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<head><title>Estrogen and brain aging in men and women: Depression, energy, stress</title></head>
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<h1>
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Estrogen and brain aging in men and women: Depression, energy, stress
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</h1>
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<p></p>
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<p>
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Although the incidence of Alzheimer's disease is 2 or 3 times as high among women as among men, there is a
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major campaign under way to convince the public that taking estrogen supplements will prevent the disease.
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Estrogen is now mainly promoted to prevent osteoporosis (another problem that is more common in women) and
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heart disease (which is more common in men).
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</p>
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<p>
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This substance, which came into medical use as "the female hormone" for the treatment of "female problems,"
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especially for improving fertility, and then for preventing fertility as the oral contraceptive, is now
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being aimed primarily at the post-reproductive population, for problems that are essentially unrelated to
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femininity. It is, in fact, being presented to the public as something to prevent major age-related
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conditions.
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</p>
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<p>
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Brain degeneration, like osteoporosis, takes years to develop. Analysis of letters written by young women,
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for example, showed limited mental functioning in those who many years later developed Alzheimer's disease,
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and young women who have small bones are the ones most likely to develop osteoporosis later.<strong>
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It seems clear that the course of degenerative aging processes is set in young adulthood (or even
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earlier), and that it is never too early to be concerned with correcting processes that are going in the
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wrong direction.</strong> (See Walker, et al., 1988, and Smith, et al., 1992.)
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</p>
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<p>
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In "The Biological Generality of Progesterone" (1979) I proposed that the life-long trajectory of energy
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production and longevity was strongly influenced by prenatal nutrition and progesterone. This idea was based
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on work by people such as Marion Diamond, who showed that prenatal progesterone enlarges the cortex of the
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brain, and that estrogen makes it smaller, and Leonell Strong, who showed that a treatment that lowered the
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estrogen function in a young mouse could produce cancer-free offspring for several generations. Strong's
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work was very encouraging, because it showed that biological problems that had been "bred in" over many
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generations could be corrected by some simple metabolic treatments.
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</p>
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<p>
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Seeing these profoundly toxic long-range effects of estrogen, which shaped the animal's growth, development,
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function, and even its heredity, made it important to learn how estrogen works, because such fundamental
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changes covering the whole range of biology, produced by a simple little molecule, promised to reveal
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interesting things about the nature of life.
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</p>
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<p>
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Aging is an energy problem, and in the brain, which has extremely high energy requirements, interference
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with the energy supply quickly causes cells to die.
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</p>
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<p>
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I believe that estrogen's "principle," in all of its actions, is to interfere with the respiratory mode of
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energy production. This is an integrating principle that explains estrogen's immediate, direct effects on
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cells and organisms, which aren't explained by the idea that it acts on the genes through a specific
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"estrogen receptor." (It's hard to imagine, for example, how the "estrogen receptor" doctrine could explain
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the fact that a single injection of estrogen can kill a large portion of brain cells.) It explains why
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estrogen causes cells to take up water, allowing calcium to enter, activating various enzymes and cell
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division. On the organismic level, it explains why estrogen mimics "shock," releasing histamine and
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activating the nervous and glandular stress response system. The inefficiency of metabolism which doesn't
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use oxygen in the normal way causes glucose to be used rapidly, and this in itself is enough to trigger the
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release of pituitary ACTH and adrenal cortisol. The ACTH, and related hormones, liberate free fatty acids,
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which cells take up instead of glucose, and this (in the so-called Randall cycle) further limits the body's
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ability to oxidize glucose.
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</p>
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<p>
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People have spoken of "cascades" in relation to the adrenal glucocorticoids (e.g., cortisol) and estrogen,
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leading to cell damage, but really both of these hormonal cascades have to be seen as part of a more general
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collapse of adaptive systems, as a result of both chronic and immediate inadequacies of energy production.
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</p>
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<p>
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<strong>Estrogen activates the adrenal stress reaction by way of the hypothalamus and pituitary, by direct
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actions on the adrenal glands, and by a variety of indirect effects, such as the increase of free fatty
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acids. It activates the excitotoxic glutamic acid pathway, and interferes with protective adenosine
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inhibition of nerves. It has both direct and indirect ways of promoting the formation of nitric oxide
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and carbon monoxide. These, and other estrogen-promoted factors, quickly and seriously interfere with
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mitochondrial respiration. Many of these effects contribute to increased intracellular calcium and free
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radical production, contributing to both the excitatory excess and the energy deficit.</strong>
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</p>
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<p>
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The biochemical details of these cascades are mainly interesting because they show how many different kinds
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of stress converge on a few physiological processess--mitochondrial energy production, cellular excitation,
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and intercellular communication--which, when damaged thousands of times, lead to the familiar states of old
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age. These few functions, damaged by an infinite variety of stresses, have their own complexly adaptive ways
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of deteriorating, producing the various degenerative diseases.
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</p>
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<p>
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This perspective brings dementia, heart failure, autoimmunity, immunodeficiency and other diseases of aging
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together, in ways that allow generalized therapeutic and preventive approaches.
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</p>
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<p>
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The antistress, antiestrogen approaches become fundamental to prevention of aging.
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</p>
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<p>
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The pro-estrogenic nature of the unsaturated fatty acids is probably the biggest barrier to the radical
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elimination of degenerative diseases. Various saturated fatty acids, including butyric, octanoic, and
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palmitic, have protective effects on mitochondrial respiration.
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</p>
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<p>
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<strong>Progesterone is the basic brain-protective antiestrogen. It works to protect the brain at many
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levels (preventing lipid peroxidation, exitotoxicity, nitric oxide damage, energy deficit, edema, etc.)
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and it promotes repair and recovery.</strong>
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</p>
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<p>
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Progesterone in most cases has effects opposite to estrogen's, improving mitochondrial energy production
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while preventing excessive excitation. Along with pregnenolone, progesterone is recognized as a neurosteroid
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with anti-excitotoxic actions, with the ability to promote repair and regeneration of the nervous system.
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(Roof, Stein, Faden; Schumacher, et al.; Baulieu.)
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</p>
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<p>
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The use of aspirin, which reduces inflammation and inhibits the formation of neurotoxic prostaglandins, is
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known to be associated with a lower incidence of Alzheimer's disease, and in other contexts, it offers
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protection against estrogen. Naloxone, the antiendorphin, has been found to reverse some of the cumulative
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effects of stress, restoring some pituitary and ovarian function, and it promotes recovery after brain
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injury<strong>;</strong> in a variety of ways, it corrects some of estrogen's toxic effects.
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</p>
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<p>
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Adenosine helps to maintain brain glycogen stores, which are lost in stress and aging. Vitamin B12 protects
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against nitric oxide, and improves alertness.
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</p>
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<p>
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Pyruvic acid has brain-protective effects, apparently through its decarboxylation (producing carbon dioxide)
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rather than through its use as an energy source, since other ketoacids are similarly protective. (The
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ketoacids occur in some natural foods.) The directly brain-protective effect of carbon dioxide offers many
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clues that should be interpreted in relation to estrogen's toxicity, since many of their effects on nerves
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are opposite. <strong>
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Estrogen blocks the production of energy while it stimulates nerve cells to use energy more rapidly, and
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carbon dioxide promotes the production of energy, while restraining the excitation which expends energy.
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</strong>
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The presence of carbon dioxide is an indicator of proper mitochondrial respiratory functioning.
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</p>
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<p>
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Pharmaceutical blockers of glutamic acid transmission, and of calcium and sodium uptake, prevent some
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deterioration following brain injury, but the most physiological way to protect against those toxic
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processes is to maintain metabolic energy at a high level. Magnesium, which is protective against excitatory
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damage and is a calcium antagonist, tends to be retained in proportion to the activity of thyroid hormone.
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</p>
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<p>
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As I have discussed previously, progesterone alone has brought people out of post-epileptic dementia and
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senile dementia, but it is reasonable to use a combined physiological approach, including thyroid.
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</p>
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<p>
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Besides providing new insights into biological energy and aging, the recognition that estrogen activates the
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stress hormone system--the pituitary-adrenal system--also provides clear insights into other problems, such
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as the polycystic ovary syndrome, hirsutism, adrenal hyperplasia, Cushing's disease, etc.
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</p>
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<p><h3>REFERENCES</h3></p>
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<p>
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[The references are clustered into groups, showing estrogen's indirect toxicity through its activation of
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the adrenal hormones, its direct brain-toxicity, and some of the interactions between these and fats, nitric
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oxide, etc.]
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</p>
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<p><em>.</em></p>
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<p>
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Stress 1996 Jul;1(1):1-19 <strong>
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Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion.</strong>
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Sapolsky RM Department of Biological Sciences, Stanford University, Stanford, CA 94305. <strong>An extensive
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literature demonstrates that glucocorticoids (GCs), the adrenal steroids secreted during stress, can
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have a broad range of deleterious effects in the brain. The actions occur predominately, but not
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exclusively, in the hippocampus, a structure rich in corticosteroid receptors and particularly sensitive
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to GCs. The first half of this review considers three types of GC effects: a) GC-induced atrophy, in
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which a few weeks' exposure to high GC concentrations or to stress causes reversible atrophy of
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dendritic processes in the hippocampus; b) GC neurotoxicity where, over the course of months, GC
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exposure kills hippocampal neurons; c) GC neuroendangerment, in which elevated GC concentrations at the
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time of a neurological insult such as a stroke or seizure impairs the ability of neurons to survive the
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insult. The second half considers the rather confusing literature as to the possible mechanisms
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underlying</strong> these deleterious GC actions. Five broad themes are discerned: a) that GCs induce a
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metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that GCs exacerbate various steps
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in a<strong>
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damaging cascade of glutamate excess, calcium mobilization and oxygen radical generation. In a review a
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number of years ago, I concluded that these two components accounted for the deleterious GC effects.
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Specifically, the energetic vulnerability induced by GCs left neurons metabolically compromised, and
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less able to carry out the costly task of containing glutamate, calcium and oxygen radicals. More recent
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work has shown this conclusion to be simplistic, and GC actions are shown to probably involve at least
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three additional components: c) that GCs impair a variety of neuronal defenses against neurologic
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insults; d) that GCs disrupt the mobilization of neurotrophins; e) that GCs have a variety of
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electrophysiological effects which can damage neurons.
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</strong>The relevance of each of those mechanisms to GC-induced atrophy, neurotoxicity and
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neuroendangerment is considered, as are the likely interactions among them.
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</p>
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<p>
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J Clin Endocrinol Metab 1996 Oct;81(10):3639-43 <strong>Short-term estradiol treatment enhances
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pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men.</strong>
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Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers M, Rohleder N, Untiedt A, Hanker J, Pirke
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KM, Hellhammer DH Center for Psychobiological, University of Trier, Germany. <strong>
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Evidence from animal studies and clinical observations suggest that the activity of the
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pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated
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how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate
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responses to mental stress in healthy men.
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</strong>In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and
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age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they
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were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience).
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In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in
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both experimental groups (all P < 0.0001). However, the<strong>
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estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002)
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responses compared to the placebo group. Also, the norepinephrine area under the response curve was
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greater in the estradiol group
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</strong>
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(P < 0.05). Although heart rate responses differences failed to reach statistical significance, they,
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too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor
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ratings of the perception of the stressor could explain the observed endocrine response differences. In
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conclusion, <strong>short term estradiol administration resulted in hyperresponses of the pituitary-adrenal
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axis and norepinephrine to psychosocial stress in healthy young men independent of psychological
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effects,
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</strong>as assessed in this study.
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</p>
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<p>
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J Appl Physiol 1996 Mar;80(3):931-9 <strong>
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Treadmill exercise training and estradiol increase plasma ACTH and prolactin after novel
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footshock.</strong> White-Welkley JE, Warren GL, Bunnell BN, Mougey EH, Meyerhoff JL, Dishman RK "We
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examined whether rats that were treadmill exercise trained (Tr) or chronically immobilized (CI) had similar
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responses by the hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and whether the HPA
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responses interacted with the hypothalamic-pituitary-gonadal (HPG) axis." <strong>"[ACTH] and
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[prolactin</strong>] after<strong>
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footshock were higher in Tr rats with E2 compared with CI and sedentary rats without E2;</strong>
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recovery levels for sedentary animals were higher after Run compared with Im. The elevation in
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[corticosterone] from minute 1 to 15 of recovery was higher after the familiar Run and Im conditions. Our
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findings are consistent with an increased responsiveness of the HPA axis to novel footshock after treadmill
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exercise training that is additionally modulated by the HPG axis."
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</p>
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<p>
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Endocrinology 1992 Sep;131(3):1261-9. <strong>
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Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and
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glucocorticoid receptor-mediated functions in female rats.</strong> Burgess LH, Handa RJ "The effect of
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estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats."
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"...the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a
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specific glucocorticoid receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than
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0.05), <strong>but not in E-treated animals.</strong> These data suggest that E can impair glucocorticoid
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receptor-mediated delayed or slow negative feedback." "Thus, E<strong>
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treatment results in a loss of the glucocorticoid receptor's ability to autoregulate; this suggests that
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E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears
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normal. These findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis after
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stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative
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feedback."
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</strong>
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</p>
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<p>
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Am J Physiol 1994 Jul;267(1 Pt 1):E32-8 <strong>Lesions of hypothalamic paraventricular nuclei do not
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prevent the effect of estradiol on energy and fat balance.</strong>
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Dagnault A, Richard D. <strong>"Plasma levels of corticosterone and ACTH were higher in E2-treated rats than
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in animals receiving the placebo treatment. The present results provide evidence that the hypothalamic
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PVH is not an essential neuroanatomical structure in the effects of E2 on energy and fat balances."
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</strong>
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</p>
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<p>
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Fertil Steril 1994 Oct;62(4):738-43 <strong>
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Ovarian suppression reduces clinical and endocrine expression of late-onset congenital adrenal
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hyperplasia due to 21-hydroxylase deficiency.</strong>
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Carmina E, Lobo RA "OBJECTIVE: To determine the effectiveness of GnRH-agonist (GnRH-a) treatment in women
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with late onset congenital adrenal hyperplasia." "CONCLUSIONS: Suppression of the ovary with GnRH-a
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treatment was beneficial in these patients with late-onset congenital adrenal hyperplasia. An ovarian
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influence on the clinical and biochemical findings of the disorder is suggested."
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</p>
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<p>
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Life Sci 1995;57(9):833-7. <strong>
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Effects of sex hormones on the steroidogenic activity of dispersed adrenocortical cells of the rat
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adrenal cortex.</strong> Nowak KW, Neri G, Nussdorfer GG, Malendowicz LK "The effect of 17
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beta-estradiol and testosterone on glucocorticoid secretion were studied in vitro by using dispersed inner
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adrenocortical cells obtained from gonadectomized female and male rats. Independently of the sex of animals,
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estradiol enhanced basal, but not ACTH-stimulated corticosterone (B) secretion; conversely, testosterone
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inhibited ACTH-stimulated, but not basal B output." "Testosterone inhibited by about 30% ACTH-stimulated
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PREG production and by about 54% total post-PREG secretion (B was decreased to 56% of the control value, and
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other steroid hormones were below the limit of sensitivity of our assay system). These findings indicate
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that sex hormones directly affect rat adrenocortical secretion,<strong>
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mainly by acting on the rate-limiting step of steroidogenesis (i.e. the conversion of cholesterol to
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PREG); moreover, they suggest that testosterone is also able depress the activity of the enzymes
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operating distally to cholesterol side-chain cleavage."
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</strong>
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</p>
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<p>
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J Endocrinol 1995 Feb;144(2):311-21 <strong>
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The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female
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rat.</strong> Carey MP, Deterd CH, de Koning J, Helmerhorst F, de Kloet ER "The present study examined
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the association between hypothalamic- pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA
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activity determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in
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intact female rats as a function of oestrous cycle stage under resting conditions and after exposure to a 20
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min restraint stress. To delineate the roles of oestradiol and progesterone in HPA axis modulation, plasma
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concentrations of ACTH and B were determined in ovariectomised (OVX) animals treated with oestradiol and/or
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progesterone under resting conditions and during exposure to the stress of a novel environment. The effects
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of these steroid treatments on the transcription and/or binding properties of the two corticosteroid
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receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors, were also examined in hippocampal
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tissue, (i) Fluctuations in basal and<strong>
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stress-induced plasma ACTH and B concentrations were found during the oestrous cycle with highest levels
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at late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and stress-induced activity was
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enhanced in oestradiol and oestradiol plus progesterone-treated animals compared with OVX controls."
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</strong>
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"In conclusion, we find that sex steroids modulate HPA activity and<strong>
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suggest that the observed effects of these steroids on hippocampal MR may underlie their concerted
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mechanism of action in inducing an enhanced activity at the period of late pro-oestrus."
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</strong>
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</p>
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<p>
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J Clin Endocrinol Metab 1995 Feb;80(2):603-7 <strong>The impact of estrogen on adrenal androgen sensitivity
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and secretion in polycystic ovary syndrome.</strong> Ditkoff EC, Fruzzetti F, Chang L, Stancyzk FZ, Lobo
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RA <strong>"Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO).
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</strong>
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This may be due to enhanced adrenal sensitivity to ACTH.<strong>
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Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the
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role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism
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exists in PCO."
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</strong>"Steroid ratio<strong>
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responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of
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A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal
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E2 administration."</strong> "In conclusion, these data provide<strong>
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evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and
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may help explain the frequent finding of adrenal hyperandrogenism in this syndrome."
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</strong>
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</p>
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<p>
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Endocrinology 1993 Nov;133(5):2284-91 <strong>
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Estrogen and hydroxysteroid sulfotransferases in guinea pig adrenal cortex: cellular and subcellular
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distributions.</strong> Whitnall MH, Driscoll WJ, Lee YC, Strott CA "The high concentration of EST
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immunoreactivity in nuclei suggests that EST may play a role in modulating the<strong>
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ability of active estrogens to regulate gene expression in ACTH-responsive cells. The distribution of
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HST labeling suggests that sulfonation of adrenocortical 3-hydroxysteroids takes place largely within
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smooth endoplasmic reticulum in the zona reticularis in adult guinea pigs."
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</strong>
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</p>
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<p>
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J Clin Endocrinol Metab 1993 Sep;77(3):754-8. <strong>Interaction of insulin-like growth factor-II and
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estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate
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production.
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</strong>
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Mesiano S, Jaffe RB
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</p>
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<p>
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J Clin Endocrinol Metab 1993 Aug;77(2):494-7. <strong>Estradiol stimulates cortisol production by adrenal
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cells in estrogen-dependent primary adrenocortical nodular dysplasia.</strong>
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Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, Lamothe JJ, Barrow R. Adrenal glands from
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a patient with ACTH-independent Cushing's syndrome, whose symptoms worsened during pregnancy and oral
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contraceptive use, were cultured in different concentrations of estradiol. Estradiol stimulated cortisol
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secretion in a dose-response manner in the absence of ACTH." . "This is the first description of estradiol
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stimulation of cortisol production by cultured adrenal cells in ACTH-independent Cushing's syndrome."
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</p>
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<p>
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Endocrinology 1992 Nov;131(5):2430-6 <strong>
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Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal
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axis: evidence for a neuroendocrine-immunological sexual dimorphism.</strong> Spinedi E, Suescun MO,
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Hadid R, Daneva T, Gaillard RC "Bacterial lipopolysaccharide (LPS) stimulates the
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hypothalamo-pituitary-adrenal axis by a mechanism involving the release of cytokines, which activate the
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CRH-ACTH system and, as a result, increase glucocorticoid secretion. <strong>
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In the present study we investigated the possibility that endogenous sex hormones modulate the in vivo
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endotoxin-stimulated adrenal and immune responses in adult BALB/c mice."</strong> "Our results indicate
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that 1)<strong>
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randomly cycling female mice have significantly more pronounced corticosterone secretion than males 2 h
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after endotoxin
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</strong>
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injection, although the tumor necrosis factor responses were similar....".
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</p>
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<p>
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J Neurosci Res 1995 Oct 1;42(2):228-35 <strong>
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Activation of the hypothalamo-anterior pituitary corticotropin- releasing hormone, adrenocorticotropin
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hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the
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ovariectomized monkey.</strong> Kerdelhue B, Jones GS, Gordon K, Seltman H, Lenoir V, Melik
|
|
Parsadaniantz S, Williams RF, Hodgen GD. "These results suggest that there<strong>
|
|
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."
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
Biol Reprod 1995 Nov;53(5):996-1002 <strong>
|
|
Activation of the baboon fetal pituitary-adrenocortical axis at midgestation by estrogen: responsivity
|
|
of the fetal adrenal gland to adrenocorticotropic hormone in vitro.</strong> Berghorn KA, Albrecht ED,
|
|
Pepe G.J.
|
|
</p>
|
|
<p>
|
|
Fertil Steril 1996 May;65(5):950-3 <strong>
|
|
Ovarian hyperstimulation augments adrenal dehydro- epiandrosterone sulfate secretion.</strong> Casson
|
|
PR, Kristiansen SB, Umstot E, Carson SA, Buster JE.
|
|
</p>
|
|
<p>
|
|
Hinyokika Kiyo 1997 Apr;43(4):275-8 <strong>
|
|
[A case of concurrent bilateral adrenocortical adenoma causing Cushing's syndrome].</strong> 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<strong>
|
|
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."
|
|
</strong>
|
|
</p>
|
|
|
|
<p>
|
|
Endocrinology 1991 Nov;129(5):2503-11 <strong>
|
|
Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the
|
|
rat.</strong> Viau V, Meaney MJ. <strong>"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
|
|
</strong>
|
|
compared to the estrous and diestrous phases." "In response to<strong>
|
|
stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups.
|
|
</strong>
|
|
|
|
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,<strong>
|
|
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'</strong> (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, <strong>as progesterone appears to inhibit the facilitatory effects of estrogen on
|
|
ACTH release during stress.
|
|
</strong>
|
|
|
|
Taken together, these results suggest an ovarian influence on both activational and inhibitory components of
|
|
HPA activity."
|
|
</p>
|
|
<p>
|
|
Semin Reprod Endocrinol 1997 May;15(2):137-57 <strong>Adrenal involvement in polycystic ovary syndrome.
|
|
</strong>
|
|
Gonzalez F. "Whereas 17,20 lyase hyperactivity diagnosed by defined criteria in response to pharmacological
|
|
ACTH may be an intrinsic genetic defect, <strong>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.
|
|
</strong>The latest in vitro data suggest the estrogen may elicit its effect on the adrenal cortex through a
|
|
receptor mediated mechanism."
|
|
</p>
|
|
<p>
|
|
Metabolism 1997 Aug;46(8):902-7. <strong>
|
|
Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does
|
|
idiopathic hirsutism exist?</strong> Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho
|
|
J, Varela C <strong>"Basal and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations were
|
|
reduced with ovarian suppression,</strong> but their net increment and ratio to the increase of F in
|
|
response to ACTH remained unchanged, <strong>
|
|
reflecting the ovarian contribution to the secretion of these steroids."</strong>.
|
|
</p>
|
|
<p>
|
|
Am J Physiol 1997 Apr;272(4 Pt 2):R1128-34.<strong>
|
|
Modulation of ovine fetal adrenocorticotropin secretion by androstenedione and 17beta-estradiol.</strong
|
|
> Saoud CJ, Wood CE "Parturition in sheep is initiated by increases in activity of the fetal
|
|
hypothalamic-pituitary-adrenal axis. We<strong>
|
|
have previously reported that cortisol negative feedback efficacy is decreased at the end of gestation.
|
|
</strong>The present study was designed to test the hypothesis that<strong>
|
|
increasing plasma estrogen and/or androgen concentrations in the fetus might increase plasma
|
|
adrenocorticotropic hormone (ACTH) concentration, either by stimulating ACTH secretion or by altering
|
|
the negative feedback</strong>
|
|
effect of cortisol on ACTH." "We conclude that increased fetal cortisol and ACTH secretion at the end of
|
|
gestation may be due to the combined effects of the gonadal steroids in that<strong>
|
|
estradiol increases basal plasma ACTH secretion while androstenedione reduces cortisol negative feedback
|
|
efficacy."
|
|
</strong>
|
|
</p>
|
|
|
|
<p>
|
|
J Clin Endocrinol Metab 1998 Sep;83(9):3083-8. <strong>
|
|
Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather
|
|
than raised circulating androgen levels.</strong> Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD,
|
|
Perry LA, Grossman AB, Besser GM, Trainer PJ.
|
|
</p>
|
|
<p>
|
|
Eur J Endocrinol 1998 Apr;138(4):430-5. <strong>
|
|
Hypothalamo-pituitary-adrenal axis and adrenal function before and after ovariectomy in premenopausal
|
|
women.</strong> De Leo V, la Marca A, Talluri B, D'Antona D, Morgante G <strong>
|
|
The hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few data exist on the
|
|
relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone
|
|
(CRH).</strong> The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of
|
|
ACTH, cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in nine
|
|
premenopausal women (44-48 years of age), before and after ovariectomy. The CRH test was performed before
|
|
and 8 days after ovariectomy.<strong>
|
|
A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed
|
|
after ovariectomy.
|
|
</strong>
|
|
|
|
The ratio of deltamax androstenedione/17-OHP after CRH stimulation was substantially the same before and
|
|
after ovariectomy, whereas <strong>deltamax 17-OHP/cortisol was significantly lower in
|
|
ovariectomized</strong> women showing increased 21- and 11beta-hydroxylase activity. The results show
|
|
that the acute estrogen deficit induces changes in the HPA xis characterized by <strong>reduced stimulated
|
|
secretion of ACTH and steroids</strong> but normal stimulated cortisol production.
|
|
</p>
|
|
<p>
|
|
Biokhimiia 1987 Sep;52(9):1501-11 <strong>
|
|
[Activation of lipolysis and ketogenesis in tumor-bearing animals as a reflection of chronic stress
|
|
states].</strong> [Article in Russian] Chekulaev VA, Shelepov VP, Pasha-zade GR, Shapot VS In order to
|
|
elucidate the peculiarities of brain metabolism in tumour-bearing organisms, the arterio-venous (A-V)
|
|
content of glucose, acetoacetate (Ac-Ac), beta-hydroxybutyrate (beta-HB) and non-esterified fatty acids
|
|
(NEFA) in growing Zajdela ascite hepatoma (ZAH) and solid hepatoma 27 (H-27) was compared. Analysis of
|
|
metabolic patterns of healthy, starving and fed recipients (ZAH and H-27) revealed the inadequacy of the
|
|
concepts on anorexia as being the cause of carbohydrate-lipid metabolic disturbances. In tumour-bearing
|
|
organisms <strong>lipolysis and ketogenesis reflect the tumour-induced chronic stress.</strong> Absorption
|
|
of beta-HB and release of Ac-Ac by brain were observed at all stages of malignant growth. <strong>This is
|
|
probably due to a partial switch-over of brain metabolism to non-carbohydrate energy sources.
|
|
</strong>Besides, certain stages of tumour growth are associated with <strong>active assimilation of NEFA by
|
|
brain.</strong> A correlation between the A-V difference with respect to glucose and Ac-Ac as well as
|
|
between the glucose and NEFA contents was established. It was assumed that the A-V difference in glucose is
|
|
the main regulator of ketone body metabolism.
|
|
</p>
|
|
|
|
<p>
|
|
R. Sanchez Olea, et al., <strong>
|
|
"Inhibition by polyunsaturated fatty acids of cell volume regulation and osmolyte fluxes in
|
|
astrocytes,"</strong> Amer. J. of Physiology--cell physiology 38(1), C96-C102, 1995. <strong>"...potent
|
|
blockers of regulatory volume decrease and of the swelling-activated efflux of taurine,
|
|
D-aspartate,</strong> inositol, and I-125 (used as marker of Cl). <strong>
|
|
...oleic and ricinoleic acids and saturated fatty acids were ineffective." "...polyunsaturated fatty
|
|
acids directly inhibit the permeability pathways correcting cell volume after swelling in cultured
|
|
astrocytes."</strong>
|
|
</p>
|
|
<p>
|
|
P. H. Chan and R. A. Fishman, "<strong>Brain edema: Induction in cortical slices by polyunsaturated fatty
|
|
acids</strong>," Science 201, 358-369, 1978. "This cellular edema was specific, since <strong>
|
|
neither saturated fatty acids nor a fatty acid containing a single double bond had such effect</strong
|
|
>."
|
|
</p>
|
|
<p>
|
|
Endocrinology 1992 Aug;131(2):662-8 <strong>Estradiol selectively regulates agonist binding sites on the
|
|
N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus.</strong> Weiland NG.
|
|
Laboratory of Neuroendocrinology, Rockefeller University. <strong>
|
|
"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...."</strong> "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." <strong>
|
|
"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."</strong>
|
|
</p>
|
|
|
|
<p>
|
|
J Neurochem 1994 Sep;63(3):953-62 <strong>
|
|
Corticosterone regulates heme oxygenase-2 and NO synthase transcription and protein expression in rat
|
|
brain.</strong> Weber CM, Eke BC, Maines MD.<strong>"We suggest that glucocorticoid-mediated deficits in
|
|
hippocampal functions may reflect their negative effect on messenger-generating systems."
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
Gen Pharmacol 1993 Nov;24(6):1383-6 <strong>
|
|
Changes in microtubular tau protein after estrogen in a cultured human neuroblastoma cell line.</strong>
|
|
Lew GM. <strong>"4. The estrogen (10(-7) M) also caused a 31% reduction in the total number of
|
|
cells."</strong>
|
|
</p>
|
|
<p>
|
|
Rodriguez, P; Fernandez-Galaz, C; Tejero, A. <strong>Controlled neonatal exposure to estrogens: A suitable
|
|
tool for reproductive aging studies in the female rat.</strong>
|
|
|
|
Biology of Reproduction, v.49, n.2, (1993): 387-392.
|
|
</p>
|
|
<p>
|
|
O'Rourke, M T; Lipson, S F; Ellison, P T. <strong>Ovarian function in the latter half of the reproductive
|
|
lifespan.</strong> American Journal of Human Biology, v.8, n.6, (1996): 751-759.
|
|
</p>
|
|
<p>
|
|
Schumacher, M; Robel, P; Baulieu, E-E. <strong>Development and regeneration of the nervous system: A role
|
|
for neurosteroids.</strong> Developmental Neuroscience, v.18, n.1-2, (1996): 6-21.
|
|
</p>
|
|
<p>
|
|
Life Sci 1996;58(17):1461-7 <strong>The endogenous estrogen metabolite 2-methoxyestradiol induces apoptotic
|
|
neuronal cell death in vitro.</strong> Nakagawa-Yagi Y, Ogane N, Inoki Y, Kitoh N. "We examined the
|
|
effects of 2-methoxyestradiol, a metabolite of estradiol, on cell death in retinoic acid (RA)-differentiated
|
|
neuroblastoma SH-SY5Y cell cultures. <strong>Cell death was induced by 2-methoxyestradiol in a
|
|
concentration- dependent manner</strong>."<strong> [</strong>Provides evidence]<strong>
|
|
"...for an endogenous neuroactive steroid metabolite in the etiology of some neurodegenerative
|
|
diseases."</strong>
|
|
</p>
|
|
<p>
|
|
Recent Prog Horm Res 1997;52:279-303 <strong>
|
|
Aging of the female reproductive system: a window into brain aging.</strong>
|
|
Wise PM, Kashon ML, Krajnak KM, Rosewell KL, Cai A, Scarbrough K, Harney JP, McShane T, Lloyd JM, Weiland NG
|
|
<strong>"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</strong> contribute to the timing of the menopause."
|
|
</p>
|
|
<p>
|
|
Neuroendocrinology 1989 Nov;50(5):605-612 <strong>
|
|
N-methyl-aspartic acid lesions of the arcuate nucleus in adult C57BL/6J mice: a new model for
|
|
age-related lengthening of the estrous cycle.</strong>
|
|
May PC, Kohama SG, Finch CE. "We report a new effect of the excitotoxin N-methyl-aspartic acid (NMA) on
|
|
adult mice. Besides confirming cell loss in the arcuate nucleus of animals treated as adults, we also
|
|
observed lengthened estrous cycles. Cycling female C57BL/6J mice were treated with subcutaneous injections
|
|
of NMA and estrous cycles monitored for 30 days. NMA treatment lengthened average estrous cycle length by 1
|
|
day, to 5.6 days."<strong>
|
|
"Consistent with the regional pattern of cell loss, little specific binding of any glutamatergic ligand
|
|
was observed in the VMN. NMA caused weight gain in all age groups." "The transition from 4-day to 5- and
|
|
6-day estrous cycles produced by NMA treatment mimics the early age-related changes in estrous cycle
|
|
patterns in rodents."</strong> This new model will be useful in analyzing the contributions of
|
|
neuroendocrine changes in the arcuate nucleus to reproductive senescence."
|
|
</p>
|
|
<p>
|
|
<strong>Pathologic effect of estradiol on the hypothalamus.</strong> Brawer JR; Beaudet A; Desjardins GC;
|
|
Schipper HM. 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>
|
|
<p>
|
|
<strong>Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity</strong>.
|
|
Desjardins GC; Beaudet A; Schipper HM; Brawer JR. Endocrinology, 1992 Nov, 131:5, 2482-4 <strong>"Estradiol
|
|
valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in
|
|
the hypothalamic arcuate nucleus."</strong>
|
|
</p>
|
|
<p>
|
|
<strong>Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic
|
|
aging.</strong>
|
|
Desjardins GC; Beaudet A; Meaney MJ; Brawer JR. Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67 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.<strong>
|
|
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.</strong>
|
|
|
|
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
|
|
<strong>
|
|
destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus
|
|
</strong>while leaving other neuronal populations spared. This loss of opioid neurons is prevented by
|
|
treatment with antioxidants indicating that it results from <strong>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.</strong> 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 <strong>suppression
|
|
of the pattern of LHRH release, and subsequently that of LH.</strong> Indeed, prevention of the
|
|
neuroendocrine effects of estradiol by antioxidant treatment also <strong>
|
|
prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity.</strong> 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.
|
|
</p>
|
|
<p>
|
|
<strong>The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic
|
|
beta-endorphin in adult female rats.</strong> Schipper HM; Desjardins GC; Beaudet A; Brawer JR. Brain
|
|
Res, 1994 Jul 25, 652:1, 161-3 <strong>
|
|
"A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and
|
|
beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats."</strong>
|
|
</p>
|
|
|
|
<p>
|
|
J Neurochem 1998 Sep;71(3):1187-93 <strong>
|
|
Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity.</strong>
|
|
Brooke SM, Howard SA, Sapolsky RM "The HIV envelope glycoprotein, gp120, a well documented neurotoxin, may
|
|
be involved in AIDS-related dementia complex. gp120 works through an NMDA receptor- and calcium-dependent
|
|
mechanism to damage neurons. We have previously demonstrated that both natural and synthetic glucocorticoids
|
|
(GCs) exacerbate gp120-induced neurotoxicity and calcium mobilization in hippocampal mixed cultures. GCs,
|
|
steroid hormones secreted during stress, are now shown to work in conjunction with gp120 to decrease ATP
|
|
levels and to work synergistically with gp120 to decrease the mitochondrial potential in hippocampal
|
|
cultures. <strong>
|
|
Furthermore, energy supplementation blocked the ability of GCs to worsen gp120's effects on neuronal
|
|
survival and calcium mobilization.</strong> A GC-induced reduction in glucose transport in hippocampal
|
|
neurons, as previously documented, may contribute to this energetic dependency. These results may have
|
|
clinical significance, considering the common treatment of severe cases of Pneumocystis carinii pneumonia,
|
|
typical of HIV infection, with large doses of synthetic GCs."
|
|
</p>
|
|
<p>
|
|
Acta Otolaryngol Suppl (Stockh) 1990;476:32-6. <strong>Glutamate neurotoxicity in the cochlea: a possible
|
|
consequence of ischaemic or anoxic conditions occurring in ageing.</strong>
|
|
Pujol R, Rebillard G, Puel JL, Lenoir M, Eybalin M, Recasens M.
|
|
</p>
|
|
|
|
<p>
|
|
Br J Pharmacol 1996 Jan;117(1):189-95.<strong>
|
|
Metabotropic glutamate receptors, transmitter output and fatty acids: studies in rat brain slices.
|
|
</strong>Lombardi G, Leonardi P, Moroni F. "The requirement of both unsaturated fatty acids and 1S,3R-ACPD
|
|
in the facilitation of transmitter exocytosis may play an important role in the regulation of synaptic
|
|
plasticity."
|
|
</p>
|
|
<p>
|
|
Adv Exp Med Biol 1992;318:147-58 <strong>
|
|
A role for the arachidonic acid cascade in fast synaptic modulation: ion channels and transmitter uptake
|
|
systems as target proteins.</strong>
|
|
Volterra A, Trotti D, Cassutti P, Tromba C, Galimberti R, Lecchi P, Racagni G. "Recent evidence indicates
|
|
that arachidonic acid (AA) and its metabolites play a fast messenger role in synaptic modulation in the
|
|
CNS." "Other types of K+ channels in vertebrate excitable cells have been found to be<strong>
|
|
sensitive to arachidonic acid, lipoxygenase products, and polyunsaturated fatty acids (PUFA). In the
|
|
mammalian CNS, arachidonic acid is released upon stimulation of N-methyl-D-aspartate (NMDA)-type
|
|
glutamate receptors." "Polyunsaturated fatty acids mimic arachidonate with a rank of potency parallel to
|
|
the degree of unsaturation. Since the effect of glutamate on the synapses is terminated by diffusion and
|
|
uptake, a slowing of the termination process may potentiate glutamate synaptic efficacy. However,
|
|
excessive extracellular accumulation of glutamate may lead to neurotoxicity."
|
|
</strong>
|
|
</p>
|
|
|
|
<p>
|
|
J Neurochem 1999 Jan;72(1):129-38<strong>. Transient inhibition of glutamate uptake in vivo induces
|
|
neurodegeneration when energy metabolism is impaired.
|
|
</strong>
|
|
Sanchez-Carbente MR, Massieu L<strong>. </strong>
|
|
"Impairment of glutamate transport during ischemia might be related to the elevation of the extracellular
|
|
concentration of glutamate and ischemic neuronal damage. Additionally, impairment of energy metabolism in
|
|
vivo leads to neurodegeneration apparently mediated by a secondary excitotoxic mechanism. In vitro
|
|
observations show that glucose deprivation and inhibition of energy metabolism exacerbate the toxic effects
|
|
of glutamate." <strong>
|
|
"Our results show that glutamate uptake inhibition leads to marked neuronal damage in energy-deficient
|
|
rats but not in intact animals...."</strong>
|
|
</p>
|
|
<p>
|
|
J Neurochem 1998 Nov;71(5):1993-2005. <strong>
|
|
Glia modulate NMDA-mediated signaling in primary cultures of cerebellar granule cells.</strong>
|
|
Beaman-Hall CM, Leahy JC, Benmansour S, Vallano ML "Nordihydroguaiaretic acid, a lipoxygenase inhibitor,
|
|
blocked NMDA-mediated toxicity in astrocyte-poor cultures, raising the possibility<strong>
|
|
that glia effectively reduce the accumulation of highly diffusible and toxic arachidonic acid
|
|
metabolites in</strong> neurons. Alternatively, glia may alter neuronal development/phenotype in a
|
|
manner that selectively reduces susceptibility to NR-mediated toxicity."
|
|
</p>
|
|
|
|
<p>
|
|
J Neurosci 1997 Dec 1;17(23):9060-7<strong>. Pyruvate protects neurons against hydrogen peroxide-induced
|
|
toxicity.
|
|
</strong>
|
|
Desagher S, Glowinski J, Premont J<strong>. "Pyruvate strongly protected neurons against both H2O2 added to
|
|
the external medium and H2O2 endogenously produced through the redox cycling of the experimental quinone
|
|
menadione. The neuroprotective effect of pyruvate appeared to result rather from the ability of
|
|
alpha-ketoacids to undergo nonenzymatic decarboxylation in the presence of H2O2 than from an improvement
|
|
of energy metabolism. Indeed, several other alpha-ketoacids, including alpha-ketobutyrate, which is not
|
|
an energy substrate, reproduced the neuroprotective effect of pyruvate. In contrast, lactate, a neuronal
|
|
energy substrate, did not protect neurons from H2O2."</strong> "Together, these results indicate that
|
|
pyruvate efficiently protects neurons against both exogenous and endogenous H2O2. Its low toxicity and its
|
|
capacity to cross the blood-brain barrier open a new therapeutic perspective in brain pathologies in which
|
|
H2O2 is involved."<strong> </strong>
|
|
</p>
|
|
<p>
|
|
J Neurosci 1998 Jan 1;18(1):156-63<strong>. Neuroprotective effects of creatine and cyclocreatine in animal
|
|
models of Huntington's disease.
|
|
</strong>Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF<strong>
|
|
.
|
|
</strong>
|
|
</p>
|
|
|
|
<p>
|
|
M. C. Diamond, <strong><em>Enriching Heredity: The Importance of the Environment on the Anatomy of the
|
|
Brain.</em></strong> Free Press, N.Y., 1988.
|
|
</p>
|
|
<p>
|
|
C. Finch and L. Hayflick, <strong><em>Handbook of the Biology of Aging.</em></strong>
|
|
Van Nostrand Reinhold, N.Y., 1977.
|
|
</p>
|
|
<p>
|
|
Swanson RA <strong>Physiologic coupling of glial glycogen metabolism to neuronal activity in brain.</strong>
|
|
Can J Physiol Pharmacol, 1992, 70 Suppl:, S138-44. Brain glycogen is localized almost exclusively to glia,
|
|
where it undergoes continuous utilization and resynthesis. We have shown that glycogen utilization increases
|
|
during tactile stimulation of the rat face and vibrissae.<strong>
|
|
Conversely, decreased neuronal activity during hibernation and anesthesia is accompanied by a marked
|
|
increase in brain glycogen content</strong>. These observations support a link between neuronal activity
|
|
and glial glycogen metabolism. The energetics of glycogen metabolism suggest that glial glycogen is
|
|
mobilized to meet increased metabolic demands of glia rather than to serve as a substrate for neuronal
|
|
activity. An advantage to the use of glycogen may be the potentially faster generation of ATP from glycogen
|
|
than from glucose. Alternatively, glycogen could be utilized if glucose supply is transiently insufficient
|
|
during the onset of increased metabolic activity. Brain glycogen may have a <strong>dynamic role as a buffer
|
|
between the abrupt increases in focal metabolic demands that occur during normal brain activity and the
|
|
compensatory changes in focal cerebral blood flow or oxidative metabolism.</strong>
|
|
</p>
|
|
|
|
<p>
|
|
<strong>"Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis in rats."
|
|
</strong>
|
|
Widmaier EP; Rosen K; Abbott B. <em>Endocrinology,</em>
|
|
<strong> </strong>
|
|
1992 Nov, 131:5, 2313-8. "Intravenous administration of Intralipid 10% increases blood levels of essential
|
|
free fatty acids." "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." "At 60 min, plasma ACTH levels were significantly elevated to over 1500 pg/ml in
|
|
Intralipid-infused rats, but were unchanged in saline controls. <strong>This dose of Intralipid increased
|
|
corticosterone levels by nearly 20-fold at 120 min. At 180 min, corticosterone levels were still
|
|
significantly greater</strong> 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 results suggest that high circulating FFA levels activate, rather than inhibit, the
|
|
HPA axis in rats. Since stress activates glucocorticoid production and<strong>
|
|
increases FFA levels due to lipolysis, it is possible that FFA and the HPA axis constitute a previously
|
|
unrecognized positive feedback loop."</strong>
|
|
</p>
|
|
<p>
|
|
<strong>"Impairment of glucose disposal by infusion of triglycerides in humans: role of glycemia,"
|
|
</strong>
|
|
Felley CP; Felley EM; van Melle GD; Frascarolo P; J"quier E; Felber JP, Am J Physiol, 1989 Jun, 256:6 Pt 1,
|
|
E747-52. <strong>"These results suggest the existence of physiological regulatory mechanisms by which 1) the
|
|
rise in plasma free fatty acid inhibits both oxidative and nonoxidative glucose disposal, and 2) the
|
|
rise in glycemia stimulates predominantly nonoxidative glucose disposal."</strong>
|
|
</p>
|
|
<p>
|
|
Nature 1998 Jan 15;391(6664):281-5<strong>. Prostaglandins stimulate calcium-dependent glutamate release in
|
|
astrocytes.</strong>
|
|
Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A<strong>.
|
|
</strong>Astrocytes in the brain form an intimately associated network with neurons. They respond to
|
|
neuronal activity and synaptically released glutamate by raising intracellular calcium concentration
|
|
([Ca2+]i), which could represent the start of back-signalling to neurons.<strong>
|
|
Here we show that coactivation of the AMPA/kainate and metabotropic glutamate receptors (mGluRs) on
|
|
astrocytes stimulates these cells to release glutamate through a Ca2+-dependent process mediated by
|
|
prostaglandins. Pharmacological inhibition of prostaglandin synthesis prevents glutamate release,
|
|
whereas application of prostaglandins (in particular PGE2) mimics and occludes the releasing action of
|
|
GluR agonists. PGE2 promotes Ca2+-dependent glutamate release from cultured astrocytes and also from
|
|
acute brain slices under conditions that suppress neuronal exocytotic release.
|
|
</strong>When applied to the CA1 hippocampal region, PGE2 induces increases in [Ca2+]i both in astrocytes
|
|
and in neurons. The [Ca2+]i increase in neurons is mediated by glutamate released from astrocytes, because
|
|
it is abolished by GluR antagonists.<strong>
|
|
Our results reveal a new pathway of regulated transmitter release from astrocytes and outline the
|
|
existence of an integrated glutamatergic cross-talk between neurons and astrocytes in situ that may play
|
|
critical roles in synaptic plasticity and in neurotoxicity.
|
|
</strong>
|
|
</p>
|
|
<p>
|
|
Prog Neurobiol 1998 Jan;54(1):99-125<strong>. Microglia as effector cells in brain damage and repair: focus
|
|
on prostanoids and nitric oxide.
|
|
</strong>Minghetti L, Levi G.<strong> </strong>
|
|
"The present article deals with two classes of compounds that activated microglial cells can produce in
|
|
large amounts: prostanoids (that derive from arachidonic acid through the cyclooxygenase pathway), and
|
|
nitric oxide (that is synthesized from arginine by nitric oxide synthase). Prostanoids and nitric oxide have
|
|
a number of common targets, on which they may exert similar or opposite actions, and have a crucial role in
|
|
the regulation of inflammation, immune responses and cell viability. Their synthesis can massively increase
|
|
when the inducible isoforms of cyclooxygenase and nitric oxide synthase are expressed."
|
|
</p>
|
|
<p>
|
|
In Vitro Cell Dev Biol Anim 1998 Mar;34(3):265-74<strong>. Prostaglandins act as neurotoxin for
|
|
differentiated neuroblastoma cells in culture and increase levels of ubiquitin and beta-amyloid.
|
|
</strong>Prasad KN, La Rosa FG, Prasad JE<strong>. </strong>
|
|
|
|
"Although chronic inflammatory reactions have been proposed to cause neuronal degeneration associated with
|
|
Alzheimer's disease (AD), the role of prostaglandins (PGs), one of the secretory products of inflammatory
|
|
reactions, in degeneration of nerve cells has not been studied. Our initial observation that <strong
|
|
>PGE1-induced differentiated neuroblastoma (NB) cells degenerate in vitro more rapidly than those inducedby
|
|
RO20-1724, an inhibitor of cyclic nucleotide phosphodiesterase, has led us to postulate that PGs act as
|
|
a neurotoxin.</strong> This study has further investigated the effects of PGs on differentiated NB cells
|
|
in culture. Results showed that PGA1 was more effective than PGE1 in causing degeneration of differentiated
|
|
NB cells as shown by the cytoplasmic vacuolation and fragmentation of soma, nuclei, and neurites. Because
|
|
increased levels of ubiquitin and beta-amyloid have been implicated in causing neuronal degeneration, we
|
|
studied the effects of PGs on the levels of these proteins during degeneration of NB cells in vitro...."
|
|
"Results showed that PGs increased the intracellular levels of ubiquitin and beta-amyloid prior to
|
|
degeneration, whereas the degenerated NB cells had negligible levels of these proteins. <strong>These data
|
|
suggest that PGs act as external neurotoxic signals</strong> which increase levels of ubiquitin and
|
|
beta-amyloid that represent one of the intracellular signals for initiating degeneration of nerve cells."
|
|
</p>
|
|
<p>
|
|
Brain Res Bull 1998 Apr;45(6):637-40. <strong>
|
|
The fatty acid composition of maternal diet affects the response to excitotoxic neural injury in
|
|
neonatal rat pups.</strong>Valencia P, Carver JD, Wyble LE, Benford VJ, Gilbert-Barness E, Wiener DA,
|
|
Phelps C<strong>
|
|
Fatty acids and their derivatives play a role in the response to neural injury.</strong> The effects of
|
|
prenatal and postnatal dietary fatty acid composition on excitotoxic neural injury were investigated in
|
|
neonatal rat pups."
|
|
</p>
|
|
|
|
<p>
|
|
Proc Soc Exp Biol Med 1998 Nov;219(2):120-5<strong>. Prostaglandins as putative neurotoxins in Alzheimer's
|
|
disease.</strong> Prasad KN, Hovland AR, La Rosa FG, Hovland PG<strong>. </strong>
|
|
"Chronic inflammatory reactions in the brain appear to be one of the primary etiological factors in the
|
|
pathogenesis of Alzheimer's disease (AD). This is supported by the fact that the secretory products of
|
|
inflammatory reactions, which include cytokines, complement proteins, adhesion molecules, and free radicals,
|
|
are neurotoxic. We have recently reported that prostaglandins (PGs), which are also released during
|
|
inflammatory reactions, cause rapid degenerative changes in differentiated murine neuroblastoma cells (NB)
|
|
in culture." "The mechanisms underlying Abeta-induced neuronal degeneration have been under intense
|
|
investigation, and several mechanisms of action have been proposed. We postulate that PG-induced elevation
|
|
of Abeta may lead to an increased binding of Abeta to the 20S proteasome, resulting in a reduction of 20S
|
|
proteasome-mediated degradation of ubiquitin-conjugated proteins. This is predicted to lead to an increase
|
|
in an accumulation of abnormal proteins, which ultimately contribute to neuronal degeneration and death.
|
|
Based on our hypothesis and on studies published by others, we propose that a combination of nonsteroidal
|
|
anti-inflammatory drugs, which inhibit the synthesis of PGs, and antioxidant vitamins, which quench free
|
|
radicals and both of which have been recently reported to be of some value in AD treatment when
|
|
used-individually, may be much more effective in the prevention and treatment of AD than the individual
|
|
agents alone."
|
|
</p>
|
|
<p>
|
|
Mol Chem Neuropathol 1998 May;34(1):79-101<strong>. Effects of EGb 761 on fatty acid reincorporation during
|
|
reperfusion following ischemia in the brain of the awake gerbil.
|
|
</strong>
|
|
|
|
Rabin O, Drieu K, Grange E, Chang MC, Rapoport SI, Purdon AD<strong>. </strong>
|
|
</p>
|
|
<p>
|
|
<strong>Regulation of arcuate nucleus synaptology by estrogen.</strong> Leedom L; Lewis C; Garcia-Segura LM;
|
|
Naftolin F. Ann N Y Acad Sci, 1994 Nov 14, 743:, 61-71 "Estrogen modulates the synaptology of the
|
|
hypothalamic arcuate nucleus during sexual differentiation of the rat brain in both males and females. In
|
|
<strong>
|
|
males, testosterone of gonadal origin is converted to estrogen in the brain</strong> by an enzyme,
|
|
aromatase, which is also present in females. The exposure of the male's hypothalamus to relatively high
|
|
levels of estrogen (following a perinatal testosterone surge) leads to the development of a pattern of
|
|
synaptogenesis<strong>
|
|
which does not support an estrogen-induced gonadotrophin surge in the adult.</strong> In female rats,
|
|
hypothalamic development <strong>occurs with permissively low levels</strong> of estrogen, enabling a
|
|
midcycle estrogen-induced gonadotrophin surge and ovulation in adulthood. During adult reproductive life in
|
|
female rats, circulating estrogen modulates the synaptology of the arcuate nucleus. <strong>The most
|
|
physiological example of this is the 30-50% loss of axosomatic synapses following the preovulatory
|
|
estrogen surge on diestrus-proestrus.</strong>
|
|
|
|
Studies on post-synaptic membranes of the arcuate nucleus reveal sex differences in membrane organization
|
|
and protein content which are estrogen-dependent. <strong>
|
|
Estrogen apparently stimulates endocytosis of areas of post-synaptic membrane that are dense with small
|
|
intramembranous protein particles, resulting in a reduction in the number of small intramembranous
|
|
particles. This also appears to be the physiologic mechanism of neuronal changes in females during the
|
|
estrus cycle.</strong> Repeated exposure to preovulatory levels of estrogen may lead to an age-related
|
|
decline in reproductive capacity in female rats. Aging females lose the estrogen-induced gonadotrophin surge
|
|
responsible for ovulation. <strong>This loss of function may result from a cumulative estrogen effect during
|
|
the repeated ovarian cycles which results in a reorganization of the synaptology</strong> on which
|
|
regulates the estrogen-induced gonadotrophin surge." ". . .recent research has shown that GABA, the
|
|
monoamines, and several neuropeptides are participants in the estrogen-sensitive network which regulates
|
|
GNRH secretion. In this regard, present work shows estrogen-induced changes in GABA and dopamine synapses in
|
|
the arcuate nucleus."
|
|
</p>
|
|
<p>
|
|
<strong>17 beta Estradiol-induced increase in brain dopamine D-2 receptor: antagonism by MIF-1.</strong>
|
|
<strong>
|
|
Rajakumar G</strong>; Chiu P; Chiu S; Johnson RL; <strong>Mishra RK</strong> Department of Psychiatry,
|
|
Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada. Peptides, 1987 Nov-Dec, 8:6,
|
|
997-1002 Animal behavioral and neurochemical studies implicate dopaminergic systems<strong>
|
|
in the neurological sequelae induced by estrogen.</strong> In the present study, we demonstrated for the
|
|
first time that MIF-1, a neuropeptide unrelated to classical dopamine agonists, when given prior to,
|
|
concurrently with, and after 17 beta-estradiol, antagonized significantly the estrogen-induced increase in
|
|
the<strong> density of dopamine D-2 receptor</strong> both in the striatum and the mesolimbic area of male
|
|
rat brain. The current findings have implications for the prophylactic and therapeutic potential for MIF-1
|
|
in <strong>extrapyramidal motor disorders caused by estrogen imbalance in humans.</strong>
|
|
</p>
|
|
<p>
|
|
Eur J Clin Invest 1984 Dec;14(6):431-4 <strong>
|
|
Effect of ovulation on haem metabolism in rabbits.</strong> Lindahl J, Werner B, Lerner R<strong>. "To
|
|
investigate the origin of the cyclic changes in the rate of endogenous carbon-monoxide production (nCO)
|
|
during the menstrual cycle, haem turnover was determined before and after chorion gonadotropic
|
|
hormone-induced ovulation in six female rabbits. 14C-labelled delta-aminolevulinic acid and glycine were
|
|
administered and the excretion rate of 14CO (A14CO) was measured for determination of hepatic
|
|
and</strong>
|
|
bone-marrow haem turnover, respectively." <strong>
|
|
". . . nCO was increased 34% (P less than 0.05) during the post-ovulation period. As the increase in
|
|
'unassigned' haem turnover was small and may be unaccompanied by a contemporary increase in bilirubin/CO
|
|
production, it was concluded that the increase in nCO during the post-ovulation period essentially
|
|
depends on increased destruction of circulating red cells in the rabbit."</strong>
|
|
</p>
|
|
|
|
<p>
|
|
J Neurotrauma 1993 Winter;10(4):373-84. <strong>
|
|
Beneficial effect of the nonselective opiate antagonist naloxone hydrochloride and the
|
|
thyrotropin-releasing hormone (TRH) analog YM-14673 on long-term neurobehavioral outcome following
|
|
experimental brain injury in the rat.
|
|
</strong>
|
|
McIntosh TK, Fernyak S, Hayes RL, Faden AI
|
|
</p>
|
|
<p>
|
|
J Neurosci 1990 Nov;10(11):3524-30. <strong>
|
|
Opiate antagonist nalmefene improves intracellular free Mg2+, bioenergetic state, and neurologic outcome
|
|
following traumatic brain injury in rats.
|
|
</strong>
|
|
Vink R, McIntosh TK, Rhomhanyi R, Faden AI. "Treatment of CNS trauma with the opiate antagonist naloxone
|
|
improves outcome, though the mechanisms of action remain speculative."
|
|
</p>
|
|
<p>
|
|
Brain Res 1989 Mar 20;482(2):252-60. <strong>
|
|
Magnesium protects against neurological deficit after brain injury.</strong>
|
|
|
|
McIntosh TK, Vink R, Yamakami I, Faden AI.
|
|
</p>
|
|
<p>
|
|
Adv Neurol 1988;47:531-46. <strong>
|
|
Role of thyrotropin-releasing hormone and opiate receptor antagonists in limiting central nervous system
|
|
injury.</strong> Faden AI. "Opiate antagonists, including receptor antagonists and physiologic
|
|
antagonists, have been shown to produce beneficial effects in a variety of models of CNS injury and in a
|
|
variety of species. Opiate antagonists improve spinal cord blood flow, electrical conduction of the spinal
|
|
cord, pathological changes, and motor recovery following traumatic spinal cord injury in cats. TRH appears
|
|
to be superior to naloxone in this regard, although direct comparisons between receptor-selective opiate
|
|
receptor antagonists and TRH have not been made."
|
|
</p>
|
|
<p>
|
|
Exp Neurol 1994 Sep;129(1):64-9.<strong>Progesterone facilitates cognitive recovery and reduces secondary
|
|
neuronal loss caused by cortical contusion injury in male rats.</strong> Roof RL, Duvdevani R, Braswell
|
|
L, Stein DG.
|
|
</p>
|
|
<p>
|
|
Exp Neurol 1996 Apr;138(2):246-51. <strong>
|
|
Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective.</strong
|
|
> Roof RL, Duvdevani R, Heyburn JW, Stein DG.
|
|
</p>
|
|
<p>
|
|
Mol Chem Neuropathol 1997 May;31(1):1-11. <strong>
|
|
Progesterone protects against lipid peroxidation following traumatic brain injury in rats.</strong> Roof
|
|
RL, Hoffman SW, Stein DG.
|
|
</p>
|
|
<p>
|
|
Jiang N, et al. <strong>Progesterone is neuroprotective after transient middle cerebral artery occlusion in
|
|
male rats.</strong> Brain Res. 1996 Sep 30;735(1):101-7.
|
|
</p>
|
|
<p>
|
|
Roof RL, et al. <strong>Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is
|
|
still effective.</strong> Exp Neurol. 1996 Apr;138(2):246-51.
|
|
</p>
|
|
|
|
<p>
|
|
Duvdevani R, et al. <strong>Blood-brain barrier breakdown and edema formation following frontal cortical
|
|
contusion: does hormonal status play a role?</strong> J Neurotrauma. 1995 Feb;12(1):65-75.
|
|
</p>
|
|
<p>
|
|
Exp Neurol 1997 Dec;148(2):453-63. <strong>
|
|
Endogenous repair after spinal cord contusion injuries in the rat.
|
|
</strong>
|
|
Beattie MS, Bresnahan JC, Komon J, Tovar CA, Van Meter M, Anderson DK, Faden AI, Hsu CY, Noble LJ, Salzman
|
|
S, Young W.<strong>
|
|
"In addition to signs of regeneration, we noted evidence for the proliferation of cells located in the
|
|
ependymal zone surrounding the central canal at early times following contusion injuries."</strong>
|
|
</p>
|
|
|
|
© Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
|
|
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