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246 lines
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<head>
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<title>
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The Progesterone Deceptions
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</title>
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</head>
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<body>
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<h1>
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The Progesterone Deceptions
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</h1>
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<p>
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In the 1930s, it was demonstrated that estrogen, even in small doses, produced abortions, and that when it
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is given early enough, even a very small dose will prevent implantation of the fertilized embryo.
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Progesterone was known, by the early 1940s, to protect against the many toxic effects of estrogen, including
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abortion, but it was also known as nature's contraceptive, since it can prevent pregnancy without harmful
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side-effects, by different mechanisms, including prevention of sperm entry into the uterus. That is,
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progesterone prevents the miscarriages which result from excess estrogen (1,2), but if used before
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intercourse, it prevents conception, and thus is a true contraceptive, while estrogen is an abortifacient,
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not a contraceptive.
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</p>
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<p>
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In the 1950s, there was a search for chemicals which would prevent ovulation. According to Carl Djerassi (),
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drug companies were extremely reluctant to risk a religious backlash against their other products, and so
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hesitated to market contraceptives. Obviously, the induction of monthly abortions would have been even
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harder to sell.
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</p>
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<p>
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According to Djerassi (3), "Until the middle 1940s ti was assumed that progesterone's biological activity
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was extremely specific and that almost any alteration of the molecule would diminish or abolish its
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activity." This would obviously discourage interest from the drug companies, who could patent a substance
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which they had chemically modified, but could not patent a simple natural substance. However, many
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substances--even non-steroidal chemicals--were known to have estrogenic action. (4)
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</p>
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<p>
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By 1942, Hans Selye had demonstrated that natural steroids retain their activity when administered orally.
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But every drug company with a steroid patent had an obvious interest in having the public believe that there
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is a reason that the natural steroids cannot be conveniently used. The doctrine that natural steroids are
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destroyed by stomach acid appeared, was promoted, and was accepted--without any supporting evidence. In the
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manufacture of progesterone, the precursor steroid is boiled in hydrochloric acid to free it from its
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glucose residue. No one seriously believed that stomach acid hurts progesterone, except the public--and the
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doctors, who had seen the claim in their medical journals, and had heard it from drug salesmen.
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</p>
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<p>
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The myth stopped the use of the cheap tablets of progesterone, as tablets of the synthetic "progestins" came
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on the market, at a much higher price. Doctors who insisted on using real progesterone were forced to buy it
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in an injectable form. As a result, solubility became an issue. Progesterone is extremely insoluble in
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water, and, though it is vastly more soluble in vegetable oil than in water, it does not stay in solution at
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room temperature even at the low concentration of 1 part in 1000 parts of a typical vegetable oil.
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</p>
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<p>
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When people speak of an allergy to progesterone (or even to penicillin) they generally are not aware of the
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presence of a very toxic solvent.(5) For a time, progesterone was often sold dissolved in benzyl benzoate.
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The Physician's Desk Reference warned of possible allergic reactions to progesterone. Now, it is supposedly
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sold dissolved in vegetable oil, with about 10% benzyl alcohol as--supposedly--a "bacteriostatic agent."
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</p>
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<p>
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Bacteriostatic water contains 0.9% to 1.9% benzyl alcohol, and can irreversibly harm nerves. (6,7) Its use
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in hospitals killed thousands of babies. Awareness of benzyl alcohol's toxicity goes back to 1918 at least;
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it was proposed as an effective insecticide, and was found to be toxic to many animal systems. The safe
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systemic dose (7) is exceeded with an injection of 150 mg. of progesterone, yet the local concentration is
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far higher. It can cause a severe reaction even when used at a lower concentration, in bacteriostatic water.
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(5)
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</p>
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<p>
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Other alcohols, including ethanol, have been used as solvents, but since they (ethanol even more than benzyl
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alcohol) have an affinity for water, the solution decomposes in contact with tissue water.
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</p>
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<p>
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In spite of the toxicity of the vehicle, several beneficial effects can be obtained with injected
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progesterone, in serious conditions such as epilepsy or caner of the breast or uterus. Many researchers have
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commented on the very obvious difficulty of giving very large amounts of progesterone. (8) My comparisons of
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oral progesterone in tocopherol with other forms and methods of administration show a roughly similar
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efficiency for oral and inject progesterone, and about 1/20 the effect for suppositories. Crystals of
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progesterone are visible in the suppositories I have examined, and this material is obviously wasted.
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</p>
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<p>
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An old theory of vitamin E's mechanism of action in improving fertility was that it spares progesterone.(9)
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It is established that some of the effects of vitamin E and progesterone are similar, for example, both
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prevent oxygen waste and appear to improve mitochondrial coupling of phosphorylation with respiration. I
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suspected that if they actually both work at the same mitochondrial site, then they must have a high mutual
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solubility.
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</p>
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<p>
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Knowing the long-standing problem of administering large doses of progesterone without a toxic solvent, I
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applied for and was granted a patent for the composition of progesterone in tocopherol. One of my reasons
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for publishing in the form of patents is that I have had many years of experience in having my discoveries
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taken up by others without acknowledgment, if they are compatible with conventional prejudices. Typically,
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an editor rejects a paper, and then a few months later publishes a very similar paper by someone else. My
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dissertation research, which established that an estrogen excess kills the embryo by suffocation, and that
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progesterone protects the embryo by promoting the delivery of both oxygen and glucose, didn't strike a
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responsive chord in the journals which are heavily influenced by funds from the drug industry.
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</p>
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<p>
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According to a consultant for a major medical journal, the idea ""of dissolving progesterone, a fat soluble
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steroid hormone, in vitamin E which is then incorporated into chylomicrons absorbed via the lymphatics, and
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thus avoids the liver on the so called first pass" "is so simple it is amazing that the pharmaceutical
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companies have not jumped on it." (A more sophisticated writer might have said ""stomped on it.")
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</p>
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<p>
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In the powder form, direct and intimate contact with a mucous membrane allows lipid phase to lipid phase
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transfer of progesterone molecules. Instead of by-passing the liver, much of the progesterone is picked up
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in the portal circulation, where a major part of it is glucuronidated, and made water soluble for prompt
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excretion.
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</p>
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<p>
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Since this glucuronide form cross-reacts to some extent with the ordinary progesterone in the assay process,
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and since 50% of the ordinary free progesterone is carried inside the red blood cells (10,11), and 50% is
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associated with proteins in the plasma, while the glucuronide hardly enters the red blood cells at all, it
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is better to judge by clinical efficacy when comparing different oral forms. My comparisons show several
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times higher potency in the tocopherol composition than in powder form.
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</p>
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<p>
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Since progesterone's use as a drug antedates the 1938 law requiring special federal approval, its legal
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status is similar to that of thyroid hormone. Unfortunately, for both thyroid and progesterone, there is a
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tendency to cut corners for the sake of a bigger profit margin.
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</p>
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<p>
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For example, steroid acetates are generally a little cheaper than the simple natural steroid. Some people
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assume that an acetate or butyrate can be substituted for the steroid itself. This can cause dangerous
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reactions.
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</p>
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<p>
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Medroxyprogesterone acetate is considered a progestin (though it is not supportive of gestation), because it
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modifies the uterus in approximately the wasy progesterone does, but it is luteolytic, and lowers the
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ovaries' production of progesterone while progesterone itself has a positive effect on the corpus luteum,
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stimulating progesterone synthesis. Defining "progestin" in a narrow way allows many synthetics to be sold
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as progestogens, though some of them are strongly estrogenic, allowing them to function as
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contraceptives--it is odd that contraceptives and agents which suppress progesterone synthesis should be
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officially called "supported of pregnancy." It is probably partly the acetate group in the
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medroxyprogesterone acetate molecule which makes it bind firmly to receptors, yet causes it to block the
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enzymes which would normally be involved in progesterone metabolism. (I think testosterone, even, might be a
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safer progestin than medroxyprogesterone acetate.) Pregnenolone acetate similarly blocks the enzymes which
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normally metabolize pregnenolone. (12) In aspirin, it has been found that it is the acetyl group which (by a
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free radical action) blocks an enzyme involved in prostaglandin synthesis.
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</p>
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<p>
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If the category called "progestogens" or "progestins" is to be defined on the basis of a single tissue
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reaction, then it is possible to classify progesterone with the toxic synthetic substances, but then it
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becomes highly deceptive to imply that progesterone is <strong><em>just</em></strong> a progestin, or that
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it has any of the <strong><em>other properties </em></strong>
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of the toxic synthetics, but this continues to be done. The warnings about "progestins causing birth
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defects," for example, cause epileptic women t use conventional anti-seizure drugs (all of which cause birth
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defects) during pregnancy, and to avoid natural progesterone, which generally could control their seizures.
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Thus, a false message attached to progesterone creates precisely the harm it claims to want to prevent. In
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my communications with the regulatory agencies, I have concluded that their attempts to deceive are too
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blatant to ascribe to incompetence. Whether it's the Forest Service the FDA, the principle is the same: The
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regulatory agencies have been captured by the regulated industries.
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</p>
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<p>
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Another place to cut costs is in the tocopherol. Tocopherol acetate does have vitamin E activity, but sine
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it is only about half as efficiently absorbed as the simple tocopherol (13), it is a mistake to save a few
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dollars an ounce, at the expense of losing half of the therapeutic effect. People who have compared natural
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progesterone in natural tocopherols with other compositions have insisted that the other compositions must
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not contain progesterone.
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</p>
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<p>
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The taste of natural vitamin E is stronger than that of the synthetic forms, but since the mixture is
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absorbed by any tissue it contacts, including various parts of the bowel, it can be taken in a capsule. If a
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small amount of olive oil is used with it, absorption through the skin is very rapid. Many women use it
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vaginally, spread onto a diaphragm, to hold it in contact with the membranes. The efficiency of absorption
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by all routes is so high that patients should be warned against its anesthetic effect, until their dosage
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requirement is known approximately. Some physicians prefer concentrations higher than 10%, but the risk of
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accidental drunkenness or anesthesia is higher with the stronger solutions.
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</p>
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<p>
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It is an indication of the tocopherol solution's high availability that medical researchers such as Roy
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Hertz (8), who thought they were administering maximal doses by combining injections with suppositories,
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never mentioned the problem of an anesthetic effect from an overdose. Similarly, it si evidence of the
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extremely poor availability of the micropulverized progesterone that the researchers have administered
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hundreds of milligrams per day, without mentioning the symptoms of an overdose. Because of the difficulties
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involved in scientifically studying the clinical effectiveness of various formulations, I think the most
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practical way of evaluating the effectiveness of different progesterone formulations is to measure the
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amount extractable from the red blood cells, a few hours after the peak serum level has been reached. This
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will reasonably reflect the amounts reaching brain cells, adrenal glands, and the various other cells on
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which progesterone has its therapeutic action.
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</p>
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<h3>REFERENCES</h3>
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<p>
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1. A A. Gidley-Baird, et aI., Failure of implantation in human in vitro fertilization and embryo transfer
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patients: the effects of altered progesterone/estrogen ratios in humans and mice, Fertility and Sterility
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45(1): 69-74, 1986.
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</p>
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<p>
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2. J. L. Yovich, et aI., Early luteal serum progesterone concentrations are higher in pregnancy cycles,
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Fertility and Sterility 44 (1): 185-189, 1985.
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</p>
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<p>
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3. C. Djerassi, The making of the pill, Science 84: 127-129, 1984.
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</p>
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<p>
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4. R. Kehl, Les Glandes Endocrines, Presses Universitaires de France, Paris, 1952.
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</p>
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<p>
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5. J. A. Grant, et aI., New England Journal of Medicine 306(2): 108, 1982, Unsuspected benzyl alcohol
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hypersensitivity.
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</p>
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<p>
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6. T. E. Feasby, et aI., Neurotoxicity of bacteriostatic water, New England Journal of Medicine 308(6):
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966-7, 1983.
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</p>
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<p>
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7. E. T. Kimura, et aI., Parenteral toxicity studies with benzyl a1cohol,Toxicol Appl Pharmacol18: 60-68,
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1971.
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</p>
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<p>
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8. A. White, editor, Symposium on Steroids in Experimental and Clinical Practice, The Blakiston Co., N.Y.,
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1951, p. 401.
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</p>
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<p>
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9. A. Fraschini, II Metodo Biologico di Rinvigorimento, Edizioni Minerva Medica, Milan, 1954.
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</p>
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<p>
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10. E. Mulder, et aI., Metabolism of free and conjugated steroids by intact and haemolysed mammalian
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erythrocytes, Biochim. Biophys. Acta 263: <em>290-297, </em>
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1972.
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</p>
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<p>
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11. M. Holzbauer, The association of steroids with blood cells in vivo, J. of Steroid Biochemistry 3:
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579-592, 1972.
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</p>
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<p>
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12. S. Lieberman, et aI., A heuristic proposal for understanding steroidogenic processes, Endocrine Reviews
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5(1): 128-148, 1984.
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</p>
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<p>
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13. L. J. Machlin and E. Gabriel, Kinetics of tissue alpha-tocopherol uptake and depletion, following
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administration of high levels of
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</p>
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<p>
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vitamin E, p. 48 in annals of the N.Y. Academy of Science 393,B. Lubin and I. J. Machlin, editors, New York,
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1982.
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</p>
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© Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com
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</body>
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</html>
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