Estrogen and brain aging in men and women: Depression, energy, stress

Discussion in 'Articles' started by SHINE, Dec 14, 2012.

  1. SHINE

    SHINE MuscleHead

    Oct 11, 2010
    Estrogen and brain aging in men and women: Depression, energy, stress

    Although the incidence of Alzheimer's disease is 2 or 3 times as high among women as among men, there is a major campaign under way to convince the public that taking estrogen supplements will prevent the disease. Estrogen is now mainly promoted to prevent osteoporosis (another problem that is more common in women) and heart disease (which is more common in men).

    This substance, which came into medical use as "the female hormone" for the treatment of "female problems," especially for improving fertility, and then for preventing fertility as the oral contraceptive, is now being aimed primarily at the post-reproductive population, for problems that are essentially unrelated to femininity. It is, in fact, being presented to the public as something to prevent major age-related conditions.

    Brain degeneration, like osteoporosis, takes years to develop. Analysis of letters written by young women, for example, showed limited mental functioning in those who many years later developed Alzheimer's disease, and young women who have small bones are the ones most likely to develop osteoporosis later. It seems clear that the course of degenerative aging processes is set in young adulthood (or even earlier), and that it is never too early to be concerned with correcting processes that are going in the wrong direction. (See Walker, et al., 1988, and Smith, et al., 1992.)

    In "The Biological Generality of Progesterone" (1979) I proposed that the life-long trajectory of energy production and longevity was strongly influenced by prenatal nutrition and progesterone. This idea was based on work by people such as Marion Diamond, who showed that prenatal progesterone enlarges the cortex of the brain, and that estrogen makes it smaller, and Leonell Strong, who showed that a treatment that lowered the estrogen function in a young mouse could produce cancer-free offspring for several generations. Strong's work was very encouraging, because it showed that biological problems that had been "bred in" over many generations could be corrected by some simple metabolic treatments.

    Seeing these profoundly toxic long-range effects of estrogen, which shaped the animal's growth, development, function, and even its heredity, made it important to learn how estrogen works, because such fundamental changes covering the whole range of biology, produced by a simple little molecule, promised to reveal interesting things about the nature of life.

    Aging is an energy problem, and in the brain, which has extremely high energy requirements, interference with the energy supply quickly causes cells to die.

    I believe that estrogen's "principle," in all of its actions, is to interfere with the respiratory mode of energy production. This is an integrating principle that explains estrogen's immediate, direct effects on cells and organisms, which aren't explained by the idea that it acts on the genes through a specific "estrogen receptor." (It's hard to imagine, for example, how the "estrogen receptor" doctrine could explain the fact that a single injection of estrogen can kill a large portion of brain cells.) It explains why estrogen causes cells to take up water, allowing calcium to enter, activating various enzymes and cell division. On the organismic level, it explains why estrogen mimics "shock," releasing histamine and activating the nervous and glandular stress response system. The inefficiency of metabolism which doesn't use oxygen in the normal way causes glucose to be used rapidly, and this in itself is enough to trigger the release of pituitary ACTH and adrenal cortisol. The ACTH, and related hormones, liberate free fatty acids, which cells take up instead of glucose, and this (in the so-called Randall cycle) further limits the body's ability to oxidize glucose.

    People have spoken of "cascades" in relation to the adrenal glucocorticoids (e.g., cortisol) and estrogen, leading to cell damage, but really both of these hormonal cascades have to be seen as part of a more general collapse of adaptive systems, as a result of both chronic and immediate inadequacies of energy production.

    Estrogen activates the adrenal stress reaction by way of the hypothalamus and pituitary, by direct actions on the adrenal glands, and by a variety of indirect effects, such as the increase of free fatty acids. It activates the excitotoxic glutamic acid pathway, and interferes with protective adenosine inhibition of nerves. It has both direct and indirect ways of promoting the formation of nitric oxide and carbon monoxide. These, and other estrogen-promoted factors, quickly and seriously interfere with mitochondrial respiration. Many of these effects contribute to increased intracellular calcium and free radical production, contributing to both the excitatory excess and the energy deficit.

    The biochemical details of these cascades are mainly interesting because they show how many different kinds of stress converge on a few physiological processess--mitochondrial energy production, cellular excitation, and intercellular communication--which, when damaged thousands of times, lead to the familiar states of old age. These few functions, damaged by an infinite variety of stresses, have their own complexly adaptive ways of deteriorating, producing the various degenerative diseases.

    This perspective brings dementia, heart failure, autoimmunity, immunodeficiency and other diseases of aging together, in ways that allow generalized therapeutic and preventive approaches.

    The antistress, antiestrogen approaches become fundamental to prevention of aging.

    The pro-estrogenic nature of the unsaturated fatty acids is probably the biggest barrier to the radical elimination of degenerative diseases. Various saturated fatty acids, including butyric, octanoic, and palmitic, have protective effects on mitochondrial respiration.

    Progesterone is the basic brain-protective antiestrogen. It works to protect the brain at many levels (preventing lipid peroxidation, exitotoxicity, nitric oxide damage, energy deficit, edema, etc.) and it promotes repair and recovery.

    Progesterone in most cases has effects opposite to estrogen's, improving mitochondrial energy production while preventing excessive excitation. Along with pregnenolone, progesterone is recognized as a neurosteroid with anti-excitotoxic actions, with the ability to promote repair and regeneration of the nervous system. (Roof, Stein, Faden; Schumacher, et al.; Baulieu.)

    The use of aspirin, which reduces inflammation and inhibits the formation of neurotoxic prostaglandins, is known to be associated with a lower incidence of Alzheimer's disease, and in other contexts, it offers protection against estrogen. Naloxone, the antiendorphin, has been found to reverse some of the cumulative effects of stress, restoring some pituitary and ovarian function, and it promotes recovery after brain injury; in a variety of ways, it corrects some of estrogen's toxic effects.

    Adenosine helps to maintain brain glycogen stores, which are lost in stress and aging. Vitamin B12 protects against nitric oxide, and improves alertness.

    Pyruvic acid has brain-protective effects, apparently through its decarboxylation (producing carbon dioxide) rather than through its use as an energy source, since other ketoacids are similarly protective. (The ketoacids occur in some natural foods.) The directly brain-protective effect of carbon dioxide offers many clues that should be interpreted in relation to estrogen's toxicity, since many of their effects on nerves are opposite. Estrogen blocks the production of energy while it stimulates nerve cells to use energy more rapidly, and carbon dioxide promotes the production of energy, while restraining the excitation which expends energy. The presence of carbon dioxide is an indicator of proper mitochondrial respiratory functioning.

    Pharmaceutical blockers of glutamic acid transmission, and of calcium and sodium uptake, prevent some deterioration following brain injury, but the most physiological way to protect against those toxic processes is to maintain metabolic energy at a high level. Magnesium, which is protective against excitatory damage and is a calcium antagonist, tends to be retained in proportion to the activity of thyroid hormone.

    As I have discussed previously, progesterone alone has brought people out of post-epileptic dementia and senile dementia, but it is reasonable to use a combined physiological approach, including thyroid.

    Besides providing new insights into biological energy and aging, the recognition that estrogen activates the stresshormone system--the pituitary-adrenal system--also provides clear insights into other problems, such as the polycystic ovary syndrome, hirsutism, adrenal hyperplasia, Cushing's disease, etc.
    SO it's a good idea and to use an AI with amortizable hormones and keep estrogen down!!! The Old school Idea of using an estrogen blocker only if needed is right down being stupid :)

    Last edited: Dec 14, 2012
    Halo likes this.
  2. SHINE

    SHINE MuscleHead

    Oct 11, 2010
    [The references are clustered into groups, showing estrogen's indirect toxicity through its activation of the adrenal hormones, its direct brain-toxicity, and some of the interactions between these and fats, nitric oxide, etc.]


    Stress 1996 Jul;1(1):1-19 Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion. Sapolsky RM Department of Biological Sciences, Stanford University, Stanford, CA 94305. An extensive literature demonstrates that glucocorticoids (GCs), the adrenal steroids secreted during stress, can have a broad range of deleterious effects in the brain. The actions occur predominately, but not exclusively, in the hippocampus, a structure rich in corticosteroid receptors and particularly sensitive to GCs. The first half of this review considers three types of GC effects: a) GC-induced atrophy, in which a few weeks' exposure to high GC concentrations or to stress causes reversible atrophy of dendritic processes in the hippocampus; b) GC neurotoxicity where, over the course of months, GC exposure kills hippocampal neurons; c) GC neuroendangerment, in which elevated GC concentrations at the time of a neurological insult such as a stroke or seizure impairs the ability of neurons to survive the insult. The second half considers the rather confusing literature as to the possible mechanisms underlying these deleterious GC actions. Five broad themes are discerned: a) that GCs induce a metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that GCs exacerbate various steps in a damaging cascade of glutamate excess, calcium mobilization and oxygen radical generation. In a review a number of years ago, I concluded that these two components accounted for the deleterious GC effects. Specifically, the energetic vulnerability induced by GCs left neurons metabolically compromised, and less able to carry out the costly task of containing glutamate, calcium and oxygen radicals. More recent work has shown this conclusion to be simplistic, and GC actions are shown to probably involve at least three additional components: c) that GCs impair a variety of neuronal defenses against neurologic insults; d) that GCs disrupt the mobilization of neurotrophins; e) that GCs have a variety of electrophysiological effects which can damage neurons. The relevance of each of those mechanisms to GC-induced atrophy, neurotoxicity and neuroendangerment is considered, as are the likely interactions among them.

    J Clin Endocrinol Metab 1996 Oct;81(10):3639-43 Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers M, Rohleder N, Untiedt A, Hanker J, Pirke KM, Hellhammer DH Center for Psychobiological, University of Trier, Germany. Evidence from animal studies and clinical observations suggest that the activity of the pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate responses to mental stress in healthy men. In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience). In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in both experimental groups (all P < 0.0001). However, the estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) responses compared to the placebo group. Also, the norepinephrine area under the response curve was greater in the estradiol group (P < 0.05). Although heart rate responses differences failed to reach statistical significance, they, too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor ratings of the perception of the stressor could explain the observed endocrine response differences. In conclusion, short term estradiol administration resulted in hyperresponses of the pituitary-adrenal axis and norepinephrine to psychosocial stress in healthy young men independent of psychological effects, as assessed in this study.

    J Appl Physiol 1996 Mar;80(3):931-9 Treadmill exercise training and estradiol increase plasma ACTH and prolactin after novel footshock. White-Welkley JE, Warren GL, Bunnell BN, Mougey EH, Meyerhoff JL, Dishman RK "We examined whether rats that were treadmill exercise trained (Tr) or chronically immobilized (CI) had similar responses by the hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and whether the HPA responses interacted with the hypothalamic-pituitary-gonadal (HPG) axis." "[ACTH] and [prolactin] after footshock were higher in Tr rats with E2 compared with CI and sedentary rats without E2; recovery levels for sedentary animals were higher after Run compared with Im. The elevation in [corticosterone] from minute 1 to 15 of recovery was higher after the familiar Run and Im conditions. Our findings are consistent with an increased responsiveness of the HPA axis to novel footshock after treadmill exercise training that is additionally modulated by the HPG axis."

    Endocrinology 1992 Sep;131(3):1261-9. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Burgess LH, Handa RJ "The effect of estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats." "...the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a specific glucocorticoid receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than 0.05), but not in E-treated animals. These data suggest that E can impair glucocorticoid receptor-mediated delayed or slow negative feedback." "Thus, E treatment results in a loss of the glucocorticoid receptor's ability to autoregulate; this suggests that E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears normal. These findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis after stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative feedback."

    Am J Physiol 1994 Jul;267(1 Pt 1):E32-8 Lesions of hypothalamic paraventricular nuclei do not prevent the effect of estradiol on energy and fat balance. Dagnault A, Richard D. "Plasma levels of corticosterone and ACTH were higher in E2-treated rats than in animals receiving the placebo treatment. The present results provide evidence that the hypothalamic PVH is not an essential neuroanatomical structure in the effects of E2 on energy and fat balances."

    Fertil Steril 1994 Oct;62(4):738-43 Ovarian suppression reduces clinical and endocrine expression of late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Carmina E, Lobo RA "OBJECTIVE: To determine the effectiveness of GnRH-agonist (GnRH-a) treatment in women with late onset congenital adrenal hyperplasia." "CONCLUSIONS: Suppression of the ovary with GnRH-a treatment was beneficial in these patients with late-onset congenital adrenal hyperplasia. An ovarian influence on the clinical and biochemical findings of the disorder is suggested."

    Life Sci 1995;57(9):833-7. Effects of sex hormones on the steroidogenic activity of dispersed adrenocortical cells of the rat adrenal cortex. Nowak KW, Neri G, Nussdorfer GG, Malendowicz LK "The effect of 17 beta-estradiol and testosterone on glucocorticoid secretion were studied in vitro by using dispersed inner adrenocortical cells obtained from gonadectomized female and male rats. Independently of the sex of animals, estradiol enhanced basal, but not ACTH-stimulated corticosterone (B) secretion; conversely, testosterone inhibited ACTH-stimulated, but not basal B output." "Testosterone inhibited by about 30% ACTH-stimulated PREG production and by about 54% total post-PREG secretion (B was decreased to 56% of the control value, and other steroid hormones were below the limit of sensitivity of our assay system). These findings indicate that sex hormones directly affect rat adrenocortical secretion, mainly by acting on the rate-limiting step of steroidogenesis (i.e. the conversion of cholesterol to PREG); moreover, they suggest that testosterone is also able depress the activity of the enzymes operating distally to cholesterol side-chain cleavage."

    J Endocrinol 1995 Feb;144(2):311-21 The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female rat. Carey MP, Deterd CH, de Koning J, Helmerhorst F, de Kloet ER "The present study examined the association between hypothalamic- pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA activity determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in intact female rats as a function of oestrous cycle stage under resting conditions and after exposure to a 20 min restraint stress. To delineate the roles of oestradiol and progesterone in HPA axis modulation, plasma concentrations of ACTH and B were determined in ovariectomised (OVX) animals treated with oestradiol and/or progesterone under resting conditions and during exposure to the stress of a novel environment. The effects of these steroid treatments on the transcription and/or binding properties of the two corticosteroid receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors, were also examined in hippocampal tissue, (i) Fluctuations in basal and stress-induced plasma ACTH and B concentrations were found during the oestrous cycle with highest levels at late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and stress-induced activity was enhanced in oestradiol and oestradiol plus progesterone-treated animals compared with OVX controls." "In conclusion, we find that sex steroids modulate HPA activity and suggest that the observed effects of these steroids on hippocampal MR may underlie their concerted mechanism of action in inducing an enhanced activity at the period of late pro-oestrus."

    J Clin Endocrinol Metab 1995 Feb;80(2):603-7 The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome. Ditkoff EC, Fruzzetti F, Chang L, Stancyzk FZ, Lobo RA "Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism exists in PCO." "Steroid ratio responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal E2 administration." "In conclusion, these data provide evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and may help explain the frequent finding of adrenal hyperandrogenism in this syndrome."

    Endocrinology 1993 Nov;133(5):2284-91 Estrogen and hydroxysteroid sulfotransferases in guinea pig adrenal cortex: cellular and subcellular distributions. Whitnall MH, Driscoll WJ, Lee YC, Strott CA "The high concentration of EST immunoreactivity in nuclei suggests that EST may play a role in modulating the ability of active estrogens to regulate gene expression in ACTH-responsive cells. The distribution of HST labeling suggests that sulfonation of adrenocortical 3-hydroxysteroids takes place largely within smooth endoplasmic reticulum in the zona reticularis in adult guinea pigs."

    J Clin Endocrinol Metab 1993 Sep;77(3):754-8. Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production. Mesiano S, Jaffe RB

    J Clin Endocrinol Metab 1993 Aug;77(2):494-7. Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, Lamothe JJ, Barrow R. Adrenal glands from a patient with ACTH-independent Cushing's syndrome, whose symptoms worsened during pregnancy and oral contraceptive use, were cultured in different concentrations of estradiol. Estradiol stimulated cortisol secretion in a dose-response manner in the absence of ACTH." . "This is the first description of estradiol stimulation of cortisol production by cultured adrenal cells in ACTH-independent Cushing's syndrome."

    Endocrinology 1992 Nov;131(5):2430-6 Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal axis: evidence for a neuroendocrine-immunological sexual dimorphism. Spinedi E, Suescun MO, Hadid R, Daneva T, Gaillard RC "Bacterial lipopolysaccharide (LPS) stimulates the hypothalamo-pituitary-adrenal axis by a mechanism involving the release of cytokines, which activate the CRH-ACTH system and, as a result, increase glucocorticoid secretion. In the present study we investigated the possibility that endogenous sex hormones modulate the in vivo endotoxin-stimulated adrenal and immune responses in adult BALB/c mice." "Our results indicate that 1) randomly cycling female mice have significantly more pronounced corticosterone secretion than males 2 h after endotoxin injection, although the tumor necrosis factor responses were similar....".

    J Neurosci Res 1995 Oct 1;42(2):228-35 Activation of the hypothalamo-anterior pituitary corticotropin- releasing hormone, adrenocorticotropin hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the ovariectomized monkey. Kerdelhue B, Jones GS, Gordon K, Seltman H, Lenoir V, Melik Parsadaniantz S, Williams RF, Hodgen GD. "These results suggest that there may be a marked activation of the hypothalamo-anterior pituitary-adrenal axis during the negative and positive feedback phases of the E2B-induced LH surge in the ovariectomized monkey."

    Biol Reprod 1995 Nov;53(5):996-1002 Activation of the baboon fetal pituitary-adrenocortical axis at midgestation by estrogen: responsivity of the fetal adrenal gland to adrenocorticotropic hormone in vitro. Berghorn KA, Albrecht ED, Pepe G.J.

    Fertil Steril 1996 May;65(5):950-3 Ovarian hyperstimulation augments adrenal dehydro- epiandrosterone sulfate secretion. Casson PR, Kristiansen SB, Umstot E, Carson SA, Buster JE.

    Hinyokika Kiyo 1997 Apr;43(4):275-8 [A case of concurrent bilateral adrenocortical adenoma causing Cushing's syndrome]. Koga F, Sumi S, Umeda H, Maeda S, Honda M, Hosoya Y, Yano M, Konita A, Suzuki S, Yoshida K. "All 14 previously reported cases of bilateral adrenocortical adenoma (BAA) causing Cushing's syndrome as well as the present case were concurrent and dominant in females of reproductive age. This suggests that some cofactors other than ACTH, such as estrogen, contribute to the pathogenesis of BAA."

    Endocrinology 1991 Nov;129(5):2503-11 Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Viau V, Meaney MJ. "In cycling rats, we found significantly higher peak ACTH (P less than 0.01) and B (P less than 0.05) responses to stress during proestrus compared to the estrous and diestrous phases." "In response to stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups. Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the termination of stress than did the O' group. Within the 20 min stress period, ACTH levels in the E' group were significantly (P less than 0.05) higher at 5, 10, and 15 min after the onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' group at 5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared to the EP' and O' group. beta-endorphin-like immunoreactive responses to restraint stress were also significantly higher in the E' group compared to the EP' (P less than 0.05) and O' (P less than 0.01) groups. In contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection in the E' group were comparable to O' animals. There was no effect of E2 on ACTH clearance, whereas B clearance was enhanced in E' treated animals vs. O'-treated animals. These results indicate that the HPA axis in the female rat is most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on ACTH release during stress. Taken together, these results suggest an ovarian influence on both activational and inhibitory components of HPA activity."

    Semin Reprod Endocrinol 1997 May;15(2):137-57 Adrenal involvement in polycystic ovary syndrome. Gonzalez F. "Whereas 17,20 lyase hyperactivity diagnosed by defined criteria in response to pharmacological ACTH may be an intrinsic genetic defect, increases in 17,20 lyase activity and adrenal androgen hyper-responsiveness to ACTH in response to physiological ACTH may be promoted by the functional elevation of estrogen of ovarian origin in PCOS. The latest in vitro data suggest the estrogen may elicit its effect on the adrenal cortex through a receptor mediated mechanism."

    Metabolism 1997 Aug;46(8):902-7. Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist? Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C "Basal and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations were reduced with ovarian suppression, but their net increment and ratio to the increase of F in response to ACTH remained unchanged, reflecting the ovarian contribution to the secretion of these steroids.".

  3. Halo

    Halo MuscleHead

    Jul 5, 2011
    Great post Shine, thanks brother!
    SHINE likes this.
  4. LadySparten

    LadySparten New Member

    Jul 12, 2015
    Thank you!

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