722 lines
56 KiB
HTML
722 lines
56 KiB
HTML
<html>
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<head><title>Aging, estrogen, and progesterone</title></head>
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<body>
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<h1>
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Aging, estrogen, and progesterone
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</h1>
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<p>
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<em>"Estrogen" refers not just to a family of steroids but to a class of substances that can produce
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approximately the same effects as estradiol and its metabolites.
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</em>
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</p>
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<em>
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<p>
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Even before the pure substance was isolated in the 1930s, the effects of fluid from ovarian follicles
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were studied. It was soon discovered that many chemicals could produce similar effects.
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</p>
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<p>
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By the middle of the century, many toxic effects of the estrogens were known, and more are being
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discovered.
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</p>
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<p>
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Cancer, abnormal blood clotting, and infertility were known to be caused by estrogen before 1940, but at
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the same time the drug companies began calling estrogen "the female hormone," and claiming that it would
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improve fertility.
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</p>
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<p>
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Since the 19th century, some people argued that aging was caused by hormonal deficiency; for example,
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the symptoms of thyroid deficiency resembled aging. The estrogen industry exploited this idea to create
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the "hormone replacement" business.
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</p>
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<p>
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Some hormones do decrease with aging, but others increase.
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</p>
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<p>
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All of the unpleasant consequences of estrogen excess happen to resemble some of the events of aging.
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</p>
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<p>
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If aging involves the same processes that are created by estrogen, then our knowledge of how to protect
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ourselves against estrogen can be used to protect ourselves against aging.
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</p>
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<p>
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Estrogen steals oxygen from mitochondria, shifting patterns of growth and adaptation.
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</p></em>
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<hr />
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<p>
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The balance between what a tissue needs and what it gets will govern the way that tissue functions, in both
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the short term and the long term. When a cell emits lactic acid and free radicals and the products of lipid
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peroxidation, it's reasonable to assume that it isn't getting everything that it needs, such as oxygen and
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glucose. With time, the cell will either die or adapt in some way to its deprived conditions.
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</p>
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<p>
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In aging, tissues generally atrophy, with loss of both substance and activity. Ordinarily, organisms react
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to stress with increased activity of the appropriate functional system, but when the stress is inescapable,
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organisms adopt the strategy of decreasing their demands, as in hibernation or the defensive inhibition that
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has been called <strong><em>parabiosis</em></strong>, the state of being "not fully alive." In many
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situations, serotonin (which is closely associated with estrogen) seems to be an important inducer of this
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state. There are many indications that estrogen is a factor [e.g., Shvareva & Nevretdinova, 1989,
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Saltzman, et al., 1989] in functionally suppressed states such as hibernation, social subordination, learned
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helplessness and depression. Social subordination in animals often involves high estrogen and reduced
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fertility.
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</p>
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<p>
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In good health, an animal's systems are designed so that certain tissues will be intensely but briefly
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stimulated by estrogen. This stimulation by estrogen doesn't produce the normal amount of carbon dioxide, so
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the tissue experiences oxygen deprivation, leading to swelling and cell division. (Along with the reduced
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carbon dioxide production, there is increased lipid peroxidation).<strong><em>
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Any similar stimulaton, whether it's produced by soot, or suffocation, or irradiation, will produce
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the broad range of estrogen's effects, beginning with inflammation but ending with atrophy or cancer
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if it is too prolonged.
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</em></strong>
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</p>
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<p>
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Although, as the 21st century begins, the US government hasn't decided whether to classify estrogen as a
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carcinogen, it was identified as a carcinogen in the first half of the 20th century--and a variety of
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carcinogens were found to be estrogenic.
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</p>
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<p>
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Many people studying estrogen's biological effects observed that certain of its effects resembled the
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changes seen in aging, such as fibrotic changes of connective tissues, accelerated accumulation of age
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pigment, a tendency to miscarry, or the production of degenerative changes in various organs. But as far as
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I know, I was the first one to suggest that aging itself involves increased estrogen dominance. (Taking this
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perspective suggests many specific things to do for aging. And, if radiation injury, and stress, are
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"estrogenic," it suggests that specific anti-estrogenic treatments could be appropriate.) I based my
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argument on the identity of the biochemical and tissue effects produced by aging and by estrogenic excess.
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At that time, techniques for the accurate measurement of very small amounts of estrogen hadn't been fully
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developed. I felt that the situation should have been clear, because of the previous decades of research,
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and I used that as the context for arguing that the reason for age-related infertility was the same as for
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estrogen-induced infertility or stress-related infertility, namely, the inability to deliver oxygen to the
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embryo. I thought of the developing embryo as a sensitive indicator of processes that occur throughout the
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body during aging and stress, and that the destruction of the embryo by the excessive estrogen of the birth
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control pill was closely analogous to the progressive loss of function that occus in so many tissues during
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normal aging.
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</p>
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<p>
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After I wrote my dissertation, Terry Parkening, who had worked in the same lab, sent me data from rats,
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showing that his measurements confirmed the increase of estrogen with aging. Since then, many others have
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shown that either the absolute levels of estrogen, or the ratio of estrogen to the antiestrogens, increases
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with aging in a wide variety of organisms of both sexes, including humans.
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</p>
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<p>
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In the 1970s, the claims about estrogen curing osteoporosis apparently had been debunked. At the time, that
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appeared to be the last of the major claims for the therapeutic properties of estrogen. Studies in dogs were
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starting to show that estrogen was an important cause of degenerative bone disease, as well as kidney
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disease, liver disease, thyroid disease, etc. Hormones used in contraceptives were producing cancer in dogs,
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as well as many other diseases, so dog research was widely abandoned by the drug industry/FDA, in favor of
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animals that were less sensitive, or differently sensitive, to the hormones. The claims that the industry
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was making were contradicted by the dog research, so they sought new animal "models" that wouldn't so
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clearly contradict their claims.
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</p>
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<p>
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A great advantage, for the drug industry, of using rats instead of dogs is that expensive, and often
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embarrassing, long-term experiments aren't possible in such short-lived animals. Rats die when their tissues
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still appear to be relatively young. Although excess prolactin (resulting from excess estrogen) in humans is
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an important cause of osteoporosis, in rats at a certain age and on a certain diet, hyperprolactinemia can
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stimulate bone growth. [Piyabhan, et al., 2000, Yeh, et al., 1996] This trait of rats could be very
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advantageous to the estrogen industry.
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</p>
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<p>
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All of the maladies caused by estrogen excess appear to develop in the same way that it interferes with
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pregnancy, by driving the tissue to require more energy and oxygen than can be delivered to it. Necrosis,
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the death of sections of tissue, was produced acutely by extreme overdoses of estrogen, or gradually by less
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extreme overdoses, and if the estrogenic stimulation was milder but very prolonged, the result would usually
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be tumors, sometimes developing in the midst of atrophy or necrosis. An overdose of estrogen was used to
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shrink breasts and prevent lactation, and an even larger dose was used to kill breast tissue in treating
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cancer. <strong><em>
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A recent study (Toth, et al., 2000) shows that, at least in women, estrogen is closely associated
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with the general loss of fat-free tissue with aging.</em></strong> This shows a close association
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between the generalized atrophy of aging and the amount of estrogen in the tissues.
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</p>
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<p>
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In the case of the embryo that can't implant in the aged or estrogenized uterus, it is because oxygen is
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being consumed so fast by the uterus that very little is available for the embryo. The uterus is,
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effectively, in an inflamed state, and the embryo is in a state that requires abundant oxygen. The general
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loss of tissue that Toth associated with increased estrogen follows many of the same steps that occur in the
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failure of the embryo to implant in the uterus<strong>:</strong> Glycogen is depleted in futile oxidative
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cycles, protein synthesis is inhibited, lipid peroxides and free radicals accumulate, cellular defensive and
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repair processes replace normal functioning.
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</p>
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<p>
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(With aging, the loss of glycogen in the brain has serious consequences, including insomnia. Estrogen's
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depletion of glycogen in other tissues is probably important for their functioning, and thyroid and
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progesterone are known to help maintain the glycogen stores.)
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</p>
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<p>
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In the last several years, according to the medical literature estrogen would seem to have outgrown nearly
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all of its bad traits. It protects the brain, the heart, the blood vessels, even the fetus, and it prevents
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many kinds of cancer, and improves memory, mood, and immunity. And it would still seem to be of great
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promise in treating breast cancer and prostate cancer, if we took some medical journals seriously. It
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achieves many of these nice things by functioning as an antioxidant and by increasing circulation, often
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acting through nitric oxide and serotonin or melatonin. Even though I have read thousands of the articles
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that said otherwise, the near unanimity of the current research literature can almost give me the feeling
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that things might not be exactly as they had seemed.
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</p>
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<p>
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In fact they aren't, but the change is in what passes for science, rather than in the way organisms respond
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to estrogen. Many little pictures are being presented, that seem to add up to a very different big picture.
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It is clear that this new picture is being painted by those who fund the research, and by some of those
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whose careers depend on that funding. The people who do the odd little studies of estrogen and cytokines,
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nitric oxide, regulatory genes, and so on, are usually getting the data they claim to get, and if they draw
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speculative conclusions about what their study means medically, that's their privilege. But hundreds of
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these little publications that would be harmless individually, add up to national policy endorsed by the FDA
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and other powerful agencies--they add up to the same sort of criminal conspiracy that the tobacco industry
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and its researchers perpretrated throughout the twentieth century.
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</p>
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<p>
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Journals that are considered to be the best in their field publish many papers that simply misrepresent some
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of the basic facts, while interpreting experimental results that would otherwise have unpleasant commercial
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implications.
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</p>
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<p>
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For example, the follicular phase is a time of low steroid production by the ovary, until near the end of
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the phase, just before ovulation, when estrogen rises. The luteal phase is a time of high estrogen and high
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progesterone synthesis. Many publications describe the follicular phase as a time of high estrogen, and the
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luteal phase as a time of low estrogen, roughly the opposite of the actual situation. And an even larger
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number of studies get the results they want by using a short exposure to estrogen to study something which
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takes a long time to develop.
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</p>
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<p>
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In the last few years, one of the most common tricks of estrogen promotion is to argue that estrogen
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protects against heart disease and Alzheimer's disease because it relaxes blood vessels, by increasing the
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formation of nitric oxide. It does generally increase the formation of nitric oxide, but nitric oxide is a
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toxic free radical that plays a major role in degenerative diseases. And the inappropriate relaxation of
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blood vessels, coupled with increased clottability of the blood, is a major cause of pulmonary embolisms and
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venous disorders.
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</p>
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<p>
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In studies of tendons, excess estrogen, aging, and cooking (the phenomenon of the curling pork chop) all
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caused hardening and contraction of the collagen. When people get to be 90 or 100 years old, the opening
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between their eyelids is sometimes contracted, presumably because of this process of collagen shrinkage. If
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this shrinkage of connective tissue affects the large blood vessels, they become narrower and stiffer, so
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that the blood has to travel faster if the same amount is to be delivered in the same time.
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</p>
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<p>
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Ultrasound can be used to measure the velocity of the blood flow, and increased velocity will correspond to
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constriction of the channel, if the same amount of blood is being delivered. But many people praise
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estrogen's vascular benefits on the basis of tests showing <strong><em>increased</em></strong>
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blood velocity in large arteries such as the aorta, without evidence that more blood is being circulated.
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With aging, as arteries become constricted, increased blood velocity is taken as evidence of the pathology.
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Velocity measurements have to be interpreted in the contexts of tissue perfusion, cardiac output, etc. When
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the diameter of the artery is considered along with the velocity of the blood, the volume of flow can be
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determined, and then it appears that progesterone increases blood flow, while estrogen can decrease it.
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[Dickey and Hower, 1996.] This would be consistent with the known ability of an estrogen excess to cause
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retarded growth of the fetus, as well as specific birth defects.
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</p>
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<p>
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<strong><em>Estrogen does increase the blood flow to particular organs, but apparently less than it
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increases their oxygen demand, as can be seen from the color change of estrogenized tissues, toward
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purple, rather than pink.</em></strong>
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Measurements of oxygen tension in the tissue show that estrogen decreases the relative availability of
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oxygen. And when the level of estrogen is very high, metabolically demanding tissues, such as the kidney and
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adrenal cortex, simply die, especially under conditions that restrict blood flow. [E.g., Kocsis, et al.,
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1988, McCaig, et al., 1998, Yang, et al., 1999.] When estrogen's effects overlap with the stimulating
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effects of other hormones, such as pituitary hormones, particular organs undergo something similar to
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"excitotoxicity." When estrogen overlaps with endotoxin (as it tends to do), multiple organ failure is the
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result.
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</p>
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<p>
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The simple need for more oxygen is a stimulus to increase the growth of blood vessels, and estrogen's
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stimulation of non-mitochondrial oxygen consumption with the production of lactic acid stimulates blood
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vessel formation. Progesterone, by increasing oxidative efficiency, opposes this "angiogenic"
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(neovascularization) effect of estrogen.
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</p>
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<p>
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Szent-Gyorgyi spent most of his career studying muscles--from the anal sphincter to pigeon breast to tense
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goats. One of his most interesting experiments investigated the effects of estrogen and progesterone on the
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heart muscle. He showed that estrogen excess prevents the increase of stroke volume as the speed increases,
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but that progesterone increases the stroke volume as the heart accelerates, making pumping more effective
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without unnecessary acceleration of the heart rate. These effects are parallel to Selye's observation that
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estrogen imitates the shock reaction.
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</p>
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<p>
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In shock, the blood pressure decreases, mainly because the blood volume decreases. Water is taken up by the
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tissues, out of the blood. Much of the remaining blood volume is accumulated in the relaxed veins, and
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little is returned to the heart, yet the increased need for circulation accelerates the heart, causing each
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stroke to pump only a small amount. The reduced blood pressure caused many people to think that adrenaline
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would help to improve the circulation, but actually the "resistance arteries," small arteries that provide
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blood to the arterioles and capillaries, are constricted in shock, (Lin, et al., 1998,) and adrenaline
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usually makes the situation worse. When tissue is poorly oxygenated (or is exposed to estrogen) it takes up
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water, swelling and becoming more rigid, turgid. (It also takes up calcium, especially under the influence
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of estrogen, causing muscles to contract.) This swelling effect will be much more noticeable in small
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arteries than in major arteries with very large channels, but when the effect is prolonged, it will affect
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even the heart, causing it to "stiffen," weakening its ability to pump. There is some evidence that estrogen
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can make large arteries stiffen, over a span of a few months. (Giltay, et al., 1999)
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</p>
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<p>
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Estrogen, by creating an oxygen deficiency, stimulates first swelling, and then collagen synthesis. Collagen
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tends to accumulate with aging.
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</p>
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<p>
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In shock, the cells are in a very low energy state, and infusions of ATP have been found to be therapeutic,
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but simple hypertonic solutions of glucose and salt are probably safer, and are very effective. The low
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energy of cells causes them to take up water, but it also causes the veins (which always receive blood after
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most of its oxygen and nutrients have been extracted) to lose their tone, allowing blood to pool in them,
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instead of returning to the heart. (Abel and Longnecker, 1978) This contributes to varicose veins
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(Ciardullo, et al., 2000), and to orthostatic hypotension, which is seen in women who are exposed to too
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much estrogen, and very frequently in old people.
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</p>
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<p>
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The energy failure resulting from estrogen excess has been remarkably well characterized (but the meaning of
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this for the cell hasn't been explored). The electron transfer process of the mitochondria is interrupted by
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the futile redox cycling catalyzed by estrogens.
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</p>
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<p>
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Good sleep requires fairly vigorous metabolism and a normal body temperature. In old age, the metabolic rate
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is decreased, and sleep becomes defective. Protein synthesis declines with aging, as the metabolic rate
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slows. At least in the brain, protein synthesis occurs most rapidly in deep sleep. [Nakanishi, et al., 1997;
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Ramm and Smith, 1990]
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</p>
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<p>
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In old age, the catabolic hormones such as cortisol are relatively dominant [Deuschle, et al., 1998], and
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even in youth, cortisol rises during darkness, reaching its peak around dawn. Even in young women, bone loss
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occurs almost entirely during the night, when cortisol is high. The hormones that are commonly said to
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prevent bone loss, estrogen and growth hormone, are high at night, rising along with cortisol. Estrogen
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causes growth hormone to increase, and in the morning, young women's growth hormone has been found to be 28
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times higher than men's.[Engstrom, et al., 1999] The growth hormone response to estrogen is probably the
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result of the changed use of glucose under estrogen's influence, making it necessary to mobilize free fatty
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acids from tissues. While estrogen is usually highest at night, progesterone is lowest during the night.
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These observations should suggest that progesterone, not estrogen, is the bone protective substance.
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</p>
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<p>
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The disappearance of water from the blood, as it moves into the tissues during the night, makes sleep
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resemble a state of shock or inflammation. Since rats, that are active at night, experience the same blood
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thickening, it's actually the darkness, rather than sleep, that creates this "inflammatory" state. Estrogen
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increases, and acts through, the inflammatory mediators, serotonin and histamine, to increase vascular
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leakiness, at the same time that it causes cells to take up water and calcium. The formation of lactic acid,
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in place of carbon dioxide, tends to coordinate these effects.
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</p>
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<p>
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In sleep, as in shock, hyperventilation is common, and it sometimes produces extreme vasoconstriction,
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because of the loss of carbon dioxide.
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</p>
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<p>
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Since glucose and salt are used to treat shock (intravenous 7.5% salt solutions are effective), it seems
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appropriate to use carbohydrate (preferably sugar, rather than starch) and salty foods during the night, to
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minimize the stress reaction. They lower adrenalin and cortisol, and help to maintain the volume and
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fluidity of blood. Thyroid, to maintain adequate carbon dioxide, is often all it takes to improve the blood
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levels of salt, glucose, and adrenalin.
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</p>
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<p>
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Temperature falls during sleep. Recent experiments show that hypothermia during surgery exacerbates the
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edema produced by stress, and that hypertonic (hyperosmotic or hyperoncotic) solutions alleviate the
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swelling. It is possible that light's action directly on the cells helps them to prevent swelling, and that
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the body's infrared emissions have a similar function. Whatever the mechanism is, adequate temperature
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improves sleep, and an excessive nocturnal temperature drop probably increases edema, with all of its
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harmful consequences.
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</p>
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<p>
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At least some of the redox cycles involving NAD/NADH and NADP/NADPH keep electrons from moving beyond
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ubiquinone (coQ10) and energizing the mitochondria. The cycle that makes nitric oxide is one of these, but
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some forms of estrogen participate directly as catalysts in this energy-stealing process. One of the effects
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of blocking electron transfer in the mitochondria is to lower the energy charge of the cells, mimicking the
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function of the age-damaged mitochondria. Glutathione and protein sulfhydryls are oxidized, because the
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normal energy pathways that maintain them have been disrupted.
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</p>
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<p>
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Estrogen directly lowers the temperature, while progesterone raises the temperature. Estrogen sets the
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brain's temperature regulator lower, but, acting through serotonin and other mediators, it can actually
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lower the metabolic rate, too.
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</p>
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<p>
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Far from being just the "hormone of estrus," estrogen, in the form of estradiol and the related steroids,
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plays a role in organisms as diverse as yeasts, worms and mollusks, and in modifying the function of
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practically every type of animal cell--skin, nerve, muscle, bone, hair, gland, etc. But, as more and more of
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its functions come to be understood, it turns out that many toxic chemicals and stressful physical processes
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can activate the same functions, and that estrogen's association with the functions of stress makes it a
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kind of window into some universal biological functions.
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</p>
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<p>
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When Hans Selye brought it to our attention that "stress" was a general life process, he began a process of
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generalization that led people to be able to see that the changes of aging were also the result of complex
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interactions between organisms and their environment, rather than some genetic program that operates like a
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clock running down.
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</p>
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<p>
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When W. Donner Denckla demonstrated that the removal of an animal's pituitary (or, in the case of an
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octopus, its equivalent optic gland) radically extended the animal's life span, he proposed the existence of
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a death hormone in the pituitary gland. But the case of the octopus makes it clear that the catabolic,
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death-inducing hormone is produced by the ovary, under the influence of the optic gland's gonadotropins.
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This sacrifice of "the old" (the individual) for "the new" (the progeny) is analogous to the tissue wasting
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we see under the influence of estrogen, as it stimulates cell division.
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</p>
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<p>
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In Selye's classical stress, the destruction of tissues by the catabolic hormones makes sense in terms of
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the "functional system" described by Anokhin, in which the hormones of adaptation dissolve one tissue for
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use by the system which is adaptively functioning, with the production of carbon dioxide by the functional
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tissue, stabilizing it and regulating the adequate delivery of blood.
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</p>
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<p>
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Progesterone is both an anticatabolic hormone and an antiestrogenic hormone, and in both cases, it protects
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the functional systems from atrophy.
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</p>
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<p>
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The extreme generality of the phenomenon of "estrogenicity" that was built up during the twentieth century
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has taken the concept beyond the specific functions of estrus, and reproduction, and the activation of
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genetic programs of the female animal, to make it necessary to see it as a way that living substance
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responds to certain kinds of stimulus. And these ways of responding turn out to be involved in the complex
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but coherent ways that organisms respond to aging.
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</p>
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<p>
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Selye gave various names to the biology of stress, but the "general adaptation syndrome" expressed the idea
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accurately. But the biology of estrogenicity, like the biology of aging, is so central that any name is
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likely to be misleading. The historical accident of naming a hormone for estrus shouldn't keep us from
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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>
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</p>
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<p>
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Bone 1996 May;18(5):443-50.<strong>
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Ovariectomy-induced high turnover in cortical bone is dependent on pituitary hormone in rats.
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</strong>
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Yeh JK, Chen MM, Aloia JF.. "Our results confirmed that OV increased and HX suppressed systemic and
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periosteal bone formation parameters in both bone sites, OV increased and HX suppressed the gain in bone
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size and bone mass. When OV rats were HX, the serum levels of osteocalcin and periosteal bone formation
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parameters of the tibial shaft and the fifth lumbar vertebrae were, however, depressed and did not differ
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from that of the HX alone. DXA results show that the effect of OV on bone size and bone mass is also
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abolished by HX. In conclusion, we have demonstrated that OV increases tibial and lumbar vertebral bone
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formation and bone growth and this effect is pituitary hormone dependent."
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</p>
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<p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
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