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