1343 lines
95 KiB
HTML
1343 lines
95 KiB
HTML
<html>
|
|
<head>
|
|
<title>Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion.</title>
|
|
</head>
|
|
<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 & 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, & 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>
|
|
|
|
© Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com
|
|
</body>
|
|
</html>
|