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- <html>
- <head><title>Aging, estrogen, and progesterone</title></head>
- <body>
- <h1>
- Aging, estrogen, and progesterone
- </h1>
-
- <p>
- <em>"Estrogen" refers not just to a family of steroids but to a class of substances that can produce
- approximately the same effects as estradiol and its metabolites.
- </em>
- </p>
- <em>
- <p>
- Even before the pure substance was isolated in the 1930s, the effects of fluid from ovarian follicles
- were studied. It was soon discovered that many chemicals could produce similar effects.
- </p>
- <p>
- By the middle of the century, many toxic effects of the estrogens were known, and more are being
- discovered.
- </p>
- <p>
- Cancer, abnormal blood clotting, and infertility were known to be caused by estrogen before 1940, but at
- the same time the drug companies began calling estrogen "the female hormone," and claiming that it would
- improve fertility.
- </p>
- <p>
- Since the 19th century, some people argued that aging was caused by hormonal deficiency; for example,
- the symptoms of thyroid deficiency resembled aging. The estrogen industry exploited this idea to create
- the "hormone replacement" business.
- </p>
- <p>
- Some hormones do decrease with aging, but others increase.
- </p>
-
- <p>
- All of the unpleasant consequences of estrogen excess happen to resemble some of the events of aging.
- </p>
- <p>
- If aging involves the same processes that are created by estrogen, then our knowledge of how to protect
- ourselves against estrogen can be used to protect ourselves against aging.
- </p>
- <p>
- Estrogen steals oxygen from mitochondria, shifting patterns of growth and adaptation.
- </p></em>
-
- <hr />
-
- <p>
- The balance between what a tissue needs and what it gets will govern the way that tissue functions, in both
- the short term and the long term. When a cell emits lactic acid and free radicals and the products of lipid
- peroxidation, it's reasonable to assume that it isn't getting everything that it needs, such as oxygen and
- glucose. With time, the cell will either die or adapt in some way to its deprived conditions.
- </p>
- <p>
- In aging, tissues generally atrophy, with loss of both substance and activity. Ordinarily, organisms react
- to stress with increased activity of the appropriate functional system, but when the stress is inescapable,
- organisms adopt the strategy of decreasing their demands, as in hibernation or the defensive inhibition that
- has been called <strong><em>parabiosis</em></strong>, the state of being "not fully alive." In many
- situations, serotonin (which is closely associated with estrogen) seems to be an important inducer of this
- state. There are many indications that estrogen is a factor [e.g., Shvareva & Nevretdinova, 1989,
- Saltzman, et al., 1989] in functionally suppressed states such as hibernation, social subordination, learned
- helplessness and depression. Social subordination in animals often involves high estrogen and reduced
- fertility.
- </p>
-
- <p>
- In good health, an animal's systems are designed so that certain tissues will be intensely but briefly
- stimulated by estrogen. This stimulation by estrogen doesn't produce the normal amount of carbon dioxide, so
- the tissue experiences oxygen deprivation, leading to swelling and cell division. (Along with the reduced
- carbon dioxide production, there is increased lipid peroxidation).<strong><em>
- Any similar stimulaton, whether it's produced by soot, or suffocation, or irradiation, will produce
- the broad range of estrogen's effects, beginning with inflammation but ending with atrophy or cancer
- if it is too prolonged.
- </em></strong>
- </p>
- <p>
- Although, as the 21st century begins, the US government hasn't decided whether to classify estrogen as a
- carcinogen, it was identified as a carcinogen in the first half of the 20th century--and a variety of
- carcinogens were found to be estrogenic.
- </p>
- <p>
- Many people studying estrogen's biological effects observed that certain of its effects resembled the
- changes seen in aging, such as fibrotic changes of connective tissues, accelerated accumulation of age
- pigment, a tendency to miscarry, or the production of degenerative changes in various organs. But as far as
- I know, I was the first one to suggest that aging itself involves increased estrogen dominance. (Taking this
- perspective suggests many specific things to do for aging. And, if radiation injury, and stress, are
- "estrogenic," it suggests that specific anti-estrogenic treatments could be appropriate.) I based my
- argument on the identity of the biochemical and tissue effects produced by aging and by estrogenic excess.
- At that time, techniques for the accurate measurement of very small amounts of estrogen hadn't been fully
- developed. I felt that the situation should have been clear, because of the previous decades of research,
- and I used that as the context for arguing that the reason for age-related infertility was the same as for
- estrogen-induced infertility or stress-related infertility, namely, the inability to deliver oxygen to the
- embryo. I thought of the developing embryo as a sensitive indicator of processes that occur throughout the
- body during aging and stress, and that the destruction of the embryo by the excessive estrogen of the birth
- control pill was closely analogous to the progressive loss of function that occus in so many tissues during
- normal aging.
- </p>
- <p>
- After I wrote my dissertation, Terry Parkening, who had worked in the same lab, sent me data from rats,
- showing that his measurements confirmed the increase of estrogen with aging. Since then, many others have
- shown that either the absolute levels of estrogen, or the ratio of estrogen to the antiestrogens, increases
- with aging in a wide variety of organisms of both sexes, including humans.
- </p>
- <p>
- In the 1970s, the claims about estrogen curing osteoporosis apparently had been debunked. At the time, that
- appeared to be the last of the major claims for the therapeutic properties of estrogen. Studies in dogs were
- starting to show that estrogen was an important cause of degenerative bone disease, as well as kidney
- disease, liver disease, thyroid disease, etc. Hormones used in contraceptives were producing cancer in dogs,
- as well as many other diseases, so dog research was widely abandoned by the drug industry/FDA, in favor of
- animals that were less sensitive, or differently sensitive, to the hormones. The claims that the industry
- was making were contradicted by the dog research, so they sought new animal "models" that wouldn't so
- clearly contradict their claims.
- </p>
-
- <p>
- A great advantage, for the drug industry, of using rats instead of dogs is that expensive, and often
- embarrassing, long-term experiments aren't possible in such short-lived animals. Rats die when their tissues
- still appear to be relatively young. Although excess prolactin (resulting from excess estrogen) in humans is
- an important cause of osteoporosis, in rats at a certain age and on a certain diet, hyperprolactinemia can
- stimulate bone growth. [Piyabhan, et al., 2000, Yeh, et al., 1996] This trait of rats could be very
- advantageous to the estrogen industry.
- </p>
- <p>
- All of the maladies caused by estrogen excess appear to develop in the same way that it interferes with
- pregnancy, by driving the tissue to require more energy and oxygen than can be delivered to it. Necrosis,
- the death of sections of tissue, was produced acutely by extreme overdoses of estrogen, or gradually by less
- extreme overdoses, and if the estrogenic stimulation was milder but very prolonged, the result would usually
- be tumors, sometimes developing in the midst of atrophy or necrosis. An overdose of estrogen was used to
- shrink breasts and prevent lactation, and an even larger dose was used to kill breast tissue in treating
- cancer. <strong><em>
- A recent study (Toth, et al., 2000) shows that, at least in women, estrogen is closely associated
- with the general loss of fat-free tissue with aging.</em></strong> This shows a close association
- between the generalized atrophy of aging and the amount of estrogen in the tissues.
- </p>
- <p>
- In the case of the embryo that can't implant in the aged or estrogenized uterus, it is because oxygen is
- being consumed so fast by the uterus that very little is available for the embryo. The uterus is,
- effectively, in an inflamed state, and the embryo is in a state that requires abundant oxygen. The general
- loss of tissue that Toth associated with increased estrogen follows many of the same steps that occur in the
- failure of the embryo to implant in the uterus<strong>:</strong> Glycogen is depleted in futile oxidative
- cycles, protein synthesis is inhibited, lipid peroxides and free radicals accumulate, cellular defensive and
- repair processes replace normal functioning.
- </p>
-
- <p>
- (With aging, the loss of glycogen in the brain has serious consequences, including insomnia. Estrogen's
- depletion of glycogen in other tissues is probably important for their functioning, and thyroid and
- progesterone are known to help maintain the glycogen stores.)
- </p>
- <p>
- In the last several years, according to the medical literature estrogen would seem to have outgrown nearly
- all of its bad traits. It protects the brain, the heart, the blood vessels, even the fetus, and it prevents
- many kinds of cancer, and improves memory, mood, and immunity. And it would still seem to be of great
- promise in treating breast cancer and prostate cancer, if we took some medical journals seriously. It
- achieves many of these nice things by functioning as an antioxidant and by increasing circulation, often
- acting through nitric oxide and serotonin or melatonin. Even though I have read thousands of the articles
- that said otherwise, the near unanimity of the current research literature can almost give me the feeling
- that things might not be exactly as they had seemed.
- </p>
- <p>
- In fact they aren't, but the change is in what passes for science, rather than in the way organisms respond
- to estrogen. Many little pictures are being presented, that seem to add up to a very different big picture.
- It is clear that this new picture is being painted by those who fund the research, and by some of those
- whose careers depend on that funding. The people who do the odd little studies of estrogen and cytokines,
- nitric oxide, regulatory genes, and so on, are usually getting the data they claim to get, and if they draw
- speculative conclusions about what their study means medically, that's their privilege. But hundreds of
- these little publications that would be harmless individually, add up to national policy endorsed by the FDA
- and other powerful agencies--they add up to the same sort of criminal conspiracy that the tobacco industry
- and its researchers perpretrated throughout the twentieth century.
- </p>
- <p>
- Journals that are considered to be the best in their field publish many papers that simply misrepresent some
- of the basic facts, while interpreting experimental results that would otherwise have unpleasant commercial
- implications.
- </p>
- <p>
- For example, the follicular phase is a time of low steroid production by the ovary, until near the end of
- the phase, just before ovulation, when estrogen rises. The luteal phase is a time of high estrogen and high
- progesterone synthesis. Many publications describe the follicular phase as a time of high estrogen, and the
- luteal phase as a time of low estrogen, roughly the opposite of the actual situation. And an even larger
- number of studies get the results they want by using a short exposure to estrogen to study something which
- takes a long time to develop.
- </p>
- <p>
- In the last few years, one of the most common tricks of estrogen promotion is to argue that estrogen
- protects against heart disease and Alzheimer's disease because it relaxes blood vessels, by increasing the
- formation of nitric oxide. It does generally increase the formation of nitric oxide, but nitric oxide is a
- toxic free radical that plays a major role in degenerative diseases. And the inappropriate relaxation of
- blood vessels, coupled with increased clottability of the blood, is a major cause of pulmonary embolisms and
- venous disorders.
- </p>
-
- <p>
- In studies of tendons, excess estrogen, aging, and cooking (the phenomenon of the curling pork chop) all
- caused hardening and contraction of the collagen. When people get to be 90 or 100 years old, the opening
- between their eyelids is sometimes contracted, presumably because of this process of collagen shrinkage. If
- this shrinkage of connective tissue affects the large blood vessels, they become narrower and stiffer, so
- that the blood has to travel faster if the same amount is to be delivered in the same time.
- </p>
- <p>
- Ultrasound can be used to measure the velocity of the blood flow, and increased velocity will correspond to
- constriction of the channel, if the same amount of blood is being delivered. But many people praise
- estrogen's vascular benefits on the basis of tests showing <strong><em>increased</em></strong>
- blood velocity in large arteries such as the aorta, without evidence that more blood is being circulated.
- With aging, as arteries become constricted, increased blood velocity is taken as evidence of the pathology.
- Velocity measurements have to be interpreted in the contexts of tissue perfusion, cardiac output, etc. When
- the diameter of the artery is considered along with the velocity of the blood, the volume of flow can be
- determined, and then it appears that progesterone increases blood flow, while estrogen can decrease it.
- [Dickey and Hower, 1996.] This would be consistent with the known ability of an estrogen excess to cause
- retarded growth of the fetus, as well as specific birth defects.
- </p>
- <p>
- <strong><em>Estrogen does increase the blood flow to particular organs, but apparently less than it
- increases their oxygen demand, as can be seen from the color change of estrogenized tissues, toward
- purple, rather than pink.</em></strong>
- Measurements of oxygen tension in the tissue show that estrogen decreases the relative availability of
- oxygen. And when the level of estrogen is very high, metabolically demanding tissues, such as the kidney and
- adrenal cortex, simply die, especially under conditions that restrict blood flow. [E.g., Kocsis, et al.,
- 1988, McCaig, et al., 1998, Yang, et al., 1999.] When estrogen's effects overlap with the stimulating
- effects of other hormones, such as pituitary hormones, particular organs undergo something similar to
- "excitotoxicity." When estrogen overlaps with endotoxin (as it tends to do), multiple organ failure is the
- result.
- </p>
- <p>
- The simple need for more oxygen is a stimulus to increase the growth of blood vessels, and estrogen's
- stimulation of non-mitochondrial oxygen consumption with the production of lactic acid stimulates blood
- vessel formation. Progesterone, by increasing oxidative efficiency, opposes this "angiogenic"
- (neovascularization) effect of estrogen.
- </p>
-
- <p>
- Szent-Gyorgyi spent most of his career studying muscles--from the anal sphincter to pigeon breast to tense
- goats. One of his most interesting experiments investigated the effects of estrogen and progesterone on the
- heart muscle. He showed that estrogen excess prevents the increase of stroke volume as the speed increases,
- but that progesterone increases the stroke volume as the heart accelerates, making pumping more effective
- without unnecessary acceleration of the heart rate. These effects are parallel to Selye's observation that
- estrogen imitates the shock reaction.
- </p>
- <p>
- In shock, the blood pressure decreases, mainly because the blood volume decreases. Water is taken up by the
- tissues, out of the blood. Much of the remaining blood volume is accumulated in the relaxed veins, and
- little is returned to the heart, yet the increased need for circulation accelerates the heart, causing each
- stroke to pump only a small amount. The reduced blood pressure caused many people to think that adrenaline
- would help to improve the circulation, but actually the "resistance arteries," small arteries that provide
- blood to the arterioles and capillaries, are constricted in shock, (Lin, et al., 1998,) and adrenaline
- usually makes the situation worse. When tissue is poorly oxygenated (or is exposed to estrogen) it takes up
- water, swelling and becoming more rigid, turgid. (It also takes up calcium, especially under the influence
- of estrogen, causing muscles to contract.) This swelling effect will be much more noticeable in small
- arteries than in major arteries with very large channels, but when the effect is prolonged, it will affect
- even the heart, causing it to "stiffen," weakening its ability to pump. There is some evidence that estrogen
- can make large arteries stiffen, over a span of a few months. (Giltay, et al., 1999)
- </p>
- <p>
- Estrogen, by creating an oxygen deficiency, stimulates first swelling, and then collagen synthesis. Collagen
- tends to accumulate with aging.
- </p>
- <p>
- In shock, the cells are in a very low energy state, and infusions of ATP have been found to be therapeutic,
- but simple hypertonic solutions of glucose and salt are probably safer, and are very effective. The low
- energy of cells causes them to take up water, but it also causes the veins (which always receive blood after
- most of its oxygen and nutrients have been extracted) to lose their tone, allowing blood to pool in them,
- instead of returning to the heart. (Abel and Longnecker, 1978) This contributes to varicose veins
- (Ciardullo, et al., 2000), and to orthostatic hypotension, which is seen in women who are exposed to too
- much estrogen, and very frequently in old people.
- </p>
- <p>
- The energy failure resulting from estrogen excess has been remarkably well characterized (but the meaning of
- this for the cell hasn't been explored). The electron transfer process of the mitochondria is interrupted by
- the futile redox cycling catalyzed by estrogens.
- </p>
- <p>
- Good sleep requires fairly vigorous metabolism and a normal body temperature. In old age, the metabolic rate
- is decreased, and sleep becomes defective. Protein synthesis declines with aging, as the metabolic rate
- slows. At least in the brain, protein synthesis occurs most rapidly in deep sleep. [Nakanishi, et al., 1997;
- Ramm and Smith, 1990]
- </p>
-
- <p>
- In old age, the catabolic hormones such as cortisol are relatively dominant [Deuschle, et al., 1998], and
- even in youth, cortisol rises during darkness, reaching its peak around dawn. Even in young women, bone loss
- occurs almost entirely during the night, when cortisol is high. The hormones that are commonly said to
- prevent bone loss, estrogen and growth hormone, are high at night, rising along with cortisol. Estrogen
- causes growth hormone to increase, and in the morning, young women's growth hormone has been found to be 28
- times higher than men's.[Engstrom, et al., 1999] The growth hormone response to estrogen is probably the
- result of the changed use of glucose under estrogen's influence, making it necessary to mobilize free fatty
- acids from tissues. While estrogen is usually highest at night, progesterone is lowest during the night.
- These observations should suggest that progesterone, not estrogen, is the bone protective substance.
- </p>
- <p>
- The disappearance of water from the blood, as it moves into the tissues during the night, makes sleep
- resemble a state of shock or inflammation. Since rats, that are active at night, experience the same blood
- thickening, it's actually the darkness, rather than sleep, that creates this "inflammatory" state. Estrogen
- increases, and acts through, the inflammatory mediators, serotonin and histamine, to increase vascular
- leakiness, at the same time that it causes cells to take up water and calcium. The formation of lactic acid,
- in place of carbon dioxide, tends to coordinate these effects.
- </p>
- <p>
- In sleep, as in shock, hyperventilation is common, and it sometimes produces extreme vasoconstriction,
- because of the loss of carbon dioxide.
- </p>
- <p>
- Since glucose and salt are used to treat shock (intravenous 7.5% salt solutions are effective), it seems
- appropriate to use carbohydrate (preferably sugar, rather than starch) and salty foods during the night, to
- minimize the stress reaction. They lower adrenalin and cortisol, and help to maintain the volume and
- fluidity of blood. Thyroid, to maintain adequate carbon dioxide, is often all it takes to improve the blood
- levels of salt, glucose, and adrenalin.
- </p>
- <p>
- Temperature falls during sleep. Recent experiments show that hypothermia during surgery exacerbates the
- edema produced by stress, and that hypertonic (hyperosmotic or hyperoncotic) solutions alleviate the
- swelling. It is possible that light's action directly on the cells helps them to prevent swelling, and that
- the body's infrared emissions have a similar function. Whatever the mechanism is, adequate temperature
- improves sleep, and an excessive nocturnal temperature drop probably increases edema, with all of its
- harmful consequences.
- </p>
- <p>
- At least some of the redox cycles involving NAD/NADH and NADP/NADPH keep electrons from moving beyond
- ubiquinone (coQ10) and energizing the mitochondria. The cycle that makes nitric oxide is one of these, but
- some forms of estrogen participate directly as catalysts in this energy-stealing process. One of the effects
- of blocking electron transfer in the mitochondria is to lower the energy charge of the cells, mimicking the
- function of the age-damaged mitochondria. Glutathione and protein sulfhydryls are oxidized, because the
- normal energy pathways that maintain them have been disrupted.
- </p>
-
- <p>
- Estrogen directly lowers the temperature, while progesterone raises the temperature. Estrogen sets the
- brain's temperature regulator lower, but, acting through serotonin and other mediators, it can actually
- lower the metabolic rate, too.
- </p>
- <p>
- Far from being just the "hormone of estrus," estrogen, in the form of estradiol and the related steroids,
- plays a role in organisms as diverse as yeasts, worms and mollusks, and in modifying the function of
- practically every type of animal cell--skin, nerve, muscle, bone, hair, gland, etc. But, as more and more of
- its functions come to be understood, it turns out that many toxic chemicals and stressful physical processes
- can activate the same functions, and that estrogen's association with the functions of stress makes it a
- kind of window into some universal biological functions.
- </p>
- <p>
- When Hans Selye brought it to our attention that "stress" was a general life process, he began a process of
- generalization that led people to be able to see that the changes of aging were also the result of complex
- interactions between organisms and their environment, rather than some genetic program that operates like a
- clock running down.
- </p>
- <p>
- When W. Donner Denckla demonstrated that the removal of an animal's pituitary (or, in the case of an
- octopus, its equivalent optic gland) radically extended the animal's life span, he proposed the existence of
- a death hormone in the pituitary gland. But the case of the octopus makes it clear that the catabolic,
- death-inducing hormone is produced by the ovary, under the influence of the optic gland's gonadotropins.
- This sacrifice of "the old" (the individual) for "the new" (the progeny) is analogous to the tissue wasting
- we see under the influence of estrogen, as it stimulates cell division.
- </p>
- <p>
- In Selye's classical stress, the destruction of tissues by the catabolic hormones makes sense in terms of
- the "functional system" described by Anokhin, in which the hormones of adaptation dissolve one tissue for
- use by the system which is adaptively functioning, with the production of carbon dioxide by the functional
- tissue, stabilizing it and regulating the adequate delivery of blood.
- </p>
- <p>
- Progesterone is both an anticatabolic hormone and an antiestrogenic hormone, and in both cases, it protects
- the functional systems from atrophy.
- </p>
-
- <p>
- The extreme generality of the phenomenon of "estrogenicity" that was built up during the twentieth century
- has taken the concept beyond the specific functions of estrus, and reproduction, and the activation of
- genetic programs of the female animal, to make it necessary to see it as a way that living substance
- responds to certain kinds of stimulus. And these ways of responding turn out to be involved in the complex
- but coherent ways that organisms respond to aging.
- </p>
- <p>
- Selye gave various names to the biology of stress, but the "general adaptation syndrome" expressed the idea
- accurately. But the biology of estrogenicity, like the biology of aging, is so central that any name is
- likely to be misleading. The historical accident of naming a hormone for estrus shouldn't keep us from
- thinking about the way estrogen affects our energetics and structure, and how those processes relate to
- aging, atrophy, cancerization, etc.
- </p>
- <p>
- While progesterone is probably the most perfect antiestrogenic hormone, and therefore an anti-stress and
- anti-aging hormone, the recognition of a wide variety of estrogen's effects has made it possible to adjust
- many things in our diet and environment to more perfectly oppose the estrogenic and age-accelerating
- influences.
- </p>
- <p><h3>REFERENCES</h3></p>
- <p>
- Adv Shock Res 1978;1:19-27. <strong>Alterations in venous compliance in hemorrhagic shock.</strong> Abel FL,
- Longnecker DE "Nine dogs and one primate were placed on total cardiopulmonary bypass and subjected to a
- simulated hemorrhagic shock procedure." "These results are interpreted as indicating a different response of
- the two vascular beds,<strong>
- particularly an increase in IVC [inferior vena caval] arteriolar resistance with a decrease in venous
- tone. To the extent that the splanchnic bed contributes to the IVC system changes, they are contrary to
- the concept of a maintained venous tone and decreased arteriolar tone after hemorrhagic shock."</strong>
- </p>
-
- <p>
- Acta Physiol Scand 1990 Sep;140(1):85-94. <strong>Effects of hypertonic NaCl solution on microvascular
- haemodynamics in normo- and hypovolaemia.</strong> Bouskela E, Grampp W, Mellander S. "The aims of this
- study were to investigate possible resuscitation effects of a single, 10-min, 350-microliters intravenous
- infusion of 7.5% NaCl in hamsters in hemorrhagic shock and to compare the effects of such infusion with an
- identical one of 0.9% NaCl on the hamster cheek pouch microcirculation during normovolaemia and after acute
- bleeding to a hypotension level of about 40 mmHg. No significant differences could be detected between the
- effects of either infusion given to normovolaemic normotensive hamsters. In the animals subjected<strong>
- to haemorrhage, upon bleeding, arterioles larger than 40 microns constricted,</strong> arterioles
- smaller than 40 microns dilated and venular diameter did not change, while blood flow decreased in all
- vessels." "Central nervous and/or reflex excitation of the sympathetic nervous system could account for the
- constriction of venules and larger arterioles, while a direct effect of hyperosmolarity could explain the
- dilatation of the smaller arterioles. The study can therefore help to explain some of the mechanisms
- underlying the reported resuscitation effect of 7.5% NaCl infusion in animals during severe haemorrhagic
- hypovolaemia."
- </p>
- <p>
- Medicina (B Aires) 1998;58(4):367-73. <strong>[Physiopathologic effects of nitric oxide and their
- relationship with oxidative stress].</strong> [Article in Spanish] Carrizo PH, Dubin M, Stoppani AO.
- Nitric oxide (NO.) is produced from L-arginine, as result of a reaction catalyzed by the enzyme nitric oxide
- synthase (NOS). The reaction is the sole source of NO. in animal tissues. NO. can control physiological
- processes (or systems) such as (a) blood pressure; (b) relaxation of arterial smooth muscle; (c) platelet
- aggregation and adhesion; (d) neurotransmission; (e) neuroendocrine secretion. NO. contributes to the
- killing of pathogenic microorganisms and tumoral cells by phagocytes. NO. reacts with superoxide anion thus
- producing peroxynitrite, a cytotoxic ion capable of destroying many biological targets. The
- superoxide/peroxinitrite balance determines the ONOO- production and, accordingly, is <strong>essential for
- the development of hypertension, atherosclerosis, neurodegenerative diseases, viral infections,
- ischemia-reperfusion injury, and cancer.</strong>
- </p>
-
- <p>
- Stress 1998 Dec;2(4):281-7. <strong>Effects of major depression, aging and gender upon calculated diurnal
- free plasma cortisol concentrations: a re-evaluation study.</strong> Deuschle M, Weber B, Colla M,
- Depner M, Heuser I<strong>. "Depression, aging and female gender are associated with increased diurnal
- concentrations of total plasma cortisol."</strong> "This finding is in line with the observation that
- <strong>in both conditions medical problems triggered and/or maintained by glucocorticoids (e.g.
- osteoporosis) are frequently seen."</strong>
- </p>
- <p>
- Adv Exp Med Biol 1975;53:359-69. <strong>The effect of nutritional regimes upon collagen concentration and
- survival of rats.</strong> Deyl Z, Juricova M, Stuchlikova E "It has been demonstrated that food
- restriction put upon animals at any stage of the individual's life, if chronic, produces a distinct increase
- in the lifespan."<strong>
- "Collagen starts to accumulate in the kidneys and liver of experimental animals roughly ten months
- before 90 percent of the population dies out. Thus an increase in collagen concentration can be
- indicative of involutional changes in the organ</strong>
-
- (and perhaps organism)."
- </p>
- <p>
- Early Pregnancy 1996 Jun;2(2):113-20. <strong>Relationship of estradiol and progesterone levels to uterine
- blood flow during early pregnancy.</strong> Dickey RP, Hower JF. "After correction for gestational age,
- estradiol was negatively related to uterine artery flow volume (p < 0.05), diameter (p < 0.05),
- pulsatility index (p < 0.05) and resistance index (p < 0.01) for weeks 5-16 and to diameter (p <
- 0.05) after week 9. Progesterone was positively related <strong>to volume (p < 0.05) and velocity (p <
- 0.01) for weeks 5-16 and to volume (p < 0.05) for weeks 5 to 9. S</strong>piral artery indices of
- resistance were unrelated to hormone levels. These<strong>
- results indicate that before the 10th gestational week, uterine blood flow volume is related to
- progesterone, but not estradiol levels, and suggest that high estradiol levels during and after the 10th
- week may be associated with decreased uterine blood flow volume."</strong>
- </p>
- <p>
- Ann Surg 1998 Jun;227(6):851-60. <strong>Microvascular changes explain the "two-hit" theory of multiple
- organ failure.</strong> Garrison RN, Spain DA, Wilson MA, Keelen PA, Harris PD "Acute bacteremia<strong>
- alone results in persistent intestinal vasoconstriction and mucosal hypoperfusion. Little experimental
- data exist to support the pathogenesis of</strong> vascular dysregulation during sequential physiologic
- insults." <strong>"Acute bacteremia, with or without prior hemorrhage, caused significant large-caliber A1
- arteriolar constriction with a concomitant decrease in blood flow. This</strong> constriction was
- blunted at 24 hours after hemorrhage but was restored to control values by 72 hours." "These data indicate
- that there is altered endothelial control of the intestinal microvasculature after hemorrhage in favor of
- enhanced dilator mechanisms in premucosal vessels <strong>with enhanced constrictor forces in inflow
- vessels."</strong>
- </p>
-
- <p>
- Am J Physiol 1998 Jul;275(1 Pt 2):H292-300.<strong>
- Estrogen reduces myogenic tone through a nitric oxide-dependent mechanism in rat cerebral
- arteries.</strong>
- Geary GG, Krause DN, Duckles SP. <strong>"Gender differences in the incidence of stroke and migraine appear
- to be related to circulating levels of estrogen; however, the underlying mechanisms are not yet
- understood.
- </strong>
- Using resistance-sized arteries pressurized in vitro, we have found that myogenic tone of rat cerebral
- arteries differs between males and females. This difference appears to result from estrogen enhancement of
- endothelial nitric oxide (NO) production."<strong> </strong>
- </p>
- <p>
- Free Radic Res 1999 Feb;30(2):105-17. <strong>Inactivation of myocardial dihydrolipoamide dehydrogenase by
- myeloperoxidase systems: effect of halides, nitrite and thiol compounds.</strong> Gutierrez-Correa J,
- Stoppani AO. "The summarized observations support the hypothesis that peroxidase-generated "reactive
- species" oxidize essential thiol groups at LADH catalytic site."
- </p>
-
- <p>
- Medicina (B Aires) 1998;58(2):171-8. <strong>[Myeloperoxidase as a factor of oxidative damage of the
- myocardium: inactivation of dihydrolipoamide dehydrogenase].</strong>
- Gutierrez Correa J, Stoppani AO. "Myocardial dihydrolipoamide dehydrogenase (LADH) is inactivated after
- incubation at 30 degree C, with myeloperoxidase (MPO)-dependent systems."
- </p>
- <p>
- J Natl Cancer Inst 1981 Aug;67(2):455-9. <strong>Synergism of estrogens and X-rays in mammary carcinogenesis
- in female ACI rats.</strong> Holtzman S, Stone JP, Shellabarger CJ.
- </p>
- <p>
- Br J Exp Pathol 1988 Apr;69(2):157-67. <strong>Effect of the anti-oestrogen tamoxifen on the development of
- renal cortical necrosis induced by oestrone + vasopressin administration in rats.
- </strong>
- Kocsis J, Karacsony G, Karcsu S, Laszlo FA. Bilateral renal cortical necrosis was observed after vasopressin
- administration in rats pretreated with oestrone acetate. Histochemical (succinic dehydrogenase, trichrome,
- periodic acid Schiff) and electronmicroscopic methods were used to examine how the anti-oestrogen,
- Tamoxifen, influences the development of this renal cortical necrosis. The experiments revealed that in most
- rats vasopressin did not induce renal tubular necrosis if the anti-oestrogen was administered
- simultaneously, even during oestrogen pretreatment<strong>. The results suggest that oestrogen receptors in
- the kidney are involved in the induction of renal cortical necrosis by vasopressin.</strong>
- </p>
-
- <p>
- Br J Exp Pathol 1987 Feb;68(1):35-43.<strong>
- Histochemical and ultrastructural study of renal cortical necrosis in rats treated with oestrone +
- vasopressin, and its prevention with a vasopressin antagonist.</strong> Kocsis J, Karacsony G, Karcsu S,
- Laszlo FA. <strong>Renal cortical necrosis was induced by the administration of vasopressin to
- oestrogen-pretreated rats.</strong> Histochemical (succinic dehydrogenase, trichrome, perjod acid
- Schiff) and electronmicroscopic methods were applied to examine how the vasopressin antagonist
- d(CH2)5Tyr(Met)AVP influences the development of this renal cortical necrosis. The experiments revealed that
- vasopressin did not induce hypoxia or necrosis in the renal tubules if the antagonist was administered
- simultaneously, even after oestrogen pretreatment. The conclusion is drawn that this pressor antagonist may
- be of value for the prevention of renal cortical necrosis in rats or in human beings.
- </p>
- <p>
- Invest Radiol 1979 Jul-Aug;14(4):295-9. <strong>Serioangiographic study of renal cortical necrosis induced
- by administration of estrin and vasopressin in rats.</strong> Kocsis J, Szabo E, Laszlo FA. We report a
- serioangiographic method in rats which permits assessment of the course and dimensions of the renal
- arteries, the durations of the arterial and venous phases, and the intensity and uniformity of the renal
- parenchymal filling. The procedure was employed to study the mechanism by which administration of
- vasopressin to rats pretreated with estrin leads to renal cortical necrosis. The pathogenetic significance
- of the spasm localized on the larger renal arteries was proved directly; the possible role of the
- arteriovenous shunt in the development of the renal ischemia was excluded.
- </p>
-
- <p>
- Contrib Nephrol 1981;28:1-216.<strong>
- Renal cortical necrosis. Experimental induction by hormones.</strong> Laszlo FA.
- </p>
- <p>
- Morphol Igazsagugyi Orv Sz 1974 Jan;14(1):8-12 <strong>[The effect os estrogen, ACTH and cortisone
- administration, as well as hypophysectomy on histological changes in unilateral renal hilus
- ligation].</strong> [Article in Hungarian] Laszlo F, Monus Z.
- </p>
- <p>
- Eur J Neurosci 1997 Feb;9(2):271-9. <strong>Positive correlations between cerebral protein synthesis rates
- and deep sleep in Macaca mulatta.</strong> Nakanishi H, Sun Y, Nakamura RK, Mori K, Ito M, Suda S, Namba
- H, Storch FI, Dang TP, Mendelson W, Mishkin M, Kennedy C, Gillin JC, Smith CB, Sokoloff L.
- </p>
-
- <p>
- Can J Physiol Pharmacol 2000 Oct;78(10):757-65. <strong>Changes in the regulation of calcium metabolism and
- bone calcium content during growth in the absence of endogenous prolactin and during hyperprolactinemia:
- a longitudinal study in male and female Wistar rats.</strong> Piyabhan P, Krishnamra N, Limlomwongse L
- "Since endogenous prolactin has been shown to enhance food consumption, calcium absorption, and bone calcium
- turnover in the pregnant rat, the role of endogenous prolactin in the regulation of calcium metabolism was
- investigated in 3-day balance studies of female Wistar rats from the age of 3 to 11 weeks." "Results showed
- that rapid growth occurred between 3 and 6 weeks with maximum fractional calcium absorption and calcium
- retention at 5 weeks of age in both sexes. The data also showed a physiological significance of endogenous
- prolactin in enhancing calcium absorption and retention in 5 week old rats. In an absence of prolactin, peak
- calcium absorption was delayed in 7-week old animals, and vertebral calcium content of 11-week old animals
- was reduced by 18%. <strong>Hyperprolactinemia in the AP group was found to enhance fractional calcium
- absorption and calcium retention at 7, 9, and 11 weeks and increased the femoral calcium content by
- 16%.</strong> It could be concluded that a physiological role of prolactin is the stimulation of calcium
- absorption and maintainance of bone calcium content during growth and development."
- </p>
- <p>
- Physiol Behav 1990 Nov;48(5):749-53. <strong>Rates of cerebral protein synthesis are linked to slow wave
- sleep in the rat.</strong> Ramm P, Smith CT. Using L-[1-14C]leucine autoradiography, rates of cerebral
- and local cerebral protein synthesis were studied during wakefulness, slow wave sleep (SWS) and REM sleep in
- the rat. In the cerebrum as a whole, the rate at which labelled leucine was incorporated into tissues
- <strong>was positively correlated with the occurrence of slow wave sleep. We failed to observe a significant
- correlation of protein synthesis rate with either wakefulness or REM sleep.</strong> As in the cerebrum
- as a whole, most discrete brain regions showed moderate positive correlations between the occurrence of SWS
- and rates of protein synthesis. There were no brain regions in which rates of protein synthesis showed
- striking correlations with sleep-wake states. Thus, the occurrence of SWS is associated with higher rates of
- protein synthesis throughout the brain. These data suggest that SWS sleep favors the restoration of cerebral
- proteins.
- </p>
-
- <p>
- Surgery 1991 Oct;110(4):685-8; discussion 688-90. <strong>The effect of hypertonic saline resuscitation on
- bacterial translocation after hemorrhagic shock in rats.</strong> Reed LL, Manglano R, Martin M, Hochman
- M, Kocka F, Barrett J. "Recent work suggests that moderate hypovolemia causes gut arteriolar constriction,
- which is ameliorated by hypertonic saline resuscitation. Bacterial translocation should, therefore, be
- reduced when hypertonic saline (HS) is used as the resuscitative fluid." "Compared to autotransfusion,
- hemodilutional resuscitation from hemorrhagic shock with<strong>
- hypertonic saline resulted in a significant reduction in bacterial translocation (p values were 0.03 and
- 0.04 for 3% and 7.5% hypertonic saline, respectively). The reduction in translocation after hypertonic
- saline resuscitation may be the consequence of microcirculatory alterations preventing gut
- hypoperfusion."</strong>
- </p>
- <p>
- Am J Physiol 1999 Feb;276(2 Pt 2):H563-71. <strong>Changes in resistance vessels during hemorrhagic shock
- and resuscitation in conscious hamster model.</strong>
- Sakai H, Hara H, Tsai AG, Tsuchida E, Johnson PC, Intaglietta M. "The unanesthetized hamster dorsal skinfold
- preparation was used to monitor<strong>
- diameters and blood flow rates in resistance arteries (small arteries, A0: diameter, 156</strong> +/- 23
- micrometers) and capacitance vessels (small veins, V0: 365 +/- 64 micrometers), during 45 min of hemorrhagic
- shock at 40 mmHg mean arterial pressure (MAP) and resuscitation. <strong>A0 and V0 vessels constricted
- significantly to 52 and 70% of the basal values,
- </strong>
-
- respectively, whereas precapillary arterioles (A1-A4, 8-60 micrometers) and collecting venules (VC-VL, 26-80
- micrometers) did not change or tended to dilate. <strong>Blood flow rates in the microvessels declined to
- <20% of the basal values."</strong>
- </p>
- <p>
- Horm Behav 1998 Feb;33(1):58-74. <strong>Suppression of cortisol levels in subordinate female marmosets:
- reproductive and social contributions.</strong> Saltzman W, Schultz-Darken NJ, Wegner FH, Wittwer DJ,
- Abbott DH "Cortisol levels of cycling females were significantly higher than those of subordinates at all
- parts of the cycle, but were significantly higher than those of ovariectomized females only during the
- midcycle elevation. Unexpectedly, subordinates had significantly lower cortisol levels than ovariectomized
- females,<strong>
- as well as higher estradiol and estrone levels and lower progesterone and luteinizing hormone (LH)
- levels</strong>."
- </p>
- <p>
- Zh Evol Biokhim Fiziol 1989 Jan-Feb;25(1):52-9. <strong>[Seasonal characteristics of the functioning of the
- hypophysis-gonad system in the suslik Citellus parryi].</strong> Shvareva NV, Nevretdinova ZG "In
- experiments on the arctic ground squirrel C. parryi, studies have been made on seasonal changes in the
- weight of testes, follicular diameter in the ovaries and the content of sex and gonadotropic hormones in the
- peripheral blood. Testicular involution and arrest of follicular development were observed in prehibernation
- period. During hibernation, follicular growth and the increase in the weight of testes take place." <strong
- >"Estradiol secretion was noted in hibernating females, whereas progesterone</strong> was found in the blood
- only in May."
- </p>
-
- <p>
- Maturitas 1984 Nov;6(3):269-78. <strong>Spontaneous skin flushing episodes in the aging female rat.</strong>
- Simpkins JW. It is well known that with the loss of gonadal function most women experience hot flushes,
- characterized by a rapid regional increase in cutaneous blood flow. Animal models for this vasomotor
- syndrome have been elusive, thus hampering efforts to evaluate the endocrine and neuronal substrates of the
- hot flush. In this report, evidence is reported for the occurrence in aging female rats of spontaneous tail
- skin temperature (TST) fluctuations which are similar in amplitude, duration and frequency to hot flushes
- reported for peri-menopausal women<strong>. Paradoxically, these TST pulses occur in animals with senescent
- reproductive states in which serum estrogen levels are moderately elevated and ovariectomy eliminates
- these rat flushing episodes.</strong> This demonstration of steroid-dependent, spontaneous flushing
- episodes indicates that the aging female rat can be used to evaluate the neuronal and hormonal basis of
- vasomotor instability.
- </p>
- <p>
- Carcinogenesis 1994 Nov;15(11):2637-43. <strong>The metabolism of 17 beta-estradiol by lactoperoxidase: a
- possible source of oxidative stress in breast cancer.</strong> Sipe HJ Jr, Jordan SJ, Hanna PM, Mason
- RP. Electron spin resonance (ESR) spectroscopy and <strong>oxygen consumption measurements using a
- Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by
- lactoperoxidase.</strong> Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl
- radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced
- glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline
- N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO,<strong>
- molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical.
- Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine
- dinucleotide (NADH) to generate the NAD. radical.</strong>
- <strong>The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide
- radical,</strong> which is then spin-trapped by DMPO. The superoxide generated may either spontaneously
- dismutate to form hydrogen peroxide <strong>or react with another NADH to form NAD., thus propagating a
- chain reaction leading to oxygen consumption and hydrogen peroxide accumulation.</strong> Ascorbate
- inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by
- reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate
- radical. <strong>These results demonstrate that 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.</strong> The accumulation of
- intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently
- reported for female breast cancer tissue.
- </p>
-
- <p>
- Endocrinol Metab Clin North Am 1995 Sep;24(3):531-47<strong>. Idiopathic edema. Pathogenesis, clinical
- features, and treatment.
- </strong>
- Streeten DH. "Idiopathic edema is usually orthostatic." "It occurs almost exclusively in post-pubertal
- women. . . ."
- </p>
- <p>
- Carcinogenesis 1995 Apr;16(4):891-5. <strong>Mitochondrial enzyme-catalyzed oxidation and reduction
- reactions of stilbene estrogen.</strong> Thomas RD, Roy D. "We have demonstrated for the first time that
- mitoplasts (i.e. mitochondria without outer membrane) were able to convert stilbene estrogen
- (diethylstilbestrol, DES) to reactive metabolites, which covalently bind to mitochondrial (mt)DNA. Depending
- on the cofactor used, mitochondrial enzymes catalyzed the oxidation and/or reduction of DES. DES was
- oxidized to DES quinone by peroxide-supported mitochondrial enzyme." "DES quinone was reduced to DES by
- mitoplasts in the presence of NADH." "DES quinone was also reduced to DES by pure diaphorase, a
- mitochondrial reducing enzyme, in the presence of NADH." "These data provide direct evidence of
- mitochondrial enzyme-catalyzed oxidation and reduction reactions of DES. In the cell, activation of DES in
- the mitochondria (the organelle in which mtDNA synthesis, mtDNA repair and transcription systems are
- localized) is of utmost importance, because an analogous in vivo mitochondrial metabolism of DES through
- covalent modifications in mitochondrial genome may produce instability in the mitochondrial genome of the
- cells. These modifications may in turn play a role in the development of DES-induced hepatocarcinogenicity."
- </p>
- <p>
- J Clin Endocrinol Metab 2000 Apr;85(4):1382-7. <strong>Regulation of protein metabolism in middle-aged,
- premenopausal women: roles of adiposity and estradiol.</strong> Toth MJ, Tchernof A, Rosen CJ, Matthews
- DE, Poehlman ET. <strong>The age-related loss of fat-free mass (FFM) is accelerated in women during the
- middle-age years and continues at an increased rate throughout the postmenopausal period. Because
- protein is the primary structural component of fat-free tissue, changes in FFM are largely due to
- alterations in protein metabolism. Knowledge of the hormonal and physiological correlates of
- protein</strong>
- <hr />
- </p>
-
- <p>
- J Korean Med Sci 1999 Jun;14(3):277-85. <strong>The metabolic effects of estriol in female rat
- liver.</strong> Yang JM, Kim SS, Kim JI, Ahn BM, Choi SW, Kim JK, Lee CD, Chung KW, Sun HS, Park DH,
- Thurman RG. <strong>"Basal oxygen consumption of perfused liver increased significantly in estriol or
- ethanol-treated rats."</strong>
- <strong>"These findings suggest that the metabolic effects of estriol (two mg per 100 mg body wt) can be
- summarized to be highly toxic in rat liver, and these findings suggest that oral administration of
- estrogens may induce hepatic dysfunctions and play a role in the development of liver disease."</strong>
- </p>
- <p>
- Bone 1996 May;18(5):443-50.<strong>
- Ovariectomy-induced high turnover in cortical bone is dependent on pituitary hormone in rats.
- </strong>
- Yeh JK, Chen MM, Aloia JF.. "Our results confirmed that OV increased and HX suppressed systemic and
- periosteal bone formation parameters in both bone sites, OV increased and HX suppressed the gain in bone
- size and bone mass. When OV rats were HX, the serum levels of osteocalcin and periosteal bone formation
- parameters of the tibial shaft and the fifth lumbar vertebrae were, however, depressed and did not differ
- from that of the HX alone. DXA results show that the effect of OV on bone size and bone mass is also
- abolished by HX. In conclusion, we have demonstrated that OV increases tibial and lumbar vertebral bone
- formation and bone growth and this effect is pituitary hormone dependent."
- </p>
- <p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
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