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<h1>Epilepsy and Progesterone</h1>
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<div style="text-align: center;">
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<a href="/"><img class="epic" src="/icons/chads/chad.png"></a>
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<hr>
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<p class="nav"><span class="nav-left">Listed under <a href="/ray-peat.html">Ray Peat</a>.</span><span class="nav-right"><a href="/theme.html">Theme</a></span></p>
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<p>From the <a href="https://raypeat.com/articles/articles/epilepsy-progesterone.shtml" target="_blank">original article</a> in 2006. Author: <a href="https://raypeat.com/" target="_blank">Ray Peat</a>.</p>
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<p>The
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length of the life-span, and of the period of youth or immaturity, is
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closely associated with the size of the brain, and the brain has a very
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high rate of metabolism. When something interferes with this very high
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metabolic rate, the consequences may be instantanteous,* or developmental,
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or chronic and degenerative, or even transgenerational. The issue of
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epilepsy centers on questions of brain metabolism, and so it has all
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of those dimensions.</p>
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<p>As
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I discuss the mechanisms known to predispose a person to epilepsy, I
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will emphasize the centrality of oxidative energy production, and show
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how "stroke," "stress," "hyperactivity,"
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"dementia," and other brain syndromes are related to "epilepsy."
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(Similar processes are being studied in the heart and other tissues;
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eventually, we might have a general language that will make it easier
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to understand the parallels in the various kinds of "seizure"
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in any organ.)</p>
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<p>As
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an old term, "epilepsy" has aquired a burden of pseudoscientific
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ideas, covering old superstitions with an overlay of new superstitions.
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[Hereditary epilepsy has been discussed in countless textbooks and medical
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journals, but I think a much better case could be made for the inheritance
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of a tendency to offer stupid genetic explanations.] "Hereditary
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epilepsy" and "idiopathic epilepsy" are seriously pathogenic
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terms; "brain scar" sometimes has a factual basis, but most
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often the term is an evasion of understanding.</p>
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<p>As
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long as we realize that the essential meaning of the word is "something
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that grabs you," "epilepsy" is a convenient way to refer
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to a cluster of convulsive states, fainting spells, night-terrors and
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nightmares, and strange sensations.</p>
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<p>Seizures can be caused by lack
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of glucose, lack of oxygen, vitamin B6 deficiency, and magnesium deficiency.
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They are more likely to occur during the night, during puberty, premenstrually,
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during pregnancy, during the first year of life, and can be triggered
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by hyperventilation, running, strong emotions, or unusual sensory stimulation.
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Water retention and low sodium increase susceptibility to seizures.
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When I was in high school, our dog found and ate a pint of bacon grease,
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and shortly afterward had a convulsive seizure. I knew of veterinarians
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who treated seizures in dogs with a vermifuge, so it seemed obvious
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that a metabolic disturbance, especially if combined with intestinal
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irritation, could cause fits.</p>
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<p>It was undoubtedly such observations
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that led some physicians to advocate removal of the colon as treatment
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for epilepsy. Pregnancy and the menstrual cycle have been recognized
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as having something to do with seizures, but when seizures occurred
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only during pregnancy, they were classified as nonepileptic, and when
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they had a clear premenstrual occurrence, they were likely to be classified
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as "hysterical fits," to be treated with punishment.
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</p>
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<p>It has been observed that all
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"recognized" anti-seizure drugs are teratogenic, and women
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who are taking such drugs are told that pregnancy might kill them if
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they stop the drug, but that their babies will have a greatly increased
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risk of birth defects if they take the drugs during pregnancy. This
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is why a better understanding of epilepsy is very important. Old therapies
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are mainly important for the insight they can give into the nature of
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the physiological problem. Some of the well established clinical-laboratory
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observations (F. Mora, and C. S. Babel, for example) give strong hints
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as to the physiological problem, for example, low albumin, high prealbumin,
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low magnesium and high calcium all suggest hypothyroidism. (Problems
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with the bowel, liver, and sex hormones are highly associated with hypothyroidism,
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both as causes and as effects.) Water retention was so clearly involved
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in seizures that increased water intake was used as a diagnostic procedure.
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(R. Grinker) Unfortunately, animal experiments showed that water intoxication
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increased susceptibility to seizures even in normal individuals. Low
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sodium content in the body fluids also predisposed to seizures, so that
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someone with hyponatremia (low blood sodium) would be more susceptible
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to induction of a seizure by excessive water intake. (Excessive water
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uptake is still recognized as a factor in seizures, but now it is seen
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as part of a complex process, involving energy, hormones, and transmitter
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substances. E.g., Kempski; Chan.) </p>
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<p>Hypothyroid
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people tend to lose sodium easily, and unopposed estrogen increases
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water retention, without an equivalent sodium retention, so low thyroid,
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high estrogen people have two of the conditions (edema and hyponatremia)
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known to predispose to seizures. Another outstanding feature of seizures
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of various sorts is that they are most likely to occur at night, especially
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in the early pre-dawn hours. Low blood sugar and high adrenalin predominate
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during those hours. Hypoglycemia, in itself, like oxygen deprivation,
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is enough to cause convulsions.</p>
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<p>Progesterone
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and thyroid promote normal energy production, and their deficiency causes
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a tendency toward hypoglycemia, edema and instability of nerves.
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</p>
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<p>Twenty years ago, a woman who
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was considered demented visited me. From the age of 21, she had been
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increasingly disabled by premenstrual migraines. When she was 35 she
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was a school teacher, and during the summer a neurologist told her that
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dilantin would help her headaches, because "migraine is similar
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to epilepsy." Although she told the neurologist that the drug made
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her "too stupid to teach school," he offered her no alternatives,
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and didn't mention that sudden withdrawal from the drug could trigger
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a seizure. When classes started she discontinued the dilantin and had
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a seizure. The neurologist said the seizure proved that migraines were
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a form of epilepsy. At the age of 52, she spent about 20 hours a day
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in bed, and couldn't go outside by herself, because she would get lost.
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After using a little progesterone for a few days, she stopped having
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seizures, discontinued her drugs, and was able to work. When she returned
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to graduate school, she got straight As, and earned her masters' degree
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in gerontology. But she had lost 17 years because the drug industry
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had covered up the role of the hormones in epilepsy, migraine, and the
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perimenstrual syndrome.</p>
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<p>The
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most popular anticonvulsant drugs are both neurotoxic and teratogenic,
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that is, they damage the patient's brain, and greatly increase the incidence
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of birth defects. The Nazis justified their horrible medical experiments
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as "science," but the effects of epilepsy medicine in the
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last half century have been similar in effect, grander in scale, and
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without any scientific justification.</p>
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<p>Besides
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the specific promotional efforts of the drug industry and their branch
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of government, there is a broader situation that makes their work easier.
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It is a culture of goony ideas, that ultimately emanates from the academic
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elite, which (since Descartes, and before) places "thought"
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above evidence. In biology, "genes" and "membranes"
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are confused ideas that are used to justify actions that aren't based
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on evidence. For the Nazis, "cultural degeneracy" was a medical-biological-political
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category based on that style of thinking. In the United States, "genes"
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for epilepsy, hyperactivity, language development, IQ, eclampsia, etc.,
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are "found" at Harvard/MIT/Stan- ford/Yale/Univ. of California,
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etc., by an elite whose wits have been dulled by environmental deprivation,
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that is, by a lack of criticism.</p>
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<p>By manipulating the diet and environment,
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animals can be made more or less seizure-prone, and it happens that
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the changes that affect the brain affect all other organs, in ways that
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are now fairly well understood. Examining the cellular events associated
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with a seizure is useful for therapy and prevention of seizures, but
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the same methods are helpful for many other conditions. It is now clearly
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established that stress can cause brain damage, as well as other diseases.
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Now that our public health establishment has eliminated smoking from
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public places, maybe they can find a way to reduce stress and disease
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by removing morons from positions of power.</p>
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<p>Excitotoxicity,
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in its simplest sense, is the harmful cellular effect (death or injury)
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caused by an excitatory transmitter such as glutamate or aspartate acting
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on a cell whose energetic reserves aren't adequate to sustain the level
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of activity provoked by the transmitter. Once an excitotoxic state exists,
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the consequences of cell exhaustion can increase the likelihood that
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the condition will spread to other cells, since any excitation can trigger
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a complex of other excitatory processes. As calcium enters cells, potassium
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leaves, and enzymes are activated, producing free fatty acids (linoleic
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and arachidonic, for example) and prostaglandins, which activate other
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processes, including lipid peroxidation and free radical production.
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Protein kinase C (promoted by unsaturated fats and estrogen) facilitates
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the release of excitatory amino acids. (See J. W. Phillis and M. H.
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O'Regan, "Mechanisms of glutamate and aspartate release in the
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ischemic rat cerebral cortex," Br. Res. 730(1-2), 150-164, 1996.)
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Estrogen supports acetylcholine release, which leads to increased extracellular
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potassium and excitatory amino acids. (See R. B. Gibbs, et al., "Effects
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of estrogen on potassium-stimulated acetylcholine release in the hippocampus
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and overlying cortex of adult rats," Br. Res. 749(1), 143-146,
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1997.)</p>
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<p>Estrogen
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also stimulates the production of free radicals. Calcium, free radicals,
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and unsaturated free fatty acids impair energy production, decreasing
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the ability to regulate potassium and calcium. The increased estrogen
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associated with seizures is associated with reduced serum calcium (Jacono
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and Robertson, 1987). Feedback self-stimulation of free radicals, free
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fatty acids, and prostaglandins create a bias toward increased excitation.
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</p>
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<p>Ammonia
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is produced by stimulated nerves, and normally its elimination helps
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to eliminate and control the excitotoxic amino acids, glutamate and
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aspartate. The production of urea consumes aspartic acid, converting
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it to fumaric acid, but this requires carbon dioxide, produced by normal
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mitochondrial function. A deficiency of carbon dioxide would reduce
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the delivery of oxygen to the brain by constricting blood vessels and
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changing hemoglobin's affinity for oxygen (limiting carbon dioxide production),
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and the failure to consume aspartate (in urea synthesis) and glutamate
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(as alpha-ketoglutarate) and aspartate (as oxaloacetate) in the Krebs
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cycle, means that as energy becomes deficient, excitation tends to be
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promoted. This helps to explain the fact that seizures can be induced
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by hypoxia. (Balloonists and mountain climbers at extremely high elevations
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have mentioned suffering from severe insomnia. The mechanisms of excitotoxicity
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are probably involved in other forms of insomnia, too.) Antioxidants
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help to control seizures, by reducing the excitatory contribution of
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free radicals and lipid peroxidation. Since excitation can promote the
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toxic forms of oxidation, many surprising substances turn out to have
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an "antioxidant" function. Magnesium, sodium (balancing calcium
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and potassium), thyroid and progesterone (increasing energy production),
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and in some situations, carbon dioxide. Aspirin, by inhibiting prostaglandin
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synthesis (and maybe other mechanisms) often lowers free radical production.
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Adenosine seems to have a variety of antioxidant functions, and one
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mechanism seems to be its function as an antiexcitatory transmitter.
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One of estrogen's excitant actions on the brain probably involves its
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antagonism to adenosine (Phillis and O'Regan, 1988).
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</p>
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<p>Albumin,
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besides maintaining blood volume and preventing edema, serves to protect
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respiration, by binding free fatty acids. Estrogen blocks the liver's
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ability to produce albumin, and increases the level of circulating free
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fatty acids. Free fatty acids cause brain edema. This is probably another
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aspect of estrogen's contribution to seizure susceptibility. Magnesium
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sulfate has been used for generations in India to treat eclampsia and
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"toxemia" of pregnancy, and its effectiveness is gradually
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coming to be recognized in the U.S. Increasingly, magnesium deficiency
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is recognized as a factor that increases susceptibility to seizures.
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(Valenzuela and Benardo, 1995; Slandley, et al., 1995). Hypothyroidism
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reduces the ability of cells to retain magnesium. Thyroid does
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many things to protect against seizures. It keeps estrogen and adrenal
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hormones low, and increases production of progesterone and pregnenolone.
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It facilitates retention of magnesium and of sodium, and prevents edema
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in a variety of ways.</p>
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<p>Progesterone,
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because of its normal anesthetic function (which prevents the pain of
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childbirth when its level is adequate), directly quiets nerves, and
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in this way suppresses many of the excitotoxic processes. It has direct
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effects on mitochondria, promoting energy production, and it facilitates
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thyroid hormone functions in various ways. It promotes the elimination
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of estrogen from tissues, and is a "diuretic" in several benign
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ways, that are compatible with maintenance of blood volume. It antagonizes
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the mineralocorticoids and the glucocorticoids, both of which promote
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seizures. (Roberts and Keith, 1995.) The combination of hypoglycemia
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with elevation of cortisone probably accounts for the nocturnal incidence
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of seizures.</p>
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<p>If
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progesterone's antiepileptic effectiveness were not enough (and it is
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very effective even in irrational pharmaceutical formulations), the
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fact that it reduces birth defects, and promotes brain development and
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nerve repair should assure its general use in women with a history of
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seizures, until it is established that they are no longer "epileptic."
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Although thyroid, progesterone, and a high quality protein diet will
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generally correct the epilepsy problem, it is important to mention that
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the involvement of unsaturated fats and free radicals in seizure physiology
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implies that we should minimize our consumption of the unsaturated fats.
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Even years after eliminating them from the diet, their release from
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tissue storage can prolong the problem, and during that time the use
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of vitamin E is likely to reduce the intensity and frequency of seizures.
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Coconut oil lowers the requirement for vitamin E, and reduces the toxicity
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of the unsaturated fats (see Cleland, et al.), favoring effective respiration
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and improving thyroid and progesterone production. Endotoxin formed
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in the bowel can block respiration and cause hormone imbalances contributing
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to instability of the nerves, so it is helpful to optimize bowel flora,
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for example with a carrot salad; a dressing of vinegar, coconut oil
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and olive oil, carried into the intestine by the carrot fiber, suppresses
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bacterial growth while stimulating healing of the wall of the intestine.
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The carrot salad improves the ratio of progesterone to estrogen and
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cortisol, and so is as appropriate for epilepsy as for premenstrual
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syndrome, insomnia, or arthritis.</p>
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<p>NOTES: </p>
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<p>When
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the brain loses its oxygen supply, consciousness is lost immediately,
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before there is much decrease in the ATP concentration. This has led
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to the proposal of interesting "electronic" ideas of consciousness,
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but there is another way of viewing this. While ATP constitutes a kind
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of reservoir of cellular energy, the flow of carbon dioxide through
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the brain cell is almost the mirror image of the flow of oxygen. Oxygen
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scarcity leads directly to carbon dioxide scarcity. The "sensitive
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state," consciousness, might require the presence of carbon dioxide
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as well as ATP, to sustain a cooperative, semi-stable, state of the
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cytoplasmic proteins. The ability of ordinary light to trigger a conformation
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change in the hemoglobin-carbon monoxide-carbon dioxide system shows
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how sensitive a system with only a few elements can be. At the other
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extreme from consciousness, there is the evidence that carbon dioxide
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is essential for even the growing/living state of protozoa, algae, and
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bacteria.(O. Rahn, 1941.)</p>
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<p>O. Rahn, "Protozoa need carbon
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dioxide for growth," Growth 5, 197-199, 1941. "On page 113
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of this volume, the statement of Valley and Rettger that all bacteria
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need carbon dioxide for growth had been shown to apply to young as well
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as old cells." "...it is possible...to remove it as rapidly
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as it is produced, and under these circumstances, bacteria cannot multiply."
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</p>
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<h2>References</h2>
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<small>
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<p>E. Tauboll, et al., "The
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progesterone metabolite 5-alpha-pregnan-3-alpha-ol-20-one reduces K+-induced
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GABA and glutamate release from identified nerve terminals in rat hippocampus--a
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semiquantitative immunocytochemical study," Brain Research 623(2),
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329-333, 1993.</p>
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<p>E. Tauboll and S. Lindstrom, similar
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article in Epilepsy Research 14(1), 17-30, 1993.</p>
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<p>G. K. Herkes, et al., "Patterns
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of seizure occurrence in catamenial epilepsy," Epilepsy Research
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15(1), 47-52, 1993. (Seizures are more frequent at ovulation, during
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the two days before menstruation, and during menstruation.)</p>
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<p>M. S. Myslobodsky, "Proconvulsant
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and anticonvulsant effects of stress--the role of neuroactive steroids,"
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Neuroscience & Biobehavioral Reviews 17(2_, 129-139, 1993. (Discusses
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steroid-induced sedation, excitatory steroids, stress and epilepsy,
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GABA and respiratory functions, and asymmetric brain injury.)</p>
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<p>P. Berbel, et al., "Organization
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of auditory callosal connections in hypothyroid adult rats," European
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J. of Neuroscience 5(11), 1465-1478, 1993.(Changes in cortical connectivity
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related to epilepsy associated with early hypothyroidism.)</p>
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<p>D. A. Marks and B. L. Ehrenberg,
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"Migraine-related seizures in adults with epilepsy, with EEG correlation,"
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Neurology 43(12), 2475-2483, 1993. ("Patients with catamenial epilepsy
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and patients with migraine with aura were at an increased risk for an
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association between..." migraine and epilepsy.)</p>
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<p>R. D. Brinton, "The neurosteroid
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3-alpha-hydroxy-5-alpha-pregnan-20-one induces cytoarchitectural regression
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in cultured fetal hippocampal neurons," J. of Neuroscience 145(5
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part 1), 2763-2774, 1994. J. W. Phillis and M. H. O'Regan, "Effects
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of estradiol on certain cortical neurons and their responses to adenosine,"
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Br. Res. Bull. 20(2), 151-155, 1988.</p>
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<p>J. O. McNamara, "Human hypoxia
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and seizures: Effects and interactions," Advances in Neurology
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26, S. Fahn, et al., eds., Raven Press, N.Y., 1979. (Seizures can cause
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hypoxia, etc.)</p>
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<p>M. R. Liebowitz, et al., "Lactate
|
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provocation of panic attacks: 2. Biochemical and physiological findings."
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Arch. Gen. Psychiatry 42(7), 709-719, 1985. "Before receiving lactate,
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patients showed higher heart rates than controls and also signs of hyperventilation."
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R. H. Mattson, et al., "Treatment of seizures with medroxyprogesterone
|
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acetate: Preliminary report," Neurology 34, 1255-7, 1984. M. W.
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Newmark, et al, "Catamenial epilepsy: A review," Epilepsia
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21, 281-300, 1980.</p>
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<p>J. W. Phillis and M. H. O'Regan,
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"Effects of estradiol on cerebral cortex neurons and their responses
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to adenosine," Br. Res. Bull. 20(2), 151-155, 1966. (Antagonism
|
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to endogenous adenosine may account for the excitant actions of estradiol
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in the brain.)</p>
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<p>J. W. Phillis, et al., "Acetylcholine
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output from the ischemic rat cerebral cortex: Effects of adenosine agonists,"
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Br. Res. 613(2), 337-340, 1993. (Acetylcholine enhances excitotoxicity,
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could contribute to ischemic brain injury.)</p>
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<p>T. Backstrom, "Epileptic
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seizures in women related to plasma estrogen and progesterone during
|
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the menstrual cycle," Acta Neurol. Scand. 54, 321-347, 1976. (Seizures
|
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are more frequent at menstruation and ovulation.) T. Backstrom, et al.,
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"Effects of intravenous progesterone infusion on the epilepsy discharge
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frequency in women with partial epilepsy," Acta Naurol. Scan. 69(4),
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240-248, 1984.</p>
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<p>A. W. Zimmerman, "Hormones
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and epilepsy," Neurol. Clin. 4(4), 853-861, 1985. "Progesterone
|
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appears to be especially effective in treating seizures." J. Bauer,
|
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et al., "Catamenial seizures--an analysis," Nervenarzt 66(10),
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760-769, 1995. "...when anticonvulsants have failed to suppress
|
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seizures, progesterone or progesterone-derivates have been administered
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with success." R. H. Mattson, et al., "Seizure frequency and
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the menstrual cycle: a clinical study," Epilepsia 22, 242, 1981.
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J. Logothetis, et al., "The role of estrogens in catamenial exacerbation
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of epilepsy," Neurology (Minneap) 9, 352-360, 1959. J Laidlaw,
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"Catamenial epilepsy," Lancet 2, 1235-7, 1956. S. Landgren
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and O. Selstam, "Interaction between 17-beta-oestradiol and 3alpha-hydroxy-5alpha
|
|
pregnane- 20-one in the control of neuronal excitability in slices from
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the hippocampus in vitro of guinea-pigs and rats," Acta Physiologica
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Scandinavica 154(2), 165-176, 1995. C. A. Frye, "The neurosteroid
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3 alpha, 5 alpha-THP has antiseizure and possible neuroprotective effects
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in an animal model of epilepsy," Brain Research 696(1-2), 113-120,
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1995.</p>
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<p>G. K. Herkes, "Drug treatment
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of catamenial epilepsy," CNS Drugs 3(4), 260-266, 1995. (Mentions
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use of diuretics, progesterone, and the very high incidence of premenstrucal
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seizure, and of abnormal menstrual cycles in women with epilepsy.)</p>
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<p>E. Spiegel and H. Wycis, "Anticonvulsant
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effects of steroids," J. Lab. Clin. Med. 33, 945-957, 1947.</p>
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<p>G. Holmes, "Anticonvulsant
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effect of hormones on seizures in animals," 265-268, in: R. Porter,
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R. H. Mattson, A. Ward, and M. Dam, eds., Advances in Epileptology,
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15th Epilepsy International Symposium, New York, Raven Press, 1984.</p>
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<p>H. W. Zimmerman, et al., "Medroxyprogesterone
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acetate in the treatment of seizures associated with menstruation,"
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J. Pediatr. 83, 959-963, 1973. R. H. Mattson, et al., "Medroxy-progesterone
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treatment of women with uncontrolled seizures," Epilepsia 22, 242,
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1981. A. Rosenfield, et al., "The Food and Drug Administration
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and medroxyprogesterone acetate: What are the issues?" JAMA 249,
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2922-2928. 1983. V. Valenzuela and L. S. Benardo, "An in vitro
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model of persistent epileptiform activity in neocortex," Epilepsy
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Research 21(3), 195-204, 1995. C. A. Slandley, et al., "Magnesium
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sulfate reduces seizures induced by central administration of the excitatory
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amino acid N-methyl-D-aspartate in rats," Hypertension in Pregnancy
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14(2), 235-244, 1995. ("Magnesium is a physiological blocker of
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the NMDA receptor.") M. Simonale, et al., "Adenosine JA(1)
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receptors in the rat brain in the kindled model of epilepsy," Eur.
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J. of Pharmac. 265(3), 121-124, 1994. (Adenosine has potent anticonvulsive
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effects in various seizure models.) P. S. Timiras and H. F. Hill, Chapter
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43, in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. Glaser,
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et al, Raven Press, N.Y., 1980. (Estrogens increase cortical excitability,
|
|
lower convulsive thresholds, and are clearly associated with certain
|
|
cases of petit mal epilepsy. "The mechanisms of this so-called
|
|
'catamenial' epilepsy are unknown. Water retention and electrolyte changes
|
|
in the brain...have been implicated..." "...acetazolamide
|
|
(diamox), a carbonic anhydrase inhibitor and diuretic, is successful
|
|
in the treatment of many cases of these seizures, and in refractory
|
|
cases progestational agents are effective." "...seizures were
|
|
more severe and frequent during the estrogen-dominated preovulatory
|
|
phase of the menstrual cycle than in the progesterone-dominated postovulatory
|
|
phase." "...ACTH may trigger epileptic convulsions by increasing
|
|
intracellular sodium concentration throughout the body." "Progesterone
|
|
can effectively reduce the frequency and severity of intractable seizures
|
|
associated with menstruation..." "Considering the markedly
|
|
proconvulsant effects of estrogens, it is surprising that the differential
|
|
effects of sex hormones on central neurotransmitter mechanisms have
|
|
been only sparingly investigated." "...estradiol decreases
|
|
monoamine oxidase activity and increases choline acetyltransferase activity
|
|
in various brain regions." "...hypothyroidism in perinatal
|
|
animals has striking suppressant effects on GABA metabolism and also
|
|
causes a persistent lowering of electroconvulsive threshold.")</p>
|
|
|
|
<p>P. S. Timiras and H. F. Hill,
|
|
"Antiepileptic drugs," Chapter 43; E. Roberts, "Epilepsy
|
|
and antiepileptic drugs: A speculative synthesis," Chapter 44,
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in Antiepileptic Drugs: Mechanisms of Action, ed. by G. H. Glaser, et
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al., Raven Press, New York, 1980. E. V. Nikushkin, et al.,"Relationship
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between peroxidation and phospholipase hydrolysis of lipids in synaptosomes,"
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B.E.B.M.107(2)183-186, 1989. Free unsaturated fatty acids are liberated
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in nerve endings and contribute to lipid peroxidation in epileptic seizures.
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P. A. Long, et al., "Importance of abnormal glucose tolerance (hypoglycemia
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and hyperglycemia) in the aetiology of pre-eclampsia," Lancet 1,
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923-925, 1977.</p>
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<p>M. M. Singh, "Carbohydrate
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metabolism in pre-eclampsia," Br. J. Obstet. Gynaecol. 83, 124-131,
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1976.</p>
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<p>N. A. Ziboh, et al., Prostaglandins
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5, 233, 1974. (Eicosatrienoic (20:3 n-9) acid is a potent inhibitor
|
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of prostaglandin synthetase.) C. Galli and C. Spagnuolo, "The release
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of brain free fatty acids during ischaemia in essential fatty acid-deficient
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rats," J. of Neurochemistry 26, 401-404, 1976.</p>
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<p>B. Meldrum, "Excitatory amino
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acids and anoxic-ischemic brain damage," Trends Neurosci. 8, 47-48,
|
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1985.</p>
|
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<p>B. Halliwell, "Oxidants and
|
|
human disease: Some new concepts," FASEB J. 1, 358-364, 1987. "...injury
|
|
to the brain causes release of metal ions that stimulate lipid peroxidation."
|
|
"..lipid peroxidation...could be important in spreading injury
|
|
to adjacent cells...." P.H. Chan, et al., "Effects of excitatory
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neurotransmitter amino acids on swelling of rat brain cortical slices,"
|
|
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J. Neurochem. 33, 1309, 1979. P. H. Chan and R. A. Fishman, "Alterations
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of membrane integrity and cellular constituents by arachidonic acid
|
|
in neuroblastoma and glioma cells," Brain Res. 248, 151, 1982.</p>
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<p>T. O. Kokate, et al., "Neuroactive
|
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steroids protect against pilocarpine- and kainic acid-induced limbic
|
|
seizures and status epilepticus in mice," Neuropharmacology 35(8),
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1049-1056, 1996. (With a second dose, "complete protection from
|
|
the...limbic seizures and status epilepticus was obtained.") J.
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W. Phillis, et al., "Effect of adenosine receptor agonist on spontaneous
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and K+-evoked acetylcholine release from the in vivo rat cerebral cortex,"
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Brain Res. 605(2), 293-297, 1993.</p>
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<p>J. W. Phillis, et al., "Acetylcholine
|
|
output from the ischemic rat cerebral cortex: Effectss of adenosine
|
|
agonists," Brain Res. 613(2), 337-340, 1993. (Acetylcholine enhances
|
|
excitotoxic depolarization, intracellular calcium levels, and neural
|
|
degeneration, and could contribute to ischemic brain injury.</p>
|
|
|
|
<p>R. L. Grief, "Thyroid status
|
|
influences calcium ion accumulation and retention by rat liver mitochondria,"
|
|
Proc. Soc. Exp. Biol. & Med. 189(1), 39-44, 1988.</p>
|
|
<p>L. G. Cleland, et al., "Effects
|
|
of dietary n-9 eicosatrienoic acid on the fatty acid composition of
|
|
plasma lipid fractions and tissue plasma lipids," Lipids 31(8),
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829-837, 1996. "Dietary enrichment with ETrA warrants further investigation
|
|
for possible beneficial effects in models of inflammation and autoimmunity,
|
|
as well as in other conditions in which mediators derived from n-6 fatty
|
|
acids can affect homeostasis adversely." A. A. Starkov, et al.,
|
|
"Regulation of the energy coupling in mitochondria by some steroid
|
|
and thyroid hormones," Bioch. Biophys. Acta 1318(1-2), 173-183,
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1997. (Thyroid and progesterone improve respiratory efficiency, lowering
|
|
oxygen consumption which restoring energy production.) R. B. Gibbs,
|
|
et al., "Effects of estrogen on potassium stimulated acetylcholine
|
|
release in the hippocampus and overlying cortex of adult rats,"
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|
|
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Brain Res. 749(1), 143-146, 1997. (Increased response.) I. V. Gusakov,
|
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et al., "Investigation of the role of free-radical processes in
|
|
epilepsy and epileptogenesis," Bull. Exp. Biol. & Medicine
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117(2), 206, 1994.</p>
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<p>B. K. Shakenova, "A new treatment
|
|
of epilepsy resistant to traditional antiseizure pharmacotherapy,"
|
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Bull. Exp. Biol. & Medicine 117(2), 227, 1994. (Antihypoxant with
|
|
antioxidant activity.) R. N. Rzaev and M. N. Aliev, "The use of
|
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antioxidants in the treatment of tic-accompanied hyperkineses in children,"
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Bull. Exp. Biol. & Medicine 117(2), 222, 1994.</p>
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|
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<p>D. A. Sutkovoi and N. I. Lisyanyi,
|
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"Relationship between the kinetics of lipid peroxidation and autoimmune
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|
reactions after craniocerebral injury," Bull. Exp. Biol. &
|
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Medicine 117(2), 2, 1994. Winfried G. Rossmanith, "Gonadotropin
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|
secretion during aging in women: Review article," Exp. Gerontology
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30(3/4) 369-381, 1995. "...major functional derangements, primarily
|
|
at a hypothalamic rather than a pituitary site, have been determined
|
|
as concomitants of aging in women." "...aging may impair the
|
|
negative feedback sensitivity to ovarian sex steroids...." Hormonal
|
|
changes at menopause "may represent the sum of functional aberrations
|
|
that were initiated much earlier in life...." "...prolonged
|
|
estrogen exposure facilitates the loss of hypothalamic neurons...."</p>
|
|
|
|
<p>J. R. Brawer, et al., "Ovary-dependent
|
|
degeneration in the hypothalamic arcuate nucleus," Endocrinology
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|
107, 274-279, 1980. J. Herbert and S. Zuckerman, "Ovarian stimulation
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from cerebral lesion in ferrets," J. Endocrinology 17(4), 433-443,
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1958. G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin
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|
neuron loss: A possible model of hypothalamic aging," Exp. Gerontology
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|
30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented
|
|
by treatment with antioxidants indicating that it results from estradiol-induced
|
|
formation of free radicals." "...this beta-endorphin cell
|
|
loss is followed by a compensatory upregulation of mu opioid receptors
|
|
in the vicinity of LHRH cell bodies." Resulting supersensitivity
|
|
of the cells results "in chronic opioid suppression of the pattern
|
|
of LHRH release, and subsequently that of LH." The neurotoxic effects
|
|
of estradiol cause a "cascade of neuroendocrine aberrations resulting
|
|
in anovulatory acyclicity." Treatment with an opiod antagonist
|
|
|
|
"reversed the cystic morphology of ovaries and restored normal
|
|
ovarian cycles" in estrogen-treated rats. G. B. Melis, et al.,
|
|
"Evidence that estrogens inhibit LH secretion through opioids in
|
|
postmenopausal women using naloxone," Neuroendocrinology 39, 60-63,
|
|
1984.</p>
|
|
<p>H. J. Sipe, et al., "The
|
|
metabolism of 17 beta-estradiol by lactoperoxidase: A possible source
|
|
of oxidative stress in breast cancer," Carcinogenesis 15(11), 2637-2643,
|
|
1994. "...molecular oxygen is consumed by a sequence of reactions
|
|
initiated by the glutathione thiyl radical. ...the estradiol phenoxyl
|
|
radical abstracts hydrogen from...NADH to generate the NAD radical."
|
|
"...the futile metabolism of micromolar quantities of estradiol
|
|
catalyzes the oxidation of much greater concentrations of biochemical
|
|
reducing cofactors, such as glutathione and NADH, with hydrogen peroxide
|
|
produced as a consequence." S. Santagati, et al., "Estrogen
|
|
receptor is expressed in different types of glial cells in culture,"
|
|
|
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J. Neurochem. 63(6), 2058-2064, 1994. "...in all three types of
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|
glial cell analyzed in almost equal amounts..." D. X. Liu and L.
|
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P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical
|
|
generated in vivo," Free Radical Biol. Med. 18(3), 571-576, 1995.
|
|
"Free radicals and some free fatty acids, such as arachidonic acid
|
|
metabolites...may form a feedback loop in which generation of one type
|
|
leads to formation of the other." "Prostaglandin F-2 alpha
|
|
dramatically increased in response to hydroxyl radical generation...."
|
|
J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs
|
|
by arachidonic acid and prostaglandin F-2 alpha," Brain Res. 691(1-2),
|
|
223-228, 1995. "These findings suggest that high levels of AA and
|
|
its metabolites may bias neurons towards excitation." [Estrogen
|
|
appears to support this excitatory system at every level, while prostaglandin
|
|
F2 alpha alters steroid balance, by suppressing progesterone synthesis.]
|
|
J. G. Liehr, et al., "4-hydroxylation of estradiol by human uterine
|
|
myometrium and myoma microsomes: Implications for the mechanism of uterine
|
|
tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995.
|
|
|
|
"... elicits biological activities distinct from estradiol, most
|
|
notably an oxidant stress response induced by free radicals generated
|
|
by metabolic redox cycling reactions."</p>
|
|
<p>J. G. Liehr and D. Roy, "Free
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|
radical generation by redox cycling of estrogens," Free Rad. Biol.
|
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Med. 8, 415-423, 1990. P. Aschheim, "Resultats fournis par la greffe
|
|
heterochrone des ovaires dan l'etude de la regulation hypothalamo-hypophyso-ovarienne
|
|
de la ratte senile," Gerontologia 10, 65-75, 1964/65. "Our
|
|
last experiment, grafting ovaries...into senile rats which had been
|
|
castrated (ovariectomized) when young, and its result, the appearance
|
|
of estrous cycles, seems explicable by this hypothesis. Everything happens
|
|
as if the long absence of ovarian hormones... had kept the cells of
|
|
the hypothalamus in the state of youth. It's as if the messages of the
|
|
circulating steroids fatigued the hypothalamic memory." "What
|
|
are the factors that cause this diminution of the hypothalamic sensitivity...?
|
|
Kennedy incriminates a decrease in the cellular metabolism in general...." </p>
|
|
<p>P. Ascheim, "Aging in the
|
|
hypothalamic-hypophyseal-ovarian axis in the rat," pp. 376-418
|
|
in: A. V. Everitt and J. A. Burgess, editors, Hypothalamus, Pituitary
|
|
and Aging, C. C. Thomas, Springfield, 1976. C. A. Frye and J. D. Sturgis,
|
|
|
|
"Neurosteroids affect spatial reference, working, and long-term
|
|
memory of female rats," Neurobiol. Learn. Memory 64(1), 83-96,
|
|
1995. [Female rats take longer to acquire a spatial task during behavioral
|
|
estrus.] (CA Frye, boston univ., dept biol, behavioral neurosci lab,
|
|
boston 02215) "Estrus-associated decrements in a water maze task
|
|
are limited to acquisition," Physiol. Behav. 57(1), 5-14, 1995. </p>
|
|
<p>C. A. Kristensen, et al., "Effect
|
|
of estrogen withdrawal on energy-rich phosphates and prediction of estrogen-dependence
|
|
monitored by in vivo 31P magnetic resonance spectoscopy of four human
|
|
breast cancer xenografts," Cancer Research 55(8), 1664-1669, 1995.
|
|
This is a very important confirmation of the idea that estrogen, by
|
|
blocking energy, constrains cell function.</p>
|
|
<p>A. J. Roberts and L. D. Keith,
|
|
"Corticosteroids enhance convulsion susceptibility via central
|
|
mineralocorticoid receptors," Psychoneuroendocrinology 20(8), 891-902,
|
|
1995. ("...increase corticosterone levels are associated with increased
|
|
severity of ethanol, pentobarbitol, and diazepam withdrawal. Further
|
|
work with chemical convulsants suggests that mineralocorticoid receptors
|
|
mediate excitatory effects of corticosteroids on convulsion susceptibility.
|
|
The circadian rhythm in convulsion susceptibility varies with the circadian
|
|
rhythm of plasma corticosterone levels and MR binding." "...MR
|
|
are substantially bound at rest and maximally occupied during the circadian
|
|
peak in corticosteroid levels and during stressor exposure, these receptors
|
|
are implicated in the maintenance of and in changes in the arousal state
|
|
of animals.") L. Murri, et al., "Neuroendocrine evaluation
|
|
in catamenial epilepsy," Funct. Neurol. 1(4) 399-403, 1986. "Our
|
|
data showed a reduction of luteal phase progesterone secretion; an imbalanced
|
|
secretion of ovarian steroids plays a role in the catamenial exacerbation
|
|
of epilepsy." S. Bag, et al., "Pregnancy and epilepsy,"
|
|
|
|
J. Neurol. 236(5), 311-313, 1989. </p>
|
|
<p>"Patients with increased
|
|
seizure frequency had significantly higher oestrogen levels, lower level
|
|
of progesterone...." "...abortions and status epilepticus
|
|
had high serum oestrogen levels." M. I. Balabolkin, et al., "The
|
|
role of the female sex hormones in the pathogenesis of catamenial epileptic
|
|
seizures," Ter. Arkh. 66(4), 68-71, 1994. "...a tendency to
|
|
deficient luteal phase and relative hyperestrogenemia in all the cycle
|
|
phases." C. A. Guerreiro, "Ovulatory period and epileptic
|
|
crisis," Arq. Neuropsiquiatr. 49(2), 198-203, 1991. "We think
|
|
the estrogen peak is probably the main cause of the increased frequency
|
|
of epileptic seizures during the ovulatory period."</p>
|
|
|
|
<p>U. Bonuccelli, et al., "Unbalanced
|
|
progesterone and estradiol secretion in catamenial epilepsy," Epilepsy
|
|
Res. 3(2), 100-106, 1989. (Luteal secretion ratio, progesterone to estrogen,
|
|
was significantly reduced in patients versus controls.)</p>
|
|
<p>T. Backstrom, "Epilepsy in
|
|
women," Experientia 32(2), 248-249, 1976. "...a significant
|
|
positive correlation between estrogen/progesterone ratio and scores
|
|
of fits."</p>
|
|
<p>A. G. Herzog, "Hormonal changes
|
|
in epilepsy," Epilepsia 36(4), 323-326, 1995. A. G. Herzog, "Progesterone
|
|
therapy in women with partial and secondary generalized seizures,"
|
|
|
|
Neurology 45(9), 1660-1662, 1995. A. G. Herzog, "Reproductive endocrine
|
|
considerations and hormonal therapy for women with epilepsy," Epilepsia
|
|
32(Suppl.6), S27-33, 1991. "Seizure frequency varies with the serum
|
|
estradiol to progesterone ratio." "... propensity for onset
|
|
at menarch and exacerbation of seizures during the months or years leading
|
|
up to menopause..." polycystic ovarian syndrome and hypogonadotropic
|
|
hypogonadism are significantly overrepresented among women with epilepsy.</p>
|
|
<p>R.H. Mattson and J. A. Cramer,
|
|
"Epilepsy, sex hormones, and antiepileptic drugs," Epilepsia
|
|
26(Suppl. 1), S40-51, 1985. There were fewer seizures during the luteal
|
|
phase but they increased when the progesterone level declined.</p>
|
|
<p>J.J. Jacono and J. M. Robertson,
|
|
"The effects of estrogen, progesterone, and ionized calcium on
|
|
seizures during the menstrual cycle of epileptic women," Epilepsia
|
|
28(5), 571-577, 1987. A positive relation of serum estrogen and seizures,
|
|
negative relation between serum ionized calcium and seizures, and negative
|
|
relation between serum estrogen and calcium. F. E. Jensen, et al., "Epileptogenic
|
|
effect of hypoxia in the immature rodent brain," Ann. Neurol. 29(6),629-836,
|
|
1991. E. C. Wirrell, et al., "Will a critical level of hyperventilation-induced
|
|
hypocapnia always induce an absence seizure?" Epilepsia 37(5),
|
|
459-462, 1996. A. Nehlig, et al., "Absence seizures induce a decrease
|
|
in cerebral blood flow: Human and animal data," J. Cereb. Blood
|
|
Flow Metab. 16(1), 147-155, 1996.</p>
|
|
|
|
<p>Some clinical laboratory findings
|
|
in epilepsy: Folic acid, serum decrease, R. E. Davis, et al., "Serum
|
|
pyridoxal, folate, and vitamin B12 levels in institutionalized epileptics,"
|
|
Epilepsia 16, 463-8, 1975.</p>
|
|
<p>Serum GGT, constantly elevated.
|
|
Ewen and Griffiths, "Gamma-glutamyl transpeptidase: Elevated activities
|
|
in certain neurologic diseases," Am. J. Clin. Pathol. 59, 2-9,
|
|
1973.</p>
|
|
<p>IgA, CSF decreased, F. Mora, et
|
|
al.</p>
|
|
<p>Iron-binding capacity, total,
|
|
serum decrease. F. Mora, et al. Magnesium, serum, decreased; between
|
|
seizures. C S Babel, et al Prealbumin, CSF, increased, the only protein
|
|
to increase in epileptics. F. Mora, et al.</p>
|
|
<p>Pyridoxine, serum, sometimes decreased.
|
|
R. L. Searcy, Diagnostic Biochemistry, McGraw-Hill, 1969.</p>
|
|
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|
|
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