O estrogênio na degeneração do cérebro de homens e mulheres: mecanismos de ação [Parte 2 de 2]
O estrogênio corporal é um grande problema no envelhecimento.
[Imagem: 10-priznakov-demencii-2477]
[Continuação da nota -1 de 2 ]
Ou seja, de uma maneira geral, o princípio básico de ação do estrogênio e dos hormônios que ele aciona, é o de interferir rapidamente e seriamente com a respiração mitocondrial; como resultado, teremos a retenção de cálcio intracelular, como foi mencionado, mas também a produção de radicais livres contribuindo, ambos, para um processo excitatório que leva ao acúmulo de mais déficit de energia.
O organismo estrogenizado está na defensiva, declinou para o subótimo em termos de produção de energia.
Exatamente, esse processo promovido pelo estrogênio – claramente agindo como hormônio do estresse - converge naquela mesma direção comprometimento da produção de energia e excitação celular. É um processo que, ocorrendo muitos milhares de vezes, leva ao que nós conhecemos como os estágios do envelhecimento. Do mau envelhecimento tal como nos é familiar, associado a múltiplas doenças degenerativas.
E é assim porque aqueles danos, aquelas funções que vão sendo danificadas por uma infinita variedade de tipos de estresse – a partir do estrogênio, cortisol e demais hormônios do estresse - , vão determinando suas próprias respostas adaptativas, complexas, somando deterioração nos sistemas. E, ao final, produzindo problemas como Alzheimer, diabetes, doença cardiovascular, doenças autoimunes, endometriose e vários tipos de câncer.
Pensar nessa perspectiva, nos permite juntar “demência, falência cardíaca, doenças autoimunes, imunodeficiências e outras doenças do envelhecimento como processos semelhantes, que agem ao mesmo tempo, de forma que isso permite abordagens terapêuticas gerais e preventivas” [R. Peat].
A “abordagem antiestresse, antiestrógenos se torna fundamental na prevenção do envelhecimento” [R. Peat]. Do mau envelhecimento mais precisamente.
Sempre lembrando que “a natureza pró-estrogênica dos óleos insaturados é provavelmente a maior barreira para a eliminação radical da doença degenerativa” [R. Peat], sendo o papel das gorduras saturadas exatamente o contrário.
E, em especial, temos o papel da progesterona.
Boa parte do planejamento terapêutico pode ser concebida a partir da consciência de que a progesterona cumpre papel estratégico contra o estrogênio. E papel central no combate – junto com tireoide – contra a dominância estrogênica.
“Progesterona é o protetor básico anti-estrogênio no cérebro. Opera no sentido de proteger o cérebro em vários níveis [prevenindo a peroxidação lipídica, e citotoxicidade, danos pelo óxido nítrico, déficit de energia, edema etc.] e promove reparo e recuperação " [R. Peat].
Mais de uma vez foi examinado neste blog o antagonismo entre progesterona e estrogênio e como é central o papel da progesterona na modulação da ação do estrogênio para que esta se mantenha nos limites fisiológicos.
Ambos, portanto, progesterona e estrogênio, incidem diretamente sobre a produção de energia celular. É dessa forma que cumprem seu papel. O problema é que a progesterona declina com a idade [N], em um processo inseparável daquele do hipotireoidismo que também tende a ser frequentemente uma parte central do envelhecimento tal como se dá no nosso meio e com a alimentação usual.
Portanto, de uma maneira geral e na maioria dos casos, “a progesterona tem efeitos opostos ao estrogênio promovendo a produção de energia mitocondrial, ao mesmo tempo em que previne excitação excessiva. Junto com a pregnenolona, a progesterona é reconhecida como um neuroesteroide com ações anti-citotóxicas, com a capacidade de promover reparo e regeneração do sistema nervoso"[R. Peat].
Trabalhos científicos já evidenciaram que injeções de progesterona se mostraram terapêuticas, e capazes de reduzir edema craniano [C] em animais machos e fêmeas que sofreram lesão neuronal causada por traumas tipo contusão [B][D][E]. Progesterona funciona, portanto, como um neuroprotetor de primeira grandeza [F][G][M]. [Ver aqui ]
Na direção contrária, múltiplas evidências apontam para o papel neurotóxico dos estrógenos [H], inclusive na menopausa [I]. Em pesquisas [J] estrogênio também aparece implicado com comprometimento cognitivo e atividade epiléptica; e degeneração cerebral [K][O][Q] [S] e reprodutiva [L]. Estrogênio, por outro lado, comprovadamente, derruba a dopamina no cérebro [P]
Já foi explicado que o estrogênio ativa o cortisol e é carcinogênico [Ver aqui e aqui].
Estrogênio age sobre a glândula adrenal.
Estrogênio aciona ácidos graxos livres no plasma, liberando os óleos insaturados para exercerem sua ação nefasta. E vice-versa, óleos insaturados liberam o estrogênio do seu carreador proteico, tornando-o ativo, tóxico [T].
“O estrogênio ativa a reação de estresse adrenal através de hipotálamo e da hipófise e, por ações diretas sobre as glândulas adrenais, e através de uma variedade de efeitos indiretos, tais como o aumento dos ácidos graxos livres.
Também ativa a via bioquímica e citotóxica do ácido glutâmico e interfere com a inibição protetora da adenosina sobre os nervos. Tem efeitos direto e indireto na formação do óxido nítrico e do monóxido de carbono” [R. Peat], efeitos que, como foi já mencionado, interferem com a respiração mitocondrial.
Dessa forma, na perspectiva dessa abordagem energética e metabólica aqui referenciada, é bem importante entender que existe um elemento coerente que atravessa os vários processos degenerativos e que vai impactar na respiração celular com as consequências citadas lá atrás.
Nesse sentido entender o estrogênio com um hormônio que vai muito além do aparelho reprodutor e dos efeitos sobre o corpo feminino, permite um reposicionamento terapêutico de primeira ordem, já que dessa forma estaremos entrando na esfera mais determinante dos problemas degenerativos, em particular do cérebro.
Ficar refém das caixinhas, como a medicina dominante faz, tomando o estrogênio como hormônio “sexual” e o envelhecimento e/ou degeneração do cérebro como outra coisa, de outra esfera [e outra especialidade, a exemplo da geriatria] é a receita para o desastre terapêutico, para a compartimentalização terapêutica e, como já foi argumentado, para deixar de entender que as diferentes doenças crônicas são atravessadas /mediadas pelos mesmos fundamentos; pelas mesmas moléculas do estresse, pela básica inibição da respiração celular oxidativa [OXPHOS – fosforilação oxidativa].
Isto é, entender o papel do estrogênio no envelhecimento e no cérebro do homem e da mulher permite entender processos derivados de energia e nos quais o excesso de estrogênio explica processos degenerativos que vão desde a depressão até osteoporose.
Isso tudo significa que o estrogênio, para além dos seus efeitos fisiológicos, ao atuar em excesso [e sem oposição da progesterona] promove efeitos degenerativos e tóxicos de longo prazo que vão impactar o crescimento, desenvolvimento do animal, suas funções e a própria hereditariedade.
É como se o estrogênio – e demais hormônios do estresse – operassem como alter ego ou outra face da mesma moeda da doença crônico-degenerativa. Um fato. Embora não ainda o seja para a medicina oficial que continua alimentando a lenda do estrogênio “terapêutico” para osteoporose, para menopausa e que tais. E omitindo seu papel nas doenças, por exemplo, do aparelho reprodutor feminino, a exemplo da endometriose.
E, no entanto, as noções acima, sobre o protagonismo patogênico do estrogênio, são de primeira importância para o conjunto da clínica e da medicina em geral: conhecer até o final os efeitos dessa simples molécula e o impacto que ela tem sobre a vida e a própria natureza da vida entre nós.
Ou, no argumento de R. Peat, além de oferecer novos insights sobre energia biológica envelhecimento o reconhecimento de que o estrogênio ativa o sistema de hormônios do estresse - através da hipófise e adrenal - e opera como neurotóxico [impactando o cérebro] também nos traz claros insights em outros problemas tais como síndrome do ovário policístico, hirsutismo, hiperplasia adrenal, Cushing e outras afecções.
E a razão de fundo: o estrogênio está vinculado à intoxicação da produção de energia celular quando em excesso ou sem a oposição da progesterona.
GM Fontes, Brasília 18-4-24
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 ____________
[As referências abaixo integram - quase todas - o artigo de R. Peat intitulado Estrogen and brain aging in men and women: depression, energy, stress]
[A] SMITH D A WALKER B E, 1992. Evidence of hypothalamic involvement in the mechanism of transplacental carcinogenesis by diethylstilbestrol. Cancer Lett. 1992 Oct 30;67(1):55-9. doi: 10.1016/0304-3835(92)90008-j. PMID: 1423245 DOI: 10.1016/0304-3835(92)90008-j “Disruption of hypothalamic sex differentiation in the fetus is one hypothesis to explain female reproductive system anomalies and cancer arising from prenatal exposure to diethylstilbestrol (DES). To further test this hypothesis, breeding performance and behavior were monitored in a colony of mice exposed prenatally to DES, using a schedule previously shown to produce anomalies and cancer of the female reproductive system. Fertility decreased with age more rapidly in DES-exposed females than in control females. DES-exposed females were less accepting of the male than control females. These observations support the hypothesis of abnormal hypothalamic sex differentiation as a basic mechanism in DES transplacental carcinogenesis”.
[B] ROOF R L DUVDEVANI R, 1994. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp Neurol. 1994 Sep;129(1):64-9. doi: 10.1006/exnr.1994.1147. PMID: 7925843 DOI: 10.1006/exnr.1994.1147 “The ability of progesterone to reduce the cerebral edema associated with traumatic brain damage first became apparent when we observed that males had significantly more edema than females after cortical contusion. In addition, edema was almost absent in pseudopregnant female rats, a condition in which progesterone levels are high relative to estrogen. Progesterone injections given after injury also reduced edema and were equally effective in both males and females. The present experiment was done to determine if the progesterone-induced reduction in edema could also prevent secondary neuronal degeneration and reduce the behavioral impairments that accompany contusion of the medial frontal cortex. Progesterone-treated rats were less impaired on a Morris water maze spatial navigation task than rats treated with the oil vehicle. Progesterone-treated rats also showed less neuronal degeneration 21 days after injury in the medial dorsal thalamic nucleus, a structure that has reciprocal connections with the contused área”.
[C] ROOF R L DUVDEVANI R HEYBURN J W, 1996. Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective. Exp Neurol. 1996 Apr;138(2):246-51. doi: 10.1006/exnr.1996.0063. PMID: 8620923 DOI: 10.1006/exnr.1996.0063 “Cerebral edema is a serious side effect of traumatic brain injury. We have previously established that progesterone injections, initiated within 1 h after cortical contusion injury, reduced edema when assessed 3 days later. To determine how rapidly progesterone can reduce edema, male and female rats were given the hormone 1 h after damage to the medial frontal cortex, and edema levels were assessed between 2 h and 7 days postinjury. Progesterone decreased edema with 6 h of the injury and continued to be effective for the duration of treatment. In addition, we assessed whether progesterone injections are effective when delays are imposed between injury and initiation of treatment. Male and female rats received progesterone after postinjury delays 6, 24, or 48 h. Progesterone was effective in reducing edema when treatment was delayed until 24 h after injury”.
[D] ROOF R L HOFFMAN S W STEIN D G, 1997. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol. 1997 May;31(1):1-11. doi: 10.1007/BF02815156. PMID: 9271001 DOI: 10.1007/BF02815156 “The gonadal hormone, progesterone, has been shown to have neuroprotective effects in injured nervous system, including the severity of postinjury cerebral edema. Progesterone's attenuation of edema is accompanied by a sparing of neurons from secondary neuronal death and with improvements in cognitive outcome. In addition, we recently reported that postinjury blood-brain barrier (BBB) leakage, as measured by albumin immunostaining, was significantly lower in progesterone treated than in nontreated rats, supporting a possible protective action of progesterone on the BBB. Because lipid membrane peroxidation is a major contributor to BBB breakdown, we hypothesized that progesterone limits this free radical-induced damage. An antioxidant action, neuroprotective in itself, would also account for progesterone's effects on the BBB, edema, and cell survival after traumatic brain injury. To test progesterone's possible antiperoxidation effect, we compared brain levels of 8-isoprostaglandin F2 alpha (8-isoPGF2 alpha), a marker of lipid peroxidation, 24, 48, and 72 h after cortical contusion in male rats treated with either progesterone or the oil vehicle. The brains of progesterone treated rats contained approximately one-third of the 8-isoPGF2 alpha found in oil-treated rats. These data suggest progesterone has antioxidant effects and support its potential as a treatment for brain injury”.
[E] GALANI R HOFFMAN S W STEIN D G, 2001. Effects of the duration of progesterone treatment on the resolution of cerebral edema induced by cortical contusions in rats. Restor Neurol Neurosci. 2001;18(4):161-6. PMID: 11847439 “PURPOSE. The aim of the present study was to assess the effect of different durations of administration of progesterone (4 mg/kg) on the resolution of edema 6 days after medial frontal cortex contusions (MFC) in male adult rats. Methods: Animals sustaining injury were injected with progesterone or its vehicle for 3 days or for 5 days beginning the first hour after surgery. On the 6th day the rats were killed and their brain water content was measured. Results: We confirmed the presence of edema six days after MFC. However, both 3 and 5 days of treatment with progesterone significantly reduced edema in the injured brains but the five days of treatment were more effective. The effects of progesterone depend upon the duration of the treatment because there are two waves of edema. The first phase begins within a few hours of the injury and the second starts several days later. Conclusions: Our data are consistent with earlier findings showing that longer durations of progesterone administration lead to more complete behavioral recovery as well as to an increased number of surviving neurons”.
[F] JIANG N CHOPP M STEIN D, 1996. Progesterone is neuroprotective after transient middle cerebral artery occlusion in male rats. Brain Res. 1996 Sep 30;735(1):101-7. doi: 10.1016/0006-8993(96)00605-1. PMID: 8905174 DOI: 10.1016/0006-8993(96)00605-1 “Progesterone (PROG) is a neurosteroid, possessing a variety of functions in the central nervous system. Exogenous PROG has been shown to reduce secondary neuronal loss in conjunction with attenuated brain edema after cerebral contusion and to reduce brain edema after focal cerebral ischemia. In the present study, we assessed the neuroprotective potential of PROG in a model of focal cerebral ischemia in the rat. Forty-eight male Wistar rats were randomly assigned to 4 groups, i.e. pretreatment with water soluble PROG, or dimethyl sulfoxide (DMSO) dissolved PROG, or DMSO as control or delayed treatment with DMSO dissolved PROG. Middle cerebral artery occlusion (MCAO) was induced by insertion of an intraluminal suture and reperfusion was performed by withdrawing the suture. Pretreatments were initiated 30 min before MCAO via intraperitoneal injection. Delayed treatment was initiated upon reperfusion following 2 h of MCAO. Infarct volume, body weight loss, and neurological deficit were measured 48 h after MCAO. Pre- and delayed treatment with DMSO dissolved PROG resulted in a 39% (P < 0.05) and 34% (P < 0.05) reduction in cerebral infarction, respectively, along with decreased body weight loss and improved neurological function as compared to control animals, whereas no statistically significant reduction in infarct volume by water soluble PROG was found. We demonstrated that administration of PROG to the male rat before or 2 hours after onset of MCAO reduces ischemic cell damage and improves physiological and neurological function 2 days after stroke. These results suggests potential therapeutic properties of PROG in the management of stroke”.
[G] SCHUMACHER M ROBEL P BAULIEU E E, 1996. Development and regeneration of the nervous system: a role for neurosteroids. Dev Neurosci. 1996;18(1-2):6-21. doi: 10.1159/000111391. PMID: 8840083 DOI: 10.1159/000111391 “Several steroids, termed 'neurosteroids', are synthesized from cholesterol within both the central and peripheral nervous systems. These include pregnenolone and its sulfate ester, progesterone and its 5 alpha-reduced metabolites. Dehydroepiandrosterone, mainly in its sulfated form, also remains present in the brain long after removal of the steroidogenic endocrine glands. Its biosynthesis in brain remains an open possibility, but the pathways involved are unknown. Little information is available concerning the role of neurosteroids during the maturation of the nervous system, although they are already synthesized by glial cells and by some populations of neurons during embryonic life. Cell culture experiments suggest that neurosteroids may increase the survival and differentiation of both neurons and glial cells. In the adult nervous system, neurosteroids modulate neurotransmission by acting directly on the neuronal membrane and also produce structural changes in neurons and in astrocytes. Studies of neurosteroid levels are currently conducted to examine their possible role during aging. We have recently reported that progesterone, synthesized by Schwann cells, promotes the formation of new myelin sheaths after lesion of the mouse sciatic nerve. Thus, neurosteroids may also play an important role during regeneration of the nervous system”.
[H] NAKAGAWA-YAGI Y OGANE N, 1996. The endogenous estrogen metabolite 2-methoxyestradiol induces apoptotic neuronal cell death in vitro. Life Sci. 1996;58(17):1461-7. doi: 10.1016/0024-3205(96)00116-6. PMID: 8622572 DOI: 10.1016/0024-3205(96)00116-6 “We examined the effects of 2-methoxyestradiol, a metabolite of estradiol, on cell death in retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cell cultures. Cell death was induced by 2-methoxyestradiol in a concentration-dependent manner. Estradiol and 2-methoxyestradiol failed to induce cell death. The cell death response to 2-methoxyestradiol was sensitive to the protein synthesis inhibitor cycloheximide and the apopain inhibitor Ac-Asp-Glu-Val-Asp-H(aldehyde). 2-Methoxyestradiol also induced internucleosomal for and endogenous neuroactive steroid metabolite in the etiology of some neurodegenerative diseases”.
[I] WISE P M KASHON M L K, 1997. Aging of the female reproductive system: a window into brain aging. Recent Prog Horm Res. 1997:52:279-303; discussion 303-5. PMID: 9238857 “The menopause marks the permanent end of fertility in women. It was once thought that the exhaustion of ovarian follicles was the single, most important explanation for the transition to the menopause. Over the past decade, this perception has gradually changed with the realization that there are multiple pacemakers of reproductive senescence. We will present evidence that lends credence to the hypothesis that the central nervous system is a critical pacemaker of reproductive aging and that changes at this level contribute to the timing of the menopause. Studies demonstrate that an increasing de-synchronization of the temporal order of neuroendocrine signals may contribute to the accelerated rate of follicular loss that occurs during middle age. We suggest that the dampening and destabilization of the precisely orchestrated ultradian, circadian, and infradian neural signals lead to miscommunication between the brain and the pituitary-ovarian axis. This constellation of hypothalamic-pituitary-ovarian events leads to the inexorable decline of regular cyclicity and heralds menopausal transition”.
[J] WEILAND N G, 1992. Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus. Endocrinology. 1992 Aug;131(2):662-8. doi: 10.1210/endo.131.2.1353442. PMID: 1353442 DOI: 10.1210/endo.131.2.1353442 “Estradiol alters cognitive function and lowers the threshold for seizures in women and laboratory animals. Both of these activities are modulated by the excitatory neurotransmitter glutamate in the hippocampus. To assess the hypothesis that estradiol increases the sensitivity of the hippocampus to glutamate activation by increasing glutamate binding sites, the densities of N-methyl-D-aspartate (NMDA) agonist sites (determined by NMDA displaced glutamate), competitive antagonist sites (CGP 39653), noncompetitive antagonist sites (MK801) as well as the non-NMDA glutamate receptors for kainate and AMPA (using kainate and CNQX, respectively) were measured using autoradiographic procedures. Two days of estradiol treatment increased the density of NMDA agonist, but not of competitive nor noncompetitive NMDA antagonist binding sites exclusively in the CA1 region of the hippocampus. The density of noncompetitive NMDA antagonist sites, however, was decreased in the dentate gyrus by estradiol treatment. Ovarian steroids had no effect on the density of kainate or AMPA receptors in any region of the hippocampus examined. These data indicate that the agonist and antagonist binding sites on the NMDA receptor/ion channel complex are regulated independently by an as yet unidentified mechanism, and that this regulation exhibits regional specificity in the hippocampus. The increase in NMDA agonist sites with ovarian hormone treatment should result in an increase in the sensitivity of the hippocampus to glutamate activation which may mediate some of the effects of estradiol on learning and epileptic seizure activity”.
[K] LEW G M, 1993. Changes in microtubular tau protein after estrogen in a cultured human neuroblastoma cell line. Gen Pharmacol. 1993 Nov;24(6):1383-6. doi: 10.1016/0306-3623(93)90423-u. PMID: 7906661 DOI: 10.1016/0306-3623(93)90423-u “1. Cultured human SH-SY5Y neuroblastoma cells were used to determine whether 17-beta-estradiol affects the metabolism of microtubular tau protein. 2. After 24-hr treatment 17-beta-estradiol (10(-7) M) increased 50 kDa tau protein in the cytoplasmic (supernatant) fraction and decreased it in the membrane (pellet) fraction. 3. The increase in cytoplasmic tau was accompanied by increases in total protein in both cytoplasmic and membrane fractions, 50 and 70%, respectively. 4. The estrogen (10(-7) M) also caused a 31% reduction in the total number of cells”.
[L] RODRIGUEZ P FERNÃNDEZ-GALAZ C, 1993. Controlled neonatal exposure to estrogens: a suitable tool for reproductive aging studies in the female rat. Biol Reprod. 1993 Aug;49(2):387-92. doi: 10.1095/biolreprod49.2.387. PMID: 8373965 DOI: 10.1095/biolreprod49.2.387 Erratum in Biol Reprod 1993 Dec;49(6):1384 “The present study was designed to determine whether the modification of exposure time to large doses of estrogens provided a reliable model for early changes in reproductive aging. Silastic implants containing estradiol benzoate (EB) in solution were placed into 5-day-old female Wistar rats and removed 1 day (Ei1 group) or 5 days (Ei5) later. In addition, 100 micrograms [corrected] EB dissolved in 100 microliters corn oil was administered s.c. to another group (EI). Control rats received either vehicle implants or 100 microliters corn oil. Premature occurrence of vaginal opening was observed in all three estrogenized groups independently of EB exposure. However, females bearing implants for 24 h had first estrus at the same age as their controls and cycled regularly, and neither histological nor gonadal alterations could be observed at 75 days. Interestingly, they failed to cycle regularly at 5 mo whereas controls continued to cycle. On the other hand, the increase of EB exposure (Ei5, EI) resulted in a gradual and significant delay in the onset of first estrus and in a high number of estrous phases, as frequently observed during reproductive decline. At 75 days, the ovaries of these last two groups showed a reduced number of corpora lutea and an increased number of large follicles. According to this histological pattern, ovarian weight and progesterone (P) content gradually decreased whereas both groups showed higher estradiol (E2) content than controls. This resulted in a higher E2:P ratio, comparable to that observed in normal aging rats.(ABSTRACT TRUNCATED AT 250 WORDS)”.
[M] SCHUMACHER M ROBERT F BAULIEU E E, 1999. [Neurosteroids: trophic effects in the nervous system] [Article in French] J Soc Biol. 1999;193(3):285-92. PMID: 10542959 “Some steroids, named "neurosteroïds", can be synthesized from cholesterol within both the central and peripheral nervous systems. Thus, pregnenolone and progesterone persist in the brain and in peripheral nerves long after removal of the steroidogenic endocrine glands by castration and adrenalectomy. The role of neurosteroids during the development of the nervous system is not well known, although they are synthesized by glial cells and some populations of neurons already during embryonic life. Cell culture experiments suggest that neurosteroids may influence the survival and differentiation of neurons and glial cells. In the adult nervous system, neurosteroids play an important role during regeneration. Progesterone is indeed synthesized by Schwann cells in peripheral nerves, where it plays an important role in the formation of new myelin sheaths after lesion. This is the first demonstration of a vital role for a neurosteroid in the nervous system”.
[N] O´ROURKE M T LIPSON S F, 1996. Ovarian function in the latter half of the reproductive lifespan. Am J Hum Biol. 1996;8(6):751-759. doi: 10.1002/(SICI)1520-6300(1996)8:6<751::AID-AJHB7>3.0.CO;2-W PMID: 28561458 DOI: 10.1002/(SICI)1520-6300(1996)8:6<751::AID-AJHB7>3.0.CO;2-W “The relationship of age to four aspects of ovarian function was investigated: daily progesterone levels, pulsatile progesterone secretion, follicular and luteal estradiol levels, and preovulatory estradiol levels. Daily progesterone levels decrease after age 40. Pulsatile progesterone secretion remains approximately stable with age, though older women have somewhat higher late luteal activity. Daily follicular and luteal estradiol levels decrease with advancing age, but preovulatory peak estradiol remains stable. Some of these changes undoubtedly have negative effects on fecundity, such as lower follicular estradiol and average progesterone, via effects on endometrial development and support. But other changes identified, such as stability of preovulatory estradiol levels and thereby presumptive capacity to stimulate a luteinizing hormone (LH) surge despite lower follicular and luteal levels, as well as increased pulsatile progesterone secretion around the time of implantation, appear designed to conserve and maintain function. Thus, ovarian endocrine function over the course of reproductive life represents a process of change, but not one of generalized functional decline. Rather, aging with respect to ovarian endocrine function may proceed on a track, or on multiple tracks, which are largely separable from the continual depletion of oocyte stores which occurs over the lifetime”. © 1996 Wiley-Liss, Inc”.
[O] BRAWER J R BEAUDET A DESJARDINS G C, 1993. Pathologic effect of estradiol on the hypothalamus. Biol Reprod, 1993 Oct, 49:4, 647-52. "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."
[P] SHEBA M MOHANKUMAR J BADRINARAYANAN S, 2011. Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia. Am J Physiol Regul Integr Comp Physiol. 2011 Mar; 300(3): R693–R699. Published online 2010 Dec 22. doi: 10.1152/ajpregu.00481.2010 PMCID: PMC3064273 PMID: 21178126 “Estrogens are known to cause hyperprolactinemia, most probably by acting on the tuberoinfundibular dopaminergic (TIDA) system of the hypothalamus. Dopamine (DA) produced by TIDA neurons directly inhibits prolactin secretion and, therefore, to stimulate prolactin secretion, estrogens inhibit TIDA neurons to decrease DA production. However, the mechanism by which estrogen produces this effect is not clear. In the present study, we used a paradigm involving chronic exposure to low levels of estradiol-17β (E2) to mimic prolonged exposures to environmental and endogenous estrogens. We hypothesized that chronic exposure to low levels of E2 induces oxidative stress in the arcuate nucleus (AN) of the hypothalamus that contains TIDA neurons and causes nitration of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA. This results in a significant decrease in DA and consequently, hyperprolactinemia. To investigate this, adult, intact female cycling rats were implanted with slow-release E2 pellets (20 ng/day) for 30, 60, or 90 days and were compared with old (16–18 mo old) constant estrous (OCE) rats. Chronic E2 exposure significantly increased the expression of glial fibrillary acidic protein and the concentrations of interleukin-1β (IL-1β) and nitrate in the AN that contains perikarya of TIDA neurons and increased nitration of TH in the median eminence (ME) that contains the terminals. These levels were comparable to those seen in OCE rats. We observed a significant decrease in DA concentrations in the ME and hyperprolactinemia in an exposure-dependent manner similar to that seen in OCE rats. It was concluded that chronic exposure to low levels of E2 evokes oxidative stress in the AN to inhibit TIDA neuronal function, most probably leading to hyperprolactinemia”. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064273/#:~:text=PMID%3A%2021178126-,Chronic%20estradiol%20exposure%20induces%20oxidative%20stress%20in%20the%20hypothalamus,hypothalamic%20dopamine%20and%20cause%20hyperprolactinemia
[Q] DESJARDINS G C BEAUDET A SCHIPPER H M, 1992. Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity. Endocrinology, 1992 Nov, 131:5, 2482-4 "Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in the hypothalamic arcuate nucleus."
[R] VATASSERY G T TIMOTHY B, 1999. High doses of vitamin E in the treatment of disorders of the central nervous system in the aged2. The American Journal of Clinical Nutrition Volume 70, Issue 5, November 1999, Pages 793-801 https://doi.org/10.1093/ajcn/70.5.793Get rights and content “Oxidative stress is a putative factor in the pathogenesis of many human disorders of the central nervous system. Therefore, antioxidants such as vitamin E have become attractive as therapeutic agents in the treatment of several diseases. In addition, vitamin E seems to play a specific role in the nervous system. As a result, vitamin E has been used in pharmacologic doses in the treatment of disorders such as Parkinson disease, Alzheimer disease, and tardive dyskinesia. One investigation showed that the use of 2000 IU all-rac-α-tocopheryl acetate is beneficial in the treatment of Alzheimer disease. Similar doses of vitamin E, however, were not beneficial for delaying the progression of Parkinson disease. In other studies, dosages ≥400 IU vitamin E/d were found to be beneficial in the treatment of tardive dyskinesia, although this finding was not confirmed in a larger cooperative study conducted by the Veterans Administration. Even though the efficacy of vitamin E in the management of cardiovascular disease has been shown, the potential role of vitamin E in the treatment of cerebrovascular disease remains essentially unknown. The experience from 2 large clinical trials involving the oral intake of 2000 IU vitamin E/d suggests that vitamin E is relatively safe at this dosage for periods <2 y. However, the safety and efficacy of supplemental vitamin E over periods of many years in the prevention of neurologic diseases has not been adequately explored”.
[S] 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”.
[T] WIDMAIER E P ROSEN K ABBOTT B, 1992. Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis in rats. Endocrinology. 1992 Nov;131(5):2313-8. doi: 10.1210/endo.131.5.1330498. PMID: 1330498 DOI: 10.1210/endo.131.5.1330498 “Intravenous administration of Intralipid 10% increases blood levels of essential free fatty acids. In rats and man, this is associated with an inhibition of GH secretion from the anterior pituitary. Because GH is lipolytic, the inhibition of its secretion may represent a negative feedback action of the fats on pituitary sensitivity to GH-releasing hormone. Since corticosterone, the final secretory product of the rat hypothalamic-pituitary-adrenocortical (HPA) axis, is also lipolytic, we tested the hypothesis that FFA would inhibit the HPA axis. Rats were cannulated via the jugular vein and infused with different doses of heparin-Intralipid 10% or heparin-saline; sequential blood samples were obtained and analyzed for ACTH, corticosterone, FFA, and glucose. Intralipid at 2.85 ml/kg increased plasma FFA to over 3 meq/liter by 15 min, with a return to baseline by 60-90 min. There was no effect of the infusion on plasma osmolarity or pH. At 60 min, plasma ACTH levels were significantly elevated to over 1500 pg/ml in Intralipid-infused rats, but were unchanged in saline controls. This dose of Intralipid increased corticosterone levels by nearly 20-fold at 120 min. At 180 min, corticosterone levels were still significantly greater than those in saline controls. Lower doses of Intralipid also significantly elevated both FFA and corticosterone levels, but by 180 min, levels of both were similar to those in controls. The effects of Intralipid on corticosterone secretion could not be attributed to the presence of glycerol in the suspension, since glycerol infusions had no significant effect on steroid levels compared to those in saline controls. In dexamethasone-pretreated rats, there was no significant rise in plasma corticosterone after either of two Intralipid doses, suggesting that the action of Intralipid was at a site within the HPA axis above the adrenal gland. This finding also suggested that the high steroid levels after Intralipid treatment were not due to interference with the corticosterone RIA. This was verified by the finding that there was no increase in plasma immunoreactive corticosterone after Intralipid infusion into adrenalectomized rats. Intralipid also caused an increase in plasma glucose levels that was first significant at 60 min and declined to baseline by 180 min, possibly reflecting increased autonomic activity or peripheral insensitivity to insulin. The results suggest that high circulating FFA levels activate, rather than inhibit, the HPA axis in rats. Since stress activates glucocorticoid production and increases FFA levels due to lipolysis, it is possible that FFA and the HPA axis constitute a previously unrecognized positive feedback loop.(ABSTRACT TRUNCATED AT 400 WORDS)”
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