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    <head><title>Preventing and treating cancer with progesterone.</title></head>
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        <h1>
            Preventing and treating cancer with progesterone.
        </h1>

        <em>"The energy of the mind is the essence of life." Aristotle</em>
        <p></p>
        <p>
            All through the last century, as more and more resources were devoted to solving "the cancer problem," the
            death rate from cancer increased every year. Something was clearly wrong with the way the problem was being
            approached.
        </p>
        <p>
            If you grind up a computer and dissolve it in acid, you can find out exactly what substances it was made of,
            but you won't learn from that information how the computer worked. Twentieth century biologists became fond
            of emulsifying cells and studying the soluble parts. By the end of the century, they had identified so many
            parts that the government was financing projects to use supercomputers to try to understand how the parts
            interacted.
        </p>
        <p>
            If some essential information was lost in studying the parts, supercomputation isn't the way to find it.
            Even with infinite computing capacity, a description of the electrons on carbon and hydrogen atoms on amino
            acids in protein molecules won't lead to the reality of how those atoms would have functioned in the living
            state.
        </p>

        <p>
            The image of a cell as a watery solution contained in an elastic membrane bag is still having a radically
            stupefying effect on biology and medicine. The idea that a cell can be understood by using a computer to
            model a network of interactions between genes and gene products is nothing more than a technologizing of the
            primitive understanding of life that was promulgated by the Weismann-Mendel-Morganist school. It was the
            dogmatic insistence of that genetic determinist school that cancer originated with a genetic mutation.
        </p>
        <p>
            By the middle of the 20th century, that dogma had excluded the most important parts of biology from the
            schools and the journals. Ideas of a developmental field, cellular coherence, and holistic cooperativity
            were denounced as unscientific vitalism. Returning to the idea of a "cancer field" is an essential first
            step in thinking realistically about preventing and treating cancer, but that idea has hardly progressed
            since the 1930s.
        </p>
        <p>
            In the last few years, interest in cloning and stem cells and tissue regeneration has revived interest in
            studying the factors that contribute to the spatial and temporal ordering of cell growth.
        </p>
        <p>
            The idea of a developmental field was a fundamental part of embryology in the first half of the 20th
            century. It was an empirical idea, supported most commonly by evidence that diffusing substances and
            secreted materials governed the differentiation of cells and tissues, but the form-generating effects of
            bioelectric fields were also often demonstrated, and there was some evidence that tissue radiations played a
            role. The extracellular matrix secreted by cells served to transmit information between cells, but its form
            was regulated by cells, and its structure was a factor governing the cells' differentiation.
        </p>

        <p>
            Experiments in amphibians showed that regeneration of organs had a reciprocal relationship with the
            development of cancer--a tumor could be turned into a tail, for example, if it was grafted onto the stump
            following amputation of the tail, but factors that weakened regeneration could cause a tumor to develop. In
            these experiments, the normal organism's morphogenetic or epimorphic field overrode the disordered
            developmental field of the tumor.
        </p>
        <p>
            In the absence of overriding external influences, the disordered system of the tumor, in which cells emitted
            many products of their disordered metabolism, could interfere with the normal functions of the organism. All
            of the products of the injured cells, including their altered extracellular matrix, constituted the cancer
            field.
        </p>
        <p>
            The recent recognition of the "bystander effect" of radiation exposure, in which cells that haven't been
            irradiated undergo genetic changes or death when they are exposed to irradiated cells, has provided an
            opportunity to return to the "field" idea in cancer, because the stress-induced factors emitted by
            irradiated cells are the same toxic factors emitted by cells undergoing carcinogenesis from other causes,
            such as over-exposure to estrogen.
        </p>

        <p>
            H. J. Muller, one of T. H. Morgan's students and colleagues, studied the mutagenic effects of x-rays, and
            the genetic determinists argued that the random changes produced in the genetic material by ionizing
            radiation provided a model of the evolutionary process. Randomly altered genes and natural selection would
            explain everything, including cancer. Every time cells divide, their genes supposedly become more
            susceptible to random changes, so increased replication of cells would increase the risk of producing
            genetic changes leading to cancer. This idea is so simple and so widely believed that many people focus only
            on the rate of proliferation, and the random mutations that supposedly occur during proliferation, when they
            try to explain carcinogenesis. They feel that it's reasonable to discuss cancer without bothering to
            understand the physiology of the cell or the organism.
        </p>
        <p>
            The organism can only be understood in its environments, and a cell can't be understood without reference to
            the tissue and organism in which it lives. Although the geneticists were at first hostile to the idea that
            nutrition and geography could have anything to do with cancer, they soon tried to dominate those fields,
            insisting that mutagens and ethnicity would explain everything. But the evidence now makes it very clear
            that environment and nutrition affect the risk of cancer in ways that are not primarily genetic.
        </p>
        <p>
            Every tumor, like every person, has a uniqueness, but valid and practical empirical generalizations can be
            made, if we understand some of their properties and the conditions that govern their development and
            survival.
        </p>
        <p>
            Percival Potts' observation of scrotal cancer in chimney sweeps eventually led to the study of soot
            carcinogenesis, and then to the study of the properties of the polycyclic aromatic hydrocarbons in soot. The
            similarities of those properties to estrogen's soon became apparent.
        </p>

        <p>
            Over the decades, many studies have confirmed that prolonged, continuous exposure to estrogen is
            carcinogenic, and that progesterone offsets those effects.
        </p>
        <p>
            Following the animal studies that showed that carcinogenesis by estrogen could be prevented or reversed by
            progesterone, studies of the endogenous hormones in women showed that those with a natural excess of
            estrogen, and/or deficiency of progesterone, were the most likely to develop uterine or breast cancers.
        </p>
        <p>
            The Morganist school of genetic determinism moved into endocrinology with a doctrine that hormones act only
            through hormone receptors, proteins which activate certain genes.
        </p>
        <p>
            Many researchers -- physical chemists, biochemists, cytologists, embryologists, reproductive and
            developmental biologists, gerontologists, physiologists, neurologists, endocrinologists -- were
            investigating estrogen's properties and actions, and had made great progress by the 1950s, despite the
            medical frauds being perpetrated by the estrogen industry (Rothenberg, 2005).
        </p>
        <p>
            All of this complex and subtle work was of no interest to a small group of people who wanted to impose their
            genetic views onto biology.
        </p>
        <p>
            The inventor of the estrogen receptor, Elwood Jensen, has written that the results of certain of his
            experiments "caused the demise of the transhydrogenation hypothesis and convinced all but the most diehard
            enzymologists that estradiol binds to a characteristic component of target cells to exert its physiological
            effect without itself being chemically altered." The hypothesis he referred to was just part of a large
            fairly systematic international effort.
        </p>

        <p>
            How he did away with the opposition, who were studying the complex metabolic actions of estrogen, was by
            synthesizing isotope-labeled estradiol and estrone, and claiming to observe that they weren't metabolically
            altered, as they produced their hormonal effect. Since the experiment was extremely expensive, and required
            the cooperation of the Atomic Energy Commission, it wasn't easily repeated. However, many experiments have
            subsequently demonstrated that practically every tissue in the body (and plants and bacteria) metabolize the
            estrogens, causing estradiol to change into estrone, and estrone, into estradiol. Jensen's decisive and
            historically crucial experiment was false.
        </p>
        <p>
            But it served its purpose, and (with help from the pharmaceutical industry and government granting agencies)
            marginalized the work of those "enzymologists" and everyone else who persisted in studying the complex
            actions of estrogen.
        </p>
        <p>
            The enzyme that converts the weaker estrone into the stronger estradiol is an important factor in
            determining estrogen's effects on a particular tissue. Progesterone is able to regulate the cell's
            metabolism, so that the oxidative pathway, forming estrone from estradiol, predominates. Estrogen-dominated
            tissues are likely to have a balance in the direction of reduction rather than oxidation, increasing the
            amount of the active estradiol.
        </p>

        <p>
            The immediate effects of estrogen and progesterone on cells, that occur long before genes can be activated,
            were simply ignored or denied by the promoters of the estrogen receptor doctrine. Some of these excitatory
            or antiexcitatory effects are probably structural changes, that involve the mobilization of calcium inside
            cells, and the activation or inhibition of reactions involving phosphoric acid. Although they have been
            known for many years, they are always referred to as "novel" or "non-classical" effects, and are called
            "membrane effects," because that's the only way the reductionists are able to identify changes that happen
            immediately throughout the cell.
        </p>
        <p>
            Cellular excitation involves an increase of intracellular calcium and the activation of phosphorylating
            enzymes in cells. Some experiments suggest (Improta-Brears, et al., 1999) that the estrogen receptor
            mediates estrogen's ability to mobilize calcium (leading to the activation of cell division, mitosis).
            Whether or not it does, the recognition that estrogen activates calcium, leading to activation of the
            phosphorylation system, should "cause the demise of" the "classical estrogen receptor" doctrine, because the
            phosphorylation system alters the expression of genes, much as the estrogen receptor was supposed to do by
            its direct actions. <strong>But before it alters the expression of genes, it alters the activities of
                enzymes.</strong> When estrogen activates calcium and phosphorylation independently of the estrogen
            receptor, the situation is even worse for the Jensen dogma.
        </p>

        <p>
            Progesterone's opposition to those early excitatory effects of estrogen are so basic, that there shouldn't
            be any difficulty in thinking of it as an antiestrogen, that stops cell division primarily by opposing the
            excitatory effects of estrogen and other mitogens. Progesterone's opposition to the calcium-activating and
            phosphorylating effects of estrogen affects everything in the cell, according to the cell's specific nature.
        </p>
        <p>
            But the reductionists don't like "nongenomic" explanations of anything, even when they are triggered by the
            estrogen receptor rather than by a membrane-event. So, to argue that progesterone's opposition to estrogen
            is general, it's necessary to examine each of estrogen's actions, where those actions are clearly known, and
            to evaluate progesterone's effects on the same events.
        </p>

        <p>
            When a cell is stimulated or slightly stressed, homeostatic mechanisms are activated that help it to return
            to its normal resting state. The mobilization of calcium and the phosphorylation system is followed by
            increased synthesis of cholesterol and the formation of glucose from glycogen. Cholesterol itself is
            protective, and in some cells it is massively converted into progesterone, which is even more effective in
            restoring homeostasis.
        </p>
        <p>
            In the ovary, the enzymes that synthesize cholesterol, along with the production of progesterone, are
            activated by the pituitary hormone, FSH, but also by estrogen. In the liver and uterus and vascular
            endothelium, which aren't specialized for the production of progesterone, stimulation by estrogen activates
            the enzymes to increase the formation of cholesterol.
        </p>
        <p>
            When cells are injured or seriously stressed, instead of being able to directly recover their normal
            quiescence, they may instead mobilize their systems for growing and replicating, to replace damaged or
            destroyed cells.
        </p>
        <p>
            Prolonged exposure to estrogen, that can't be offset by the homeostatic factors, such as progesterone,
            typically causes cells to enter a growth phase. (But so do other excitatory processes, such as ionizing
            radiation.)
        </p>
        <p>
            One of the basic reactions to injury is to shift the cell away from oxidative metabolism to glycolytic
            metabolism, which is inefficient, but can support cell division. Chemical stains show that during cell
            division cells are in a reduced state, with abundant sulfhydryl groups including reduced glutathione and
            protein sulfhydryls. This shift in itself increases the formation of active estradiol from estrone.
        </p>

        <p>
            In the inflamed or estrogen dominated cell, enzymes such as the cyclooxidases (COX), that convert
            arachidonic acid into prostaglandins, are activated. Beta-glucuronidase and sulfatases are activated, and
            these cause intracellular estrogen to increase, by removing the water soluble sulfate and glucuronate
            portions from estrogens that had been inactivated. The detoxifying enzymes that attach those molecules to
            estrogen are inactivated in the estrogen dominated cell. The prostaglandin formed from arachidonic acid
            stimulates the formation of the enzyme aromatase or estrogen synthetase, that converts androgens into
            estrogen.
        </p>
        <p>
            Those processes, initiated by excitation or injury, increase the amount of estrogen in the cell, which
            intensifies the excitation.
        </p>
        <p>
            Progesterone opposes all of those processes, decreasing the amount of estrogen in the cell by modifying the
            activities of those five types of enzyme.
        </p>
        <p>
            Although many kinds of protein (including enzymes) bind estrogen, the protein that Jensen called "the
            estrogen receptor" is largely responsible for the ability of the uterus and breasts to retain high
            concentrations of estrogen. Various kinds of stimulation or stress (including heat and oxygen deprivation)
            cause its appearance, and estrogen itself increases the amount of the estrogen receptor in a cell. The
            estrogen receptor doesn't just "activate genes," as the Jensen dogma claimed. For example, the estrogen
            receptor directly binds and inactivates the "tumor suppressor" p53 protein, which otherwise would restrain
            the replication of damaged cells.
        </p>
        <p>
            Progesterone causes the estrogen receptor to be eliminated. (Batra; Boling and Blandau; Resko, et al.)
        </p>
        <p>
            Among the cell activating factors, other than estrogen, are proteins that are considered to be "oncogenes,"
            because of their involvement in cancer. Several of these proteins are activated by estrogen, inhibited by
            progesterone. The term "oncogene" refers to any gene that contributes to the development of cancer, but it
            is so burdened by ideology that it shouldn't be used as if it had a simple clear meaning.
        </p>

        <p>
            A variety of proteins promote cell activity and replication, under the influence of estrogen. The "composite
            transcription factor activating protein 1," AP-1 which integrates the effects of other transcription
            factors, is important in a variety of cell types, and its activity is increased by estrogen and decreased by
            progesterone.
        </p>
        <p>
            When the "progesterone receptor" <strong>lacks progesterone,</strong> it has the opposite effect of
            progesterone, and this feature has been used propagandistically, by infecting cells with a virus carrying
            the progesterone receptor protein, and then suggesting that the disturbed functions of the cell reflect a
            potential effect of progesterone. The receptor, lacking progesterone, tells the cell that it has a
            progesterone deficiency, but too many molecular endocrinologists are trying to say that the receptor protein
            is the same as the progesterone.
        </p>
        <p>
            The generality of the process of excitation/activation can be clearly seen in the effects of the
            nerve-inhibiting GABA and the nerve-exciting glutamate or NMDA. In cultured breast cancer cells, GABA
            inhibits growth, NMDA increases growth. As in the brain, progesterone supports the actions of GABA, and
            opposes those of NMDA or the excitatory amino acids, while estrogen in general promotes the effects of the
            excitatory amino acids, and opposes those of GABA.
        </p>

        <p>
            Both the excitatory amino acids and a peptide that promotes inflammation, tumor necrosis factor (TNF),
            activate the enzyme which makes estrogen, aromatase. Estrogen, by activating NF kappaB, increases the
            formation of TNF, which in itself can promote the growth and metastasis of cancer. Various antiinflammatory
            agents, including aspirin, progesterone, testosterone, saturated fats, and glycine, can inhibit the
            production of NF kappaB.
        </p>
        <p>
            An enzyme that has been thought of mainly in relation to the brain is catechol-O-methyl transferase, which
            is inhibited by estrogen (producing effects similar to cocaine), leading to brain excitation.The enzyme
            detoxifies catecholestrogen (Creveling, 2003), protecting cells from DNA damage (Lavigne, et al., 2001).
            When the activity of this enzyme is low, there is increased risk of breast cancer (Matsui, et al., 2000).
            Progesterone increases its activity (Inoue and Creveling, 1991, 1995).
        </p>
        <p>
            Another enzyme system that affects the body's reactions to stress and modifies processes of inflammation and
            growth, the monoamino-oxidases, is affected oppositely by estrogen and progesterone. Estrogen's effects are
            partly mediated by increased formation of serotonin, progesterone's, by decreasing it. Histamine is another
            promoter of inflammation that is increased by estrogen, decreased by progesterone.
        </p>
        <p>
            Estrogen's effects in the nervous system go beyond the production of cocaine-like hypomania, or chorea, or
            epilepsy, and include the activation of the basic stress hormones, increasing the formation in the
            hypothalamus of pro-opiomelanocortin (POMC), which is a precursor of ACTH to activate the adrenals, and
            endorphins ("endogenous opiates"), which stimulate growth processes. Both endorphins and ACTH can be found
            in tumors such as breast cancer. The ACTH stimulates the production of cortisol, that protects against some
            of the immediate causes of inflammation and growth, but that contributes to the loss of resistance, and
            increases estrogen synthesis.
        </p>

        <p>
            A protein called the sigma receptor, known for its role in cocaine's action, binds progesterone, and can
            inhibit the growth of cancer. Some anesthetics have similar effects on tumors, acting through this protein.
            The sigma receptor, in association with progesterone or pregnenolone, is protective against the excitatory
            amino acids.
        </p>
        <p>
            The extracellular medium changes during the development of a tumor. Irritated hypoxic cells, and
            estrogen-stimulated cells, increase their production of collagen, and the increase of collagen interferes
            with normal cell functions. Progesterone reduces the formation of collagen, and probably contributes to its
            removal.
        </p>
        <p>
            Naloxone or naltrexone, which blocks the actions of the endorphins and morphine, is being used to inhibit
            the growth of various kinds of cancer, including breast cancer and prostate cancer. Leptin (which is
            promoted by estrogen) is a hormone produced by fat cells, and it, like estrogen, activates the POMC-related
            endorphin stress system. The endorphins activate histamine, another promoter of inflammation and cell
            division.
        </p>
        <p>
            Progesterone opposes those various biochemical effects of estrogen in multiple ways, for example by
            inhibiting the ACTH stress response, by restraining cortisol's harmful actions, and by inhibiting leptin.
        </p>
        <p>
            Mediators of the radiation bystander effect include NO, TNF, COX, and prostaglandins. These are produced by
            other things that cause inflammation and injury, including estrogen.
        </p>

        <p>
            Cell division, when it is part of the body's continuous renewal and adaptation, isn't a source of mutations
            or degeneration, but when it is induced by the mediators of inflammation produced in response to injury, it
            leads to inherited changes, loss of differentiated function, and eventually to genetic instability.
        </p>
        <p>
            When cell division is so disturbed that the number of chromosomes becomes abnormal, the instability of these
            cells decreases their ability to survive, but when the causes of the inflammation persist, they will
            continue to be replaced by other abnormal cells. The toxic products of dying cells can reach a point at
            which the debris can't be removed, adding to the injury and inflammation. The damaged bystander cells spread
            their influence through a cancer field, injuring more cells.
        </p>
        <p>
            One of the "field" effects of cancer is the stimulation of new blood vessel development, angiogenesis.
            Lactic acid stimulates the formation of new blood vessels, the secretion of collagen, and tumor growth. Low
            oxygen, nitric oxide, carbon monoxide, prostaglandins and other products of tissue stress can stimulate the
            growth of new blood vessels, at the same time that they stimulate tumor growth and impair oxidative
            metabolism. Several of these agents promote each other's activity.
        </p>
        <p>
            Therapeutic thinking has been influenced by the doctrine of the mutant cell as the initiator of cancer,
            leading to the idea that only things which kill the cancer cells can cure cancer. But when the body stops
            activating the processes of inflammation and growth, normal processes of tissue repair have an opportunity
            to eliminate the tumor. Even the fibroblasts which normally secrete collagen can participate in its removal
            (Simoes, et al., 1984). Something as simple as eliminating lactate can change their functions.
        </p>

        <p>
            Although the angiogenic action of lactate has been known for several decades, some researchers believed that
            a specific anti-angiogenic peptide could be found which would stop the growth of cancer cells. The interest
            in angiogenesis tacitly acknowledges that there is a cancer field, but the faith that cancer could be cured
            only by killing the mutant cells seems to have guided the search for a single antiangiogenic substance. Such
            a substance would be toxic to normal tissues, since blood vessels are constantly being renewed.
        </p>
        <p>
            The more advanced a tumor is, the more numerous the growth-promoting factors are likely to be, and the
            weaker the body's ability becomes to control them.
        </p>
        <p>
            The search for toxic factors to kill the cancer cells is unlikely to lead to a generally effective
            treatment. Even immunological approaches that think in terms of destroying a tumor might be misconceiving
            the nature of the problem. For example, the protein called "tumor necrosis factor" (TNF) or cachectin was
            discovered as a result of Lawrence Burton's work in the 1960s. He extracted proteins from the blood that
            could shrink some tumors in mice with amazing speed. In the right setting, TNF is involved in the
            destruction of tumors, but when other factors are missing, it can make them worse. Burton was focussing on
            factors in the immune system that could destroy cancer, but he ignored the basic problem of tissue
            degeneration that produces tumors which are complex and changing.
        </p>
        <p>
            If the cancer-productive field is taken into account, all of the factors that promote and sustain that field
            should be considered during therapy.
        </p>

        <p>
            Two ubiquitous carcinogenic factors that can be manipulated without toxins are the polyunsaturated fatty
            acids (PUFA) and estrogen. These closely interact with each other, and there are many ways in which they can
            be modulated.
        </p>
        <p>
            For example, keeping cells in a well oxygenated state with thyroid hormone and carbon dioxide will shift the
            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>
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        <p>
            Obstetrics and gynecology New York 2001 vol.97 no.4 (Supplement) page S10. Topical progesterone cream has
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        </p>

        <p>
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            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>
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            NO
        </p>
        <p>
            Endocrinology 1976 Nov; 99(5): 1178-81. <strong>Unconjugated estradiol in the myometrium of
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            Batra S.
        </p>
        <p>
            J Steroid Biochem 1989 Jan;32(1A):35-9. <strong>
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        </p>
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            </strong>

            Borthwick GM, Johnson AS, Partington M, Burn J, Wilson R, Arthur HM.
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        <p>
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                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>
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        </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
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            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.
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        </p>
        <p>
            Gynecol Endocrinol. 2001 Dec;15 Suppl 6:44-52. <strong>Biological effects of progestins in breast
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        </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&lt;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>

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