memoria e menopausa . O timing do começø da THM é fundamental. Congresso Paulista de endocrinologia. Agosto/2021 .

1. Função Cognitiva
na Peri e Pós Menopausa:
Função Cognitiva
na Peri e Pós Menopausa:
DOLORES PARDINI
dolorespardini.com.br

2. Receptores Estrogênicos
Greene et al ,1986

3. Receptores Estrogênicos

5. Fischer, B.et al/. Fertil. Steril. 2014, 101, 898–904
Verghese, J.et al .. Neurology 2000, 55, 872–874. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 373. https://doi.org/10.3390/ijms22010373

7. • WOODS, N.F.; MITCHELL, E.S.; ADAMS, C. - Memory functioning among midlife women: observations
from the Seattle Midlife Womens Health Study. Menopause 7:257-65, 2000.
É definida como o processo de obter, organizar e usar o conhecimento intelectual ,
caracterizada, como um processo mental que gera informação nova ou
experiencial.
Cognição
Aprendizagem
Memória
Percepção
Atenção
Vigilância
Raciocínio
Soluções de Problemas
Funcionamento
Psicomotor
A saúde cognitiva não existe isoladamente, sofre influência social, afetiva,
intelectual, física , que em geral se deterioram com a idade

8. ESTROGENO

9. Russel JK . Neurotherapeutics (2019) 16:649–665
Efeito Neurotrófico do Estradiol

10. Russel JK . Neurotherapeutics (2019) 16:649–665
Alterações Cognitivas e Morfológicas com a Perda do Estradiol

11. Influência do Estradiol na Densidade das Sinapses no Hipocampo
K. Sellers et al. / Frontiers in Neuroendocrinology 36 (2015) 72–
89

12. Conjugated equine estrogens and global cognitive
function in postmenopausal women: Women's
Health Initiative Memory Study
.Mark A Espeland 2004 Jun 23;291(24):2959-68.
A limitação dos estudos
observacionais é o “viés da usuário
saudável”, significa a tendência das
mulheres que recebem a THM serem
mais saudáveis e com maior
escolaridade que as não usuárias
Maki P .Am J Psychiatry 158:2, February 2001

13. Efeito da Reposição Hormonal na Transição Menopausica na Performance Cognitiva
SWAN - Study of Women’s Health Across the Nation
- 2362 mulheres 42-52a / 4 a
- memória verbal ; veloci// processual; “working memory”
Neurology® 2009;72:1850–1857
CONCLUSÃO:
Além das dificuldades de memória percebidas pelas mulheres em transição,
perimenopausal, observou-se um decréscimo no desempenho cognitivo,
referido pelas mulheres como não sendo capazes de aprender tão bem quanto
durante a pré-menopausa. A iniciação hormonal antes do período menstrual
final teve um efeito benéfico, enquanto a iniciação após o período menstrual
final teve um efeito prejudicial na performance cognitiva

14. 14
Greendale GA . JAMA;2020
62%
JANELA DE VULNERABILIDADE

15. O que já sabemos ?
★ Existem receptores alfa e beta de estradiol no cérebro, incluindo cortex , amigdala, hipo
★ A cognição pode ser afetada em vários níveis e percebida de várias formas de acordo com
★ Apesar da profunda conexão entre estradiol e cognição, dados referentes entre
a THM e os desfechos neuroprotetores ainda são controversos.
★ Os resultados de pequenos ensaios randomizados e estudos observacionais maiores suge
★ Estudos observacionais mostram um declínio de vários domínios da cognição como memó
★ Uma vez ativado o RE no SNC ele diminui a inflamação, previne dano mitocondrial,
diminui atividade oxidativa e inibe a apoptose conferindo neuroproteção

16. Obrigada
DOLORES PARDINI
dolorespardini.com.br

17. Long-Term Effects on Cognitive Function of Postmenopausal Hormone
Therapy Prescribed to Women Aged 50 to 55 Years.
Mark A. Espeland, PhD; for the WHIMSY Study Group
JAMA Internal Medicine August 12/26, 2013 Volume 173, Number 15
CONCLUSIONS AND RELEVANCE CEE-based therapies produced no overall sustained benefit or risk to cognitive
function when administered to postmenopausal women aged 50 to 55 years. We are not able to address whether
initiating hormone therapy during menopause and maintaining therapy until any symptoms are passed affects
cognitive function, either in the short or longer term.
“window of opportunity,” perhaps coincident with the loss of ovarian function during menopause, when hormone therapy may promote or preserve brain health.6
9 Meta-analyses of clinical trials and systematic literature reviews do not find consistent evidence of benefit1

18. Receptores Estrogênicos
Greene et al ,1986
Receptor E𝜶
Útero , mama, hipófise, osso, vasos sangüíneos, SNC, Hepatocitos
Próstata, intestino, cels granulosa,pulmao, leucócitos,cortex cerebral,
cerebelo, miocárdio, pulmão, esofago, pituitaria, tireoide, prostata,
testiculos, ovários, vagina, útero e mama
Receptor E β
Modular structure of estrogen receptors (ER). A: schematic representation of the two human
ERs: full-length 66 kDa ERα (595 amino acids), short-isoform 46 kDa ERα (421 amino acids),
and full-length 60 kDa ERβ (530 amino acids). For ERβ isoforms, see Thomas and Gustafsson
(395). The functional domains of the receptors include the DNA binding domain (DBD), ligand
binding domain (LBD), and two transcriptional activation functions, AF-1 and AF-2. The A/B
domain, at the amino terminus (NH2) of the protein, contains AF-1. The C domain binds to DNA
motifs called EREs. The D domain is called the hinge region and contributes to DNA binding
specificity and nuclear localization of the ERs. The E domain is called the LBD because it
interacts with estrogens or SERMs. At the carboxy terminus (COOH) is the F domain. The
percent homology shared between ERα and ERβ in the C and E domains is shown. The short-
isoform 46 kDa ERα lacks the NH2-terminal region harboring AF-1. B: spectrum of recognition of
several antibodies raised against ERα, with species (human and mouse) and isoform (66 vs. 46
kDa) ERα specificities.

19. Receptor Location Effects upon activation ERα CNS Decreases inflammation,
decreases the extent of lesion, and prevents mitochondrial damage and release
of cytochrome c, thus inhibiting apoptosis ERβ Abundant in supraoptic
nucleus of hypothalamus and other areas of CNS Decreases the extent of tissue
damage and regulates the expression of genes in neurons that encode for
vasopressin, oxytocin, and other hypothalamic hormones GPER1/GPR30 Gray
and white matter of the spinal cord Protects against free radicals and provides
antioxidant effects Abbreviations: CNS, central nervous system; E2, estradiol;
ER, estrogen receptor; GPER1/GPR30, G protein-coupled estrogen receptor 1
/ G protein-coupled receptor 30 .
e diminui a inflamação, previne dano mitocondrial, diminui atividade oxidava e inibe a apo

20. Cognitive function and cognitive disorders: despite the deep connection between estrogen
and cognition, data regarding the relationship between hormone replacement therapy and the
neuroprotective outcomes still remain conflicting. Several studies have excluded any cognitive
benefits of estrogen or combined estrogen-progestin therapy in women over the age of 65 without
underlying dementia. Young menopausal women without contraindication to MHT and with
impaired quality of life because of night sweats, vasomotor symptoms or disrupted sleep can
benefit from MHT, and in several studies, MHT does not adversely a
ect cognition in these women
reThe results of small randomized trials and larger
observational studies suggest the beneficial effect
of estrogen therapy on cognitive function in
postmenopausal women. However, the results of the
WHIMS study do not support this, at least not in
women over the age of 65 years. Further research
involving randomized clinical trials with large number
of women with different types of estrogen and/
or different mode of application, a sensitive test battery
and prospective longitudinal follow-up assessments
is, however, required to provide more definite
information on the role of estrogen therapy in
age-related cognitive decline and in the prevention
of Alzheimer.s disease.
★ Existe uma janela de “vulnerabilidade” onde os efeitos do estradiol na cognição são
mais evidentes . É um “viés da usuária saudável”.

21. O que já sabemos ?
★ Existem receptores alfa e beta de estradiol no cérebro, incluindo cortex , amigdala, hipo
★ A cognição pode ser afetada em vários níveis e percebida de várias formas de acordo com
★ Estudos observacionais mostram um declínio de vários domínios da cognição como memó
★ Estudos observacionais também mostram um declínio de vários domínios da
cognição em mulheres na pós menopausa qdo comparadas com homens de
forma significante
★ Existe uma janela de “vulnerabilidade” onde os efeitos do estradiol na cognição são
mais evidentes . É um “viés da usuária saudável”.
★ O estudo controlado WHIMS não mostrou diferença nas mulheres com THM daquelas sem
★ A Progesterona natural convertendo-se em allopregnenolona tb contribui para
um efeito neuroprotetor

22. Conclusions: Consistent with transitioning women’s perceived memory difficulties, perimenopause
was associated with a decrement in cognitive performance, characterized by women not
being able to learn as well as they had during premenopause. Improvement rebounded to premenopausal
levels in postmenopause, suggesting that menopause transition–related cognitive
difficulties may be time-limited. Hormone initiation prior to the final menstrual period had a beneficial
effect whereas initiation after the final menstrual period had a detrimental effect on cognitive
performance.
CONCLUSÃO:
Além das dificuldades de memória percebidas pelas mulheres em transição, perimeno

23. PM c/TH previa
PeM tardia
Pós M em TH

24. • WOODS, N.F.; MITCHELL, E.S.; ADAMS, C. - Memory functioning among midlife women: observations
from the Seattle Midlife Womens Health Study. Menopause 7:257-65, 2000.
Cognitive health does not exist in isolation. Quite the
contrary, it influences, and is influenced by, an array of
medical, social, affective, and functional changes that
often occur with increased age.
estrogen may be implicated in maintaining or
enhancing cognitive functioning, particularly in the working
memory, attention, and verbal learning domains
Attempts to reconcile observational study results with those of randomized trials led to
hypotheses that the timing and duration of HT use may be critical factors in determining
their effects on cognition and AD risk
É definida como o processo de obter, organizar e usar o conhecimento intelectual ,
caracterizada, como um processo mental que gera informação nova ou
experiencial.
Cognição
Aprendizagem
Memória
Percepção
Atenção
Vigilância
Raciocínio
Soluções de Problemas
Funcionamento
Psicomotor

25. Progress in Neurobiology 113 (2014) 79–87
- Esteroide Neuroativo
- Modulador Alosterico do complexo
Gabaergico
- Aumenta a Neurogenese
- Efeito neuro protetor
Progesterone, and especially allopregnanolone, is able to promote the GABAergic system inhibiting
synaptic transmission, producing what is believed to be an anti-anxiety e
ect similar to that of
benzodiazepines [19 –21 ]. In humans, decreased levels of allopregnanolone are linked with depression
and antidepressant drugs are able to determine and increase this metabolite [22 ]. The GABAergic
role of progesterone in the hippocampus explains why exogenous administration of progestins has
a negative impact on the cognitive performance of healthy women in working memory tests [23 ].
Progesterone and allopregnanolone are able to influence the dopaminergic systems with an observed
improvement in motor sensory functions during the phases of the menstrual cycle when progesterone
is higher [22 ]. The positive modulation of allopregnanolone on the release of dopamine can also have a
possible e
ect on drug abuse and depression [24 ].

26. 26
E A PROGESTERONA ????
E A PROGESTERONA ????

27. Sex differences in episodic memory in early midlife: Impact of reproductive aging Dorene M.
Rentz, Psy.D.1,2, Blair K. Weiss, B.S.3, Emily G. Jacobs, Ph.D.3,5, Sara Cherkerzian,
Sc.D.3,5, Anne Klibanski, M.D.4, Anne Remington, M.A.3, Harlyn Aizley, M.Ed.3, and Jill
M. Goldstein, Ph.D.3,5
Menopause. 2017 April ; 24(4): 400–408
Age-adjusted scores are reported by group for 6-Trial SRT Total Recall (Pre, Premenopausal,
n=32; Peri, Perimenopausal, n=28; Post, Postmenopausal n=31; Men, n=94) and Face — Name
Initial Learning: Names and Occupations (Pre, Premenopausal, n=31; Peri, Perimenopausal,
n=29; Post, Postmenopausal n=32; Men, n=93). The SRT Total Recall score represents the
average total number correct across 6 trials, with a range of 0–72. Face Name Initial Learning
represents the average total number correct for names and occupations, with a range of 0–24.
Error bars represent ± 1 SEM. *p<.05, **p<.01, ***p<.

28. Estradiol regulates spine synapses on hippocampal pyramidal neurons,
which are sites of excitatory neurotransmission important for learning and
memory. A: in the diestrus phase, which is the beginning of the estrus cycle
when estradiol levels are low, spine densities are also low. During proestrus
when ovulation occurs, estrogen levels peak and spine densities increase in
parallel. In the estrus phase, the day after proestrus, the system begins to
reset itself for the next cycle and spine densities return to baseline. [Image
adapted from McEwen and Schmeck (134a) with permission.] B: axospinous
synapse density is higher in the proestrus phase compared with the estrus
phase. C and D: in ovariectomized (OVX) rats, estradiol (E) treatment
increases dendritic spine density (C) as well as axospinous synapse density
(D). V, vehicle-treated. Histograms (B–D) are plotted from data originally
presented in Gould et al. (58) and Woolley and McEwen (236).
Influência do Estradiol na Densidade das Sinapses no Hipocampo

29. Figure 5 E2 activates both protective and reparative mechanisms in CNS injuries in vivo. Note: Different
color fonts and arrows indicate diverse biological activities of E2. Abbreviations: CNS, central nervous
system; E2, estradiol.

30. Natural menopause is associated with a selective loss of complex and strong synaptic connections in the monkey hippocampus. A: schematic diagrams illustrating sh

32. Neuroscience and Neuroeconomics 2017:6 15–29
NEUROPROTECTION
inhibition of
apoptosis and promotion of cell survival. Its antioxidant functions are useful for
scavenging reactive free radicals, which are heavily produced following a CNS
injury.
Moreover, E2 plays an important role in maintaining mitochondrial bioenergetics
for the optimal production of ATP for supporting cellular metabolism.
Abbreviations: ATP, adenosine triphosphate; CNS, central nervous system; E2,
estradiol; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; JNK,
c-Jun
N-terminal kinase.
Figure 3 E2 has genomic signaling mechanisms for modulation of expression of various proteins for its neuroprotective effects in the CNS.
Notes: Activation ERs by E2 modulates the expression of the target genes, so as to decrease the detrimental pathways, thus leading to neuroprotection.
Abbreviations: CNS, central nervous system; E2, estradiol; ERs, estrogen receptors; MMP-9, matrix metalloprotease-9; TNF-α, tumor necrosis factor-alpha.
3 E2 has genomic signaling mechanisms for modulation of expression of various proteins for its neuroprotective effects in the CNS
Activation ERs by E2 modulates the expression of the target genes, so as to decrease the detrimental pathways, thus leading to n
iations: CNS, central nervous system; E2, estradiol; ERs, estrogen receptors; MMP-9, matrix metalloprotease-9; TNF-α, tumor nec

33. A maioria, se n.o todos, dos efeitos conhecidos
dos estr.genos s.o mediados por fatores de transcri..o ativados por ligantes,
chamados de receptores de estr.geno (REs) [2]. Esses receptores s.o
pertencentes . superfam.lia de receptores nucleares e subdividem-se em
v.rios dom.nios funcionais. Os mais conhecidos e estudados subtipos de
receptores estrog.nicos s.o os receptores α (REα), o qual foi clonado em
1986, e β (REβ) clonado em ratos [3] e em humanos [4].
At. meados dos anos 90 acreditava-se que s. existia um tipo de receptor
de estr.geno, o Receptor de Estr.geno α (REα), mas outro tipo de receptor foi
encontrado, o Receptor de Estr.geno β (REβ), sendo evidenciados e estudados
em humanos e ratos [3;6].
Os dom.nios de liga..o ao DNA do
REα e REβ apresentam alto grau de homologia (97%), mas o dom.nio de
liga..o ao ligante apresenta apenas 57% de homologia, entendendo que essas
diferen.as possibilitem desenvolver ligantes REα e REβ espec.ficos
Tabela 1
Atualmente o estudo sobre receptores de estrogênios está em contínua
ascensão, ond e já se sabe que tanto o R E
α e REβ
poss
uem dist inção celular

34. A cognição é composta de múltiplos processos mentais, como atenção, percepção, memória, execução
de tarefas, noção espacial, linguagem e aprendizado. Durante o processo de envelhecimento, ocorre
piora da função cognitiva, que pode ser observada por meio da diminuição da memória, da atenção, do
desempenho das habilidades motoras e da capacidade de visão espacial. O declínio da função
cognitiva interfere no desempenho ocupacional e nas atividades sociais das pessoas. Indivíduos com
demência têm piora da função cognitiva, porém nem todos que apresentam piora dela têm demência.
Cerca de 60% das mulheres no período perimenopáusico apresentam piora da memória, com
dificuldades de lembrar palavras, números, esquecer eventos e atos praticados, sendo muito freqüentes
as queixas de dificuldade de concentração. Em geral, elas atribuem essas alterações a estresse,
problemas de saúde e idade e poucas as relacionam às alterações hormonais próprias daquele período
da vida (Woods et al., 2000).
• WOODS, N.F.; MITCHELL, E.S.; ADAMS, C. - Memory functioning among midlife women: observations
from the Seattle Midlife Womens Health Study. Menopause 7:257-65, 2000.
Segundo a Organização Mundial de
Saúde, a demência é uma alteração
progressiva da memória e da ideação,
suficientemente marcante para
prejudicar as atividades de todos os
dias, surgida pelo menos já seis meses
e associada a um distúrbio de pelo
menos uma das seguintes funções:
linguagem, calculo,
julgamento,alteração do pensamento
abstrato, coordenação motora ,
percepção ou modificação da
personalidade.Existem varias
classificações das demências sendo a

37. As part of the Multiple Outcomes of Raloxifene Evaluation trial, we studied 7478 postmenopausal women with osteoporosis (mean age, 66 years), who were enrolled at 178 sites in 25 countries
COGNITIVE FUNCTION IN POSTMENOPAUSAL WOMEN TREATED WITH RALOXIFENE

38. ception of verbal fluency, in an 18-month follow-up of pre-menopausal women [32 ]. The Study of
Women’s Health Across the Nation (SWAN) reported an impairment of cognitive performance mostly
in learning abilities during menopause transition, with subsequent improvement to pre-menopausal
levels in the post-menopausal period [33 ]. The SWAN study has been ongoing since 1996, observing
3302 women throughout the whole menopausal transition (https://www.swanstudy.org/ ); in the next
few years we believe that this study will provide a unique insight into the long-term e
ects of hormonal
changes in middle-aged women.
Greendale, G.A.; Huang, M.-H.;Wight, R.G.; Seeman, T.; Luetters, C.;Avis, N.E.; Johnston, J.; Karlamangla, A.S.
E
ects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology
2009, 72, 1850–1857. [CrossRef] [PubMed]

39. Cognitive function and cognitive disorders: despite the deep connection between estrogen
and cognition, data regarding the relationship between hormone replacement therapy and the
neuroprotective outcomes still remain conflicting. Several studies have excluded any cognitive
benefits of estrogen or combined estrogen-progestin therapy in women over the age of 65 without
underlying dementia. Young menopausal women without contraindication to MHT and with
impaired quality of life because of night sweats, vasomotor symptoms or disrupted sleep can
benefit from MHT, and in several studies, MHT does not adversely a
ect cognition in these women.
Medicina 2019, 55, 668; doi:10.3390/medicina55100668
Gava G.
Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within
the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to
generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II
diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating
estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically
compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss
could determine risk of late-onset Alzheimer’s disease. Estrogen coordinates brain and body
metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By
generating biomarker profiles that encompass peripheral metabolic changes occurring with
menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be
created. Biomarker profiles could identify women at risk while also serving as indicators of
efficacy of hormone therapy or other preventative interventions.
Rettenberg J . Front Neuroendocrinol.2014;35(1):8-30

40. Fischer, B.; Gleason, C.; Asthana, S. Effects of hormone therapy on cognition and mood. Fertil. Steril. 2014, 101, 898–904. [CrossRef] 81.
Verghese, J.; Kuslansky, G.; Katz, M.J.; Sliwinski, M.; Crystal, H.A.; Buschke, H.; Lipton, R.B. Cognitive performance in surgically
menopausal women on estrogen. Neurology 2000, 55, 872–874. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 373. https://doi.org/10.3390/ijms22010373

41. Figure 3 E2 has genomic signaling mechanisms for modulation of expression of various proteins for its
neuroprotective effects in the CNS. Notes: Activation ERs by E2 modulates the expression of the target genes, so
as to decrease the detrimental pathways, thus leading to neuroprotection. Abbreviations: CNS, central nervous
system; E2, estradiol; ERs, estrogen receptors; MMP-9, matrix metalloprotease-9; TNF-α, tumor necrosis factor-
alpha
Neuroscience and Neuroeconomics 2017:6 15–29

42. 42
Neurotherapeutics, 2019
J. K. Russell et al.
Diminuição
de
Estrógeno
Redução
da
Captação
de Glicose
Aumento
da
Cetogenesis
Redução
da
plasticidade
sináptica
- Redução da
performance cognitiva

43. Figure 3 E2 has genomic signaling mechanisms for modulation of expression of various proteins for its
neuroprotective effects in the CNS. Notes: Activation ERs by E2 modulates the expression of the target genes, so
as to decrease the detrimental pathways, thus leading to neuroprotection. Abbreviations: CNS, central nervous
system; E2, estradiol; ERs, estrogen receptors; MMP-9, matrix metalloprotease-9; TNF-α, tumor necrosis factor-
alpha
Neuroscience and Neuroeconomics 2017:6 15–29

44. Neuroscience and Neuroeconomics 2017:6 15–29
NEUROPROTECTION

45. Assim, o estrogênio exerce ações neuroprotetora, neurotrófica, de
proteção contra o estresse oxidativo, contra a hipoglicemia e contra o
dano causado pela proteína amilóide; também estimula a produção de
fatores de crescimento neural, aumenta a concentração e número de
receptores dos neurotransmissores (serotonina, dopamina e
norepinefrina), além de melhorar a perfusão cerebral (efeito
vasodilatador similar ao que ocorre nas artérias coronárias) e de
exercer importante ação antiinflamatória.
ESTRADIOL
Shepherd JE. Effects of Estrogen on Cognition, Mood, and Degenerative Brain Diseases. J Am Pharm Assoc 2001;41(2):221-228.