Estrogênio degrada o tecido cerebral – em homens e mulheres
Demência, doença de Alzheimer, déficit cognitivo – já pensou no estrogênio como uma das prováveis causasɁ
[Imagem: ssksalamat.kg]
Prolongada exposição ao estrogênio facilita a perda [morte] de neurônios hipotalâmicos, cerebrais. É a conclusão de artigo científico [A], de revisão, que pesquisou a produção de hormônios [gonadotrofinas] na mulher em envelhecimento.
A conclusão é sólida, é fundada no trabalho em humanos [mulheres menopausadas] e mostra que essa dinâmica, da agressão do estrogênio ao cérebro, é relacionada à idade e aos níveis de secreção de hormônios hipofisários [gonadrotrofinas] e mostra o impacto destrutivo do estrogênio sobre o hipotálamo. Mencionam alterações ovarianas pós-menopausa.
Todo um processo vinculado ao aumento dos níveis de estrógenos que ocorre na mulher menopausada [Ver sobre esse aumento aqui = ===]. Naturalmente não era o foco dos cientistas avaliar a progesterona nessa dinâmica nem sua queda na menopausa, permitindo que o estrogênio se imponha deleteriamente.
No entanto, certamente esta dinâmica destrutiva da relação ovário-hipófise, se expressa na dominância estrogênica [ver nota a respeito aqui].
Prolongada exposição ao estrogênio, diz o essencial sobre a patogenia do processo [e o feedback estrogênio aumentado-gonadotrofinas].
Mas a verdade é que, infelizmente, esse não é um pensamento que já tenha sido apropriado pela ginecologia ou gerontologia. São duas caixinhas que não dialogam nessa esfera. Passam longe de perceber que degenerações cerebrais no pós-menopausa e menopausa podem ser efeito do aumento do estrogênio nos tecidos nessa fase da vida; aliás, pensam exatamente o contrário, que o estrogênio sobe na menopausa e, por conta disso, adotam protocolos de “reposição” do estrogênio... [Ver nota a respeito aqui ].
No entanto, outras experiências, citadas abaixo, não deixam margem à dúvida.
O estrogênio cresce na menopausa e causa danos cerebrais.
Experiência em ratas mostrou isso [B]. Eis sua conclusão: “o fato de que injeções mensais de valerato de estradiol em ratos machos produziu o mesmo perfil de degeneração no núcleo arcuato [cérebro] sugere que o agente neuropatológico pode ser o estradiol” [B].
Ou seja, tanto faz se são ratos fêmeas ou machos, o efeito nefasto do estrogênio é o mesmo: impacta destrutivamente o cérebro. É o estrogênio sendo estrogênio, elevado e sem oposição da progesterona.
Outro trabalho em ratas mostrou que “os efeitos neurotóxicos do estradiol causam uma cascata de aberrações neuroendócrinas que resultam em aciclicidade anovulatória” [C].
Mais um grupo diferente de cientistas, trabalhando na mesma direção, conclui que “começa a emergir uma hipótese unificada do papel do estradiol na senescência reprodutiva” [C] e que é o estradiol que acelera a senescência reprodutiva. E agregam que “foi demonstrado que exposição crônica ao estradiol resulta na destruição de mais de 60% de todos os neurônios beta-endorfínicos do núcleo arcuato” [C], no cérebro.
Cientistas também demonstraram que o naltrexone [LDN] pode ser um fator terapêutico nesse sentido, considerando que opioides endógenos podem “modular o efeito inibitório exercido por estrógenos na secreção de LH em humanos” [D].
Estudiosos demonstraram mais de uma vez o efeito neurotóxico do estrogênio [F].
Capaz de inibir os opioides naturais do cérebro, o aumento dos estrógenos resulta em alteração do LH plasmático que, no tempo, pode levar a ovários anovulatórios ou policísticos. E concluem que “o efeito neurotóxico do estradiol pode contribuir para um bom número de desordens reprodutivas em humanos e animais com resultante aberração da função hipotalâmica como seu maior componente” [F].
Outro trabalho repete o achado [G] em animais e o impacto sobre hipotálamo e também o efeito em termos de inchaço da hipófise [G]; e a progressiva falta de resposta dos folículos ovarianos [H]. E é certo, ao mesmo tempo, que o impacto do estrogênio sobre o núcleo arcuato do hipotálamo certamente produzirá outros efeitos clínicos, considerando que essa região do cérebro possui múltiplas funções, não apenas sobre o aparelho reprodutivo [K].
Levando em conta, particularmente, que a exposição a estrógenos pode levar a uma “desconexão funcional-anatômica do núcleo arcuato com áreas mais anteriores do hipotálamo” [G].
Como vários outros estudos, existe um deles que é bem taxativo sobre os danos dos estrógenos ao cérebro. E que conclui: “existe evidência morfológica que indica que os efeitos aqui citados do estrogênio envolvem mudanças nos neurônios do núcleo arcuato do hipotálamo e sua glia, incluindo mudanças na organização de membranas pericariais e na sinaptologia daquele núcleo e na carga de peroxidase na astroglia” [H]. Novamente em animais machos e fêmeas.
Portanto, fica estabelecido um vínculo entre doença de Alzheimer, demência e estrógenos. Como também a predisposição maior de mulheres a essa doença.
Epidemiologicamente esse vínculo já foi estabelecido mais de uma vez, dando como resultado a maior prevalência de degeneração cerebral no envelhecimento em mulheres [I]. E que está associado a gonadotrofinas elevadas [LH e FSH] conforme destaca um trabalho [I][J].
De toda forma, “os inesperados resultados do Women´s Health Initiative Memory Study, que relataram um aumento do risco de demência e comprometimento cognitivo em mulheres pós-manopausadas usando uma combinação de estrogênio e progestina, levantou sérias questões sobre os efeitos protetores do estrogênio” [I]. Lembrando que progestina é a progesterona tóxica, patenteada, que já deveria ter sido removida do mercado, caso a ciência fosse seguida.
O fato é que estrógenos [aumentados] não estão isentos. Estão implicados como uma das causas de demência e Alzheimer tanto em humens quanto – principalmente – em mulheres.
Concluindo, o fato incontornável é que o leitor engajado em ciência pode percorrer a bibliografia, toda a pesquisa a respeito do efeito da longa exposição da pessoa a estrógenos – sem oposição da progesterona – e, invariavelmente, verá reforçada a tese do efeito patogênico do estrogênio em várias doenças “da idade”. Demência, por exemplo.
No entanto, em vez de se perguntar sobre a relação entre uso de estrogênio e demência, na mulher em particular [cujo padrão de estrogênio plasmático já é inicialmente mais alto que no homem], quela será a postura clínio-terapêutica do doutor médioɁ Será que ele vai pensar um milhão de vezes antes de “repor” estrogênio na mulher menopausadaɁ Ele irá se perguntar sobre a queda de progesterona nessa pacienteɁ Ele sabe que o estrogênio nos tecidos cresce ao longo da menopausaɁ
Ele vai advertir à mulher que estrogênio é um perigo na gênese da demência e do AlzheimerɁ Ou que o estrogênio é cancerígeno [ver aqui] e neurotóxico [ver aqui]Ɂ Ou que uma menopausa clinicamente ruim, problemática, invariavelmente pode ser causada por excesso de estrogênio [ver aqui]Ɂ Ou irá, simplesmente, ignorando – propositadamente ou não – todas as evidências, “repor” estrogênio e ignorar a raiz do problemaɁ
O que você achaɁ
GM Fontes, Brasília, 27-3-24
As informações aqui presentes não pretendem servir para uso diagnóstico, prescrição médica, tratamento, prevenção ou mitigação de qualquer doença humana. Não pretendem substituir a consulta ao profissional médico ou servir como recomendação para qualquer plano de tratamento. Trata-se de informações com fins estritamente educativos. Nenhuma das notas aqui presentes, neste blog, conseguirá atingir o contexto específico do paciente singular, nem doses, modo de usar etc. Este trabalho compete ao paciente com seu médico. Isso significa que nenhuma dessas notas - necessariamente parciais - substitui essa relação.
Referências ________________
[A] ROSSMANITH W G, 1995. Gonadotropin secretion during aging in women: review article. Exp Gerontol. 1995 May-Aug;30(3-4):369-81. doi: 10.1016/0531-5565(94)00030-7. PMID: 7556515 DOI: 10.1016/0531-5565(94)00030-7 “Biological aging during the postmenopause markedly affects the neuroendocrine control of gonadotropin release. The determination of the age-related dynamics on gonadotropin secretion in postmenopausal women have proven to be a valid approach for delineating changes as a function of progressive age. As a result, major functional derangements, primarily at a hypothalamic rather than a pituitary site, have been determined as concomitants of aging in women. Furthermore, aging may impair the negative feedback sensitivity to ovarian sex steroids, and interfere with the central neurotransmitter activity governing gonadotropin secretion. The data reviewed on gonadotropin secretion in postmenopausal women support the view that the age-related processes are related to a hypothalamic rather than to a pituitary hypofunction”.
[B] BRAWER K R SCHIPPER J 1980. Ovary-dependent degeneration in the hypothalamic arcuate nucleus. Endocrinology 107, 274-279, 1980. Endocrinology. 1980 Jul;107(1):274-9. doi: 10.1210/endo-107-1-274. PMID: 7189710 DOI: 10.1210/endo-107-1-274 “The effects of estradiol valerate and constant light exposure on the histological appearance of the arcuate nucleus were assessed in female rats. Both of these treatments caused significant increases in the numbers of reactive microglial cells and astrocytic granules in the nucleus. Ovariectomy before either treatment prevented the glial reaction, indicating that the experimental manipulations triggered the secretion of an ovarian product which appears to be selectively toxic to the arcuate nucleus. The fact that monthly injections of estradiol valerate in male rats produced the same profile of degeneration in the arcuate nucleus suggests that the neuropathological agent may itself be estradiol. Ovariectomy also significantly reduced arcuate microglial reactivity associated with normal aging, which suggests that cyclic surges of endogenous estradiol may be capable of gradually producing an arcuate lesion. This phenomenon may accout for the hypothalamic reproductive failure associated with normal aging in the rat”.
[C] DESJARDINS G C BEAUDET A MEANEY M J, 1995. Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic aging. Exp Gerontol. 1995 May-Aug;30(3-4):253-67. doi: 10.1016/0531-5565(94)00040-a. PMID: 7556506 DOI: 10.1016/0531-5565(94)00040-a “Over the course of normal aging, all female mammals with regular cycles display an irreversible arrest of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis until death. Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to emerge. Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated reproductive senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure results in the destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals. Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu opioid receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin or other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the neuroendocrine effects of estradiol by antioxidant treatment also prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin neurons along with the paradoxical opioid supersensitivity which ensues, provides a unifying framework in which to interpret the diverse features that characterize the reproductively senescent female”.
[D] MELIS G B PAOLETTI A M, 1984. Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women using naloxone. Neuroendocrinology 39, 60-63, 1984. Neuroendocrinology. 1984 Jul;39(1):60-3. doi: 10.1159/000123956 PMID: 6087184 DOI: 10.1159/000123956 “To evaluate whether ovarian steroid environment may modify endogenous opioid activity at hypothalamic-pituitary level, the effects of naloxone infusion (1.2 mg/h for 4 h) on gonadotropin secretion were studied in 5 postmenopausal women who had natural menopause 3-5 years before the study. In addition, naloxone infusion was repeated in the same subjects after chronic oral treatment with conjugated estrogens (1.25 mg/day in two divided doses for 20 days). Before treatment, both the circulating levels of estrogens and plasma gonadotropins were in the normal range for postmenopausal women and naloxone infusion did not induce any significant modification of gonadotropin secretion. In contrast, after estrogen therapy, and the consequent rise in estrogen plasma levels, naloxone infusion induced a significant LH increase (p less than 0.01) starting during the last hour of treatment. These findings seem to confirm that endogenous opioid peptides may modulate the inhibitory effect exerted by estrogens on LH secretion, in humans”.
[E] SANTAGATI S MELCANGI R C 1994. Estrogen receptor is expressed in different types of glial cells in culture. J Neurochem. 1994 Dec;63(6):2058-64. doi: 10.1046/j.1471-4159.1994.63062058.x. PMID: 7964723 DOI: 10.1046/j.1471-4159.1994.63062058.x “Estrogens derived from the aromatization of androgens are believed to be responsible for the induction of the sexual differentiation of the CNS interacting with specific estrogen receptors (ER) present in developing neurons. However, the brain cellular distribution of ER is not so well documented. The aim of this study was to investigate the qualitative and quantitative expression of ER mRNA in well characterized cultures of rat type 1 and type 2 astrocytes and of oligodendrocytes by polymerase chain reaction. A series of amplifications with a set of primers spanning along the entire ER mRNA was utilized in the different types of glial cells, in a positive control (uterus), and in a negative control (SK-N-BE cell line) previously shown to be devoid of ER. The data obtained show that ER mRNA is expressed in all three types of glial cell analyzed in almost equal amounts, which are 25-50 times lower than those in the uterus. The mRNA expressed in the glia is homologous with that expressed in the uterine tissue”.
[F] BRAWER J R BEAUDET A DESJARDINS G C, 1993. Pathologic effect of estradiol on the hypothalamus. Biol Reprod. 1993 Oct;49(4):647-52. doi: 10.1095/biolreprod49.4.647. PMID: 8218628 DOI: 10.1095/biolreprod49.4.647 “Estradiol provides physiological signals to the brain throughout life that are indispensable for the development and regulation of reproductive function. In addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major component”.
[G] BRAWER J R NAFTOLIN F MARTIN J, 1978. Effects of a single injection of estradiol valerate on the hypothalamic arcuate nucleus and on reproductive function in the female rat. Endocrinology. 1978 Aug;103(2):501-12. doi: 10.1210/endo-103-2-501. PMID: 744098 DOI: 10.1210/endo-103-2-501 “Young adult cyclic female rats were each injected with 2 mg estradiol valerate (EV) in sesame oil. Controls received an equivalent volume of sesame oil. Within 2 months after injection, most of the EV-treated animals showed persistent vaginal estrus and small polyfollicular ovaries as well as pathological changes in the hypothalamic arcuate nucleus. This pathological process was gradually progressive such that by 6 months after EV injection, the basal lateral region of the nucleus contained numerous reactive microglia, astrocytes, and degenerating elements of the neuropil. The experimental rats had elevated plasma PRL and GH concentrations which gradually diminished. Plasma estradiol concentration remained elevated 2 months after injection, while plasma LH and FSH concentrations stayed within the high and low normal range, respectively. The pituitary glands of injected animals weighed significantly more than those of controls 5.5 months after injection, but the enlarged glands did not cause hypothalamic compression. As mechanical anterior deafferentation of the medial basal hypothalamus has previously been shown to produce similar endocrine and reproductive alterations, it may be that estradiol treatment results in a functional-anatomical disconnection of the arcuate nucleus from the more anterior hypothalamic areas that regulate cyclicity. Whether this type of functional-anatomical phenomenon underlies other varieties of induced or secondary acyclicity in females remains to be determined.
[H] HUNG A J STANBURY M G SHANABROUGH M, 2003. Estrogen, synaptic plasticity and hypothalamic reproductive aging. Exp Gerontol. 2003 Jan-Feb;38(1-2):53-9. doi: 10.1016/s0531-5565(02)00183-3. PMID: 12543261 DOI: 10.1016/s0531-5565(02)00183-3 “Unlike primates who undergo ovarian failure and loss of sex steroids at the end of reproduction, aging rodents undergo constant vaginal estrus followed by constant diestrus and finally anestrus, which indicates the absence of responsive ovarian follicles. The latter state is analogous to menopause in women. The timing of the appearance of constant estrus is determined by many factors including estrogen exposure in the brain during development and the number of times that the animal gets pregnant. The chief site of this reproductive aging in rat brains is the arcuate nucleus of the hypothalamus. The transition from normal cycles to constant estrus parallels the females' gradually decreased ability to respond to administered estradiol with a cycle of inhibition followed by disinhibition of gonadotrophin-releasing hormone. Evidence has accumulated indicating this to be due to a loss of the rat's ability to respond to markedly elevated estradiol with the usual arcuate nucleus neuro-glial plasticity that supports the estrogen-induced gonadotrophin surge (EIGS). Just as male rats are not capable of an EIGS, aged females loose this ability through repeated EIGS. Experiments indicate that in male rats the hypothalamic synaptology that develops as a result of exposure to testicular androgens in the perinatal period (brain sexual differentiation) is a result of conversion of testosterone from the testes to estrogen in the brain and is therefore due to early estrogen exposure. Aging females appear to reach a synaptology similar to males and constant estrus as a result of repeated exposure to ovarian estrogens during their reproductive careers. The relative role of aging and hormonal factors remains unclear. Morphological evidence is presented that indicates the above effects of estrogen involve changes in hypothalamic arcuate nucleus neurons and glia, including changes in the organization of perikaryal membranes as well as arcuate nucleus synaptology and the load of peroxidase in the astroglia. A possible role for free radicals (reactive oxygen species) in hypothalamic reproductive aging has been proposed. Such a mechanism is supported by evidence that the anti-oxidant vitamin E delays the onset of constant estrus and the accumulation of glial peroxidase in aging female rats. However, since the synaptology and peroxidase load in constant estrus females is independent of the age at which the constant estrus occurs, it appears that the role of (repeated) estradiol exposure is more deterministic of hypothalamic failure than is aging, per se”.
[I] WEBBER K M CASADESUS G MARLATT M W, 2005. Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis. Ann N Y Acad Sci. 2005 Jun:1052:201-9. doi: 10.1196/annals.1347.020. PMID: 16024763 DOI: 10.1196/annals.1347.020 “Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids”.
[J] WEBBER K M CASADESUS G PERRY G, 2005. Gender differences in Alzheimer disease: the role of luteinizing hormone in disease pathogenesis. Alzheimer Dis Assoc Disord. 2005 Apr-Jun;19(2):95-9. doi: 10.1097/01.wad.0000165512.90864.3f. PMID: 15942328 DOI: 10.1097/01.wad.0000165512.90864.3f “Epidemiological data reporting the predisposition of women to Alzheimer disease has provided researchers with an important clue as to the identity of the driving pathogenic force and lead many to question the potential role of sex steroids, namely estrogen, in disease pathogenesis. However, while estrogen has become the primary focus of research in the field, inconclusive data regarding estrogen replacement therapy has lead some researchers to begin investigating the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. Recently, we proposed that an increase in gonadotropin concentrations, not the decrease in steroid hormone (eg, estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease. Based on this, we suggest that therapeutic interventions targeted at gonadotropins may both prevent disease in those patients currently asymptomatic or may halt, and even reverse, disease in those currently afflicted”.
[K] JOLY-AMADO A CANSELL C DENIS R G P, 2014. The hypothalamic arcuate nucleus and the control of peripheral substrates Best Pract Res Clin Endocrinol Metab. 2014 Oct;28(5):725-37. doi: 10.1016/j.beem.2014.03.003. Epub 2014 Apr 4. PMID: 25256767 DOI: 10.1016/j.beem.2014.03.003 “The arcuate nucleus (ARC) of the hypothalamus is particularly regarded as a critical platform that integrates circulating signals of hunger and satiety reflecting energy stores and nutrient availability. Among ARC neurons, pro-opiomelanocortin (POMC) and agouti-related protein and neuropeptide Y (NPY/AgRP neurons) are considered as two opposing branches of the melanocortin signaling pathway. Integration of circulating signals of hunger and satiety results in the release of the melanocortin receptor ligand α-melanocyte-stimulating hormone (αMSH) by the POMC neurons system and decreases feeding and increases energy expenditure. The orexigenic/anabolic action of NPY/AgRP neurons is believed to rely essentially on their inhibitory input onto POMC neurons and second-orders targets. Recent updates in the field have casted a new light on the role of the ARC neurons in the coordinated regulation of peripheral organs involved in the control of nutrient storage, transformation and substrate utilization independent of food intake”.
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