Menopausa

ALTERAÇÕES HORMONAIS DO
ENVELHECIMENTO
MENOPAUSA
9 º Curso Pós-Graduado
NEDO 2010
por
MANUEL NEVES-E-CASTRO
Clínica de Feminologia Holística
Lisboa
[email protected]
APRESENTAÇÃO
Introdução ao tema
Cronobiologia da Mulher
Factores endócrinos
Factores genéticos (telómeros)
Consequências da senescência: quadro
clínico, SNC, DCV, osso, imunodeficiência
• Morbilidade e Mortalidade
• Estratégias antisenescência
• Conclusões
•
•
•
•
•
+17,9 anos
Esperança média de vida aos 65 anos em 2006
Em 2050, cerca de 32% da população
portuguesa terá mais de 65 anos.
Teremos mais idosos, que viverão mais anos
Instituto Nacional de Estatística
En+velhe+cer = ficar velho = ficar idoso
•
Ageing = to grow older, to grow in age
• crescer em idade
En+Idade + mento = enidademento
•
Envelhecer = Enidadecer
ENIDADECER
(AGEING)
A idosa é aquela pessoa que tem tido a felicidade de viver uma
longa vida produtiva, de ter adquirido uma grande experiência.
Ela é uma ponte entre o passado e o presente, como a jovem é
uma ponte entre o presente e o futuro.
E é no presente que ambas se encontram.
Velha é aquela que tem carregado o peso dos anos, que
em vez de transmitir experiência às gerações vindouras,
transmite pessimismo e desilusão.
Para ela, não existe ponte entre o passado e o presente, existe
um fosso que a separa do presente pelo apego ao passado.
A idosa moderniza-se, dialoga com a juventude, procura
compreender os novos tempos.
A velha emperra-se no seu tempo, fecha-se na sua ostra e recusa
a modernidade.
A idosa leva uma vida activa, cheia de projectos e de esperanças.
Para ela o tempo passa rápido,
mas a velhice nunca chega.
Em resumo, idosa e velha, são duas pessoas que até podem
ter a mesma idade no cartório, mas têm idade bem diferente
no coração.
Se você é idosa, guarde a esperança de
nunca ficar velha.
menarca
Puberdade
Anos reproductivos
Fertilarca
crianças
menopausa
adolescentes
posmenopausa
Climatério
geronarca
Fertilpausa
adultas
idosas
anciãs
qualidade de vida
compressão
morbilidade
Medicina Cronobiológica
Tabela de tempo na vida da mulher
M.Neves-e-Castro,2008
CLIMATÉRIO
(do grego KLIMAKTER)
significa
um degrau de uma escada
ou
uma crise
Menopausa
é apenas a data da última menstruação
espontânea
Climatério
é o tempo que imediatamente a precede e
se lhe segue
O Futuro do Climatério
é uma inter-relação do
Aumento da Idade
com
a Redução das Hormonas
A Climacteric woman
is a woman (gender based medicine)
is an ageing person (geriatrics)
is perimenopausal (hormone deficient)
ENIDADECER
(AGEING)
Aging in humans
is a progressive loss of function and energy
production that is accompanied by decreasing
fertility and increasing mortality with
advancing age.
Vitetta L and Anton B;
Clinical Interventions in Aging 2007:2(4) 537–543
Senescent changes, as de novo structural and
functional alterations, are not part of the
developmental program.
Vitetta L and Anton B;
Clinical Interventions in Aging 2007:2(4) 537–543
FACTORES
ENDÓCRINOS
In humans there is a progressive decrease in
hormone synthesis as well as a loss of
hormone receptors with age.
Vitetta L and Anton B;
Clinical Interventions in Aging 2007:2(4) 537–543
Hormones known to decline as we
grow older:
•
•
•
•
•
Dehydroepiandrosterone (DHEA)
Growth Hormone
Melatonin
Testosterone
Menopausal hormones, such as estrogen
Mental Help.net. Nov 10th 2003
Hormones that are usually decreased
include:
•
•
•
•
Aldosterone
Calcitonin
Growth hormone
Renin
http://www.umm.edu/ency/article/004000.htm
Hormones that remain unchanged or
only slightly decreased include:
•
•
•
•
•
•
Cortisol
Epinephrine
Insulin
Parathyroid hormone
Thyroid hormones T3 and T4
25-hydroxyvitamin D
http://www.umm.edu/ency/article/004000.htm
Hormones that may increase include:
• Follicle-stimulating hormone (FSH)
• Luteinizing hormone (LH)
• Norepinephrine
http://www.umm.edu/ency/article/004000.htm
Human Growth Hormone and Human
Aging
With advancing age, an increasing proportion
of men and women with no clinical evidence
of pituitary pathology show decreases in GH
secretion and serum levels of insulin-like
growth factor-I (IGF-I)
Corpas E, Harman SM and Blackman MR.
Endocrine Reviews 1993;14 (1): 20-39
Human Growth Hormone and Human
Aging
Because GH deficiency and normal aging are both
associated with decreases in protein synthesis and
percent of lean body and bone mass, and with
increases in percent of body fat, it is possible that
reduced GH secretion and IGF-I levels might account,
at least in part, for one or more of the above effects
of aging
Corpas E, Harman SM and Blackman MR.
Endocrine Reviews 1993;14 (1): 20-39
Genes reveal 'biological ageing'
They eventually located a number of variants
located near a gene called TERC which, in
people carrying them, seemed to be
equivalent to an extra three or four years of
"biological ageing".
Published on 8th Feb.2010 at http://crabsalloverhealth.blogspot.com/
FACTORES GENÉTICOS
telómeros
Scientists identify first genetic variant linked to
biological ageing in humans
There are two forms of ageing –
chronological ageing i.e. how old you are in
years and
biological ageing whereby the cells of some
individuals are older (or younger) than
suggested by their actual age.
Issued on 07 February 2010 by University of Leicester at
http://www2.le.ac.uk
A longa cadeia de moléculas de ADN que
transportam os nossos genes está contida
nos cromossomas,
de cujas extremidades os telomeres
constituem o topo.
Blackburn E e Szostak J Prémio Nobel de Medicina
2009
Um português descobre mecanismo
responsável pelo fim da regeneração celular
O encurtamento dos telómeros ,à medida que as
células se dividem,desencadeia um percurso para
as mitocôndrias (fontes da energia) ,que leva à
produção de radicais livres que param a divisão
celular
João Passos et al.Feedback between p21 and reactive oxygen
production is necessary for cell senescence.Molecular Systems
Biology 2010; 6 : 347
Publicado on line em 16 Fev 2010
The best characterized function of the
telomeric complex is to protect the
chromosome ends from degradation
Werner C, Hanhoun M, Widmann T, et al.
J Am Coll Cardiol 2008;52:470–82
Os telómeros podem ser comparados às
capas plásticas protectoras das pontas
dos atacadores dos sapatos que, quando
se perdem, desfiam-se e vão
desaparecendo.
Estas
descobertas
explicam
como
as
extremidades dos cromossomas são protegidas
pelos telomeros e como estes são fabricados
pela telomerase.
Se os telomeros são encurtados, as células
envelhecem. Ao invés, se a actividade da
telomerase é intensa, o comprimento dos
telomeros é mantido e a senescência celular
atrasada.
• Most researchers now accept telomere length
is a reliable marker of cell age.
• In general, the shorter the telomere, the
functionally older and more tired the cell
Tara Parker-Pope.
The New York Times January 27, 2010.
Genes reveal 'biological ageing'
From birth, every time a cell divides, the
telomeres get shorter and there is some
evidence that people with shorter telomeres,
either because they diminish more quickly or
because they were born with shorter versions,
may be at higher risk from age-related illness.
Feb.2010 at http://crabsalloverhealth.blogspot.com/
• In addition to the protection of chromosome
ends, the components of the telomeric
complex enhance cell survival.
• Suppression of telomerase enzyme activity
promotes apoptosis
Werner C, Hanhoun M, Widmann T, et al.
J Am Coll Cardiol 2008;52:470–82
Sedentary life 'speeds up ageing'
telomeres shortened more quickly in inactive
people.
It is thought that it could signify faster cellular
ageing.
Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/7212698.stm
Published: 2008/01/29
Sedentary life 'speeds up ageing'
Leading a sedentary lifestyle may make us
genetically old before our time, a study suggests:
A study of twins found those who were physically
active during their leisure time appeared biologically
younger than their sedentary peers.
Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/7212698.stm
Published: 2008/01/29
The association between physical activity in
leisure time and leukocyte telomere length
A sedentary lifestyle (in addition to
smoking, high body mass index, and
low socioeconomic status) has an
effect on LTL (leukocyte telomere
length) and may accelerate the aging
process.
Cherkas LF et al, Arch Intern Med 2008;168(2):131-2
Leukocyte telomere length is preserved with aging in
endurance exercise-trained adults and related to
maximal aerobic capacity
• LTL is preserved in healthy older adults who
perform vigorous aerobic exercise and is positively
related to maximal aerobic exercise capacity.
• This may represent a novel molecular mechanism
underlying the "anti-aging" effects of maintaining
high aerobic fitness.
Larocca TJ, Seals DR, Pierce GL..
Mech Ageing Dev. 2010 Jan (in press)
• Physical exercise is associated with increased
serum concentrations of IGF-1
• IGF-1 enhances telomerase, delaying cellular
aging and death.
Werner C, Hanhoun M, Widmann T, et al.
J Am Coll Cardiol 2008;52:470–82
Molecular Endocrinology and Physiology of the
Aging Central Nervous System
• Exercise is also beneficial for maintaining
neurogenesis.
• In the adult mouse, running promotes
neurogenesis in the DG, which is believed to
be mediated by IGF-I
Roy G. Smith, Lorena Betancourt, and Yuxiang Sun.
Endocrine Reviews 2005 26(2):203–250
Recreational Physical Activity and the
Risk of Breast Cancer in
Postmenopausal Women
Women who engaged in the equivalent of 1.25 to
2.5 hours per week of brisk walking had an 18%
decreased risk of breast cancer (RR, 0.82; 95% CI,
0.68-0.97) compared with inactive women.
McTiernan A et al. JAMA 2003;290:1331-6
Blackburn E e Greider C
Prémios Nobel de Medicina 2009
identificaram a telomerase, a
enzima que produz o ADN dos
telómeros.
• Telomerase repairs and lengthens telomeres,
which cap and protect the ends of
chromosomes housing DNA.
• As people age, telomeres shorten and cells
become dying.
Published on 16th Sept.2008 at http://crabsalloverhealth.blogspot.com
Common variants near TERC are associated
with mean telomere length
Telomere length has a strong genetic
determination, with heritability estimates
ranging from 44% to 80%.
A locus on 3q26 that affects telomere length in
humans.
Codd V, Mangino M, van der Harst P, et al.
Nature Genetics 2010, Feb. 7 (in press)
Senescence, chromosome stability, and cell
viability are regulated by the telomeres and their
associated proteins, deoxyribonucleic acid-protein
complexes located at both ends of eukaryotic
chromosomes.
Shortening of the telomeres has been shown to be
associated with increased mortality rate from heart
disease
Werner C, Hanhoun M, Widmann T, et al.
J Am Coll Cardiol 2008;52:470–82
OVARIAN AGING
MENOPAUSA
Loci at chromosomes 13, 19 and
20 influence age at natural
menopause
Lisette Stolk , et al
Nature Genetics 2009; 41:645–647
ALOX12 gene is associated with
the onset of natural menopause
in white women
Pengyuan L; Yan L; Robert R.; et al
Menopause. 17(1):152-156, January 2010
Ovarian Aging: Mechanisms and Clinical
Consequences
The normal process of reproductive aging
varies considerably among women. This
implies that some women remain highly
fertile until the fifth decade of life, whereas
others face the loss of natural fertility
already in their mid-thirties.
Female
reproductive aging seems to be largely based
on age related changes in ovarian function.
F. J. Broekmans, M. R. Soules, and B. C. Fauser.
Endocrine Reviews 2009;30(5):165-493
Molecular Endocrinology and Physiology of the
Aging Central Nervous System
• The onset of menopause correlates with changes in
biological rhythms and alterations in CNS function
associated with reduced exposure to estradiol.
• changes in the CNS likely precede changes in
ovarian function during perimenopause.
Roy G. Smith, Lorena Betancourt, and Yuxiang Sun.
Endocrine Reviews 2005 26(2):203–250
ESTRATÉGIAS
Lifestyle and nutrition, caloric restriction,
mitochondrial health and hormones:
Scientific interventions for anti-aging
Vitetta L and Anton B;
Clinical Interventions in Aging 2007:2(4) 537–543
Clean living 'slows cell ageing'
It is the damage and death of cells that causes
ageing and disease in people.
Several factors such as smoking, obesity and
a sedentary lifestyle are associated with
shorter-than-average telomeres.
Published on 16th Sept.2008 at http://crabsalloverhealth.blogspot.com
Em mulheres de 45 a 64 anos houve
Redução de:
- 40% em todas as causas de mortalidade
- 35% em DCV
Quando:
-
comeram 5 frutos e vegetais/dia
fizeram exercício de 2,5 horas/semana
mantiveram o IMC entre 18.5 e 30
não fumaram
Am J Medicine 2007;120(7):598-603
Mediterranean Diet, Lifestyle Factors,
and 10-Year Mortality in Elderly
European Men and Women
Among individuals aged 70 to 90 years, adherence to a
mediterranean diet lifestyle is associated with a more
than 50% lower rate of all-causes and cause-specific
mortality.
Knoops K et al. JAMA 2004;292:1433-9
SLEEP
• Sleep disturbances can lead to immune
suppression and a shift to the predominance
in cancer stimulatory cytokines,
• Some studies suggest that a shortened
duration of nocturnal sleep is associated with
a higher risk of breast cancer development
Blask DE-Sleep Medicine Reviews,2008
Okinawa Island:
A model of “healthy” aging
The exceptional longevity of the Okinawa
population may result from a combination of
favorable factors and not only genetic
determinants. The association of a protect
environment with a way of life which combines
specific food habits, low energy intake, physical
activities, stress reduction, good familial support
and rich social relations could explain this exception
despite the low income in this population.
Nguyen C. NPG Neurologie-Psychiatrie-Geriatrie 2008, in press.
A Gestão do Climatério
por
Objectivos
Objectivos Críticos




O tratamento de sintomas
A eliminação de factores de risco
O diagnóstico de doenças
O tratamento de doenças
O exercício físico pode estimular as
defesas imunitárias em sobreviventes
de Ca mama, aumentando a actividade
cancerígena das NKC
“ALVOS”
DOS ESTROGÉNIOS
SINTOMAS DE CARÊNCIA
Estrogéneos
Consequências da sua redução
Sintomas
(precoces)
Sinais
(intermédios)
Doenças
(tardias)
afrontamentos
insónias
irritabilidade
alteração do humor
redução da líbido
atrofia vaginal
dores nas relações sexuais
incontinência urinária
atrofia da pele
osteoporose
D.cardiovasculares
doença de Alzheimer
MORTALIDADE
Causes of Death Among Women*
Other Cancers
Heart Disease
15%
Breast Cancer
Diabetes
Chronic Lower
Respiratory
Disease
34%
4%
3%
6%
28%
10%
Other
*Percentage of total deaths in 1999 among women aged 65 years and older.
Anderson RN. Natl Vital Stat Rep. 2001;49:1-13.
Cerebrovascular
Disease
Risco, aos 50 anos, de morrer
por
•
•
•
•
Enfarte agudo miocárdio
Fractura do colo fémur
Cancro da mama
Cancro do endométrio
31,0 %
2,8 %
2,8 %
0,7 %
Portugal
MORBILIDADE
DOENÇAS CARDIOVASCULARES
AVC
OSTEOPOROSE
SISTEMA NERVOSO CENTRAL
CANCRO DO COLON
IMUNODEFICIÊNCIA
Riscos Metabólicos
- insulin resistance
- increase in blood pressure
- changes in lipid metabolism
- decrease in immune function
- increase in stored fat
M.N.C. 10/99
SNC
Molecular Endocrinology and Physiology of the
Aging Central Nervous System
The hormones having the most significant
pivotal roles in the CNS are estradiol,
testosterone, cortisol, GH, and IGF-I.
Roy G. Smith, Lorena Betancourt, and Yuxiang Sun
. Endocrine Reviews 2005 26(2):203–250
Molecular Endocrinology and Physiology of the
Aging Central Nervous System
• The decline in estradiol levels during menopause is
associated with increased neurodegeneration.
• Neuroprotection in the cerebral cortex is apparently
mediated by ER, because estradiol is not protective
in the ER knockout mouse
Roy G. Smith, Lorena Betancourt, and Yuxiang Sun.
Endocrine Reviews 2005 26(2):203–250
Estradiol: a hormone with diverse and contradictory
neuroprotective actions
• Estrogens can not only protect against cell
death, but can also stimulate the birth of
new neurons.
• Estrogen's modulation of the immune status
may be the basic mechanism that underlies
its
ability
to
protect
against
neurodegeneration and its powerful
neuroregenerative actions.
Wise PM, Suzuki S, Brown CM.
Dialogues Clin Neurosci. 2009;11(3):297-303
Molecular Endocrinology and Physiology of the
Aging Central Nervous System
• Estrogen may act as a neuroprotective agent
by inhibiting apoptosis of hippocampal
neurons.
• long-term treatment with estrogen at
physiological doses prevents apoptosis and
ischemia-induced injury to CA1 hippocampal
neurons
Roy G. Smith, Lorena Betancourt, and Yuxiang Sun.
Endocrine Reviews 2005 26(2):203–250
Molecular Endocrinology and Physiology of the
Aging Central Nervous System
Growth and development of neurons in the DG are
modulated by IGF-I. Marked reductions in IGF-I and
neurogenesis in the DG accompany aging.
Roy G. Smith, Lorena Betancourt, and Yuxiang Sun.
Endocrine Reviews 2005 26(2):203–250
Molecular Endocrinology and Physiology of the
Aging Central Nervous System
• Recent studies show that the rate of
neurogenesis in the DG of the hippocampus
declines as a function of age perhaps
contributing to age-related cognitive changes.
• Intracerebroventricular
IGF-I
infusion
ameliorates this age-associated decline
Roy G. Smith, Lorena Betancourt, and Yuxiang Sun.
Endocrine Reviews 2005 26(2):203–250
IMUNIDADE
Hormones and immune function:
implications of aging
• Aging is associated with a decline in immunity
described as immunosenescence.
• This is paralleled by a decline in the production of
several hormones, as typically illustrated by the
menopausal loss of ovarian oestrogen
production.
Arlt W and Hewison M.
Aging Cell 2004;Vol.3(2):209–216
Vitamin D
for Cancer Prevention:
Global Perspective
Garland CF, et al
Ann Epidemiol 2009;19:468–483.
Hormones and immune function:
implications of aging
Studies, primarily in vitro, have shown that
1,25(OH)²D³ is a potent inhibitor of cell
proliferation and this has led to the
development of synthetic analogues of vitamin
D that retain the anticancer actions of
1,25(OH)²D³ while minimizing its detrimental
hypercalcaemic side-effects.
Arlt W and Hewison M.
Aging Cell 2004;Vol.3(2):209–216
Vitamin D
Vitamin D plays an important role in
controlling cell growth and thus may help
reduce risk of deadly malignancies.
Taking at least 1.000 units (preferably
2.000 units/day) of Vitamin D may reduce
risk of developing colorectal and breast
cancer by as much as 50%
Os estrogéneos estimulam no rim
uma hidroxilase que forma a
dihidroxi D3
Conclusões
1. Há pessoas que estão genéticamente
programadas para envelhecer mais depressa
2. Nestas, o envelhecimento é mais rápido se
forem expostas a ambientes “maus” para os
telómeros (tabagismo, obesidade, falta de
exercício)
Conclusões
1. Os estrogénios são terapêuticos (s.v.m.)
2. Os estrogénios são preventivos (DCV, osso,
SNC, deficiências da imunidade)
3. Os estrogénios são antisenescentes
(telómeros)
e de tudo o que foi exposto
deduz-se que...
O CONHECIMENTO DAS
ALTERAÇÕES HORMONAIS DA
PÓS-MENOPAUSA
é fundamental para dar
mais Vida aos Anos
e mais Anos à Vida
Conhecer
a doença que uma mulher tem
é tão importante como
conhecer
a mulher que tem a doença
William Osler