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    <head>
        <title>Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion.</title>
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    <body>
        <h1>
            Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion.
        </h1>

        <strong>What is Cancer? (Johns Hopkins Univ.)</strong>
        <p></p>
        <p>
            "The <strong>
                term cancer</strong> refers to a new growth which will invade surrounding tissues, metastasize (spread
            to other organs) and may eventually lead to the patient's death if untreated.
        </p>
        <p>
            A tumor is not necessarily a cancer. The word tumor simply refers to a mass. For example, a collection of
            pus is by definition a tumor. A cancer is a particularly threatening type of tumor.
        </p>
        <p>
            <strong>neoplasm-</strong>

            An abnormal new growth of tissue that grows more rapidly than normal cells and will continue to grow if not
            treated. These growths will compete with normal cells for nutrients. This is a non-specific term that can
            refer to benign or malignant growths. A synonym for tumor.
        </p>
        <p>
            <strong>tumor-</strong>
            The more commonly used term for a neoplasm. The word tumor simply refers to a mass. This is a general term
            that can refer to benign or malignant growths.
        </p>
        <p>
            <strong>benign tumor-</strong> A non-malignant/non-cancerous tumor. A benign tumor is usually localized,
            rarely spreads to other parts of the body and responds well to treatment. However, if left untreated, benign
            tumors can lead to serious disease.
        </p>
        <p>
            <strong>malignant tumor-</strong> Cancer. A malignant tumor is resistant to treatment, may spread to other
            parts of the body and often recurs after removal.
        </p>

        <p>
            <strong>cancer-</strong>
            A malignant tumor (a malignant neoplasm)."
        </p>
        <p>
            <a href="http://pathology2.jhu.edu/pancreas/pc_overview.cfm" target="_blank"><u
                >http://pathology2.jhu.edu/pancreas/pc_overview.cfm</u></a>
        </p>

        <p>
            Issues that at first seem scientific too often turn out to be merely propagandistic.<strong> </strong>

            When a claim has no scientific value, it's necessary to directly attack that claim, but the propagandist
            hopes to (and often does) control the discourse, by resorting to techniques such as censorship, public
            relations, and financial-political power. The pharmaceutical industry uses all of those anti-scientific
            powers just as effectively as the military-industrial lobby does.
        </p>
        <p>
            While Donald Rumsfeld answered the question, "where are the weapons of mass destruction?" by saying "We know
            where they are. They're in the area around Tikrit and Baghdad and east, west, south and north somewhat," the
            estrogen industry responds to the evidence that estrogen causes breast cancer, strokes, heart attacks, blood
            clots and Alzheimer's disease by saying "it's progesterone that is responsible."
        </p>
        <p>
            To deal with the antiscientific fraudulent claims of the estrogen industry, it isn't necessary to search
            every square meter of Iraq, as it was with Rumsfeld's claim; it's enough to show that there is no science
            involved in their claims, by analyzing their experimental methods. But it's also important to examine some
            of the methods they have used to further their goals, despite the absence of any factual basis.
        </p>

        <p>
            For more than 60 years, the estrogen industry has been using the techniques of public relations, including
            the placement of pseudoscientific articles in medical journals, to promote their sales. Recently, Carla
            Rothenberg documented a conspiracy of the estrogen industry in the 1940s to get medical and governmental
            approval of their products by shifting attention away from the clear evidence of estrogen's toxicity. Her
            paper competently reviews the subsequent history of "Hormone Replacement Therapy."
            <a href="http://leda.law.harvard.edu/leda/data/711/Rothenberg05.pdf" target="_blank"><u
                >http://leda.law.harvard.edu/leda/data/711/Rothenberg05.pdf</u></a>
        </p>

        <p>
            After 2002 when the Women's Health Initiative study announced some of the harmful effects of hormone
            treatment, resulting in a disastrous decrease in estrogen sales, the industry has intensified and
            diversified its public relations efforts, and has succeeded in recovering some of their lost market.
            Historically, whenever some of the claimed benefits of estrogen have been disproved, the industry shifts its
            emphasis to new, previously unmentioned "virtues" of the product. Hundreds of different benefits claimed for
            estrogen in prestigious medical journals have been proven false, but until 2002, the industry's profits grew
            steadily. Now, compensating for the annual loss of billions of dollars, they are highly motivated.
        </p>
        <p>
            Dozens of toxic effects of estrogen were demonstrated and never refuted, but a variety of techniques of
            distraction and misdirection gradually emerged, to prevent the accumulated evidence of estrogen's toxicity
            (and/or ineffectiveness) from interfering with the campaigns to market it for the widest possible variety of
            conditions.
        </p>
        <p>
            Since the WHI study involved the use of Prempro (PREMPRO<sup>TM</sup>--conjugated estrogens and
            medroxyprogesterone acetate), the emphasis of the industry has been to divert attention from the toxic
            effects of estrogen, by blaming everything on "progesterone." An intense campaign is underway to assign all
            of estrogen's harmful effects to progesterone.
        </p>

        <p>
            The pharmaceutical industry has a long history of lying about natural progesterone (and many other natural
            substances), to promote sales of their competing products. The price ratio of retail estrogen tablets to
            bulk estrogen can be 1000 to 1, while the ratio for progesterone products is often less than 10 to 1. With
            the increased use of progesterone (its sales in the US have increased more than 100-fold), the estrogen
            industry has had to develop new kinds of attack. A small shift of the market away from estrogen costs the
            drug industry hundreds of millions of dollars. The loss of estrogen sales following the 2002 WHI study, that
            convincingly demonstrated its toxicity, was huge, with the decreased sales of Wyeth alone amounting to
            billions of dollars. Wyeth has petitioned the FDA to prevent compounding pharmacies from selling the natural
            hormones.
        </p>
        <p>
            People who have made a career of research that, according to them, reveals the "benefits" of estrogen have,
            in recent years, expanded their work to argue that it is progesterone, rather than estrogen, that causes
            diabetes, heart disease, dementia, and cancer.
        </p>
        <p>
            The EPA currently has a document draft on the internet which, in relation to the evaluation of a
            carcinogenic herbicide, reviews the issue of the balance between estrogen and progesterone in the
            development of cancer in rats, and includes the observation that progesterone is not carcinogenic to
            rats,<strong>
                and that it instead is protective against cancer, because of its antiestrogenic effects.</strong>
        </p>
        <p>
            Recently, stores in California have placed warnings near their progesterone-containing cosmetics, saying
            that the State of California "knows" progesterone to be a carcinogen.
        </p>

        <p>
            Californians often talk about their state's having the world's sixth largest economy. The state accounts for
            14% of the GDP of the U.S. If the state regulates a product made in Michigan, Texas, or France, the producer
            is very likely to change the product to suit California.
        </p>
        <p>
            If an industry wants to control its competitors or potential competitors, an investment in California's
            regulatory system can pay huge rewards.
        </p>
        <p>
            California has listed progesterone as a carcinogen under the Safe Drinking Water and Toxic Enforcement Act,
            called Proposition 65. The law doesn't prevent the sale of carcinogens, it simply requires a warning.
            Warnings are posted in grocery stores and restaurants, on sports equipment, in beauty parlors, on apartments
            and parking lots, but there is so little effort spent on realistic evaluation of risks that the effect of
            the law is to allow the major polluters to go unnoticed among the ubiquitous warnings. But California has
            other laws that encourage its lawyers to sue for "unfair business practices" when they believe Prop 65 has
            been violated. That has resulted in a culture of vigilantism with bounty-hunting lawyers, some of whom try
            to enforce Prop 65 even against companies that are clearly exempt.
        </p>
        <p>
            California's regulatory board that lists progesterone as a carcinogen cites two bodies that have evaluated
            carcinogens, the US National Toxicology Program (NTP), and the UN's International Agency for Research on
            Cancer (IARC), as authoritative sources.<strong> </strong>One of those, the US National Toxicology Program
            (NTP) cites<strong> </strong>the other's, the<strong> </strong>

            IARC's, evaluation of progesterone as the basis for its own listing of progesterone, so the opinion of IARC
            has been very influential.
        </p>
        <p>
            The IARC publications discussed the toxicity of several of the synthetic progestins, and concluded that some
            of them are possible human carcinogens. The (1987) entry for medroxyprogesterone acetate, for example, has
            three sections: "A. Evidence for carcinogenicity to humans (inadequate)," "B. Evidence for carcinogenicity
            to animals (sufficient)," and C., that it can damage chromosomes<strong>. </strong>
            Eight citations, besides two IARC monographs (1974 and 1979), are given as supporting evidence.
        </p>
        <p>
            The entry for progesterone, oddly, has only two sections,<strong> "</strong>A. Evidence for carcinogenicity
            to animals (sufficient)<strong>," </strong>

            and B, that it doesn't damage chromosomes. <strong>There is no mention of human carcinogenicity at all.
            </strong>Besides the IARC monographs, only one study is mentioned, a test in beagles (I'll comment on the
            competency of that study below). At the end of the whole section, which included eleven synthetics and
            progesterone, it concludes: "Overall evaluation" "<strong>Progestins are possibly</strong> carcinogenic to
            humans (Group 2B)," oddly <strong>neglecting to distinguish progesterone from the synthetics. </strong>
        </p>
        <p>
            The corruption of the term "progestin" or "progestogen" by the industry and the drug regulators has been
            terribly consequential. The synthetic chemicals classified as progestins often have <strong><em
                >anti-progesterone</em></strong>
            actions, and shouldn't be called progestins at all, because they don't support gestation, contrary to what
            the term falsely implies. It is exactly their anti-progesterone/antigestational action that led to their use
            as contraceptives.
        </p>
        <p>
            Since the 1987 review by IARC, it seems that their only other review of progesterone's carcinogenicity was
            of a single study in 1999, and that study clearly gave evidence that progesterone prevented cancer.
        </p>
        <p>
            But California's board of "qualified experts" in the Office of Environmental Health Hazard Assessment
            (OEHHA) identify <strong>progesterone</strong>

            as known to cause cancer, and cites the group of studies listed by IARC in the medroxyprogesterone acetate
            report as their evidence. Rather than trying to clarify the confusions that exist in the IARC documents,
            this board has compounded the confusion.
        </p>
        <p>
            In the transcript of the meeting, at which they decided to list progesterone as a carcinogen, they received
            testimony from only one outside expert, Richard Edgren, who answered the chairman's question, why don't you
            want progesterone listed, by saying, because it isn't a carcinogen. He said that the inclusion of a large
            number of non-carcinogenic materials "could vitiate the use of the list."
        </p>
        <p>
            But the chairman had, early in Edgren's review of the shortcomings of animal studies of carcinogenesis,
            heard the word "metastasis," in connection with beagle dogs, and--although Edgren hadn't said that any
            metastatic cancer had been found in the progesterone test (it hadn't)--the committee's decision to list
            progesterone appears to have hinged on that word.
        </p>

        <p>
            Edgren, referring to "<strong>various</strong>
            <strong>synthetic and semi-synthetic progestogens</strong>," said that administering them by injection
            "leads to the development of mammary nodules, some of which have the characteristics of malignant tumors,
            although these tumors rarely metastasize." A little later, Kilgore said "I mean, I heard you say that it was
            rare that it metastasized. I would say any kind of metastasizing is important." Edgren isn't quoted in the
            transcript as having attempted to explain that the malignant and metastatic cancers appeared only in beagles
            treated with synthetic progestins. At best, the behavior of the chairman and the committee, as reflected in
            that transcript, was erratic and confused, or more accurately, irrational.
        </p>
        <p>
            The only biologist on the committee who spoke during the meeting, Dr. Spangler, expressed confusion and
            dissatisfaction with the evidence:
        </p>

        <p>
            ". . . in reviewing the information that was supplied to me regarding progesterone, I was confused and
            concerned by what appears to be a variety of discrepancies in the way the compound has been reviewed." "In
            one place, IARC says there is limited evidence; in another place, it says there is sufficient evidence. And
            NTP says there is sufficient evidence. And they cite as their sufficient evidence a variety of very
            convoluted experimental procedures, in which mouse mammary tumor virus positive mice were used in a study;
            and, in addition to that, some other carcinogen, some other potent carcinogen, was applied at the same time
            or after." "It was just very confusing. And I had a lot difficulty evaluating it."
        </p>
        <p>
            The State's rules explicitly state that <strong>all the relevant evidence</strong>
            is to be presented to the committee for consideration, and that the evidence must show clearly, <strong>by
                accepted scientific methods,</strong> that <strong>
                a material causes cancer (i.e., malignant tumors)</strong> before it can be listed. What is clearly
            shown by the few papers provided to the committee is that their procedures were not followed at all.
            Providing publications that didn't even claim to have involved the development of cancer, and ignoring an
            immense amount of more relevant evidence, the committee, in a parody of legal process, didn't even get a
            randomly selected sampling of the relevant evidence.
        </p>
        <p>
            In my correspondence with OEHHA, when I pressed for information regarding the criteria for selecting
            evidence, and the qualifications of the staff who had the responsibility of selecting "all relevant
            evidence," their response was that they lacked the resources to answer the question.
        </p>
        <p>
            Edgren, who had argued that progesterone wasn't a carcinogen, didn't make a very good presentation of the
            case against the few studies that had been mentioned by NTP and IARC. Even if he had been able to do that,
            in the few minutes he had (six or seven different substances were on the agenda for consideration for
            listing during that meeting), it doesn't seem likely that the committee would have been interested.
        </p>

        <p>
            In a letter he wrote to the committee before it met, Edgren said <strong>"Careful evaluation of data from a
                properly conducted oral study is a prerequisite before the carcinogenicity of any chemical can be
                adequately evaluated."</strong>
            The reason for that statement is that it had become clear in the 1970s and 1980s that the invasive
            introduction of anything into the body's tissues creates inflammation and a complex series of systemic
            stress reactions that affect the immune system, and that can lead to the development or promotion of cancer,
            no matter how inert and innocuous seeming the injected material might be. The people on the committee didn't
            even discuss that issue. Worse, the studies mentioned by IARC included some that hadn't met basic scientific
            standards of experimental design, failing to use proper experimental controls, including vehicle controls,
            and failing to describe the actual composition of the vehicle or solvent used for administering
            progesterone.
        </p>
        <p>
            Every good high school science teacher or science student knows that the experimental variables have to be
            clearly defined. The United Nations' IARC, the US's NTP, and California's Panel of Qualified Experts chose
            to draw conclusions on some studies that don't meet any standards for testing carcinogens, such as those
            published by the US government. And while disregarding basic standards of experimental design, their review
            of the literature had an even more serious flaw--it "cherry-picked" the published evidence that they
            apparently preferred, ignoring the studies which, over a period of more than 20 years, showed that
            progesterone prevents and/or cures tumors. And in an extremely unrepresentative selection of studies on the
            subject of progesterone's carcinogenicity, the selected studies presented some clear evidence of some of
            progesterone's anticarcinogenic effects, along with some results that can't be interpreted clearly.
        </p>
        <p>
            One of the early papers listed as evidence of progesterone's carcinogenicity in animals actually concluded
            that their experiments completely failed "to produce any beneficial effect by the administration of
            progesterone on the mammary cancer in mice," and cautioned that their results showed "the need for care in
            attempting to generalize results even in different strains of the same species and emphasizes the difficulty
            of attempting to carry over results obtained in experimental animals to human pathology." (Burrows and Hoch-
            Ligeti, 1946).
        </p>
        <p>
            The work (demonstrations of the anti-tumor effect of progesterone) that they were not able to confirm had
            included explicit observations that <strong>
                intermittent injections</strong> of progesterone were not effective in preventing tumors or causing them
            to regress, and emphasized the importance of continuous exposure. Knowing that, the Burrows and Hoch-Ligeti
            publication appears to have been designed propagandistically to oppose the work that was demonstrating the
            anti-tumor actions of progesterone, since they--without explanation--used the already discredited method of
            giving periodic injections of progesterone dissolved in peanut oil.
        </p>
        <p>
            Without reading the article, people seeing it included on the agencies' list of studies supposedly providing
            evidence of progesterone's carcinogenicity would assume that it provided such evidence. It didn't. If the
            agencies cite this study, why didn't they mention any of the numerous studies showing that progesterone
            prevents tumors or causes them to regress? The reason this study was done was to argue against the studies
            that had demonstrated progesterone's protective effects, so anyone reading it had to know of those other
            studies' existence, as well as knowing that this study itself provided no evidence at all of
            carcinogenicity.<em> </em>
        </p>
        <p>
            Reproducibility is the essence of science, and the anti-tumor effects of progesterone were repeatedly
            demonstrated by different investigators. The single study by Burrows and Hoch-Ligetti has never been
            replicated, and the reason for its failure to show an anti-tumor effect was already explained by the other
            workers.
        </p>

        <p>
            Since the 1920s, many studies had demonstrated that "spontaneous" cancers increase in proportion to the
            quantity of polyunsaturated fat (especially linoleic acid) in the diet. By the end of the 1960s, the
            carcinogenicity of vegetable oils, or at least their "co-carcinogenicity" or "tumor promoting" effects had
            become widely known, and one of the World Health Organization publications observed that progesterone
            carcinogenicity studies using vegetable oil as the vehicle couldn't be recognized as valid.
        </p>
        <p>
            More recently, ethanol has been found to antagonize progesterone's anticancer and anti-proliferative
            actions.
        </p>

        <p>
            Studies using implanted pellets or plastic tubes containing a solution of progesterone sometimes neglected
            to even mention the nature of the solvent used. Since implanted pieces of inert materials, such as disks of
            plastic, could be carcinogenic, it was recognized that a proper control for a hormone-containing pellet or
            tube would require the implantation of a pellet or tube without the hormone. Sometimes, instead of actually
            implanting the object, sham surgery, similar to that involved in implantation of the pellet, would be used,
            in recognition that the surgical trauma itself could have far reaching effects on the organism.
        </p>
        <p>
            Any tissue damage or irritation causes the release of cytokines and mediators of inflammation, which are
            known to be involved in tissue growth and cancer. When injected, even plain water and other normally
            harmless things are carcinogenic.
        </p>
        <p>
            The need for proper experimental controls when using implanted devices is shown by a study that analyzed the
            fibrotic tumors that had grown around implanted plastic tubes. Crystals of talc were found in the tumor,
            that were assumed to have originated from the surgical gloves used during the operation. Talc is now widely
            recognized as a carcinogen, and is suspected of causing ovarian cancer.
        </p>
        <p>
            Overlooked variables are the reason for the essentiality of repeatability and confirmation in science.
        </p>
        <p>
            In the 1970s, a new method for suspending or dissolving oily chemicals in water was being explored. A cyclic
            carbohydrate, cyclodextrin, makes it possible to wet substances that are insoluble in water, such as
            progesterone, even if the substance remains in a solid crystalline form. Several companies were promoting
            the use of these for the administration of hydrophobic drugs.
        </p>
        <p>
            In 1976, D.W. Frank reported that the cyclodextrins produced nephrosis in rats. In 1978, a study by Perrin,
            et al., reported its toxicity to the kidneys. Twenty years later, Horsky and Pitha at NIH reported that the
            cyclodextrins can synergize with carcinogens, and in 1982 a group in Japan reported that cyclodextrins can
            increase the production of kidney cancers by another carcinogen (Hiasa, et al.). The intrinsic
            carcinogenicity of a more water soluble cyclodextrin, that was considered "more toxicologically benign," was
            found to cause pathological changes in lungs, liver, and kidney, and to increase the formation of tumors in
            the pancreas and intestines of rats (Gould and Scott, 2005).
        </p>
        <p>
            In 1974, D. W. Frank and others at Upjohn had begun testing the effects of progesterone and
            medroxyprogesterone acetate in beagle dogs, using an "aqueous suspension." Their 1979 publication describing
            that four year study didn't mention the way in which the "aqueous solution" had been made, and didn't
            mention cyclodextrins at all. Frank's published observation during the beagle study that cyclodextrins are
            toxic to the kidneys suggests that someone at Upjohn had noticed a problem with the "wetting agent" that was
            already in use in the beagle study.
        </p>

        <p>
            Another remarkable feature of the four year beagle study was that, of 140 dogs that began the intended 7
            year study, 28 had died by the time they published the report, and none died of cancer, but the causes of
            death were not reported. The only experimental group in which there were no deaths by the end of four years
            was the low dose progesterone group. The dogs in the high dose progesterone group received weekly
            intramuscular injections of 1140 mg of progesterone suspended in 11.4 ml of "aqueous vehicle." 2345 ml of
            the vehicle was received by each dog during the four years. Only four dogs in that group were still alive at
            the time of publication, but the cause of death of the other 16 wasn't mentioned. Quarts of a toxic material
            that had never before been used in this way, injected into their muscles, and the unexplained deaths of so
            many animals, make this a unique experiment that is unlikely ever to be repeated.
        </p>
        <p>
            Their failure to mention injection-site muscle damage is just another indication of the study's low quality.
        </p>
        <p>
            At the time of the study, it had been known for many years that interference with the organism's detoxifying
            systems, especially the liver and kidneys, can contribute to the development of cancer. Although the study
            was planned to continue for 7 years to meet the FDA requirement, <strong>none of the eight authors ever
                published again on a related topic</strong>, and most of them <strong>didn't publish again at all.
            </strong>
        </p>

        <p>
            When I tried to contact one of the authors, he didn't respond. I assume they were embarrassed by the
            shoddiness of their methods. Richard Edgren has commented, "I can't believe how fast and how completely they
            shut down. They fired people and retrained the rest for other areas."
        </p>
        <p>
            But the regulatory agencies have tied their reputations to studies of that sort.
        </p>
        <p>
            No malignant cancers were reported in this four-year beagle study. Beagles normally have a high incidence of
            cancer, especially mammary cancer. In a different study in which 172 beagles were treated with contraceptive
            hormones, nine of them developed malignant cancers, and of those, five metastasized. (This might be why the
            chairman of the committee was thinking about metastatic cancer, but if so, he was simply confused, because
            the issue they were considering was the listing of natural progesterone, which wasn't reported to have
            produced any malignant or metastatic tumors.)
        </p>
        <p>
            Two other studies cited by the IARC and other agencies, by Jones and Bern, 1977, and Rebout and Pageaut,
            hardly seem appropriate studies to support the idea that progesterone is carcinogenic.
        </p>

        <p>
            Jones' and Bern's paper described the production, 12 months after neonatal treatment with progesterone, of
            vaginal and cervical lesions, and mammary nodules, which are also referred to as tumors. "Progesterone alone
            induced cervical lesions in only 1 of 32 mice...and induced vaginal lesions in only 2 or 32 mice.
            Furthermore, progesterone given with either dose of estrogen to intact mice reduced the incidence of
            hyperplastic lesions, compared with intact groups treated with estrogen alone." They commented (page 74)
            that their results were "mammary tumor virus dependent," and that this might account for the production of
            "hyperplastic alveolar nodules as opposed to" tumors of possible ductal origin, that had been seen in other
            studies when the carcinogen DMBA was used.
        </p>
        <p>
            In another 1977 publication, Jones, Bern, and Wong described changes seen when the mice were 1.5 to 2 years
            old. This later publication appears to clarify the meaning of nodules or tumors in the younger animals:
            <strong>
                "Although mammary tumors were observed neither in control nor in progesterone-treated intact mice, many
                of the latter group possessed hyperplastic alveolar-like mammary nodules and other dysplasias."</strong>
            Neither of these studies refers to the carcinogenicity of progesterone.
        </p>
        <p>
            The 1977 study (at the University of California, Berkeley) was explicitly motivated by Jones' and Bern's
            concern with the risks of the medical practice of treating pregnant women with DES and a synthetic
            progestin, and they used mammary tumor virus-bearing mice, and they didn't continue the study to observe the
            incidence of actual cancers. (Their choice of infant rodents to study progesterone might be questioned,
            because of earlier work showing that <strong>immature rat ovaries are able to convert progesterone to
                estrogens,</strong> unlike the tissues of other animals or humans: Quattropani and Weisz, 1973; Weniger,
            et al., 1984, later reported similar results.)
        </p>
        <p>
            Anyone working with mammary tumor virus-bearing mice in the 1970s should have been aware of the effects of
            sex hormones on the expression of virus and development of cancer in the infected mice, as studied by
            Strong, Figge, and others for about 40 years. Excess estrogen causes the virus to be expressed, progesterone
            opposes its expression.
        </p>

        <p>
            Jones and Bern injected the newborn mice with 0.02 ml of sesame oil daily for five days, with or without
            estrogen and progesterone. A newborn mouse weighs a little over a gram. On a weight and volume basis, this
            would be like injecting an adult human with more than a quart of sesame oil daily for five days. The
            proportionate weight of progesterone in an adult human would be several grams per day.
        </p>
        <p>
            This amount of progesterone is far more than the anesthetic dose. Since the authors didn't mention
            anesthesia, very little of the progesterone could have been absorbed, meaning that deposits of crystals
            would have remained in their tissues.
        </p>
        <p>
            Tissue irritation from foreign bodies and from vegetable oil, even in relatively small amounts, can produce
            severe systemic reactions, because of the reactive production of nitric oxide, prostanoids, and a great
            variety of pro-inflammatory and tumor-promoting cytokines.
        </p>
        <p>
            This study might have had the formal appearance of a scientific experiment, but the unfamiliarity of the men
            with the material they were using, their use of mice carrying the mammary tumor virus, and, more
            importantly, the extremely complex reactions produced when extraneous materials are injected into the
            tissues, make this a useless experiment. The value of Richard Edgren's statement about the need to test
            carcinogens orally, rather than by injection, is becoming clearer all the time, as the role of irritation in
            cancer development is being better understood.
        </p>
        <p>
            In their second 1977 study, Jones, Bern and Wong reported that at the age of 1.5 to 2 years, nearly two
            thirds of the progesterone treated mice had genital tract lesions. In another study published in 1977
            (Iguchi and Takasugi) neonatal mice were given the same daily amount of progesterone, but for ten days
            rather than five, <strong>giving them twice the dose. These authors reported that there were no permanent
                changes in the vaginal and uterine epithelium. This study wasn't mentioned by any of the agencies, but
                it calls the results of the California study into question.</strong>
        </p>

        <p>
            In a 1973 study by Rebout and Pageaut, progesterone was administered in a pellet, <strong>the composition of
                which was not mentioned, and there was no vehicle control at all.</strong> Each mouse received 45 mg of
            progesterone. The average mouse weighs about 30 grams. Invasive squamous carcinomas were produced by the
            carcinogen 20-methylcholanthrene, and these were more numerous in the progesterone treated mice.
            Methylcholanthrene is an extremely hydrophobic, highly irritating hydrocarbon which has often been used to
            create experimental cancers. The method of administering the carcinogen isn't clearly described: "Local
            exposure of carcinogen ... in the cervical canal for 9 weeks ... induced one invasive carcinoma in the
            vagina-exocervix and five in the endocervix." It was introduced into the cervical canal, but in what form
            and how often isn't described. Methylcholanthrene has some estrogenic properties.
        </p>
        <p>
            Estrogen increases the production of mucus in the cervix and vagina, and increases its water content and
            mobility. Abundant and fluid mucus has a cleaning action, eliminating bacteria and other material.
            Progesterone makes the mucus more viscous and less hydrophilic, and when it dominates the reproductive
            physiology, it effectively creates a plug in the cervix that prevents the entry of sperms.
        </p>
        <p>
            The choice of the cervix and vagina suggests that the authors were "engineering" the experimental outcome,
            because the effect of progesterone on cervical mucus is very well known. To apply the irritant to an area
            where it would normally be washed away by the mucus, but where it is kept in place by hormonally altering
            the mucus, is really a way of manipulating how much exposure to the irritating chemical the tissue will
            receive. It's analogous to studying the "toxicity" of an antihistamine, by applying a toxin to the nasal
            membrane of a person with a cold, and then administering the antihistamine to stop the flow of mucus,
            allowing the membrane to fully absorb the applied dose of toxin.
        </p>
        <p>
            A different chemical carcinogen, 7,12-dimethylbenz(a)anthracene was used in another 1973 study (Jabara, et
            al.), in combination with progesterone. In this experiment, the carcinogen was administered to rats in one
            dose by stomach tube, dissolved in corn oil. The progesterone was injected subcutaneously in 3 mg doses in
            corn oil three times per week. Unfortunately, there was no control group in which the corn oil was injected
            alone.
        </p>
        <p>
            The progesterone was supposedly dissolved in the corn oil, one tenth ml per dose. That amount of
            progesterone (3% weight/volume) will dissolve in hot corn oil, but as the oil cools, the progesterone
            crystallizes and precipitates. That creates doubt regarding what the animals were actually receiving.
        </p>
        <p>
            Corn oil is one of the most effective vegetable oil tumor promoters/carcinogens, and it's now considered
            improper to use it as a solvent for testing even oral carcinogens, since some chemicals that are
            carcinogenic in the oil are relatively harmless when administered without the corn oil. The animals got 2 ml
            of corn oil in the stomach feeding with the carcinogen. One of the groups (group 5) received, in addition,
            more than 6 ml of corn oil in the injections. The experiment lasted only 135 days, and in the group that
            received only the carcinogen, the mortality was only 5%, and that death occurred shortly after the
            carcinogen was administered. All of the groups receiving the corn oil and progesterone injections had higher
            mortality, two with 25%, one with 37.5% mortality. Despite the <strong>unexplained general problem with
                prematurely dying rats,</strong>

            the authors found that "The relative incidence rates indicated that <strong>pretreatment with progesterone
                inhibited tumorigenesis,</strong>
            except in the group (5) in which progesterone treatment was continued for the duration of the experiment."
            Without progesterone, it is almost certain that the additional corn oil injected would have <strong><em>
                    increased</em></strong> tumorigenesis in all experimental groups.
        </p>
        <p>
            Without that vehicle control group, the experiment can just as well be described as a test of corn oil,
            rather than of progesterone. If you claim to be testing the capacity of a substance to promote tumors, it
            shouldn't be administered in a standard tumor promoter.
        </p>
        <p>
            A 1968 publication by Glucksmann and Cherry was included in the documents offered as evidence of
            progesterone's carcinogenicity. Unfortunately, they neglected to identify the vehicle used for giving twice
            weekly intramuscular injections of 1 mg of progesterone, and they didn't have a vehicle control for the
            progesterone injections. At that time, the most common vehicle was a mixture of 9% benzyl alcohol and oil,
            usually sesame or peanut oil. Benzyl alcohol by itself is quite toxic, and was responsible for the death or
            brain damage of thousands of babies in hospitals, even in the small amounts that remained as residue in
            tubing after they had been rinsed with "bacteriostatic water," which contains 0.9% benzyl alcohol, and which
            is still used as the vehicle for many injections, such as penicillin and vitamin B12. The antitoxic (or
            "catatoxic") action of progesterone greatly reduces the toxicity of benzyl alcohol.
        </p>

        <p>
            In discussing the effects of hormones on the induction of sarcomas, Glucksmann and Cherry comment that "The
            rate of induction of sarcomas in intact rats was slowed down slightly by treatment with progesterone and not
            significantly increased in spayed animals...."
        </p>
        <p>
            In their Discussion section, they mention several previous studies in relation to their own results, and
            comment, regarding other studies, that "The effect of progesterone on the type of induced cervical cancer in
            mice consists in increasing the columnar component of mixed carcinomas in castrates <strong>. . .</strong>
            without materially affecting the induction period and tumour yield. Thus the experimental evidence in rats
            and mice<strong>
                is not as clearly antitumorigenic</strong> as that of Lipschutz (1950) for guinea pigs and the clinical
            observations (Ulfelder, 1962; Jolles, 1962)."
        </p>
        <p>
            Comparing this study to that of Burrows and Hoch-Ligetti, the dose of 2 mg per week per rat is lower, on a
            body-weight basis, than the earlier study's dose of 1 mg per week in mice, but the greater frequency came a
            little closer to the continuous treatment that Lipschutz said was necessary. This could account for the fact
            that some of their results were intermediate between those of the Lipschutz group and those of Burrows and
            Hoch-Ligetti.
        </p>

        <p>
            In Glucksmann's and Cherry's results, progesterone retarded one type of tumor and appeared to promote
            another (an epithelial tumor, which wasn't described as malignant or cancerous), but if the progesterone was
            dissolved in a tumor promoting solvent, it's impossible to ascribe the effect to progesterone. Vegetable oil
            applied to epithelium that has been exposed to a carcinogen such as the DMBA they used will typically
            increase the growth of the tumors. Without information about the vehicle, it's impossible to interpret that
            part of their results clearly, but anyway, they didn't describe any carcinogenic effect of progesterone;
            they did, however, describe a clearly <strong>anticarcinogenic</strong> action.
        </p>
        <p>
            A 1962 study, by Capel-Edwards, et al., was intended to compare the effects of prolonged administration of
            high doses of progesterone with the known toxic effects of synthetic progestagens. They didn't find any
            malignant tumors, so the study can't be taken as evidence of the carcinogenicity of progesterone. The
            vehicle used for dissolving the progesterone consisted of benzyl alcohol, ethanol, and ethyl oleate. Some of
            the solutions contained more than 10% progesterone. When this sort of solution interacts with water in the
            tissues, it causes the progesterone to crystallize out of solution. The authors reported that "subcutaneous
            tissue reactions developed at injection sites," and that these "occurred in all animals, including controls,
            and were apparent for several days after the injection." These injection-site lesions sometimes developed
            into "sterile abscesses which eventually ulcerated and healed." The only dog that died during the study was
            in the control group, and although there were "a number of pathologic findings," the exact nature of that
            dog's sickness couldn't be determined. The injections were given daily, for <strong>a total of 518
                injections in each animal,</strong>
            and each injection contained as much as 4 ml of the vehicle. Almost an ounce per week of this material,
            combined with the massive irritation produced by crystallization at hundreds of injection sites, would be
            the most likely explanation for the various inflammatory changes they saw, including osmotic fragility of
            red blood cells, and as much as a 50% enlargement of liver and kidneys.
        </p>
        <p>
            Although some of the basic ideas about canine physiology that were held when the Capel-Edwards study was
            designed have been found to be mistaken, and the toxicity of their vehicle can now be seen, and they didn't
            conclude that progesterone was carcinogenic, their study wasn't the worst of those that have been presented
            as evidence of progesterone's carcinogenicity.
        </p>
        <p>
            When an experimenter doesn't yet have a clear hypothesis, it's reasonable to do some exploratory tests, just
            to get an orientation to the possibilities so that it's possible to form a well defined hypothesis, before
            designing an experiment that will test the hypothesis. Sometimes an experimenter and journal editors will
            allow a merely exploratory experiment to be published. If they don't draw inappropriate conclusions from the
            ambiguous results, the publication can be justified, simply because it might stimulate others to investigate
            the subject more thoroughly.
        </p>

        <p>
            But often editors allow the author to draw conclusions from the experiment that are not directly implied by
            the data, especially when those conclusions support the editor's prejudices. A conclusion may be consistent
            with, though not implied by, the results of the experiment. These publications may be effective propaganda,
            but they aren't good science.
        </p>
        <p>
            But California's OEHHA identifies those eight publications as "the relevant evidence that clearly shows
            through scientifically valid testing according to generally accepted principles that progesterone causes
            cancer."
        </p>
        <p>
            In 2004, the agency was petitioned to remove progesterone from the list. In the document rejecting that
            petition, they mentioned that IARC in 1999 had reviewed newer evidence confirming the carcinogenicity of
            progesterone. After months of asking the man in charge of rejecting the petition to identify that very
            important new data, I hadn't received an answer, so I wrote to IARC, and the man in charge there responded:
        </p>
        <p>
            "The IARC (1999) review is actually an IARC Monographs volume (Vol.72) . . . . This volume focuses on
            contraception and post-menopausal therapy. Progesterone is not used for these indications and, hence, after
            a quick search in the book I found only one reference that clearly reports an experiment with progesterone."
            [<em>Wednesday, October 04, 2006 12:44 AM]</em>
        </p>

        <p>
            That article <em>(Grubbs CJ, Peckham JC &amp; McDonough KD (1983) Effect of ovarian hormones on the
                induction of 1-methyl-1-nitrosourea-induced mammary cancer. Carcinogenesis 4(4):495-497)</em>
            <strong>reported that progesterone</strong>
            <strong>
                reduced the incidence of mammary cancers caused by a carcinogen administered in vegetable oil.</strong>
        </p>
        <p>
            I don't think it's possible that anyone could read articles like this, <strong>
                that don't even claim to show that progesterone causes cancer,</strong> and conclude that they provide
            evidence of progesterone's carcinogenicity.<strong>
                The choice of "evidence" seems to have been a selection of titles of unread articles.
            </strong>And even the title of the 1999 IARC volume would have suggested to most people that it wasn't a
            review of progesterone.
        </p>
        <p>
            The lack of vehicle controls in some of the studies, the use of an unnamed vehicle in one beagle study, and
            the use of tumor-promoting vehicles in most if not all of the studies, means that no scientifically
            competent or valid studies have been cited by IARC, NTP, or the California state bureaucracy, OEHHA, to
            support California's claim that they know progesterone is a carcinogen.
        </p>
        <p>
            In their 2004 document, OEHHA mentioned 17 articles that had been submitted regarding progesterone's
            protective effects. Some of these were identified<strong>;</strong>
            two were egregiously misrepresented in a single sentence<strong>:</strong>
        </p>

        <p>
            Plu-Bureau, et al., were said to have reported "no association between breast cancer risk and progesterone
            topically applied for the treatment of mastalgia and benign breast disease..." What Plu-Bureau, et al., said
            immediately following that was "Although the <strong><hr /></strong> there was no significant difference in
            the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users."
            (RR means "relative risk," or "risk ratio," and 0.5 means a 50% reduction in risk.)
        </p>

        <p>
            Cowan, et al. (1981), according to the OEHHA document, reported "reduced premenopausal breast cancer in
            women who had a history of progesterone deficiency." What they actually said was "These women were
            categorized as to the cause of infertility into 2 groups, those with endogenous progesterone deficiency (PD)
            and those with nonhormonal causes (NH). Women in the PD group <strong>had 5.4 times the risk of
                premenopausal breast cancer</strong> as compared to women in the NH group. This excess risk could not be
            explained by differences between the 2 groups in age at menarche or age at menopause, history of oral
            contraceptive use, history of benign breast diseases, or age at 1st birth. <strong>Women in the PD group
                also experienced a 10-fold increase in deaths from all malignant neoplasm</strong> compared to the NH
            group."
        </p>
        <p>
            Ending the paragraph that mentioned those studies, the California document continues: "However, there is
            also evidence that progesterone may have a mitogenic effect. For example, Soderqvist et al. (1997) found
            that in breast cells of healthy women, cell proliferation was correlated with serum progesterone levels,
            thereby suggesting a proliferative action of progesterone."
        </p>

        <p>
            Such a suggestion is not made by that "correlation." The authors said, "Our objective was to assess
            proliferation in normal breast epithelial cells from healthy women during the follicular and luteal phases
            of the menstrual cycle." At the beginning of the luteal phase, <strong>both</strong> estrogen and
            progesterone normally rise several-fold, so the small increase in proliferative rate also correlates with
            estrogen levels. A "defective luteal phase" is common, in which the ratio of estrogen to progesterone is
            high, and in that case progesterone's well established antiproliferative, differentiative effect will be
            overridden by estrogen's proliferative stimulation.
        </p>

        <p>
            The state's reviewers didn't comment on the studies which showed that progesterone, besides inhibiting
            proliferation, also inhibits an "oncogene" which is associated with cancer, rather than just with
            proliferation. Instead, they cited a meaningless "correlation" as if it were some kind of argument against
            progesterone's anticancer effects. The authors of this document don't seem to know very much about the
            biology of cancer, but maybe they know too much about the issue of the proliferation of breast epithelium.
        </p>
        <p>
            In a paragraph "rebutting" the petitioner's point that "This new research supports that exogenous
            progesterone actually <strong><em>reduces</em></strong>

            the risk of breast cancer in humans," the authors don't mention that point at all, but instead refer to
            cancer treatment and to the various claims relating to progesterone's carcinogenicity, ending with the
            mention of "studies that suggest progesterone stimulates cell proliferation (e.g., Soderqvist et al.,
            1997)." Apparently the authors had no answer to the petitioners' point, and preferred to talk about
            proliferation of breast cells.
        </p>
        <p>
            Nearing the end of the document, the authors say "The NCI also reports on other studies of estrogens with
            <strong>progestins,</strong> which would suggest that <strong>progesterone</strong> increases the risk of
            human breast cancer," and then quotes comments on studies of estrogens with (synthetic) progestins. The
            authors cite two more studies with synthetic progestins, and then say "As discussed above, the mammary gland
            was a main target site in animal cancer bioassays providing the basis for the IARC and NTP identification of
            progesterone as carcinogenic." (The preceding discussion had mentioned the 4 year beagle study--which ended
            the careers of the researchers--and a 1993 publication by Kordon, et al., which had no control group for
            reference, and instead compared progesterone with different doses of medroxyprogesterone acetate, finding
            that the fewest tumors occurred in the progesterone group.*)
        </p>
        <p>
            The techniques of distortion, diversion and evasion in this document are so obvious that any college
            composition teacher would have returned it to the student for revision. The document says much more about
            its authors than about its subject.
        </p>
        <p>
            I think this bureaucratic behavior is understandable only if you know the composition of the group that is
            responsible for the progesterone listing, because the proliferation of breast cells has become an important
            issue for the group around USC professor Malcolm Pike.
        </p>
        <p>
            Around 1980, Malcolm Pike, a statistician from South Africa, working in epidemiology, began arguing that the
            use of oral contraceptives prevented cancer. This epidemiologist, unfamiliar with steroid physiology except
            as it filtered through the oral contraceptive industry, decided that progesterone was the primary cause of
            breast cancer, by <strong><em>stimulating</em></strong>
            cell division and increasing the tissue density of the breast.
        </p>

        <p>
            This line of reasoning gained adherents in the USC Keck School of Medicine, despite an overwhelming amount
            of contrary evidence, accumulated over more than 50 years, that progesterone protects against breast cancer,
            partly by <strong><em>inhibiting</em></strong> cell division, and that increased breast density is
            significantly associated with breast mitogens, such as serum insulin-like growth factor-I (IGF), prolactin,
            and estrogens, rather than with progesterone.
        </p>
        <p>
            Breast mitogens correspond to both breast density and the risk of breast cancer (Boyd), but progesterone
            (antimitogen) corresponds to factors associated with <strong>low risk</strong> of breast cancer<strong>.
            </strong>
            Progesterone may reduce breast density by inhibiting some growth factors, including IGF, NO (nitric oxide),
            VEGF (vascular endothelial growth factor), bcl-2 (a protein that inhibits apoptosis), polyamines, and
            prostaglandins.
        </p>
        <p>
            Much of the research at USC's Keck School has been generously funded by pharmaceutical companies with huge
            interest in estrogen-related products. The medical school website has articles by their faculty that give
            the impression that they are often more concerned with the fate of the estrogen market than with the science
            they claim to be doing. For example, commenting on the WHI evidence showing that estrogen helps to cause
            Alzheimer's disease, professor B.E. Henderson said "I continue to believe that estrogen therapy may help
            reduce a woman's risk of developing Alzheimer's disease <strong>. . . ."</strong> I noticed that there were
            hundreds of other estrogen-related items on the USC website.
        </p>

        <p>
            The medical school, some of its professors, government agencies, and private companies are involved in some
            very complex, overlapping activities that give the impression of what used to be called "conflicts of
            interest."
        </p>
        <p>
            The Keck School (a private institution), and the company, Balance Pharmaceuticals, Inc., controlled by three
            of their professors, participate in the business promotion organization operated by the State of California,
            Larta Institute, which manages Project T2, which is part of a "commercialization" system, involving awards
            of federal government money<strong>: </strong>
            "The organization will provide the awardees with assistance in all aspects of commercialization, including
            business development, funding and capital acquisition, <strong>government regulatory processes,</strong>
            intellectual property protection, licensing strategies, and merger and acquisition opportunities. SBIR Phase
            II is the research and development stage of the well-known program, with award sizes typically starting at
            $750,000 each." "Working with one of the Federal government's largest and most important agencies to assist
            SBIR awardees on the cusp of commercialization is a natural extension of everything we've done for the past
            ten years," said Larta Institute CEO Rohit Shukla.
        </p>
        <p>
            Besides the issue of giving public money to private groups to commercialize ideas, many of which were
            developed using government-funded research, adding assistance with "government regulatory processes" to the
            help given to private corporations should arouse suspicions. The idea of "privatization" is given a new
            dimension<strong>:</strong> It's all for the insiders, without the usual lip-service paid to "competition."
        </p>
        <p>
            On California's committee that chooses chemicals to put on their list of "known carcinogens" is Juliet
            Singh, who is the chief executive of <strong>Trans Pharma Corporation</strong>, a company that is developing
            transdermal drug delivery systems, for example for giving hormones by applying them to the skin. Under
            California's law, chemicals on the carcinogen list may to sold as drugs without a warning.
        </p>
        <p>
            On the committee with Singh are Anna Wu and Thomas Mack, who co-authored several papers with Malcolm Pike,
            who was the most visible promoter of the campaign against progesterone, and who with two other USC
            professors controls Balance Pharmaceuticals, Inc., which is being promoted by Larta Institute, and that's
            planning to market a contraceptive based on the idea of suppressing progesterone. Three USC professors are
            on California's carcinogen committee,<strong> </strong>more than from any of the other universities in the
            state.
        </p>
        <p>
            In a jury trial, I think this would look like a tainted jury.
        </p>

        <p>
            Comparing the California agency's parody of legitimate process in this instance with its reconsideration in
            2002 of its listing of saccharin as a carcinogen is illuminating. In that case, there was at least a
            pretense that the staff had made an attempt to provide "all relevant scientific evidence" for the committee
            to review, as specified by the agency's regulations. And in its decision, the State's Qualified Experts made
            a point of declaring, according to the language of the law, that in the opinion of the state's qualified
            experts it had not been "clearly shown through scientifically valid testing according to generally accepted
            principles to cause cancer." The Committee found that, in this case, it had to use a "'weight of evidence'
            approach to evaluate the body of information available...."
        </p>
        <p>
            Unfortunately, the committee allowed some bizarre speculations about calcium phosphate to outweigh the fact
            that saccharin is a mild carcinogen, and in evaluating the rat experiments they were in such a hurry to
            remove saccharin from the list that they neglected to notice that calcium phosphate precipitation isn't
            unique to rat urine, but very commonly occurs in human urine. Their decision to remove it from the list
            rested on that non-fact.
        </p>

        <p>
            Although the agency cited 150 studies, and went through the formality of describing some of them in their
            document, anyone reading the document justifying the delisting of saccharin, and the document rejecting the
            delisting of progesterone, will find it hard to see a principle of law that could justify removing a
            carcinogen from the list, because of uncertainty regarding the mechanism by which it causes cancer, and
            keeping progesterone on the list, despite overwhelming evidence that it protects against cancer, and a great
            amount of evidence regarding the mechanisms through which the protection occurs.
        </p>
        <p>
            The committee of experts who "weighed" speculations about calcium phosphate in the 2002 saccharin document,
            chose not to consider, either in 1987 or 2004, any of the hundreds of empirical studies showing
            progesterone's protective anticancer effects. The committee "considered" approximately half of all research
            publications on saccharin and cancer, and fewer than 1% of those relating to progesterone and cancer.
            Something other than scientific objectivity must explain those differences.
        </p>
        <p>
            The agency in charge of those processes of evaluating evidence of carcinogenicity declines to identify the
            people who made those possibly biased, certainly bizarre, selections of articles, or to list their
            qualifications for being in the crucial position of deciding what evidence would be provided to the
            Scientific Advisory Panel. And in the list of studies that the committee did receive, are two (Kwapien, et
            al., and Yager and Yager) that are about completely different chemicals, that the agency still identifies as
            evidence of progesterone's carcinogenicity.
        </p>

        <p>
            Many progesterone products have been taken off the market because of California's warning signs and labels,
            and as a result many women are having to rely on their physicians for progesterone. Too many physicians know
            only what the pharmaceutical companies want them to know about progesterone and other hormones that had been
            available for decades in places such as health food stores.
        </p>
        <p>
            An article in JAMA (Marcia Stefanick, April 11, 2006) was summed up by Stefanick in a way that seems
            designed to encourage physicians to return to prescribing estrogen<strong>:</strong> "In the estrogen and
            progestin trial those women who got on the active pills, we saw an increase in breast cancer within five
            years. In the case of estrogen only, we not only do not see an increase by 7 years, but there's actually a
            suggestion of a decrease." That is a serious misrepresentation of the study.
        </p>
        <p>
            The recently reported (December 15, 2006) decline of breast cancer incidence, coinciding with the great
            decrease in the use of menopausal estrogen treatments, also coincided with an increased use of natural
            progesterone, but if the lawyers, bureaucrats, and agents of the estrogen industry succeed in convincing the
            public that progesterone is carcinogenic, its use will decline, and breast cancer incidence could be
            expected to increase again.
        </p>
        <p>
            The studies that show cancer prevention by progesterone have, over the years, failed to resonate in the
            medical culture. The confusion created by classifying the antiprogestational, carcinogenic synthetics as
            "progestins" is largely responsible for the failure to understand the protective nature of progesterone.
        </p>
        <p>
            If the evidence showing that progesterone prevents or cures cancer could be weighed against the evidence
            purporting to show that it is carcinogenic, I think it would be clear that something like a
            cultural-commercial misogyny has been at work. The novelty of the newer misogyny is that it is so often led,
            or at least figureheaded by women.
        </p>

        <p>
            *Note: Compare the results of Kordon, et al., 1993, with the later results of Aldaz, et al.:
        </p>

        <p>
            Kordon, et al., reported 58% of the animals had tumors in the group receiving low dose MPA pellets, 98% in
            the high dose MPA group.
        </p>
        <p>
            Aldaz, et al., 1996, wrote "The synthetic progestin medroxyprogesterone acetate (MPA) was postulated by some
            authors to increase mammary tumor incidence in various rodent models. However, controversy exists regarding
            the role of MPA in experimental and human carcinogenesis." <strong>"MPA by itself did not produce any
                mammary tumors."</strong>
        </p>
        <p>
            <strong><h3>REFERENCES from IARC and OEHHA</h3></strong>
        </p>
        <p>
            1. National Toxicology Program, U.S. Department of Health and Human Services,<strong>
                Fourth Annual Report on Carcinogens (Summary),</strong> pages 392-393, 1985.
        </p>
        <p>
            2. International Agency for Research on Cancer, <strong>IARC Monographs on the Evaluation of the
                Carcinogenic Risk of Chemicals to Humans,</strong> Volume 21, pages 491-515, 1979.
        </p>
        <p>
            3. International Agency for Research on Cancer, <strong>IARC Monographs on the Evaluation of the
                Carcinogenic Risk of Chemicals to Man,</strong> Volume 6, pages 135-146, 1974.
        </p>
        <p>
            4. International Agency for Research on Cancer, <strong>IARC Monograph on the Evaluation of the Carcinogenic
                Risk of Chemicals to Humans, Supplement 4,</strong> pages 202-203, 1982.
        </p>

        <p>
            5. Burrows, H. and Hoch-Ligeti, C., <strong>Effects Of Progesterone On The Development Of Mammary Cancer In
                C3H Mice.</strong> Cancer Research, 6:608-609, 1946.
        </p>
        <p>
            6. Capel-Edwards, K., et al., <strong>Long-Term Administration Of Progesterone To The Female Beagle Dog.
            </strong>Toxicology and Applied Pharmacology 24:474-488, 1973.
        </p>
        <p>
            7. Frank, DW, et al., <strong>Mammary Tumors And Serum Hormones In The Bitch Treated With
                Medroxyprogesterone Acetate Or Progesterone For Four Years.</strong>
            Fertility and Sterility, 31(3):340-346,1979.
        </p>

        <p>
            8. Glucksmann, A. and Cherry, CP. T<strong>he effect of oestrogens, testosterone and progesterone on the
                induction of cervico-vaginal tumours in intact and castrate rats.
            </strong>British Journal of Cancer 22(3):545-562, 1968.
        </p>
        <p>
            9. Jabara, AG, et al., <strong>Effects Of Time And Duration Of Progesterone Administration On Mammary
                Tumours Induced By 7, 12-dimethylbenz(A)Anthracene In Sprague-Dawley Rats.</strong> British Journal of
            Cancer, 27:63-71,1973.
        </p>
        <p>
            10. Jones, LA and Bern, HA. <strong>Long-Term Effects Of Neonatal Treatment With</strong>
            <strong>
                Progesterone, Alone And In Combination With Estrogen, On The Mammary Gland And Reproductive Tract Of
                Female BALB/Cfc3h Mice.</strong> Cancer Research, 37:67-75,1977, [6 pages].
        </p>

        <p>
            11. Jones, LA, et al., <strong>Cervicovaginal And Mammary Gland Abnormalities In Old BALB/cCRGL Mice Treated
                Neonatally With Progesterone.</strong> Journal of Toxicology and Environmental Health, 3:360-361, 1977.
        </p>
        <p>
            12. Kwapien, RP, et al., <strong>Malignant Mammary Tumors In Beagle Dogs Dosed With Investigational Oral
                Contraceptive Steroids.</strong> Journal of the National Cancer Institute, 65(1):137-144,1980.
        </p>
        <p>
            13. Reboud, S. and Pageaut, G., <strong>Co-Carcinogenic Effect Of Progesterone On 20-Methylcholanthrene
                Induced Cervical Carcinoma In Mice.</strong> Nature, 241:398, 1973.
        </p>

        <p>
            14. Yager, JD and Yager, R., <strong>Oral Contraceptive Steroids As Promoters Of Hepatocarcinogenesis In
                Female Sprague-Dawley Rats.</strong> Cancer Research, 40:3680-3685, 1980.
        </p>
        <p>
            15. Letter addressed to Dr. Wendell Kilgore from Helen P. Shu, Ph.D., Syntex (U.S.A.) Inc., dated December
            3, 1987.
        </p>
        <p>
            <strong><h3>OTHER REFERENCES</h3></strong>
        </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</strong>
            (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."
        </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>
            Bull Cancer. 2006 Sep 1;93(9):847-55. <strong>[Breast density: a biomarker to better understand and prevent
                breast cancer]</strong> Brisson J, Berube S, Diorio C.
        </p>
        <p>
            J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108. <strong>Progestins and progesterone in hormone
                replacement therapy and the risk of breast cancer.</strong> Campagnoli C, Clavel-Chapelon F, Kaaks R,
            Peris C, Berrino F. "Controlled studies and most observational studies published over the last 5 years
            suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT),
            particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen
            alone. <strong>By contrast, a recent study suggests that the addition of natural progesterone in cyclic
                regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that
                progesterone does not have a detrimental effect on breast tissue.</strong> The increased BC risk found
            with the addition of synthetic progestins <strong>to estrogen </strong>

            could be due to the regimen and/or the kind of progestin used."
        </p>
        <p>
            Climacteric. 2004 Jun;7(2):129-37. <strong>Human breast cell proliferation and its relationship to steroid
                receptor expression.</strong>
            Clarke RB.
        </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>
            Climacteric 2002 Sep;5(3):229-35. <strong>Effects of progestogens on the postmenopausal breast.</strong> de
            Lignieres B. The potential for an increased risk of breast cancer linked to the use of synthetic progestins
            combined with oral estrogens is one of the main putative reasons for discouraging postmenopausal women from
            using any type of hormone replacement therapy (HRT) for more than a few years. Because no definitive proof
            exists, the available epidemiological results can be interpreted according to what seems biologically
            plausible to each investigator, including potential differences between various schedules of various
            steroids in various species and in vitro models. More than 60 years after the discovery of progesterone, the
            main effects of this endogenous steroid on the physiopathology of the breast during a normal luteal phase
            are still controversial. <strong>The lack of consensus on such basic knowledge concerning one of the most
                important targets of a natural ovarian hormone discovered in 1934 is amazing. In the most cited studies,
                nothing has been done to measure progesterone in plasma and to correlate the extremely disparate
                cytological results with extremely erratic steroid levels at the time of surgical stress. In a recent
                study, with a better design, the physiological rise of endogenous progesterone during the luteal phase
                coincided with a drop in proliferation of breast epithelial cells, which appears to be only slightly
                delayed in comparison with what is described in the endometrium.</strong>
            Differences in doses and schedules of treatments with various synthetic progestins have largely contributed
            to the inconsistency in clinical recommendations. Based on the analysis of proliferation markers in surgical
            biopsies from normal human postmenopausal breast tissue, it is plausible that mitogenic activity is not
            identical during therapy with unopposed estrogens versus estrogens combined with progestogens<strong>, and
                is higher during HRT that combines oral conjugated equine estrogens with medroxyprogesterone acetate
                than during HRT that combines transdermal estradiol and progesterone. It is misleading to put all
                progestogens in the same bag irrespective of their chemical structure,</strong> and, more important,
            their effect may vary according to whether it is estrone or estradiol that is mainly accumulated in the
            breast tissue. <strong>The hypothesis of progesterone decreasing the proliferative effect of estradiol in
                the postmenopausal breast remains highly plausible.</strong>
        </p>
        <p>
            Eur J Cancer. 2000 Sep;36 Suppl 4:S90-1. <strong>Progesterone receptor activation. an alternative to SERMs
                in breast cancer.</strong> Desreux J, Kebers F, Noel A, Francart D, Van Cauwenberge H, Heinen V, Thomas
            JL, Bernard AM, Paris J, Delansorne R, Foidart JM. <strong>"In postmenopausal women, adding progesterone to
                percutaneously administrated oestradiol significantly reduces the proliferation induced by
                oestradiol."</strong>
        </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>
            "Our results are consistent with the model that adipose tissue exerts an estrogen-dependent positive
            regulatory effect on primary SPI tumor growth, and promotes the formation of metastases."
        </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>
            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.
        </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 mechanism by which progesterone inhibits the
            proliferation of breast cancer cells. Utilizing breast cancer cell lines with and without progesterone
            receptors (T47-D and MDA-231, respectively) in vitro, the authors looked at apoptosis (programmed cell
            death) in response to progesterone exposure as a possible mechanism. The genetic markers for apoptosis -
            p53, bcl-2 and surviving, were utilized to determine whether or not the cells underwent apoptosis. 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>
            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>
            Int J Cancer. 1992 Nov 11;52(5):707-12. <strong>Breast cancer and timing of surgery during menstrual cycle.
                A 5-year analysis of 385 pre-menopausal women.</strong> Gnant MF, Seifert M, Jakesz R, Adler A,
            Mittlboeck M, Sevelda P.
        </p>
        <p>
            Am J Epidemiol. 2005 Nov 1;162(9):826-34. Epub 2005 Sep 21. <strong>The association of endogenous sex
                steroids and sex steroid binding proteins with mammographic density: results from the Postmenopausal
                Estrogen/Progestin Interventions Mammographic Density Study.
            </strong>Greendale GA, Palla SL, Ursin G, Laughlin GA, Crandall C, Pike MC, Reboussin BA.
        </p>

        <p>
            Am J Physiol Regul Integr Comp Physiol. 2001 Jul;281(1):R365-72. <strong>
                Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate
                angiogenesis.</strong> Gu JW, Elam J, Sartin A, Li W, Roach R, Adair TH.
        </p>
        <p>
            Cancer Research 1982 42:3232-39. <strong>Endogenous hormones as a major factor in human cancer.</strong>
            Henderson, B.E., R.K. Ross, M.C. Pike, and J.T. Casagrande.
        </p>
        <p>
            Reprod Biol Endocrinol. 2003 Oct 7;1(1):73. Epub 2003 Oct 07. <strong>Estrogen, Progesterone and Epithelial
                Ovarian Cancer.</strong> Ho SM. "New convincing data have indicated that estrogens favor neoplastic
            transformation of the OSE while progesterone offers protection against OCa development. Specifically,
            estrogens, particularly those present in ovulatory follicles, are both genotoxic and mitogenic to OSE cells.
            In contrast,<strong>
                pregnancy-equivalent levels progesterone are highly effective as apoptosis inducers for OSE and OCa
                cells. In this regard, high-dose progestin may exert an</strong>

            exfoliation effect and rid an aged OSE of pre-malignant cells."
        </p>
        <p>
            Breast Cancer Res. 2004;6(4):R352-65. Epub 2004 May 7. <strong>Cytochrome P450 1A2 (CYP1A2) activity and
                risk factors for breast cancer: a cross-sectional study.</strong> Hong CC, Tang BK, Hammond GL,
            Tritchler D, Yaffe M, Boyd NF.
        </p>
        <p>
            Zhonghua Fu Chan Ke Za Zhi 2000 Jul;35(7):423-6. <strong>[The effect of progesterone on proliferation and
                apoptosis in ovarian cancer cell]
            </strong>Hu Z, Deng X. "It is suggested in the present<strong>
                study that progesterone can inhibit the proliferation of epithelial ovarian cancer cells in vitro and
                there is an accordant dose-response relationship. Its anticancer effect seems to be due to induction of
                apoptosis which maybe a result of down-regulation of the anti-apoptotic protein bcl-2.</strong>"
        </p>

        <p>
            Endocrinol Jpn. 1977 Aug;23(4):328-32. <strong>Occurrence of permanent changes in vaginal and uterine
                epithelia in mice treated neonatally with progestin, estrogen and aromatizable or non-aromatizable
                androgens</strong>. Iguchi T, Takasugi N. "Two other groups of female mice were given neonatal
            injections with 20 microgram estradiol-17beta and <strong>100 microgram progesterone for 10 days,</strong>
            respectively." "<strong>Neonatal progesterone treatment failed to induce the permanent changes in the
                vaginal and uterine epithelia."</strong>
        </p>
        <p>
            Gynecol Oncol 2001 Jul;82(1):116-21. <strong>Production of steroids by human ovarian surface epithelial
                cells in culture: possible role of progesterone as growth inhibitor.</strong> Ivarsson K, Sundfeldt K,
            Brannstrom M, Janson PO.
        </p>

        <p>
            J Natl Cancer Inst. 2005 May 18;97(10):755-65. <strong>Serum sex steroids in premenopausal women and breast
                cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC).</strong>
            Kaaks R, &amp; 40 co-authors, Nutrition and Hormones Group, International Agency for Research on Cancer
            (<strong>IARC-WHO</strong>), Lyon, France. "The absolute risk of breast cancer for women younger than 40
            followed up for 10 years was estimated at 2.6% for those in the highest quartile of serum testosterone
            versus 1.5% for those in the lowest quartile; for the<strong>
                highest and lowest quartiles of progesterone, these estimates were 1.7% and 2.6%, respectively.</strong
            >"
        </p>
        <p>
            Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1531-43. <strong>Obesity, endogenous hormones, and
                endometrial cancer risk: a synthetic review.</strong> Kaaks R, Lukanova A, Kurzer MS. Hormones and
            Cancer Group, <strong>International Agency for Research on Cancer,</strong> 69372 Lyon, France. <a
                href="mailto:kaaks@iarc.fr"
                target="_blank"
            >kaaks@iarc.fr</a>

            "These relationships can all be interpreted in the light of the 'unopposed estrogen' hypothesis, which
            proposes that <strong>endometrial cancer may develop as a result of the mitogenic effects of estrogens, when
                these are insufficiently counterbalanced by progesterone."</strong>
            "After the menopause, <strong>when progesterone synthesis has ceased altogether, excess weight may continue
                increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels
                through the aromatization of the androgens in adipose</strong> tissue."
        </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. "Cells
            exhibited a proliferative appearance after E2 treatment, and returned to a quiescent appearance when P was
            added to E2. In both studies, P proved to be as efficient as the synthetic progestin R5020. Moreover, the
            immunocytochemical study of E2 receptors indicated that E2 increases its own receptor level whereas P and
            R5020 have the opposite effect, thus limiting the stimulatory effect of E2 on cell growth. In the HBE cell
            culture system and in long-term treatment, <strong>P and R5020 appear predominantly to inhibit cell growth,
                both in the presence and absence of E2."</strong>
        </p>

        <p>
            Ann Endocrinol (Paris). 1986;47(3):179-87.<strong>
                [Estradiol-progesterone interaction in normal and pathological human breast cells]</strong>
            Mauvais-Jarvis P, Kuttenn F, Gompel A, Malet C, Fournier S. "<strong>The antiestrogenic activity of P is
                carried out through the decrease of ER resynthesis and stimulation of 17 beta-hydroxysteroid
                dehydrogenase enzyme activity, which transforms E2 into its less active metabolite estrone (E1) in the
                target cells.</strong> These biochemical events are well documented concerning the endometrium. They
            have also been observed in normal mammary cells in primary cultures as well as in breast fibroadenomas with
            high epithelial cellularity. Moreover, data from literature indicate that E2 could be both a direct and
            indirect factor of cell multiplication in cancerous cell lines. P as well as progestins have the opposite
            effect. Recent results from this laboratory indicate that E2 and P also have antagonistic effects on the
            cell multiplication of normal human mammary cells in primary culture. Therefore, the hypothesis that a lack
            of P during a long period of the female genital like could be a factor in the promotion of breast cancer
            must be considered."
        </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.
        </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. "We report that the
            tumorigenic capacity of human ovarian carcinoma (SKOV-3) cells inoculated into the peritoneal cavity of
            athymic mice is suppressed by pretreatment with subcutaneous progesterone-releasing pellets." "<strong
            >Progesterone prevented tumors from forming on the liver. Life spans of progesterone-treated animals were
                prolonged.</strong>" "Our findings implicate a role for progesterone in ovarian cancer prophylaxis."
        </p>
        <p>
            J Natl Cancer Inst. 1986 Sep;77(3):617-20. <strong>Endogenous sex hormones, prolactin, and mammographic
                features of breast tissue in premenopausal women.</strong> Meyer F, Brisson J, Morrison AS, Brown JB.
        </p>
        <p>
            Int J Cancer. 2004 Nov 1;112(2):312-8. <strong>Endogenous sex hormones and subsequent breast cancer in
                premenopausal women.</strong>
            <hr />
            <strong>
                Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40</strong>
            <hr />
            <strong>where adjusted RR was 0.12</strong>
            <hr />
        </p>

        <p>
            Endocrinology 2002 Sep;143(9):3671-80. <strong>Ovarian hyperstimulation by LH leads to mammary gland
                hyperplasia and cancer predisposition in transgenic mice.</strong>
            Milliken EL, Ameduri RK, Landis MD, Behrooz A, Abdul-Karim FW, Keri RA.
        </p>
        <p>
            J Steroid Biochem Mol Biol 2000 Nov 30;74(5):357-64.<strong>
                Estrogens in the causation of breast, endometrial and ovarian cancers - evidence and hypotheses from
                epidemiological findings.</strong> Persson I. "Estrogens cause endometrial cancer, an effect that<strong
            >
                can be reduced, prevented or reversed by progesterone/progestin - if allowed to act for a sufficiently
                long period of each cycle."
            </strong>
        </p>

        <p>
            Endocrinology. 1973 Dec;93(6):1269-76. <strong>Conversion of progesterone to estrone and estradiol in vitro
                by the ovary of the infantile rat in relation to the development of its interstitial tissue.</strong>
            Quattropani SL, Weisz J.
        </p>
        <p>
            Ann Oncol. 1991 Apr;2(4):269-72. <strong>Timing of breast cancer surgery within the menstrual cycle:
                influence on lymph-node involvement, receptor status, postoperative metastatic spread and local
                recurrence.</strong> Rageth JC, Wyss P, Unger C, Hochuli E.
        </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>
            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>
            J Natl Cancer Inst Monogr. 1994;(16):85-90. <strong>Menstrual timing of treatment for breast cancer.
            </strong>
            Senie RT, Kinne DW.
        </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 <strong>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.</strong>
        </p>
        <p>
            Pathol Oncol Res. 2006;12(2):69-72. Epub 2006 Jun 24. <strong>Leptin--from regulation of fat metabolism to
                stimulation of breast cancer growth.</strong> Sulkowska M, Golaszewska J, Wincewicz A, Koda M, Baltaziak
            M, Sulkowski S.
        </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>
            Acta Pharmacol Toxicol (Copenh). 1983 Apr;52(4):298-304. <strong>Local muscle damage and oily vehicles: a
                study on local reactions in rabbits after intramuscular injection of neuroleptic drugs in aqueous or
                oily vehicles.</strong>
            Svendsen O.
        </p>
        <p>
            Jpn J Cancer Res 1998 Dec;89(12):1334-42. <strong>Effects of sex steroids and growth factors on invasive
                activity and 5'-deoxy-5-fluorouridine sensitivity in ovarian adenocarcinoma OMC-3 cells.
            </strong>

            Ueda M, Fujii H, Yoshizawa K, Kumagai K, Ueki K, Terai Y, Yanagihara T, Ueki M. "T<strong>he inhibitory
                effect of Prog on tumor cell invasion may depend on its inhibitory action on the motility of tumor
                cells.</strong>"
        </p>
        <p>
            Endocrinology. 1965 Oct;77(4):735-44. <strong>Estrogen and androgen production in vitro from
                7-3-H-progesterone by normal and polycystic rat ovaries.</strong> Weisz J, Lloyd CW.
        </p>
        <p>
            J Steroid Biochem. 1984 Sep;21(3):347-9. <strong>Conversion of testosterone and progesterone to oestrone by
                the ovary of the rat embryo in organ culture.</strong> Weniger JP, Chouraqui J, Zeis A.
        </p>
        <p></p>

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