONAL !

O Terrorista O Terrorista HormonalHormonal


Quero tomarQuero tomarTH !TH !


Quero tomarQuero tomarTH !TH !

Mas Mas alguns alguns médicosmédicos dizem que dizem que NÃO NÃO !...!...

HomemHomem

womanwoman

HomemHomem

MulherMulher

WHIWHI

O que se disse e ...

O que não se disse...

Quais foram as conclusões do Quais foram as conclusões do WHIWHI no que se refere a: no que se refere a:

cancro da mama?

doenças cardiovasculares?

Efeito sobre o risco de cancro da mama

WHIWHI aumento do riscoaumento do risco: RR 1.26 (CI 1.00-1.59); 26% aumento de risco AR 0.38% vs 0.30% (ie, 38 vs 30 casos anualmente por

10.000 mulheres)

NÃO SIGNIFICATIVONÃO SIGNIFICATIVO !HERS aumento do risco:

RR 1.27 (CI 0.84-1.94); 27% aumento de risco AR 0.59% vs 0.47% (ie, 59 vs 47 casos anualmente por 10.000 mulheres)

NÃO SIGNIFICATIVO !

WHIWHI(JAMA 2002;288:321-331)

Results:Results:“the difference reaches “almost nominal statistical significance” (i.e. not statistically different!)

Discussion:Discussion:“the substantial risks for CVD and breast cancer” (?!...)

MNC/04

Se os resultados do Se os resultados do WHIWHI se se calcularem, calcularem, porpor anoano, como, como

NNT NNHDCV 1428ACV 1250TEV 588Cancro da mamaCancro da mama 12501250Cancro de Cólon 1667Fracturas osteoporóticas 227(total)

Neves-e-Castro M. Menopause in crisis post-Women’s Health Initiative? A view based on personal clinical experience. Human Reproduction 2003;18:2512-8

Women’s Health Initiative (WHI)(WHI) per 10001000 pts over 5 years5 years

CHRT no HRT At Risk Event

Coronary Heart Disease 17 13 +4

Stroke 13 9 +4

Pulmonary Embolism 8 4 +4

Invasive Breast CancerInvasive Breast Cancer 1717 13 13 +4+4

Colorectal Cancer 5 8 -3

Hip Fracture 4 6 -2

Global Index 82 72

Then, why all this why all this noisenoise?...

Mainly because the conclusions ofthe conclusions of recent trials were severely recent trials were severely misinterpretedmisinterpreted by the by the medicalmedical professionalsprofessionals, the media and by the women, themselves

MNC/05

Are Are WomenWomen in a in a crisiscrisis??

YES !YES !

Why?

Because

We have a tendency to accept as valid the headlines that circulate in the media without having critically read the full papers to which they refer

We are not able to explain to our patients the meaning of those risks and how small they are compared to other risks to which they are expose

MNC/05

To begin with, and

in the light of the present evidence,

doctors and women should be reassured that the suggested HT’s for the relief of symptoms in the menopause

are safe and very effectiveare safe and very effective !

Medicina Baseada na Evidência

e/ou

Evidência Baseada na MedicinaEvidência Baseada na Medicina

?

Manuel Neves-e-Castro

Medicina Baseada na Evidência

e/ou

Medicina Baseada na InteligênciaMedicina Baseada na Inteligência

?

Lucas Viana Machado

Evidence informed practiceEvidence informed practice(A Clínica Informada pela Evidência)(A Clínica Informada pela Evidência)

• It is clearly time to It is clearly time to changechange “evidence based“evidence based medicine”medicine” to to ““evidence informed practiceevidence informed practice”.”.

• I suggest I suggest the era of evidence informedthe era of evidence informed rather rather than evidence based medicine than evidence based medicine has arrivedhas arrived

Glasziou P. Centre for Evidence-Based MedicineCentre for Evidence-Based Medicine. University of Oxford OX3 7LF. BMJ 2005;330:92

Evidence-Based Medicine implies that recommendations should be limited to thewomen for whom the studies are relevant.


The practice of medicine is ultimately based on the interpretation at any one time of the entire body of evidence currently available.


e …

eis um exemplo de um

CONTRA-SENSO…

Effects of conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy. JAMA, 2004;291:1701-1712

StrokeStroke

“In women 50-59 years not taking HT, ischemic stroke is expected to occur in 3 out of 1000 women during 5 years.

Five years use of HT would yieldFive years use of HT would yield 11 additional case of stroke/additional case of stroke/ 1000 women1000 women”

EMAS Statement; 2004.

““Estamos afogados Estamos afogados em em informaçãoinformação

mas famintos de mas famintos de sabedoriasabedoria”

John Naisbilt

O que é que parece ter mudado na O que é que parece ter mudado na interpretação dos resultados de interpretação dos resultados de

WHIWHI??

No que se refere a:

–Cancro da mama?

–Doenças cardiovasculares?

O cérebro é como um O cérebro é como um paraquedas…paraquedas…

ambos funcionam melhor ambos funcionam melhor quando se abrem !quando se abrem !

Lord Thomas Dewar

A Mortalidade Cardiovascular

é o dobro daé o dobro da Mortalidade por Cancro da Mama

BENEFITS OF HORMONE THERAPY

In women less than 60 years old, recently menopausal and without prevalent cardiovascular disease, the initiation of HT does not cause early harm and may reduce cardiovascular morbidity and mortality.

Continuation of HT beyond the age of 60 should

be decided as a part of the overall risk–benefit analysis.

IMS press statement, February 2007

Clinica Cardiovascular da Mulher

• 13% das mulheres com idade superior a 45 anos teve uma síndrome coronária aguda

• 55% da mortalidade na mulher é devido a doença cardiovascular (cardíaca, cerebral)

• As mulheres, representam 62% da mortalidade por Insuficiência Cardíaca

• A doença coronária na mulher pré-menopausa é menos prevalente, mantendo-se assim durante 10 a 15 anos até aos 70 anos, altura em que iguala o homem

Hormone replacement therapy and risk for coronary heart disease

Long-term HRT use is not associatedwith increased risk for CHD in the CORA-study.This research even supports the notion that HRT canpositively affect a number of risk factors like centraladiposity, insulin resistance and blood pressure.HRT may even protect from CHD, but adverse lifestylehabits like heavy smoking and a not sufficiently healthynutrition can offset the beneficial effects of HRT.

Windler E et al. Maturitas 2007 in press.

Hormones and the HeartHormones and the Heart

1 in 31 in 3 women will die from coronary heart disease (CHD) in the USA.

1 in 251 in 25 women will die from breast cancer

Fitzpatrick LA. JCEM 2003;88(12):5609-10

Causes of Death Among Women*

*Percentage of total deaths in 1999 among women aged 65 years and older.Anderson RN. Natl Vital Stat Rep. 2001;49:1-13.

Heart Disease

Other Cancers

Other

Diabetes

Chronic LowerRespiratory

Disease

Cerebrovascular Disease

Breast Cancer 34%

10%10%

6%6%

3%3%

15%15%

28%

4%4%

NNHNNH / Year/ Year((NNumber umber NNeeded to eeded to HHarm)arm)

(the reciprocal of the AtR, the atributable risk)(the reciprocal of the AtR, the atributable risk)

Coronary Heart DiseaseCoronary Heart DiseaseWHI WHI (RR 1.29) 1428HERS (RR 0.99) 5000

Breast CancerBreast CancerWHIWHI (RR 1.26) 1250HERS (RR 1.27) 833

MNC

““Not everything that can Not everything that can be counted be counted countscounts;;

and not everything that and not everything that countscounts can be counted” can be counted”

Albert EinsteinAlbert Einstein

“HRT is associated with a 35% reduction in mortality for women who suffered myocardial infarction”.

Shlipack MG, Angeja B, Go AS, et al Circulation 2001;104:2300-2304

Doenças cardiovasculares (WHI )

O que estava oculto

- com terapêutica combinada (E+P)?

- com terapêutica só com E?

Younger WomenYounger Women May Receive May Receive Heart ProtectionHeart Protection From From Estrogen TherapyEstrogen Therapy

In women ages 50-59 who had undergone a hysterectomy, a significant protective effect of estrogen treatment, when both primary (heart attacks and heart attack death) and secondary (coronary artery bypass surgery, angioplasty, confirmed angina pectoris) cardiac endpoints were considered.

Dr. S. Mitchell Harman, director and president of Phoenix-based Kronos Longevity Research Institute (KLRI) in Archives of Internal Medicine 2006;106:357-363

An An updateupdate of the of the WHIWHI Study ! Study !

WHI investigatorsWHI investigators reported (Feb 2006) a statistically significant (34%) lower risk for the combined endpoint of myocardial infarction (heart attack), coronary death, coronary revascularization and confirmed angina among women who were between the ages of 50 and 59 at the start of the study (RR 0.66; 95% CI 0.45-0.96).

Hsia J et al.Arch Intern Med 2006;166:357-363

Hsia J, Langer RD, Manson J et al. Conjugated equine estrogens and coronary heart disease. Arch Int Med 2006;166:357-65

Press Statement IMSIMS

The estrogen plus progestogen arm of the WHI

and the estrogen-alone arm actually showed that

HT does not HT does not

increase the risk of coronary heart disease in increase the risk of coronary heart disease in

the peri- and early menopause, the peri- and early menopause,

and may even carry beneficial effectsand may even carry beneficial effects.

Feb 2006

HormonasHormonasee

Cancro da MamaCancro da Mama

Menopausal women and theirand their doctorsdoctors are scared about the side

effects of HRT

mainly about breast cancermainly about breast cancerMNC/05

Cancro da mama (Cancro da mama (WHIWHI))

o que concluiu o WHI ?

o que estava oculto no WHI ?

WHI ...WHI ...

A VERDADE !A VERDADE !

O fluxo da Verdade O fluxo da Verdade

corre através dos seus corre através dos seus

canais de enganos ...canais de enganos ...

Rabindarath Tagore,1911

POTENTIAL SERIOUS ADVERSE EFFECTS OF HORMONE THERAPY

Women should be reassured that the possible risk of breast cancer associated with HT is small (less than 0.1% per annum).


POTENTIAL SERIOUS ADVERSE EFFECTS OF HORMONE THERAPY

Data from the WHI and Nurses’ Health Study suggest that long-term estrogen-only administration for 7 and 15 years, respectively, does not increase the risk of breast cancer in American women.

Recent European observational studies suggest that risk may increase after 5 years.


Breast Cancer Risk in Postmenopausal Women Using Estrogen-Only Therapy

Our nationwide study shows that the use of oral or transdermal estradiol for less than 5 years does not increase the risk of breast cancer, but such a risk appears with increasing duration of use in 2 to 3 extra cases of breast cancer per 1.000 women in 10 years of follow-up.

Lyytinen H et al. Obstetrics & Gynecology 2006;108(6):1354-1360

The EMAS 2006/2007 update on clinical recommendations on

postmenopausal hormone therapy

To conclude from these new publications theysuggest the absence of increased risk of breast cancer using estrogen only therapy after short periods of time (less than 10 year). An increased risk may exist thereafter, however.

Gompel A et al. Maturitas 2007;56(2);227-9

Estrogen and progestogen use in peri- and postmenopausal

women

In absolute terms, this increased risk was rare in the WHI, being 4 to 6 additional invasive cancers per 10,000 women per year who used EPT for 5 or more years.


Cancro da MamaWHI

C.I. (1.00 – 1.59)

ARC 0.30% / 10.000 / yrART 0.38% / 10.000 / yrRR 1.26 (26%)

Attributable Risk = 8/10.000 / yr = 1/ 1.250 / yr

NNHNNH = = 1.250 / yr1.250 / yr

MNC/04

Cancro da MamaHERS

C.I.(0,84-1.94)

ARC = 0,59% / 10.000 / yrART = 0,47% / 10.000 / yr

RR = 1.27 (27%)

Attributable Risk = 12 / 10.000 / yr = 1 / 833 / yr

NNHNNH = = 833 / yr833 / yr

MNC/04

Breast cancer and the use of HRTBreast cancer and the use of HRT

Considering 10.000 women on the combination HRT then for each year there would be:

Seven additional cases of heart attacks Eight cases of stroke, Eight cases of pulmonary embolus, EightEight cases cases of invasive breast cancer, Six fewer cases of hip fractures

Baum M. The Breast 2005;14-178-80

O Cancro da Mama

O risco de cancro da mama com os E+P combinados contínuos é mínimo.

É necessário tratar 1250 mulheres (NNH) durante 1 ano até que se diagnostique 1 cancro da mama (o que é equivalente ao risco relativo de 23%!)

Cancro da Mama

O Risco Relativo aumentado de Cancro da Mama com os estrogénios mais progestagénios durante 5, 6 anos é comparável ao aumento de risco de Cancro da Mama para uma mulher que consome uma bebida alcoólica por dia ou que tem um Indice de Massa Corporal de 24, em comparação com 22.

It must be emphasized that we are talking about an increased incidence ofincreased incidence of the diseasethe disease, , which does not which does not automatically translate into an increase automatically translate into an increase in deaths from the disease. in deaths from the disease.

Baum M. The Breast 2005;14:178-80

Almost 2/3 of women now diagnosed with breast cancer are likely to survive at least 20

years• Cancer Research UK researchers estimate that 64%

of women newly diagnosed with breast cancer in England and Wales will live for at least 20 years - compared with 44% in the early 1990s.

• More than 7 out of 10 women (72%) are nowMore than 7 out of 10 women (72%) are now predictedpredicted to survive for at least 10 yearsto survive for at least 10 years, compared with 54% diagnosed in the early 1990s.

• Survival in women aged 50 to 69 - the age group in which breast cancer is most commonly diagnosed - was even better, with 80% predicted to live for at 80% predicted to live for at least 10 yearsleast 10 years while while 72% survived to at least 20 72% survived to at least 20 years.years.Prof. Michel Coleman, London School of Hygiene and Tropical Medicine told reports; Oct.10, 2005.

Source: Eurocare study

53.6 40.5 49.2 51.0 84.3 76.1 65.4 EUROPE

56.7 43.5 55.0 56.3 91.0 80.0 67.0 Switzerland

57.6 42.5 52.2 54.4 90.6 82.6 67.4 Sweden

57.1 43.9 55.0 55.8 89.8 78.0 65.5 Spain

47.0 31.2 34.8 38.8 70.0 67.4 48.8 Slovenia

N/A N/A 49.0 43.5 68.9 71.9 71.9 44.0 44.0 PortugalPortugal

40.5 25.2 26.3 28.7 57.9 63.1 38.6 Poland

54.9 40.0 51.4 53.6 88.4 77.2 62.1 Norway

55.7 42.7 51.9 54.0 87.7 78.2 68.4 Netherlands

N/A N/A 35.9 53.3 65.0 74.8 39.4 Malta

55.6 41.2 51.2 52.1 82.5 80.6 63.9 Italy

N/A N/A 45.9 55.2 90.9 79.6 76.2 Iceland

55.6 44.1 50.5 54.5 89.9 75.4 75.9 Germany

57.9 44.5 55.9 58.7 85.3 81.3 75.2 France

55.8 41.4 54.0 52.7 84.0 81.4 66.5 Finland

51.2 33.5 43.2 47.6 88.0 74.9 41.5 Denmark

46.0 32.3 38.1 36.4 78.1 64.0 50.1 Czech Rep.

57.9 47.5 N/A 58.4 88.2 75.4 83.6 Austria

47.3 34.7 40.1 36.5 79.1 69.5 48.8 WALES

49.5 35.6 45.3 47.2 90.1 72.3 53.6 SCOTLAND

50.8 37.1 45.7 46.2 85.6 73.6 53.8 ENGLAND

All (F) All (M) Colon (M) Colon (F) Skin* Breast Prostate

% of patients alive five years after diagnosis

European Cancer Survival

Extended use of estrogen for

10 years increases risks by 0,5%, and by 15 years increases risks by 0,9%

but..

upon cessationupon cessation of HRT of HRT, , the the relative risk quickly returns to 1.0 !relative risk quickly returns to 1.0 !

Coombs N J, Taylor R, Wilcken N. and Boyages J. BMJ 2005;331:347-

349

Breast CancerBreast Cancer

• The diagnosisdiagnosis of a breast cancer after the initiation of a HRT (with a duration of less than 5 years) is only a proof of its is only a proof of its growth stimulatorygrowth stimulatory effecteffect (not of its carcinogenic effect)

• Therefore, the Therefore, the reversal of the risk to 1 afterreversal of the risk to 1 after thethe cessation of HRTcessation of HRT confirms again only its growth confirms again only its growth promoting effect and promoting effect and denies a carcinogenic denies a carcinogenic effect. effect.

Dietel M., Lewis MA. and Shapiro S. Human Reproduction 2005;20:2052-60

Breast CancerBreast Cancer

• The doubling timedoubling time of an initial cancer of an initial cancer cellcell, up to the diagnosis of a resultant 1cm tumor, is most likely greater than 10 years.greater than 10 years.

• This is why many many dormant cancer cellsdormant cancer cells may exist in a “normal” breast !may exist in a “normal” breast !

MNC/05

Occult Breast CancerOccult Breast Cancer

Clinically occultClinically occult in situ BC’s are frequentfrequent in young and middle-aged young and middle-aged women.women.

Nielsen M et al-Br J Cancer 1987;56:814-9

Occult Breast CancerOccult Breast Cancer

Breast Breast malignancy was malignancy was found infound in 22 women 22 women (20%)(20%)

Nielsen M et al-Br J Cancer 1987;56:814-9

Thus…

• Mammographies Mammographies give more falsegive more false negativenegative than false positive resultsthan false positive results !

• A “normal” mammography does not A “normal” mammography does not exclude the presence of cancer cellsexclude the presence of cancer cells that may “explode” a few months later…

MNC/05

Estrogen replacement therapy in Estrogen replacement therapy in patients with early breast cancerpatients with early breast cancer

The mortalitymortality rates from breast cancer for the ERT usersERT users was was 4.28%4.28% compared with compared with 22.3% in the nonusers22.3% in the nonusers.

Natrajan PK and Gambrell RD. Am J Obstet Gynecol 2002;187:289-95

HRT in Breast Cancer SurvivorsHRT in Breast Cancer Survivors:results:Matched Analysis

174 breast cancer cases taking estrogen

matched 4:1 controls with cancer not taking Estrogen.

Cases

(ERT/HRT)

Controls

(no ERT/HRT)recurrence 17/1000 30/1000

Br cancer

deaths

5/1000 16/1000

Total deaths 16/1000 30/1000

O’Meara et al, JNCI 2001

“RecurrentRecurrent breast cancer was breast cancer was found in found in 9% of HRT9% of HRT usersusers and and 15% of nonuser15% of nonuser”.”.

O’Meara ES et al.JNCI 2001;93:754-761

Mortality following development ofMortality following development of breast cancerbreast cancer while usingwhile using

oestrogen or oestrogen plus progestin:

W Chen, DB Petitti and AM Geiger.British Journal of Cancer 2005;93:392–398

This study explored survival after exposure to oestrogen or oestrogen plus progestin at or in the year prior to at or in the year prior to breast cancer diagnosisbreast cancer diagnosis

oestrogen plus progestin users oestrogen plus progestin users had had lower all-cause mortality lower all-cause mortality and breast cancer mortalityand breast cancer mortality

Chen W, Petitti DB and Geiger AM. British Journal of Cancer 2005; 93:392-398

Breast cancer survival after hormone exposure

Overall survival after hormone exposure

Breast Cancer Estrogens and Progestagens

• No significant increases in risk was observed in users of estrogens used alone (RR 1.1; 95% CI=0.8-1.6) compared with non exposed women but it was greater in combination with oral progestagens (RR 1.3; CI 1.1-1.5)

• The risk was significantly greater (p <0.001)with HRT containing synthetic progestagens (RR 1.69; CI 1.5-1.9) than with HRT containing micronized progesterone (RR 1.0; CI 0.83-1.22)

Fournier A et al. Int J Cancer 2005;114:448-454 Fournier A et al. Breast Cancer Res Treat.2007,Feb 27 in press

Reduced hormone therapy usemight be cause of steep decline in

breast cancer cases

A report presented December 14, 2006, at the29th San Antonio Breast Cancer Symposium inHouston shows a 7% drop in US breast cancerrates. The analysis suggests a link between thedecline in breast cancer and hormone therapy(HT) use.

December 2006 position statement of The North American Menopause Society

Recent declines in hormone therapy utilization and breast cancer incidence: clinical and population-based evidence

Clarke CA et all. Journal of Clinical Oncology 2006;24(33):e49-50

http://www.jco.org/content/vol24/issue33/images/large/zlj0330653400001.jpeg


breast cancer cases

Greatest decrease in breast cancer was in the number of ER+/PR+ breast cancers. There was little change in other breast cancers. The greatest decrease also occurred in the women aged 50 to 69, those most likely to be using HT.

Gass M. F.NAMS special issue released December 20,2006


breast cancer cases

Their data most likely reflect existing cancers just below the detection limit in 2002 that slowed or stopped their growing.



breast cancer cases

Another finding that is consistent with an effect

on preexisting tumors is the fact that not a single

study thus far has reported a risk increase for

noninvasive disease. If HT were initiating

(causing) new tumor formation, one would

expect to see an increase in in situ disease.


Analisemos então os

RiscosRiscos

Há riscos?

É indispensável que seja dada informação sobre as diferenças entre riscos relativos e riscos absolutos uma vez que os primeiros são a principal causa de desinformação e alarmismo, sendo os favoritos dos media…

MNC/05

E então ...

Como saber

Qual é a verdade

e

Qual não é ?

Explain the risks in a way that is understandable....

Compare the risks of HRT with other better known risks....

MNC/05

Increase incidence

Relative risk

Risk factor

+ 20%1 : 1.2Physical activity – activate : inactive

+ 60%1 : 1.6Serum lipids – normal : raised

+ 30%1 : 1.3Alcohol consumption-none:≥20 g daily

+ 30%1 : 1.3Hormone replacement-never:5 or more yrs

+ 10%1 : 1.1Oral contraceptives – never user:ever user

+ 40%1 : 1.4Age at first birth – 20 yrs : 35 yrs

+ 30%1 : 1.3Parity – multiparous : nulliparous

+ 30%1 : 1.3Age at menarche – 14 yrs: 11 yrs

+ 100%1 : 2.0Age at menopause - 42yrs : 52 yrs

+ 150%1 : 2.5Body weight-normal weight : obesity

BREAST CANCER

R. Santen, 2004

Exemplos de Risco AbsolutoRisco Absoluto,, Risco RelativoRisco Relativo, , Risco AtribuívelRisco Atribuível• Se comprar um número da lotaria, terá 1

oportunidade em um milhão de ganhar. ((risco absolutorisco absoluto).).

• Se comprar cinco números da lotaria, a oportunidade será cinco vezes maior, ou simplesmente 5 em um milhão.

• As oportunidades de ganhar aumentam 5 vezes, ((risco relativorisco relativo).).

• A diferença entre os dois riscos é de 4 em um milhão ((risco atribuívelrisco atribuível))

Risco atribuível, ou de excesso(que é o mais importante para a clínica)

A diferença entre o risco de base, subjacente, e o risco após receber TH é denominada

risco atribuível, ou de excesso.

Não confunda…

Risco Relativo com

Risco Absoluto !

Intervalo de Confiança (C.I.)

Um C.I. de 95% significa que há 95% de probabilidades de que os “valores verdadeiros” da população estejam entre os dois limites.

Se o C.I. cruza a linha de “diferença nula” ao ponto de que o benefício se converta num risco (i.e.1), pode concluir-se que os resultados não são estatísticamente significativos.

Manson J et al. Menopause2006;13(1):139.147

Linha de diferença nula

Linha de diferença nulaLinha de diferença nulaLinha de diferença nula

Efeito sobre o risco de cancro da mama

WHIWHI aumento do riscoaumento do risco: RR 1.26 (CI 1.00-1.59); 26% aumento de risco AR 0.38% vs 0.30% (ie, 38 vs 30 casos anualmente por

10.000 mulheres)

NÃO SIGNIFICATIVONÃO SIGNIFICATIVO !HERS aumento do risco:

RR 1.27 (CI 0.84-1.94); 27% aumento de risco AR 0.59% vs 0.47% (ie, 59 vs 47 casos anualmente por 10.000 mulheres)

NÃO SIGNIFICATIVO !

Ao ler estudos Epidemiológicos

POR FAVOR !Não leiam só os títulos…

Não leiam só os resumos…

Há que ler os artigos completos!!

Devemos ser críticos!

Devemos construir os nossos próprios conceitos!

MNC

Assessment of the understanding of the risks and

benefits of hormone replacement therapy (HRT) in

primary care physicians

Williams RS, Christie D and Sistrom C. Am J. Obstet Gynecol 2005;193:551-6

Respondents that overestimate the increase or decrease in risk were making the error of confusing relative risk with absolute risk difference.

There is a great need for physician education about the attributable education about the attributable risksrisks and benefits of HRTbenefits of HRT

MNC/05

Strategies to help patients understand risks

Paling J. BMJ 2003;327:745-8

Risks of women medicated with E+P (5.2 years)

women

Risks of women medicated with E only (6.8 years)

women

Risks of Breast Cancer according to different factors

Podem reduzir-se

os efeitos secundários ?

There are no really “safe” There are no really “safe” biological active drugs...biological active drugs...

There are only “safe” physicians !There are only “safe” physicians !

Kaminetzy HA 1993

“Aquele que aprende mas não pensa está perdido.

O que pensa mas não aprende é perigoso…

Confucius

mas…se aprendermos e

pensarmos…nem estaremos perdidosnem seremos perigosos

para as nossas doentes pós-menopáusicas

Wenger NK. Am J Geriatr Cardiol 2000;9:204-9

A práctica Clínica…

Conhecer

a doença que uma mulher tema doença que uma mulher tem

é tão importante comoé tão importante como

conhecer conhecer

a mulher que tem a doençaa mulher que tem a doença

William Osler

Os médicos devem dar a informação

a mulher deve acatar a sua decisão

Os médicos devem dar a informação

a mulher deve fazer o que decidiu

Qual é o melhor tratamento ?• As necessidades e preferências da mulher são

decisivas baseadas no conselho do médico• Não deve esquecer-se que apesar de haver

muitos tratamentos hormonaistratamentos hormonais disponíveis não são no entanto indispensáveisnão são no entanto indispensáveis

• Os médicos têm o dever de dar a sua melhor informação independente às suas doentes de modo a que elas possam fazer as escolhas acertadas e assim aderir aos tratamentos

• A mulher é quem toma a decisão se o médico não vir contraindicações

• Portanto o melhor tratamento é aquele que a o melhor tratamento é aquele que a mulher escolhermulher escolher

MNC

I personally believe that for the healthy early post menopausal woman the long term HT’s, other than relieving vasomotor symptoms, may play an important role in improving QoL and in the prevention of CVD, osteoporosis and Alzheimer, under surveillance.

Systemic (parenteral) estrogensSystemic (parenteral) estrogens, added when needed to vaginal progesterone or vaginal progesterone or progestagen loadedprogestagen loaded IUD’sIUD’s, may be very beneficial, largely overpassing minimal risks.

MNC/05

The conclusions of the The conclusions of the WHIWHI trial suggest trial suggest that the “safe “ woman (NNH between 600-

1000 women) to initiate HT is

- between between 50-59 years50-59 years of age of age- with vasomotor symptomswith vasomotor symptoms- less than 10 years after the menopauseless than 10 years after the menopause- being treated with statinsbeing treated with statins- with a with a good lipidgood lipid profile and profile and- with a with a Body Mass IndexBody Mass Index >25 >25

Neves-e-Castro M. Human Reproduction 2003;18:2512-2518

E...E...

que tal com os que tal com os produtos produtos

“naturais” ?...“naturais” ?...

Evitar que uma Mulher Evitar que uma Mulher beneficie de umabeneficie de uma

correcta terapêutica hormonal na pós-menopausa

pelo receio de raros efeitos pelo receio de raros efeitos secundários secundários

não me parece ser uma não me parece ser uma Medicina satisfatória…Medicina satisfatória…

M.Neves-e-Castro, 2000

O que é que temos aprendido sobre a

Menopausa ?

“Each time we learn something new, the astonishment comes from the recognition that we were wrong before.

In truth, whenever we discover a new fact, it involves the elimination of old ones.

WE ARE ALWAYS, as it turns out, fundamentally IN ERROR.”

Lewis Thomas English Biologist (1913-1993)

As convicções são inimigos mais perigosos da verdade do que as mentiras

Friedrich Wilhelm Nietzsche

What has been learned from the major observational studies and

clinical trials?

the first lessonsystematically administered progestagens may in part suppress some of the beneficial effects of estrogens and may also slightly increase the risk of breast cancer after treatments with duration greater than five years.

MNC/05


clinical trials?

the second lesson

estrogens, when given alone to histerectomized women, did not appear to minimally affect the risk for breast cancer when compared with controls

MNC/05


clinical trials?

the third lessonMetabolic effects of estrogens and progestagens, as a whole, can differ depending on the route of administration, i.e. oral vs. parentheral, and on the combination of both, in a sequential regimen or in continuous combined administration.

MNC/05


clinical trials?

the fourth lesson

Hormonal treatments are the first choice for vasomotor symptom relief as long as they are needed (on and off assessment). They should not be used for the secondary prevention of CVD, when atheroma plaques are already present.

MNC/05


clinical trials?

the fourth lesson (cont.)Conversely, they may protect from CVD if started early during the transition into the post menopause.

Hormonal treatments are preventive of osteopenia and osteoporosis at any stage in life

MNC/05

The take-home message is: (1)

Prescribe postmenopausal hormonal treatmentswhen clinically indicated,if not contraindicated!

MNC/02


The prescription of long-term hormonal treatments must depend always on a benefit/riskbenefit/risk analysis in comparison with other in comparison with other non-hormonalnon-hormonal medications and medications and strategiesstrategies..

MNC/02


No answersNo answers from ongoing clinical from ongoing clinical trials trials are indispensableare indispensable to practice to practice today a good Medicine !today a good Medicine !

MNC/02

BENEFITS OF HORMONE THERAPY

• HT remains the most effective therapy for vasomotor and estrogen-deficient urogenital symptoms.

• Quality of life and sexuality are key factors to be considered in the management of the aging individual.

• The administration of individualized HT (including androgenic preparations when appropriate) improves both sexuality and overall quality of life.


Recommendations on postmenopausal hormone therapy

• There are no reasons to place mandatory limitations on the length of treatment.

• Whether or not to continue therapy should be decided at the discretion of the well-informed hormone user and her health professional, dependent upon the specific goals and an objective estimation of benefits and an objective estimation of benefits and risks.


IMS reaction to recent breast cancer data

The use of hormones in early menopause and up to age 60 years has a very minor potential for harm, but may carry substantial benefits. Women should decide annually if they wish to continuewith treatment after consultation with their caregivers.

Press statement of IMS.December 19, 2006.

The new American way …

or …

a 180º rotation ! …MNC/05

NAMS position statement on estrogen and progestagen use in peri-and postmenopausal women

No single trial should be used to setNo single trial should be used to set publicpublic health policyhealth policy. The practice of medicine must ultimately be based on the interpretation of the entire body of evidence currently available, given that there will never be adequate clinical trials to cover all populations, eventualities, and regimens.

NAMS position statement on estrogen and progestagen use in peri-and postmenopausal women

Place no limit on ET/EPT treatmentPlace no limit on ET/EPT treatment durationduration, provided it is consistent with treatment goals; if monitored regularly, no no stipulation is made regarding when to stipulation is made regarding when to reduce or stop therapyreduce or stop therapy

Key Points: NAMS March 2007Position Statement on Hormone Therapy

The North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 2007; In press.

Copyright 2007

HT and Vasomotor Symptoms

Treatment of moderate to severe Treatment of moderate to severe vasomotor symptoms (ie, hot flashes, vasomotor symptoms (ie, hot flashes, night sweats) remains primary night sweats) remains primary indication for systemic ET/EPT indication for systemic ET/EPT

With few exceptions, every systemic ET/EPT product is government approved for this indication

Copyright 2007NAMS position statement. Menopause 2007.

EPT and Breast Cancer Risk

Breast cancer risk increases with EPT use beyond 5 years

Increased absolute risk in Increased absolute risk in WHIWHI is viewed as is viewed as rarerare (4-6 additional (4-6 additional invasive cancers/10,000 women/yr invasive cancers/10,000 women/yr when use EPT for ≥5 yrs)when use EPT for ≥5 yrs)

(cont’d)


ET and Breast Cancer Risk (cont’d)

Women in WHI’s ET arm had 8 fewer cases of invasive breast cancer/10,000 women/yr of ET use

Available evidence suggests ET for <5 yr has little breast cancer risk impact

Limited observational data suggest ET for >15 yr may increase risk


3rd International Symposium of the

Portuguese Menopause Society In Celebration of the World Menopause Day

The Transatlantic Controversies - The State of the Art October 23, 2004 Fundação Engº António Almeida Oporto – Portugal

A equipeA equipe U.S.A.

1 2 3 4

1. R. Chlebowski 2.J.Rossow 3. R. Lobo 4. Th.Clarkson

A equipeequipe Europeia

1. D.Barlow 2. H. Kuhl 4.P.Kenemans 4. A.Pines

1 2 3 4

As estrelasestrelas da Menopausa !

1 23 4

5 6 7 8 9 10 11 12

13

14 15

1.D.Barlow, 2.H.Kuhl, 3.P.Kenemans, 4.A.Pines, 5 F.Al-Azzawi, 6.J.Rossouw, 7.J.Stevenson, 8.R.Chlebowski, 9.S.Palacios, 10.Th.Clarkson, 11.M.Sousa, 12.M.Neves-e-Castro, 13.A.Genazzani, 14.J.Calaf, 15.R.Lobo

3rd International Symposium of the

Portuguese Menopause Society In Celebration of the World Menopause Day

The Transatla Algumas das NCLUSÕES ntic Controversies - The

State of the Art October 23, 2004 Fundação Engº António Almeida Oporto – PortugalCONCLUSÃO

KEEPS

Kronos Early Estrogen Prevention Study

estudo em curso em mulheres sintomáticas até 10 anos após a menopausa

Rexrode K and Manson J. Circulation 2007;115:820-2

ELITE

Early vs. Late Intervention Trial with Estradiol

estudo em curso

Não há melhor tratamento para os sintomas do climatério do que os tratamentos hormonais

•Se és um clínico tens que acreditar que sabes o que ajuda os teus doentes.Caso contrário não podes nem aconselhar nem receitar.

•Porém, se és um cientista tens que ter incertezas: um cientista que deixa de fazer perguntas é um mau cientista…

George Pickering;”Physician and scientist” Br.Med.J. 1964;2:1615-9

UMA MULHERUMA MULHER

no Outono da sua vidano Outono da sua vida

merece um merece um Verão de S.MartinhoVerão de S.Martinho

em vez de um triste Invernoem vez de um triste Inverno Greenblatt

ComoComoconcluir ?...concluir ?...

Este não é o fim,nem sequer o princípio do fim,

mas talvez seja

o fim do princípio ...

Winston Churchill

Esperando por mais...

IV Simpósio Internacional da Sociedade Portuguesa de Menopausa

The Improvement of The Improvement of

Health and Disease PreventionHealth and Disease Prevention

for the Mid-aged Woman: for the Mid-aged Woman:

The State of the ArtThe State of the Art

20 Outubro 200720 Outubro 2007

Lisboa . Portugal

Pestana Palace Hotel

visite o nosso website www.spmenopausa.pt em 4th International SymposiumSociedade Portuguesa de Menopausa Av. Almirante Reis nº 62 – 1º Esq. 1150-020 Lisboa - PortugalTelf: (+351) 21 3174356 – (+351) 93 6016522 Fax: (+351) 21 3156658e.mail: [email protected]

Hotel venue: Pestana Palace – Hotel e Monumento Nacional www.pestana.com

Participantes, até 31 Maio 2007:

Sócios da SPM e EMAS: € 200,00

Não - Sócios: € 250,00

Participantes, a partir de 31 Maio 2007:

Sócios da SPM e EMAS: € 250,00Não - Sócios: € 300,00

Inscrições

Para mais informação:

que vão encontrar que vão encontrar aqui !aqui !

http://www.spmenopausa.pt/

http://www.pestana.com/

IV Simpósio Internacional da Sociedade Portuguesa de

Menopausa

Mário de Sousa – President e da SPM

Lisboa . Portugal, Pestana Palace Hotel, 20 Outubro 2007

The Improvement of Health and The Improvement of Health and Disease Prevention for the Mid-Disease Prevention for the Mid-

aged Woman: aged Woman: The State of the ArtThe State of the Art

Manuel Neves-e-Castro – Symposium Chairman

Speakers (confirmados):

D. Sturdee (UK): “The hot Flush”;P.van der Weijer (NL): “Risks of HRT in the 50-59 year age group”; R. Lobo (USA): “Metabolic Syndrome after menopause and the role of hormones” Anne Gompel (FR): “Hyperinsulinemia, obesity and the risk of breast cancer”;D. Herrington (USA): “Postmenopausal heart disease prevention: Why the cardiologists have it all wrong?J.C.Gallagher (USA): “The role of rank L in postmenopausal bone loss and arthritis: Treatment options”;F. Naftolin (USA): “Molecular factors in maintenance of the pelvic floor in menopausal women”;C.Castelo-Branco (SP): “Definition and diagnosis of sexuality in the 21rst century: New horizons”

Chairmen: Lucas Viana Machado (Brasil) and Morris Notelovitz (USA)

(Todas as sessões serão em Inglês)

terminei !... e…

este... já pode acordar…este... já pode acordar…

Obrigado …

…por não terem ressonado !

Braga

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