1138 lines
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HTML
1138 lines
75 KiB
HTML
<html>
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<head><title>Preventing and treating cancer with progesterone.</title></head>
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<body>
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<h1>
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Preventing and treating cancer with progesterone.
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</h1>
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<em>"The energy of the mind is the essence of life." Aristotle</em>
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<p></p>
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<p>
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All through the last century, as more and more resources were devoted to solving "the cancer problem," the
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death rate from cancer increased every year. Something was clearly wrong with the way the problem was being
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approached.
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</p>
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<p>
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If you grind up a computer and dissolve it in acid, you can find out exactly what substances it was made of,
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but you won't learn from that information how the computer worked. Twentieth century biologists became fond
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of emulsifying cells and studying the soluble parts. By the end of the century, they had identified so many
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parts that the government was financing projects to use supercomputers to try to understand how the parts
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interacted.
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</p>
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<p>
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If some essential information was lost in studying the parts, supercomputation isn't the way to find it.
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Even with infinite computing capacity, a description of the electrons on carbon and hydrogen atoms on amino
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acids in protein molecules won't lead to the reality of how those atoms would have functioned in the living
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state.
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</p>
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<p>
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The image of a cell as a watery solution contained in an elastic membrane bag is still having a radically
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stupefying effect on biology and medicine. The idea that a cell can be understood by using a computer to
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model a network of interactions between genes and gene products is nothing more than a technologizing of the
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primitive understanding of life that was promulgated by the Weismann-Mendel-Morganist school. It was the
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dogmatic insistence of that genetic determinist school that cancer originated with a genetic mutation.
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</p>
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<p>
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By the middle of the 20th century, that dogma had excluded the most important parts of biology from the
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schools and the journals. Ideas of a developmental field, cellular coherence, and holistic cooperativity
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were denounced as unscientific vitalism. Returning to the idea of a "cancer field" is an essential first
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step in thinking realistically about preventing and treating cancer, but that idea has hardly progressed
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since the 1930s.
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</p>
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<p>
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In the last few years, interest in cloning and stem cells and tissue regeneration has revived interest in
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studying the factors that contribute to the spatial and temporal ordering of cell growth.
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</p>
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<p>
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The idea of a developmental field was a fundamental part of embryology in the first half of the 20th
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century. It was an empirical idea, supported most commonly by evidence that diffusing substances and
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secreted materials governed the differentiation of cells and tissues, but the form-generating effects of
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bioelectric fields were also often demonstrated, and there was some evidence that tissue radiations played a
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role. The extracellular matrix secreted by cells served to transmit information between cells, but its form
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was regulated by cells, and its structure was a factor governing the cells' differentiation.
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</p>
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<p>
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Experiments in amphibians showed that regeneration of organs had a reciprocal relationship with the
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development of cancer--a tumor could be turned into a tail, for example, if it was grafted onto the stump
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following amputation of the tail, but factors that weakened regeneration could cause a tumor to develop. In
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these experiments, the normal organism's morphogenetic or epimorphic field overrode the disordered
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developmental field of the tumor.
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</p>
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<p>
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In the absence of overriding external influences, the disordered system of the tumor, in which cells emitted
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many products of their disordered metabolism, could interfere with the normal functions of the organism. All
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of the products of the injured cells, including their altered extracellular matrix, constituted the cancer
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field.
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</p>
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<p>
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The recent recognition of the "bystander effect" of radiation exposure, in which cells that haven't been
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irradiated undergo genetic changes or death when they are exposed to irradiated cells, has provided an
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opportunity to return to the "field" idea in cancer, because the stress-induced factors emitted by
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irradiated cells are the same toxic factors emitted by cells undergoing carcinogenesis from other causes,
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such as over-exposure to estrogen.
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</p>
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<p>
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H. J. Muller, one of T. H. Morgan's students and colleagues, studied the mutagenic effects of x-rays, and
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the genetic determinists argued that the random changes produced in the genetic material by ionizing
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radiation provided a model of the evolutionary process. Randomly altered genes and natural selection would
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explain everything, including cancer. Every time cells divide, their genes supposedly become more
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susceptible to random changes, so increased replication of cells would increase the risk of producing
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genetic changes leading to cancer. This idea is so simple and so widely believed that many people focus only
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on the rate of proliferation, and the random mutations that supposedly occur during proliferation, when they
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try to explain carcinogenesis. They feel that it's reasonable to discuss cancer without bothering to
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understand the physiology of the cell or the organism.
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</p>
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<p>
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The organism can only be understood in its environments, and a cell can't be understood without reference to
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the tissue and organism in which it lives. Although the geneticists were at first hostile to the idea that
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nutrition and geography could have anything to do with cancer, they soon tried to dominate those fields,
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insisting that mutagens and ethnicity would explain everything. But the evidence now makes it very clear
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that environment and nutrition affect the risk of cancer in ways that are not primarily genetic.
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</p>
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<p>
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Every tumor, like every person, has a uniqueness, but valid and practical empirical generalizations can be
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made, if we understand some of their properties and the conditions that govern their development and
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survival.
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</p>
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<p>
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Percival Potts' observation of scrotal cancer in chimney sweeps eventually led to the study of soot
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carcinogenesis, and then to the study of the properties of the polycyclic aromatic hydrocarbons in soot. The
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similarities of those properties to estrogen's soon became apparent.
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</p>
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<p>
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Over the decades, many studies have confirmed that prolonged, continuous exposure to estrogen is
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carcinogenic, and that progesterone offsets those effects.
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</p>
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<p>
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Following the animal studies that showed that carcinogenesis by estrogen could be prevented or reversed by
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progesterone, studies of the endogenous hormones in women showed that those with a natural excess of
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estrogen, and/or deficiency of progesterone, were the most likely to develop uterine or breast cancers.
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</p>
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<p>
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The Morganist school of genetic determinism moved into endocrinology with a doctrine that hormones act only
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through hormone receptors, proteins which activate certain genes.
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</p>
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<p>
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Many researchers -- physical chemists, biochemists, cytologists, embryologists, reproductive and
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developmental biologists, gerontologists, physiologists, neurologists, endocrinologists -- were
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investigating estrogen's properties and actions, and had made great progress by the 1950s, despite the
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medical frauds being perpetrated by the estrogen industry (Rothenberg, 2005).
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</p>
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<p>
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All of this complex and subtle work was of no interest to a small group of people who wanted to impose their
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genetic views onto biology.
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</p>
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<p>
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The inventor of the estrogen receptor, Elwood Jensen, has written that the results of certain of his
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experiments "caused the demise of the transhydrogenation hypothesis and convinced all but the most diehard
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enzymologists that estradiol binds to a characteristic component of target cells to exert its physiological
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effect without itself being chemically altered." The hypothesis he referred to was just part of a large
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fairly systematic international effort.
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</p>
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<p>
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How he did away with the opposition, who were studying the complex metabolic actions of estrogen, was by
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synthesizing isotope-labeled estradiol and estrone, and claiming to observe that they weren't metabolically
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altered, as they produced their hormonal effect. Since the experiment was extremely expensive, and required
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the cooperation of the Atomic Energy Commission, it wasn't easily repeated. However, many experiments have
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subsequently demonstrated that practically every tissue in the body (and plants and bacteria) metabolize the
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estrogens, causing estradiol to change into estrone, and estrone, into estradiol. Jensen's decisive and
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historically crucial experiment was false.
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</p>
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<p>
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But it served its purpose, and (with help from the pharmaceutical industry and government granting agencies)
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marginalized the work of those "enzymologists" and everyone else who persisted in studying the complex
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actions of estrogen.
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</p>
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<p>
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The enzyme that converts the weaker estrone into the stronger estradiol is an important factor in
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determining estrogen's effects on a particular tissue. Progesterone is able to regulate the cell's
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metabolism, so that the oxidative pathway, forming estrone from estradiol, predominates. Estrogen-dominated
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tissues are likely to have a balance in the direction of reduction rather than oxidation, increasing the
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amount of the active estradiol.
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</p>
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<p>
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The immediate effects of estrogen and progesterone on cells, that occur long before genes can be activated,
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were simply ignored or denied by the promoters of the estrogen receptor doctrine. Some of these excitatory
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or antiexcitatory effects are probably structural changes, that involve the mobilization of calcium inside
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cells, and the activation or inhibition of reactions involving phosphoric acid. Although they have been
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known for many years, they are always referred to as "novel" or "non-classical" effects, and are called
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"membrane effects," because that's the only way the reductionists are able to identify changes that happen
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immediately throughout the cell.
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</p>
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<p>
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Cellular excitation involves an increase of intracellular calcium and the activation of phosphorylating
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enzymes in cells. Some experiments suggest (Improta-Brears, et al., 1999) that the estrogen receptor
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mediates estrogen's ability to mobilize calcium (leading to the activation of cell division, mitosis).
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Whether or not it does, the recognition that estrogen activates calcium, leading to activation of the
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phosphorylation system, should "cause the demise of" the "classical estrogen receptor" doctrine, because the
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phosphorylation system alters the expression of genes, much as the estrogen receptor was supposed to do by
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its direct actions. <strong>But before it alters the expression of genes, it alters the activities of
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enzymes.</strong> When estrogen activates calcium and phosphorylation independently of the estrogen
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receptor, the situation is even worse for the Jensen dogma.
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</p>
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<p>
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Progesterone's opposition to those early excitatory effects of estrogen are so basic, that there shouldn't
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be any difficulty in thinking of it as an antiestrogen, that stops cell division primarily by opposing the
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excitatory effects of estrogen and other mitogens. Progesterone's opposition to the calcium-activating and
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phosphorylating effects of estrogen affects everything in the cell, according to the cell's specific nature.
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</p>
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<p>
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But the reductionists don't like "nongenomic" explanations of anything, even when they are triggered by the
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estrogen receptor rather than by a membrane-event. So, to argue that progesterone's opposition to estrogen
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is general, it's necessary to examine each of estrogen's actions, where those actions are clearly known, and
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to evaluate progesterone's effects on the same events.
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</p>
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<p>
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When a cell is stimulated or slightly stressed, homeostatic mechanisms are activated that help it to return
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to its normal resting state. The mobilization of calcium and the phosphorylation system is followed by
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increased synthesis of cholesterol and the formation of glucose from glycogen. Cholesterol itself is
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protective, and in some cells it is massively converted into progesterone, which is even more effective in
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restoring homeostasis.
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</p>
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<p>
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In the ovary, the enzymes that synthesize cholesterol, along with the production of progesterone, are
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activated by the pituitary hormone, FSH, but also by estrogen. In the liver and uterus and vascular
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endothelium, which aren't specialized for the production of progesterone, stimulation by estrogen activates
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the enzymes to increase the formation of cholesterol.
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</p>
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<p>
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When cells are injured or seriously stressed, instead of being able to directly recover their normal
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quiescence, they may instead mobilize their systems for growing and replicating, to replace damaged or
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destroyed cells.
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</p>
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<p>
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Prolonged exposure to estrogen, that can't be offset by the homeostatic factors, such as progesterone,
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typically causes cells to enter a growth phase. (But so do other excitatory processes, such as ionizing
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radiation.)
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</p>
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<p>
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One of the basic reactions to injury is to shift the cell away from oxidative metabolism to glycolytic
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metabolism, which is inefficient, but can support cell division. Chemical stains show that during cell
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division cells are in a reduced state, with abundant sulfhydryl groups including reduced glutathione and
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protein sulfhydryls. This shift in itself increases the formation of active estradiol from estrone.
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</p>
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<p>
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In the inflamed or estrogen dominated cell, enzymes such as the cyclooxidases (COX), that convert
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arachidonic acid into prostaglandins, are activated. Beta-glucuronidase and sulfatases are activated, and
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these cause intracellular estrogen to increase, by removing the water soluble sulfate and glucuronate
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portions from estrogens that had been inactivated. The detoxifying enzymes that attach those molecules to
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estrogen are inactivated in the estrogen dominated cell. The prostaglandin formed from arachidonic acid
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stimulates the formation of the enzyme aromatase or estrogen synthetase, that converts androgens into
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estrogen.
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</p>
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<p>
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Those processes, initiated by excitation or injury, increase the amount of estrogen in the cell, which
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intensifies the excitation.
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</p>
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<p>
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Progesterone opposes all of those processes, decreasing the amount of estrogen in the cell by modifying the
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activities of those five types of enzyme.
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</p>
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<p>
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Although many kinds of protein (including enzymes) bind estrogen, the protein that Jensen called "the
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estrogen receptor" is largely responsible for the ability of the uterus and breasts to retain high
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concentrations of estrogen. Various kinds of stimulation or stress (including heat and oxygen deprivation)
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cause its appearance, and estrogen itself increases the amount of the estrogen receptor in a cell. The
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estrogen receptor doesn't just "activate genes," as the Jensen dogma claimed. For example, the estrogen
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receptor directly binds and inactivates the "tumor suppressor" p53 protein, which otherwise would restrain
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the replication of damaged cells.
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</p>
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<p>
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Progesterone causes the estrogen receptor to be eliminated. (Batra; Boling and Blandau; Resko, et al.)
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</p>
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<p>
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Among the cell activating factors, other than estrogen, are proteins that are considered to be "oncogenes,"
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because of their involvement in cancer. Several of these proteins are activated by estrogen, inhibited by
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progesterone. The term "oncogene" refers to any gene that contributes to the development of cancer, but it
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is so burdened by ideology that it shouldn't be used as if it had a simple clear meaning.
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</p>
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<p>
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A variety of proteins promote cell activity and replication, under the influence of estrogen. The "composite
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transcription factor activating protein 1," AP-1 which integrates the effects of other transcription
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factors, is important in a variety of cell types, and its activity is increased by estrogen and decreased by
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progesterone.
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</p>
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<p>
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When the "progesterone receptor" <strong>lacks progesterone,</strong> it has the opposite effect of
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progesterone, and this feature has been used propagandistically, by infecting cells with a virus carrying
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the progesterone receptor protein, and then suggesting that the disturbed functions of the cell reflect a
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potential effect of progesterone. The receptor, lacking progesterone, tells the cell that it has a
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progesterone deficiency, but too many molecular endocrinologists are trying to say that the receptor protein
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is the same as the progesterone.
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</p>
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<p>
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The generality of the process of excitation/activation can be clearly seen in the effects of the
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nerve-inhibiting GABA and the nerve-exciting glutamate or NMDA. In cultured breast cancer cells, GABA
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inhibits growth, NMDA increases growth. As in the brain, progesterone supports the actions of GABA, and
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opposes those of NMDA or the excitatory amino acids, while estrogen in general promotes the effects of the
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excitatory amino acids, and opposes those of GABA.
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</p>
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<p>
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Both the excitatory amino acids and a peptide that promotes inflammation, tumor necrosis factor (TNF),
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activate the enzyme which makes estrogen, aromatase. Estrogen, by activating NF kappaB, increases the
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formation of TNF, which in itself can promote the growth and metastasis of cancer. Various antiinflammatory
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agents, including aspirin, progesterone, testosterone, saturated fats, and glycine, can inhibit the
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production of NF kappaB.
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</p>
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<p>
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An enzyme that has been thought of mainly in relation to the brain is catechol-O-methyl transferase, which
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is inhibited by estrogen (producing effects similar to cocaine), leading to brain excitation.The enzyme
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detoxifies catecholestrogen (Creveling, 2003), protecting cells from DNA damage (Lavigne, et al., 2001).
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When the activity of this enzyme is low, there is increased risk of breast cancer (Matsui, et al., 2000).
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Progesterone increases its activity (Inoue and Creveling, 1991, 1995).
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</p>
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<p>
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Another enzyme system that affects the body's reactions to stress and modifies processes of inflammation and
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growth, the monoamino-oxidases, is affected oppositely by estrogen and progesterone. Estrogen's effects are
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partly mediated by increased formation of serotonin, progesterone's, by decreasing it. Histamine is another
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promoter of inflammation that is increased by estrogen, decreased by progesterone.
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</p>
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<p>
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Estrogen's effects in the nervous system go beyond the production of cocaine-like hypomania, or chorea, or
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epilepsy, and include the activation of the basic stress hormones, increasing the formation in the
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hypothalamus of pro-opiomelanocortin (POMC), which is a precursor of ACTH to activate the adrenals, and
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endorphins ("endogenous opiates"), which stimulate growth processes. Both endorphins and ACTH can be found
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in tumors such as breast cancer. The ACTH stimulates the production of cortisol, that protects against some
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of the immediate causes of inflammation and growth, but that contributes to the loss of resistance, and
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increases estrogen synthesis.
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</p>
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<p>
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A protein called the sigma receptor, known for its role in cocaine's action, binds progesterone, and can
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inhibit the growth of cancer. Some anesthetics have similar effects on tumors, acting through this protein.
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The sigma receptor, in association with progesterone or pregnenolone, is protective against the excitatory
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amino acids.
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</p>
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<p>
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The extracellular medium changes during the development of a tumor. Irritated hypoxic cells, and
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estrogen-stimulated cells, increase their production of collagen, and the increase of collagen interferes
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with normal cell functions. Progesterone reduces the formation of collagen, and probably contributes to its
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removal.
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</p>
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<p>
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Naloxone or naltrexone, which blocks the actions of the endorphins and morphine, is being used to inhibit
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the growth of various kinds of cancer, including breast cancer and prostate cancer. Leptin (which is
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promoted by estrogen) is a hormone produced by fat cells, and it, like estrogen, activates the POMC-related
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endorphin stress system. The endorphins activate histamine, another promoter of inflammation and cell
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division.
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</p>
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<p>
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Progesterone opposes those various biochemical effects of estrogen in multiple ways, for example by
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inhibiting the ACTH stress response, by restraining cortisol's harmful actions, and by inhibiting leptin.
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</p>
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<p>
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Mediators of the radiation bystander effect include NO, TNF, COX, and prostaglandins. These are produced by
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other things that cause inflammation and injury, including estrogen.
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</p>
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<p>
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Cell division, when it is part of the body's continuous renewal and adaptation, isn't a source of mutations
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or degeneration, but when it is induced by the mediators of inflammation produced in response to injury, it
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leads to inherited changes, loss of differentiated function, and eventually to genetic instability.
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</p>
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<p>
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When cell division is so disturbed that the number of chromosomes becomes abnormal, the instability of these
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cells decreases their ability to survive, but when the causes of the inflammation persist, they will
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continue to be replaced by other abnormal cells. The toxic products of dying cells can reach a point at
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which the debris can't be removed, adding to the injury and inflammation. The damaged bystander cells spread
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their influence through a cancer field, injuring more cells.
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</p>
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<p>
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One of the "field" effects of cancer is the stimulation of new blood vessel development, angiogenesis.
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Lactic acid stimulates the formation of new blood vessels, the secretion of collagen, and tumor growth. Low
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oxygen, nitric oxide, carbon monoxide, prostaglandins and other products of tissue stress can stimulate the
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growth of new blood vessels, at the same time that they stimulate tumor growth and impair oxidative
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metabolism. Several of these agents promote each other's activity.
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</p>
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<p>
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Therapeutic thinking has been influenced by the doctrine of the mutant cell as the initiator of cancer,
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leading to the idea that only things which kill the cancer cells can cure cancer. But when the body stops
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activating the processes of inflammation and growth, normal processes of tissue repair have an opportunity
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to eliminate the tumor. Even the fibroblasts which normally secrete collagen can participate in its removal
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(Simoes, et al., 1984). Something as simple as eliminating lactate can change their functions.
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</p>
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<p>
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Although the angiogenic action of lactate has been known for several decades, some researchers believed that
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a specific anti-angiogenic peptide could be found which would stop the growth of cancer cells. The interest
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in angiogenesis tacitly acknowledges that there is a cancer field, but the faith that cancer could be cured
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only by killing the mutant cells seems to have guided the search for a single antiangiogenic substance. Such
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a substance would be toxic to normal tissues, since blood vessels are constantly being renewed.
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</p>
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<p>
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The more advanced a tumor is, the more numerous the growth-promoting factors are likely to be, and the
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weaker the body's ability becomes to control them.
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</p>
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<p>
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The search for toxic factors to kill the cancer cells is unlikely to lead to a generally effective
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treatment. Even immunological approaches that think in terms of destroying a tumor might be misconceiving
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the nature of the problem. For example, the protein called "tumor necrosis factor" (TNF) or cachectin was
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discovered as a result of Lawrence Burton's work in the 1960s. He extracted proteins from the blood that
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could shrink some tumors in mice with amazing speed. In the right setting, TNF is involved in the
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destruction of tumors, but when other factors are missing, it can make them worse. Burton was focussing on
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factors in the immune system that could destroy cancer, but he ignored the basic problem of tissue
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degeneration that produces tumors which are complex and changing.
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</p>
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<p>
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If the cancer-productive field is taken into account, all of the factors that promote and sustain that field
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should be considered during therapy.
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</p>
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<p>
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Two ubiquitous carcinogenic factors that can be manipulated without toxins are the polyunsaturated fatty
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acids (PUFA) and estrogen. These closely interact with each other, and there are many ways in which they can
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be modulated.
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</p>
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<p>
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For example, keeping cells in a well oxygenated state with thyroid hormone and carbon dioxide will shift the
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balance from estradiol toward the weaker estrone. The thyroid stimulation will cause the liver to excrete
|
|
estrogen more quickly, and will help to prevent the formation of aromatase in the tissues. Low temperature
|
|
is one of the factors that increases the formation of estrogen. Lactic acid, serotonin, nitric oxide,
|
|
prostaglandins, and the endorphins will be decreased by the shift toward efficient oxidative metabolism.
|
|
</p>
|
|
<p>
|
|
Progesterone synthesis will be increased by the higher metabolic rate, and will tend to keep the temperature
|
|
higher.
|
|
</p>
|
|
<p>
|
|
Thyroid hormone, by causing a shift away from estrogen and serotonin, lowers prolactin, which is involved in
|
|
the promotion of several kinds of cancer.
|
|
</p>
|
|
<p>
|
|
Vitamin D and vitamin K have some antiestrogenic effects. Vitamin D and calcium lower the
|
|
inflammation-promoting parathyroid hormone (PTH).
|
|
</p>
|
|
<p>
|
|
Eliminating polyunsaturated fats from the diet is essential if the bystander effect is eventually to be
|
|
restrained. Aspirin and salicylic acid can block many of the carcinogenic effects of the PUFA. Saturated
|
|
fats have a variety of antiinflammatory and anticancer actions. Some of those effects are direct, others are
|
|
the result of blocking the toxic effects of the PUFA. Keeping the stored unsaturated fats from circulating
|
|
in the blood is helpful, since it takes years to eliminate them from the tissues after the diet has changed.
|
|
Niacinamide inhibits lipolysis. Avoiding over-production of lipolytic adrenaline requires adequate thyroid
|
|
hormone, and the adjustment of the diet to minimize fluctuations of blood sugar.
|
|
</p>
|
|
|
|
<p>
|
|
The endorphins are antagonistic to progesterone, and when they are minimized, progesterone tends to
|
|
increase, and to be more effective. The drugs naloxone and naltrexone, which block the effects of the
|
|
endorphins, have several remarkable effects that resemble progesterone's. Naltrexone has been successfully
|
|
used to treat prostate and breast cancer.
|
|
</p>
|
|
<p>
|
|
Opiates are still commonly used for pain relief in cancer patients, despite the evidence that has
|
|
accumulated for several decades indicating that they promote inflammation and cancer growth, while
|
|
suppressing immunity and causing tissue catabolism, exacerbating the wasting that commonly occurs with
|
|
cancer. Their use, rather than alternatives such as procaine, aspirin, and progesterone, is nothing but a
|
|
medical fetish.
|
|
</p>
|
|
<p>
|
|
Stress and estrogen tend to produce alkalosis, while thyroid, carbon dioxide, and adequate protein in the
|
|
diet help to prevent alkalosis.
|
|
</p>
|
|
<p>
|
|
Antihistamines and some of the antiserotonin drugs (including "dopaminergic" lisuride and bromocriptine) are
|
|
sometimes useful in cancer treatment, but the safe way to lower serotonin is to reduce the consumption of
|
|
tryptophan, and to avoid excessive cortisol production (which mobilizes tryptophan from the muscles).
|
|
Pregnenolone and sucrose tend to prevent over-production of cortisol.
|
|
</p>
|
|
<p>
|
|
In the breast, COX-2 converts arachidonic acid into prostaglandins, which activate the enzyme aromatase,
|
|
that forms estrogen from androgens. Until the tissues are free of PUFA, aspirin and salicylic acid can be
|
|
used to stop prostaglandin synthesis.
|
|
</p>
|
|
|
|
<p>
|
|
Thyroid is needed to keep the cell in an oxidative, rather than reductive state, and progesterone (which is
|
|
produced elsewhere only when cells are in a rapidly oxidizing state) activates the processes that remove
|
|
estrogen from the cell, and inactivates the processes that would form new estrogen in the cell.
|
|
</p>
|
|
<p>
|
|
Thyroid, and the carbon dioxide it produces, prevent the formation of the toxic lactic acid. When there is
|
|
enough carbon dioxide in the tissues, the cell is kept in an oxidative state, and the formation of toxic
|
|
free radicals is suppressed. Carbon dioxide therapy is extremely safe.
|
|
</p>
|
|
<p>
|
|
In the 1930s, primates as well as rodents had been used in experiments to show the carcinogenic effects of
|
|
estrogen, and the protective effects of progesterone.
|
|
</p>
|
|
<p>
|
|
By 1950, the results of animal studies of progesterone's anticancer effects were so clear that the National
|
|
Cancer Institute got involved. But the estrogen industry had already been conducting its campaign against
|
|
progesterone, and had convinced most doctors that it was inactive when taken orally, and so was inferior to
|
|
their proprietary drugs that they called "progestins." The result was that it was usually given by
|
|
injection, dissolved in vegetable oil or synthetic solvents such as benzyl benzoate or benzyl alcohol, which
|
|
are very toxic and inflammation-producing.
|
|
</p>
|
|
<p>
|
|
The NCI researchers (Hertz, et al., 1951) treated 17 women with visible cancers of the uterine cervix that
|
|
had been confirmed by biopsies. They were given daily intramuscular injections of 250 mg of progesterone in
|
|
vegetable oil. Although they described the treatment as "massive dosage with progesterone," it didn't
|
|
prevent menstruation in any of the women who had been menstruating before the treatment began. During a
|
|
healthy pregnancy, a woman produces more progesterone than that.
|
|
</p>
|
|
|
|
<p>
|
|
Their article includes some photographs of cervical tumors before treatment, and after 31 days, 50 days, and
|
|
65 days of progesterone treatment. The improvement is clear. The examining physicians described softening of
|
|
the tumor, and stopping of bleeding and pain.
|
|
</p>
|
|
<p>
|
|
"In eleven of the 17 treated patients visible and palpable evidence of regressive alteration of the tumor
|
|
mass could be demonstrated. This consisted of (a) distinct reduction in size of the visible portion of the
|
|
cancer as well as reduction of the palpable extent of the mass, (b) reduction in vascularity and friability
|
|
of the visible lesion with a clearly demonstrable epithelization of previously raw surfaces and (c) markedly
|
|
increased pliability of the previously rigid and infiltrated parametria."
|
|
</p>
|
|
<p>
|
|
"In 10 cases there was associated with this type of gross change a reduction in, or complete cessation of
|
|
vaginal bleeding and discharge."
|
|
</p>
|
|
<p>
|
|
"Only one of the 17 patients showed active progression of the carcinomatous process while under the
|
|
progesterone administration. The six patients whose lesions failed to show clearly demonstrable regressive
|
|
changes showed minor alterations in size and vascularity of insufficient degree to be convincing to all
|
|
clinical observers concerned. Nevertheless, none of the lesions under study appeared to be accelerated by
|
|
progesterone."
|
|
</p>
|
|
<p>
|
|
Observing very similar patients under similar conditions while they were waiting for surgery, but were not
|
|
receiving progesterone, they saw no such regressions of tumors.
|
|
</p>
|
|
<p>
|
|
The photographs and descriptions of the changes in the tumors were remarkable for any cancer study, but to
|
|
have been produced by a treatment that didn't even alter the patients' menstrual cycle, the reader might
|
|
expect the authors to discuss their plans for further studies of such a successful method.
|
|
</p>
|
|
|
|
<p>
|
|
But instead, they concluded "We do not consider the regressive changes observed to be sufficient to indicate
|
|
the use of progesterone as a therapeutic agent in carcinoma of the cervix."
|
|
</p>
|
|
<p>
|
|
(Their research was supported by a grant from the American Cancer Society.)
|
|
</p>
|
|
<p>
|
|
If the researchers had bothered to test progesterone on themselves or on animals, they would have discovered
|
|
that it is fully active when taken orally, dissolved in oil, and that nontoxic saturated fats could have
|
|
been used. Progesterone anesthesia was very well known at that time, so it would have been reasonable to use
|
|
doses that were at least equivalent to the concentrations present during pregnancy, even if they didn't want
|
|
to use doses that would approach the anesthetic level. The total daily doses could have been about ten times
|
|
higher, if they had been given orally as divided doses.
|
|
</p>
|
|
<p>
|
|
The solvent issue continues to impede research in the use of progesterone for treating cancer, but the main
|
|
problem is the continuing belief that "the cancer cell" is the problem, rather than the cancer field.
|
|
Substances are tested for their ability to kill cancer cells <em>in vitro</em>, because of the basic belief
|
|
that mutated genes are the cause of the disease. When progesterone is tested on cancer cells <em>in
|
|
vitro,</em>
|
|
|
|
the experimenter often sees nothing but the effects of the solvent, and doesn't realize that nearly all of
|
|
the progesterone has precipitated in the medium, before reaching the cancer cells.
|
|
</p>
|
|
<p>
|
|
The cancer industry began a few years ago to combine chemicals for chemotherapy, for example adding caffeine
|
|
to paclitaxel or platinum (cisplatin), or histamine to doxorubicin, but they do it simply to increase the
|
|
toxicity of the chemical to the tumor, or to decrease its toxicity to the patient. Doctors sometimes refer
|
|
to combined chemotherapy as a "shotgun approach," meaning that it lacks the acumen of their ideal silver
|
|
bullet approach. If cancers were werewolves, the cancer industry's search for more refined killing
|
|
technologies might be going in the right direction. But the genetic doctrine of cancer's origin is just as
|
|
mythical as werewolves and vampires.
|
|
</p>
|
|
<p>
|
|
A safe physiological approach to cancer, based on the opposition of progesterone to estrogen, would be
|
|
applicable to every type of cancer promoted by estrogen, or by factors which produce the same effects as
|
|
estrogen, and that would include all of the known types of cancer. Estrogen acts even on cells that have no
|
|
"estrogen receptors," but estrogen receptors can be found in every organ.
|
|
</p>
|
|
|
|
<p>
|
|
As estrogen's non-feminizing actions are increasingly being recognized to include contributions to other
|
|
kinds of disease, including Alzheimer's disease, heart disease, and rheumatoid arthritis, the idea of the
|
|
bystander effect, and the field of cellular degeneration, will eventually clear the way for a rational use
|
|
of the therapeutic tools that already exist.
|
|
</p>
|
|
<p>
|
|
There are several types of drug---carbonic anhydrase inhibitors, to increase carbon dioxide in the tissues,
|
|
lysergic acid derivatives, to block serotonin and suppress prolactin, anti-opiates, antiexcitotoxic and
|
|
GABAergic agents, anesthetics, antihistamines, anticholinergics, salicylic acid derivatives---that could
|
|
probably be useful in a comprehensive therapy for cancer, but their combinations won't be explored as long
|
|
as treatments are designed only to kill.
|
|
</p>
|
|
<p>
|
|
Preventing or correcting disturbances in the morphogenetic field should be the focus of attention.
|
|
</p>
|
|
<p><h3>REFERENCES</h3></p>
|
|
|
|
<p>
|
|
Biochem Biophys Res Commun. 1991 Mar 15;175(2):625-30. <strong>Antitumor activity of naltrexone and
|
|
correlation with steroid hormone receptors.</strong> Abou-Issa H, Tejwani GA.
|
|
</p>
|
|
<p>
|
|
Contraception 1981 Apr;23(4):447-55. <strong>
|
|
Comparison of plasma and myometrial tissue concentrations of estradiol-17 beta and progesterone in
|
|
nonpregnant women.</strong> Akerlund M, Batra S, Helm G.
|
|
</p>
|
|
<p>
|
|
Obstetrics and gynecology New York 2001 vol.97 no.4 (Supplement) page S10. Topical progesterone cream has
|
|
antiproliferative effect on estrogen-stimulated endometrium, Anasti, James N. Leonetti, H B. Wilson, K J.
|
|
</p>
|
|
<p>
|
|
Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6169-74. <strong>Modulation of AP-1 activity by the human
|
|
progesterone receptor in endometrial adenocarcinoma cells.</strong> Bamberger AM, Bamberger CM,
|
|
Gellersen B, Schulte HM.
|
|
</p>
|
|
|
|
<p>
|
|
J Gynecol Obstet Biol Reprod (Paris). 1990;19(3):269-74. <strong>[The in vivo effect of the local
|
|
administration of progesterone on the mitotic activity of human ductal breast tissue. Results of a pilot
|
|
study]</strong> Barrat J, de Lignieres B, Marpeau L, Larue L, Fournier S, Nahoul K, Linares G, Giorgi H,
|
|
Contesso G. <strong>"Mean mitotic activity was significantly lower in progesterone treated group (0.04/1,000
|
|
cells) than in placebo (0.10/1,000 cells) or in estradiol (0.22/1,000 cells) treated groups. High
|
|
concentration of progesterone sustained in human breast tissue in vivo during 11 to 13 days does not
|
|
increase, but actually decreases mitotic activity in normal lobular epithelial cells."</strong>
|
|
Randomized Controlled Clinical Trial
|
|
</p>
|
|
<p>
|
|
Clin Endocrinol (Oxf) 1979 Dec;11(6):603-10. <strong>Interrelations between plasma and tissue concentrations
|
|
of 17 beta-oestradiol and progesterone during human pregnancy.</strong> Batra S, Bengtsson LP, Sjoberg
|
|
NO
|
|
</p>
|
|
<p>
|
|
Endocrinology 1976 Nov; 99(5): 1178-81. <strong>Unconjugated estradiol in the myometrium of
|
|
pregnancy.</strong>
|
|
|
|
Batra S.
|
|
</p>
|
|
<p>
|
|
J Steroid Biochem 1989 Jan;32(1A):35-9. <strong>
|
|
Tissue specific effects of progesterone on progesterone and estrogen receptors in the female urogenital
|
|
tract.</strong> Batra S, Iosif CS.
|
|
</p>
|
|
<p>
|
|
Lancet. 1989 Oct 28;2(8670):1008-10. <strong>Saturation of fat and cholecystokinin release: implications for
|
|
pancreatic carcinogenesis.</strong> Beardshall K, Frost G, Morarji Y, Domin J, Bloom SR, Calam J.
|
|
</p>
|
|
<p>
|
|
FASEB J. 2006 Oct;20(12):2009-16. <strong>Therapeutic levels of aspirin and salicylate directly inhibit a
|
|
model of angiogenesis through a Cox-independent mechanism.
|
|
</strong>
|
|
|
|
Borthwick GM, Johnson AS, Partington M, Burn J, Wilson R, Arthur HM.
|
|
</p>
|
|
<p>
|
|
Br J Cancer. 2002 Oct 7;87(8):876-82. <strong>The association of breast mitogens with mammographic
|
|
densities.</strong> Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M, Hammond G, Minkin S.
|
|
</p>
|
|
<p>
|
|
Eur J Pharmacol. 1995 May 15;278(2):151-60. <strong>Sigma binding site ligands inhibit cell proliferation in
|
|
mammary and colon carcinoma cell lines and melanoma cells in culture.</strong> Brent PJ, Pang GT.
|
|
</p>
|
|
<p>
|
|
Fertil Steril 1995; 63(4):785-91.<strong>
|
|
Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell
|
|
cycle in vivo.</strong> Chang KJ, et al. The effect of transdermal estradiol (1.5 mg), transdermal
|
|
progesterone (25 mg), and combined transdermal estradiol and progesterone (1.5 mg and 25 mg) on human breast
|
|
epithelial cell cycles was evaluated in vivo. Results demonstrated that <strong>estradiol significantly
|
|
increases cell proliferation, while progesterone significantly decreases cell replication below that
|
|
observed with placebo.
|
|
</strong>
|
|
|
|
Transdermal progesterone was also shown to reduce estradiol-induced proliferation.
|
|
</p>
|
|
<p>
|
|
Br J Cancer. 1997;75(2):251-7. <strong>Type I insulin-like growth factor receptor gene expression in normal
|
|
human breast tissue treated with oestrogen and progesterone.</strong> Clarke RB, Howell A, Anderson E.
|
|
"The epithelial proliferation of normal human breast tissue xenografts implanted into athymic nude mice is
|
|
significantly increased from basal levels by oestradiol (E2), but not progesterone (Pg) treatment at serum
|
|
concentrations similar to those observed in the luteal phase of the human menstrual cycle." "The data
|
|
indicate that the IGFR-I mRNA is up-regulated by two to threefold compared with untreated levels by 7 and 14
|
|
days E2 treatment. <strong>
|
|
In contrast, 7 or 14 days Pg treatment down-regulates the receptor mRNA to approximately half that of
|
|
untreated levels,</strong> whereas combination E2 and Pg treatment produced a twofold increase in IGFR-I
|
|
mRNA levels compared with untreated tissue."
|
|
</p>
|
|
<p>
|
|
Brain Res. 2006 Dec 18;1126(1):2-26. <strong>Functional significance of the rapid regulation of brain
|
|
estrogen action: Where do the estrogens come from?</strong> Cornil CA, Ball GF, Balthazart J.
|
|
</p>
|
|
|
|
<p>
|
|
Am J Epidemiol. 1981 Aug;114(2):209-17. <strong>Breast cancer incidence in women with a history of
|
|
progesterone deficiency.</strong> Cowan LD, Gordis L, Tonascia JA, Jones GS. "Women in the PD
|
|
[progesterone deficiency] group had 5.4 times the risk of premenopausal breast cancer as compared to women
|
|
in the NH group." "Women in the PD group also experienced a 10-fold increase in deaths from all malignant
|
|
neoplasm compared to the NH group."
|
|
</p>
|
|
<p>
|
|
Growth. 1975 Dec;39(4):475-96. <strong>Cancer-related aspects of regeneration research: a review.</strong>
|
|
Donaldson DJ, Mason JM.
|
|
</p>
|
|
<p>
|
|
Int J Cancer. 1992 May 28;51(3):416-24. <strong>Capacity of adipose tissue to promote growth and metastasis
|
|
of a murine mammary carcinoma: effect of estrogen and progesterone.</strong> Elliott BE, Tam SP, Dexter
|
|
D, Chen ZQ. <strong>"Estrogen can stimulate growth of SPI in adipose tissue sites, whereas progesterone
|
|
inhibits growth.</strong>"
|
|
</p>
|
|
|
|
<p>
|
|
Breast Cancer Res Treat. 2002 Jul;74(2):167-76. <strong>Regulation of MCF-7 breast cancer cell growth by
|
|
beta-estradiol sulfation.</strong> Falany JL, Macrina N, Falany CN.
|
|
</p>
|
|
<p>
|
|
Br J Cancer 1981 Aug;44(2):177-81. <strong>Morphological evaluation of cell turnover in relation to the
|
|
menstrual cycle in the "resting" human breast.</strong> Ferguson DJ, Anderson TJ
|
|
</p>
|
|
<p>
|
|
Eur J Cancer. 1992;28A(6-7):1143-7. <strong>Fatty acid composition of normal and malignant cells and
|
|
cytotoxicity of stearic, oleic and sterculic acids in vitro.</strong> Fermor BF, Masters JR, Wood CB,
|
|
Miller J, Apostolov K, Habib NA.
|
|
</p>
|
|
|
|
<p>
|
|
Fertil Steril. 1998 May;69(5):963-9. <strong>Estradiol and progesterone regulate the proliferation of human
|
|
breast epithelial cells.</strong> Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S, de
|
|
Lignieres B. "Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal
|
|
breast epithelial cells in vivo." Randomized Controlled Trial
|
|
</p>
|
|
<p>
|
|
Mol Cell Biochem 1999 Dec;202(1-2):53-61. <strong>Bcl-2, survivin and variant CD44 v7-v10 are downregulated
|
|
and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction
|
|
of apoptosis.
|
|
</strong>
|
|
Formby B, Wiley TS."This study sought to elucidate the <strong>mechanism by which progesterone inhibits the
|
|
proliferation of breast cancer cells."</strong>
|
|
|
|
"The results demonstrated that progesterone does produce a strong antiproliferative effect on breast cancer
|
|
cell lines containing progesterone receptors, and induced apoptosis. <strong>The relatively high levels of
|
|
progesterone utilized were similar to those seen during the third trimester of human pregnancy.</strong
|
|
>"
|
|
</p>
|
|
<p>
|
|
Ann Clin Lab Sci 1998 Nov-Dec;28(6):360-9. <strong>Progesterone inhibits growth and induces apoptosis in
|
|
breast cancer cells: inverse effects on Bcl-2 and p53.</strong> Formby B, Wiley TS.
|
|
</p>
|
|
<p>
|
|
Cancer Lett 1999 Jul 1;141(1-2):63-71.<strong>
|
|
Progestins suppress estrogen-induced expression of vascular endothelial growth factor (VEGF) subtypes in
|
|
uterine endometrial cancer cells.</strong> Fujimoto J, Sakaguchi H, Hirose R, Ichigo S, Tamaya T.
|
|
</p>
|
|
<p>
|
|
Mol Cell Biol. 2006 Oct;26(20):7632-44. <strong>TReP-132 Is a Novel Progesterone Receptor Coactivator
|
|
Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by
|
|
Progesterone.
|
|
</strong>
|
|
|
|
Gizard F, Robillard R, Gross B, Barbier O, Revillion F, Peyrat JP, Torpier G, Hum DW, Staels B.
|
|
</p>
|
|
<p>
|
|
Am J Physiol. 1982 Oct;243(4):H619-27. <strong>NAD/NADH: redox state changes on cat brain cortex during
|
|
stimulation and hypercapnia.
|
|
</strong>
|
|
Gyulai L, Dora E, Kovach AG.
|
|
</p>
|
|
<p>
|
|
Drug Metab Dispos. 1995 Mar;23(3):430-2. <strong>Induction of catechol-O-methyltransferase in the luminal
|
|
epithelium of rat uterus by progesterone: inhibition by RU-486.</strong> Inoue K, Creveling CR.
|
|
</p>
|
|
<p>
|
|
Hertz R, Cromer J.K., Young J.P. and Westfall B.B., pages 366-374, in <strong><em>
|
|
Symposium on Steroids in Experimental and Clinical Practice,</em></strong>
|
|
Abraham White, Blakiston, 195.
|
|
</p>
|
|
<p>
|
|
Cancer Res. 2005 Jul 15;65(14):6450-8. <strong>Progesterone receptor in non-small cell lung cancer--a potent
|
|
prognostic factor and possible target for endocrine therapy.
|
|
</strong>Ishibashi H, Suzuki T, Suzuki S, Niikawa H, Lu L, Miki Y, Moriya T, Hayashi S, Handa M, Kondo T,
|
|
Sasano H. "Cell proliferation was inhibited by progesterone in these progesterone receptor-positive NSCLC
|
|
cells in a dose-dependent manner, which was inhibited by progesterone receptor blocker. Proliferation of
|
|
these tumor cells injected into nude mice was also dose-dependently inhibited by progesterone, with a
|
|
concomitant increase of p21 and p27 and a decrease of cyclin A, cyclin E, and Ki67. Results of our present
|
|
study suggested that progesterone receptor was a potent prognostic factor in NSCLCs and progesterone
|
|
inhibited growth of progesterone receptor-positive NSCLC cells. Therefore, progesterone therapy may be
|
|
clinically effective in suppressing development of progesterone receptor-positive NSCLC patients."
|
|
</p>
|
|
<p>
|
|
Naunyn Schmiedebergs Arch Pharmacol. 1986 Aug;333(4):368-76. <strong>Effect of progesterone on the
|
|
metabolism of noradrenaline in rabbit uterine endometrium and myometrium.</strong> Kennedy JA, de la
|
|
Lande IS.
|
|
</p>
|
|
<p>
|
|
Agressologie 1971;12(2):105-112. <strong>[The inhibiting effect of atmospheres oxygenated without CO2 on the
|
|
respiration of rat tissue slices (brain, liver). Physiopathological implications].</strong> Laborit H,
|
|
Lamothe C, Thuret F
|
|
</p>
|
|
|
|
<p>
|
|
Am J Respir Crit Care Med. 2004 Jan 1;169(1):46-56. <strong>Hypercapnic acidosis attenuates
|
|
endotoxin-induced acute lung injury.</strong> Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF,
|
|
McLoughlin P.
|
|
</p>
|
|
<p>
|
|
<em>*Endocrinology. 1996 Apr;137(4):1505-6.
|
|
</em>
|
|
</p>
|
|
<p>
|
|
<em>[Comment on: Laidlaw, et al., Endocrinology. 1995 Jan;136(1):164-71.]</em>
|
|
<strong><em>
|
|
Experiments on proliferation of normal human breast tissue in nude mice do not show that
|
|
progesterone does not stimulate breast cells.</em></strong>
|
|
<em>
|
|
Pike MC, Ursin G, Spicer DV. Letter</em>
|
|
</p>
|
|
<p>
|
|
*Endocrinology. 1995 Jan;136(1):164-71. <strong>The proliferation of normal human breast tissue implanted
|
|
into athymic nude mice is stimulated by estrogen but not progesterone.</strong> Laidlaw IJ, Clarke RB,
|
|
Howell A, Owen AW, Potten CS, Anderson E. "We conclude that E2 is sufficient to stimulate human breast
|
|
epithelial cell proliferation at physiologically relevant concentrations and that P does not affect
|
|
proliferation either alone or after E2 priming."
|
|
</p>
|
|
|
|
<p>
|
|
Agressologie 1971;12(2):105-112. <strong>[The inhibiting effect of atmospheres oxygenated without CO2 on the
|
|
respiration of rat tissue slices (brain, liver). Physiopathological implications].</strong> Laborit H,
|
|
Lamothe C, Thuret F
|
|
</p>
|
|
<p>
|
|
Endocrinology. 1995 Jan;136(1):164-71. <strong>The proliferation of normal human breast tissue implanted
|
|
into athymic nude mice is stimulated by estrogen but not progesterone.</strong> Laidlaw IJ, Clarke RB,
|
|
Howell A, Owen AW, Potten CS, Anderson E.
|
|
</p>
|
|
<p>
|
|
Int J Cancer. 2005 Nov 20;117(4):561-8. <strong>Gene regulation profile reveals consistent anticancer
|
|
properties of progesterone in hormone-independent breast cancer cells transfected with progesterone
|
|
receptor.</strong> Leo JC, Wang SM, Guo CH, Aw SE, Zhao Y, Li JM, Hui KM, Lin VC.<strong>"Progesterone
|
|
consistently suppressed the expression of genes required for cell proliferation and metastasis and
|
|
increased the expression of many tumor-suppressor genes.</strong>"
|
|
</p>
|
|
|
|
<p>
|
|
Fertil Steril. 2003 Jan;79(1):221-2. <strong>Topical progesterone cream has an antiproliferative effect on
|
|
estrogen-stimulated endometrium.</strong> Leonetti HB, Wilson KJ, Anasti JN. Randomized Controlled Trial
|
|
</p>
|
|
<p>
|
|
Prostate. 1995 Apr;26(4):194-204. <strong>Growth inhibition of androgen-insensitive human prostate carcinoma
|
|
cells by a 19-norsteroid derivative agent, mifepristone.</strong> Lin MF, Kawachi MH, Stallcup MR,
|
|
Grunberg SM, Lin FF. "Mifepristone, also known as RU 486, is a 19-norsteroid derivative. Currently,
|
|
mifepristone is being tested in clinical trials on meningioma and breast cancer.""<strong>The results
|
|
demonstrated that while both DHT and Dex alone had essentially no effect on cell growth, progesterone
|
|
alone resulted in a 20% growth inhibition, while mifepristone had more than 60% inhibition with a 16-day
|
|
exposure. At an equal concentration, the degree of growth inhibition of PC-3 cells by mifepristone or
|
|
progesterone was partially diminished by simultaneous exposure to Dex.</strong>"
|
|
</p>
|
|
<p>
|
|
Am J Pathol. 2003 Jun;162(6):1781-7. <strong>Progesterone induces cellular differentiation in MDA-MB-231
|
|
breast cancer cells transfected with progesterone receptor complementary DNA.
|
|
</strong>Lin VC, Jin R, Tan PH, Aw SE, Woon CT, Bay BH.
|
|
</p>
|
|
|
|
<p>
|
|
Endocrinology. 2003 Dec;144(12):5650-7. <strong>Distinct molecular pathways mediate progesterone-induced
|
|
growth inhibition and focal adhesion.</strong> Lin VC, Woon CT, Aw SE, Guo C.
|
|
</p>
|
|
<p>
|
|
Int J Cancer. 2005 Nov 20;117(4):561-8.<strong>
|
|
Gene regulation profile reveals consistent anticancer properties of progesterone in hormone-independent
|
|
breast cancer cells transfected with progesterone receptor.</strong> Leo JC, Wang SM, Guo CH, Aw SE,
|
|
Zhao Y, Li JM, Hui KM, Lin VC.
|
|
</p>
|
|
<p>
|
|
Int J Biometeorol. 1987 Sep;31(3):201-10. <strong>Effects of chronic normobaric hypoxic and hypercapnic
|
|
exposure in rats: prevention of experimental chronic mountain sickness by hypercapnia.</strong> Lincoln
|
|
B, Bonkovsky HL, Ou LC.
|
|
</p>
|
|
|
|
<p>
|
|
J Steroid Biochem Mol Biol. 2000 Jun;73(3-4):171-81. <strong>Progesterone effect on cell growth,
|
|
ultrastructural aspect and estradiol receptors of normal human breast epithelial (HBE) cells in
|
|
culture.</strong> Malet C, Spritzer P, Guillaumin D, Kuttenn F. "On a culture system of normal human
|
|
breast epithelial (HBE) cells, we observed an inhibitory effect on cell growth of a long-term P treatment (7
|
|
days) in the presence or absence of E2, using two methods...." "Cells exhibited a proliferative appearance
|
|
after E2 treatment, and returned to a quiescent appearance when P was added to E2." "Moreover, the
|
|
immunocytochemical study of E2 receptors indicated that <strong>E2 increases its own receptor level whereas
|
|
P and R5020 have the opposite effect, thus limiting the stimulatory effect of E2 on cell growth.</strong
|
|
> In the HBE cell culture system and in long-term treatment, P and R5020 appear predominantly to inhibit
|
|
cell growth, both in the presence and absence of E2."
|
|
</p>
|
|
<p>
|
|
Horm Res. 1987;28(2-4):212-8.<strong>
|
|
Antiestrogen action of progesterone in breast tissue.</strong> Mauvais-Jarvis P, Kuttenn F, Gompel A.
|
|
"Most data indicate that progesterone and progestins have a strong antiestrogen effect on breast cell
|
|
appreciated by the decrease of estradiol receptor content, the decrease of cell multiplication and the
|
|
stimulation of 17 beta-hydroxysteroid activity which may be considered as a marker of breast cell
|
|
differentiation dependent of progesterone receptor."
|
|
</p>
|
|
|
|
<p>
|
|
Biochem Biophys Res Commun 1982 Jan 29;104(2):570-6. <strong>Progesterone-induced inactivation of nuclear
|
|
estrogen receptor in the hamster uterus is mediated by acid phosphatase.</strong>
|
|
MacDonald RG, Okulicz WC, Leavitt WW.
|
|
</p>
|
|
<p>
|
|
Cancer Lett. 2005 Apr 18;221(1):49-53. <strong>Effects of progesterone on ovarian tumorigenesis in
|
|
xenografted mice.
|
|
</strong>
|
|
McDonnel AC, Van Kirk EA, Isaak DD, Murdoch WJ.
|
|
</p>
|
|
<p>
|
|
Int J Cancer. 2004 Nov 1;112(2):312-8. <strong>Endogenous sex hormones and subsequent breast cancer in
|
|
premenopausal women.</strong> Micheli A, Muti P, Secreto G, Krogh V, Meneghini E, Venturelli E, Sieri S,
|
|
Pala V, Berrino F.
|
|
</p>
|
|
|
|
<p>
|
|
J Clin Endocrinol Metab 2000 Sep;85(9):3442-52. <strong>Progesterone withdrawal up-regulates vascular
|
|
endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque
|
|
endometrium: potential relevance to menstruation.</strong> Nayak NR, Critchley HO, Slayden OD, Menrad A,
|
|
Chwalisz K, Baird DT, Brenner RM.
|
|
</p>
|
|
<p>
|
|
Endocrinology 1981 Dec;109(6):2273-5. <strong>
|
|
Progesterone-induced estrogen receptor-regulatory factor in hamster uterine nuclei: preliminary
|
|
characterization in a cell-free system.</strong>
|
|
Okulicz WC, MacDonald RG, Leavitt WW<strong>
|
|
In vitro studies have demonstrated a progesterone-induced activity associated with the uterine nuclear
|
|
fraction which resulted in the loss of nuclear estrogen receptor.</strong>
|
|
</p>
|
|
<p>
|
|
Mol Endocrinol. 1991 May;5(5):709-17. <strong>Progestins induce down-regulation of insulin-like growth
|
|
factor-I (IGF-I) receptors in human breast cancer cells: potential autocrine role of IGF-II.
|
|
</strong>
|
|
|
|
Papa V, Hartmann KK, Rosenthal SM, Maddux BA, Siiteri PK, Goldfine ID.
|
|
</p>
|
|
<p>
|
|
Gynecol Endocrinol. 1999 Jun;13 Suppl 4:11-9. <strong>Biological effects of progestins in breast cancer.
|
|
</strong>Pasqualini JR, Ebert C.
|
|
</p>
|
|
<p>
|
|
Gynecol Endocrinol. 2001 Dec;15 Suppl 6:44-52. <strong>Biological effects of progestins in breast
|
|
cancer.</strong> Pasqualini JR, Ebert C, Chetrite GS.
|
|
</p>
|
|
<p>
|
|
J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):221-36. <strong>Recent insight on the control of enzymes
|
|
involved in estrogen formation and transformation in human breast cancer.</strong> Pasqualini JR,
|
|
Chetrite GS.
|
|
</p>
|
|
|
|
<p>
|
|
Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):361-8. <strong>Steroid hormone levels during pregnancy and
|
|
incidence of maternal breast cancer.</strong>
|
|
Peck JD, Hulka BS, Poole C, Savitz DA, Baird D, Richardson BE. "<strong>When estrogen-to-progesterone ratios
|
|
were evaluated, there was an indication of a modest increased incidence of breast cancer for those with
|
|
high total estrogens and high estrone levels relative to progesterone.</strong>"
|
|
</p>
|
|
<p>
|
|
Br J Urol. 1990 Mar;65(3):268-70. <strong>Erythrocyte stearic to oleic acid ratio in prostatic
|
|
carcinoma.</strong> Persad RA, Gillatt DA, Heinemann D, Habib NA, Smith PJ.
|
|
</p>
|
|
<p>
|
|
Int J Cancer. 2006 Nov 9; <strong>Inflammation and IGF-I activate the Akt pathway in breast cancer.</strong>
|
|
Prueitt RL, Boersma BJ, Howe TM, Goodman JE, Thomas DD, Ying L, Pfiester CM, Yfantis HG, Cottrell JR, Lee
|
|
DH, Remaley AT, Hofseth LJ, Wink DA, Ambs S.
|
|
</p>
|
|
|
|
<p>
|
|
Biology of reproduction 15, 153-157, 1976, <strong>Sex steroids in reproductive tract tissues: Regulation of
|
|
estradiol concentrations by progesterone</strong>. Resko JA, Boling JL, Brenner RM and Blandau RJ.
|
|
</p>
|
|
<p>
|
|
Carla Rothenberg, <strong>History of hormone therapy,</strong> http:<a
|
|
href="http://leda.law.harvard.edu/leda/data/711/Rothenberg05"
|
|
target="_blank"
|
|
>leda.law.harvard.edu/leda/data/711/Rothenberg05</a>. pdf. <strong> </strong>2005.
|
|
</p>
|
|
<p>
|
|
J Clin Endocrinol Metab 1996 Apr;81(4):1495-501. <strong>Characterization of reproductive hormonal dynamics
|
|
in the perimenopause.</strong>
|
|
<hr />
|
|
<strong>altered ovarian function in the perimenopause can be observed as early as age 43 yr and include
|
|
hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion.</strong> These
|
|
hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes
|
|
this period of life."
|
|
</p>
|
|
|
|
<p>
|
|
Cancer Res. 1984 Feb;44(2):841-4. <strong>High testosterone and low progesterone circulating levels in
|
|
premenopausal patients with hyperplasia and cancer of the breast.</strong> Secreto G, Recchione C,
|
|
Fariselli G, Di Pietro S.
|
|
</p>
|
|
<p>
|
|
Gen Comp Endocrinol. 1988 Dec;72(3):443-52. <strong>Progesterone down-regulation of nuclear estrogen
|
|
receptor: a fundamental mechanism in birds and mammals.</strong>
|
|
Selcer KW, Leavitt WW.
|
|
</p>
|
|
<p>
|
|
Clin Exp Obstet Gynecol 2000;27(1):54-6. <strong>
|
|
Hormonal reproductive status of women at menopausal transition compared to that observed in a group of
|
|
midreproductive-aged women.</strong> Sengos C, Iatrakis G, Andreakos C, Xygakis A, Papapetrou P.
|
|
"<strong>CONCLUSION: The reproductive hormonal patterns in</strong>
|
|
<strong>perimenopausal women favor a relatively hypergonadotropic hyper-estrogenic milieu.</strong>"
|
|
</p>
|
|
|
|
<p>
|
|
J Natl Cancer Inst Monogr. 1994;(16):85-90. <strong>Menstrual timing of treatment for breast cancer.
|
|
</strong>
|
|
Senie RT, Kinne DW.
|
|
</p>
|
|
<p>
|
|
J Neurosci. 2001 Aug 1;21(15):5723-9. <strong>Progesterone blockade of estrogen activation of mu-opioid
|
|
receptors regulates reproductive behavior.</strong>
|
|
Sinchak K, Micevych PE.
|
|
</p>
|
|
<p>
|
|
J Clin Pathol. 2005 Oct;58(10):1033-8. <strong>Proliferating fibroblasts at the invading tumour edge of
|
|
colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative
|
|
stress.</strong>
|
|
Sivridis E, Giatromanolaki A, Koukourakis MI.
|
|
</p>
|
|
|
|
<p>
|
|
Neuroscience. 1991;42(2):309-20. <strong>Progesterone administration attenuates excitatory amino acid
|
|
responses of cerebellar Purkinje cells.</strong> Smith SS.
|
|
</p>
|
|
<p>
|
|
Cancer Causes Control. 2004 Feb;15(1):45-53. <strong>Serum levels of sex hormones and breast cancer risk in
|
|
premenopausal women: a case-control study (USA).</strong> Sturgeon SR, Potischman N, Malone KE, Dorgan
|
|
JF, Daling J, Schairer C, Brinton LA. <strong>"For luteal progesterone, the RR for the highest versus lowest
|
|
tertile was 0.55 (0.2-1.4)."</strong>
|
|
</p>
|
|
<p>
|
|
Biomed Pharmacother 1984;38(8):371-9. <strong>Breast cancer and oral contraceptives: critique of the
|
|
proposition that high potency progestogen products confer excess risk.
|
|
</strong>Sturtevant FM A recent report by Pike et al. from the U. S. A. concluded on the basis of
|
|
epidemiologic evidence that an increased risk of breast cancer was manifested by young women who had used
|
|
combination oral contraceptives (OC) with a high "potency" of progestogen over a prolonged period. This
|
|
conclusion is criticized in the present article, centering on three cardinal defects in the Pike study: (1)
|
|
The assigned potencies of OC's are fiction and were derived from out-dated delay-of-menses data; (2)
|
|
Well-known risk factors for breast cancer were ignored; (3) The method assumed no error of recall of OC
|
|
brand, dose and duration of use occurring many years before telephone interviews. Noting that others have
|
|
not been able to confirm these findings, it is concluded that there is no scientific basis for accepting the
|
|
suggestion of Pike et al.
|
|
</p>
|
|
|
|
<p>
|
|
Cancer Res. 2004 Nov 1;64(21):7886-92. <strong>Reduction of human metastatic breast cancer cell
|
|
aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment
|
|
with progestins.</strong> Sumida T, Itahana Y, Hamakawa H, Desprez PY.
|
|
</p>
|
|
<p>
|
|
Endocr Relat Cancer 1999 Jun;6(2):307-14.<strong>
|
|
Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase
|
|
is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate
|
|
these preneoplastic changes in mammary glands.</strong> Tekmal RR, Kirma N, Gill K, Fowler K "To test
|
|
directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the
|
|
aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens
|
|
resulting from the overexpression of aromatase in mammary glands lead to the induction of various
|
|
preneoplastic and neoplastic changes that are similar to early breast cancer." "Our current studies show
|
|
aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in
|
|
female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary
|
|
glands as a result of aromatase overexpression can be completely abrogated with the administration of the
|
|
aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia,<strong>
|
|
we have also seen downregulation of estrogen receptor and a decrease in cell proliferation</strong>
|
|
markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies
|
|
demonstrate that <strong>aromatase overexpression alone, without circulating estrogen, is responsible for
|
|
the induction of breast hyperplasia and these changes can be abrogated using aromatase
|
|
inhibitors."</strong>
|
|
</p>
|
|
|
|
<p>
|
|
Ann N Y Acad Sci 1986;464:106-16. <strong>
|
|
Uptake and concentration of steroid hormones in mammary tissues.</strong>
|
|
Thijssen JH, van Landeghem AA, Poortman J "For estradiol the highest tissue levels were found in the
|
|
malignant samples<strong>. No differences were seen in these levels between pre- and postmenopausal women
|
|
despite the largely different peripheral blood levels."</strong> "Striking differences were seen between
|
|
the breast and uterine tissues for the total tissue concentration of estradiol, the ratio between estradiol
|
|
and estrone, and the subcellular distribution of both estrogens. <strong>
|
|
At similar receptor concentrations in the tissues these differences cannot easily be explained.</strong
|
|
>" "<strong>Lower concentrations of DHEAS and DHEA were observed in the malignant tissues compared with the
|
|
normal ones and the benign lesions.</strong>"
|
|
</p>
|
|
<p>
|
|
Cancer. 1983 Jun 1;51(11):2100-4. <strong>Elevated serum acute phase protein levels as predictors of
|
|
disseminated breast cancer.</strong> Thompson DK, Haddow JE, Smith DE, Ritchie RF.
|
|
</p>
|
|
|
|
<p>
|
|
Crit Care Med. 2003 Nov;31(11):2705-7. <strong>Carbon dioxide: a "waste product" with potential therapeutic
|
|
utilities in critical care.</strong>
|
|
Torbati D.
|
|
</p>
|
|
<p>
|
|
J Steroid Biochem Mol Biol 2000 Jun;73(3-4):141-5. <strong>Elevated steroid sulfatase expression in breast
|
|
cancers.</strong> Utsumi T, Yoshimura N, Takeuchi S, Maruta M, Maeda K, Harada N. In situ estrogen
|
|
synthesis makes an important contribution to the high estrogen concentration found in breast cancer tissues.
|
|
Steroid sulfatase which hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone
|
|
sulfate, and cholesterol sulfate may be involved. In the present study, we therefore, assessed steroid
|
|
sulfatase mRNA levels in breast malignancies and background tissues from 38 patients by reverse
|
|
transcription and polymerase chain reaction. The levels in breast cancer tissues were significantly
|
|
increased at 1458.4+/-2119.7 attomoles/mg RNA (mean +/- SD) as compared with 535.6+/-663.4 attomoles/mg RNA
|
|
for non-malignant tissues (P<0.001). Thus, increased steroid sulfatase expression may be partly
|
|
responsible for local overproduction of estrogen and provide a growth advantage for tumor cells.
|
|
</p>
|
|
<p>
|
|
Fed Proc. 1980 Jun;39(8):2533-8. <strong>Influence of endogenous opiates on anterior pituitary
|
|
function.</strong> Van Vugt DA, Meites J.
|
|
</p>
|
|
|
|
<p>
|
|
Clin Endocrinol (Oxf) 1978 Jul;9(1):59-66. <strong>Sex hormone concentrations in post-menopausal
|
|
women.</strong>
|
|
Vermeulen A, Verdonck L. "Plasma sex hormone concentrations (testosterone, (T), androstenedione (A),
|
|
oestrone (E1) and oestradiol (E2) were measured in forty post-menopausal women more than 4 years post-normal
|
|
menopause." <strong>"Sex hormone concentrations in this group of postmenopausal women (greater than 4YPM)
|
|
did not show any variation as a function of age,</strong> with the possible exception of E2 which showed
|
|
a tendency to decrease in the late post-menopause."
|
|
</p>
|
|
<p>
|
|
J Steroid Biochem 1984 Nov;21(5):607-12. <strong>
|
|
The endogenous concentration of estradiol and estrone in normal human postmenopausal
|
|
endometrium.</strong> Vermeulen-Meiners C, Jaszmann LJ, Haspels AA, Poortman J, Thijssen JH The
|
|
endogenous estrone (E1) and estradiol (E2) levels (pg/g tissue) were measured in 54 postmenopausal, atrophic
|
|
endometria and compared with the E1 and E2 levels in plasma (pg/ml). The results from the tissue levels of
|
|
both steroids<strong>
|
|
showed large variations and there was no significant correlation with their plasma levels. The mean E2
|
|
concentration in tissue was 420 pg/g, 50 times higher than in plasma and the E1 concentration of 270
|
|
pg/g was 9 times higher.
|
|
</strong>
|
|
|
|
The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being 0.3.
|
|
<strong>We conclude that normal postmenopausal atrophic endometria contain relatively high concentrations of
|
|
estradiol and somewhat lower estrone levels.</strong> These tissue levels do not lead to histological
|
|
effects.
|
|
</p>
|
|
<p>
|
|
J Natl Cancer Inst Monogr. 2000;(27):67-73. <strong>Endogenous estrogens as carcinogens through metabolic
|
|
activation.</strong> Yager JD.
|
|
</p>
|
|
<p>
|
|
Regul Pept. 2003 Jul 15;114(2-3):101-7. <strong>Inhibition of cytosolic phospholipase A2 mRNA expression: a
|
|
novel mechanism for acetylsalicylic acid-mediated growth inhibition and apoptosis in colon cancer
|
|
cells.</strong> Yu HG, Huang JA, Yang YN, Luo HS, Yu JP, Meier JJ, Schrader H, Bastian A, Schmidt WE,
|
|
Schmitz.
|
|
</p>
|
|
|
|
<p>
|
|
Brain Res. 1999 Aug 28;839(2):313-22. <strong>Opioid growth factor and organ development in rat and human
|
|
embryos.</strong> Zagon IS, Wu Y, McLaughlin PJ.
|
|
</p>
|
|
<p>
|
|
J Biol Chem. 2005 Apr 29;280(17):17480-7. Epub 2005 Feb 22. <strong>A novel antiestrogenic mechanism in
|
|
progesterone receptor-transfected breast cancer cells.
|
|
</strong>Zheng ZY, Bay BH, Aw SE, Lin VC.
|
|
</p>
|
|
|
|
© Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com
|
|
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