The Progesterone Deceptions
by Raymond Peat
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 to sell.
在20世纪30年代，有人证明，即使是小剂量的雌激素也会导致流产，而且如果服用得足够早，即使是非常小的剂量也会阻止受精卵的植入。在20世纪40年代早期，黄体酮被认为可以防止雌激素的许多毒性作用，包括堕胎，但它也被称为自然避孕药，因为它可以通过不同的机制防止怀孕，而没有有害的副作用，包括防止精子进入子宫。也就是说，孕酮可以防止由过量雌激素引起的流产(1,2)，但如果在性交前使用，它可以防止受孕，因此是一种真正的避孕手段，而雌激素是一种流产剂，而不是避孕手段。
在20世纪50年代，人们开始寻找能够阻止排卵的化学物质。根据Carl Djerassi()的说法，制药公司极不愿意冒着受到宗教反对的风险生产其他产品，所以在销售避孕药具方面犹豫不决。显然，每月堕胎的诱导会更难推销。
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 agent.”
根据Djerassi(3)的说法，“直到20世纪40年代中期，人们一直认为孕酮的生物活性是非常特异的，几乎任何分子的改变都会减少或消除其活性。”这显然会打消制药公司的兴趣，他们可以为他们化学改性的物质申请专利，但不能为简单的自然物质申请专利。然而，许多物质——甚至是非甾体化学物质——都具有雌激素作用。（4）
到1942年，汉斯·塞利耶(Hans Selye)已经证明，口服天然类固醇仍能保持活性。但每一家拥有类固醇专利的制药公司显然都希望让公众相信，天然类固醇不能方便使用是有原因的。自然类固醇会被胃酸破坏的理论出现了，被宣扬并被接受——没有任何证据支持。在生产孕酮的过程中，将前体类固醇在盐酸中煮沸，使其从葡萄糖残渣中释放出来。除了公众和医生，没有人真的相信胃酸会伤害孕酮，他们在医学杂志上看到过这一说法，也从药品销售人员那里听说过。
随着人造“黄体酮”片剂以高得多的价格进入市场，廉价的黄体酮片剂停止了使用。坚持使用真正黄体酮的医生被迫购买可注射的黄体酮。结果，溶解性成了一个问题。黄体酮极不溶于水，尽管它在植物油中的溶解性要比在水中大得多，但它在室温下也不能保持溶解状态，即使是在1000份普通植物油中的1份。
当人们说到对黄体酮(甚至是青霉素)过敏时，他们通常不知道有一种毒性很强的溶剂存在。医生的办公桌参考警告可能对孕酮过敏反应。现在，据说它溶解在植物油中出售，含有10%的苄醇，据说是一种“抑菌剂”。
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 water. (5)
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.
抑菌水含有0.9% ~ 1.9%的苯甲醇，对神经有不可逆的伤害。(6,7)它在医院的使用导致了成千上万的婴儿死亡。人们对苄醇毒性的认识至少可以追溯到1918年;它作为一种有效的杀虫剂被提出，并被发现对许多动物系统有毒。注射150mg就超过了安全的全身剂量。黄体酮的含量，但局部浓度要高得多。即使在低浓度的抑菌水中使用，它也会引起严重的反应。(5）
其他的醇，包括乙醇，也被用作溶剂，但由于它们(乙醇甚至比苄醇更亲水)对水有亲和力，溶液在接触组织水时分解。
尽管载体具有毒性，但在癫痫或乳腺癌或子宫癌等严重情况下，注射孕酮仍可获得一些有益效果。许多研究人员都评论过给予大量孕酮的明显困难。(8)我将口服孕酮在生育酚中的作用与其他给药形式和方法进行了比较，结果表明口服和注射孕酮的效果大致相似，大约是栓剂的1/20。我检查过的栓剂中可见孕酮晶体，这显然是浪费了。
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.”)
维生素E的旧理论的作用机制在提高生育率备件黄体酮。(9)是建立一些维生素E和黄体酮的影响是相似的,例如,防止浪费和似乎改善线粒体氧耦合磷酸化与呼吸。我怀疑，如果它们实际上都在同一线粒体位点工作，那么它们一定有很高的互溶性。
我知道在没有有毒溶剂的情况下使用大剂量孕酮是一个长期存在的问题，因此我申请了孕酮在生育酚中的成分，并获得了专利。我以专利的形式发表文章的原因之一是，我有多年的经验，如果我的发现符合传统的偏见，别人就会在不承认的情况下接受我的发现。通常情况下，一个编辑会拒绝一篇论文，然后在几个月后发表另一个人的一篇非常相似的论文。我的论文研究表明，过量的雌激素通过窒息杀死胚胎，而黄体酮通过促进氧气和葡萄糖的输送来保护胚胎，但没有引起期刊的共鸣，这些期刊受到制药行业资金的严重影响。
根据一家主要医学杂志的顾问所说，“…将黄体酮(一种脂溶性类固醇激素)溶解在维生素E中，然后将其并入乳糜微粒中，通过淋巴管吸收，从而避免肝脏在所谓的第一次通过… …是如此简单，令人惊讶的是制药公司没有跳上它。(更老练的作家可能会说“……踩了它”。)
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 prompt excretion.
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.
Medroxyprogesterone acetate 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.
在粉末状时，直接与粘膜密切接触，允许脂质相向脂质相转移孕酮分子。大部分黄体酮不是绕过肝脏，而是在门静脉循环中被吸收，在门静脉循环中，它的主要部分被葡萄糖醛酸化，并使其溶于水，以便迅速排泄。
因为这葡糖苷酸形成交叉作用在某种程度上与普通的孕激素在试验过程中,由于50%的普通免费黄体酮进行红细胞内(10、11),和50%在等离子体与蛋白质有关,而葡糖苷酸不进入红细胞,比较不同口型时，以临床疗效判断较好。我的比较表明，生育酚成分的效力是粉状的好几倍。
由于孕酮作为药物的使用早于1938年通过的需要联邦政府特别批准的法律，它的法律地位与甲状腺激素类似。不幸的是，无论是甲状腺激素还是黄体酮，都倾向于为了更高的利润而偷工减料。
例如，甾体乙酸酯通常比简单的天然甾体便宜一点。有些人认为醋酸盐或丁酸盐可以代替类固醇本身。这会引起危险的反应。
醋酸甲羟孕酮被认为是一种黄体酮(尽管它并不支持妊娠)，因为它改变了子宫，就像黄体酮一样，但它是黄体溶解剂，降低卵巢产生黄体酮而黄体酮本身对黄体有积极的影响，刺激孕激素合成。对“黄体酮”的狭义定义允许许多合成药物作为孕激素出售，尽管其中一些具有很强的雌激素性，允许它们作为避孕药具——奇怪的是，抑制黄体酮合成的避孕药具和药剂竟然被官方称为“支持怀孕”。部分原因可能是醋酸甲羟孕酮分子中的醋酸基团，它使醋酸甲羟孕酮牢牢地与受体结合，同时又使它阻塞了通常参与孕酮代谢的酶。(我认为睾酮甚至可能是一种比醋酸甲羟孕酮更安全的黄体酮。)醋酸孕烯醇酮同样阻断了正常代谢孕烯醇酮的酶。(12)在阿司匹林中，已经发现乙酰基(通过自由基作用)阻止了一种参与前列腺素合成的酶。
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.
如果类别称为“孕激素”或“黄体酮”定义的基础上,一个单一的组织反应,然后是可能的分类与有毒合成孕激素物质,但后来变得高度欺骗性暗示孕酮只是一个黄体酮,或者有任何其他属性的有毒的人工合成物,但这种做法仍在继续。例如，关于“黄体酮会导致出生缺陷”的警告，会导致癫痫女性在怀孕期间不要使用传统的抗癫痫药物(所有这些药物都会导致出生缺陷)，并避免使用天然黄体酮，后者通常可以控制癫痫发作。因此，与孕激素相关的错误信息恰恰会产生它声称想要防止的伤害。在我与监管机构的沟通中，我得出结论，他们的欺骗企图太过明显，不能将其归咎于无能。无论是林业局还是食品和药物管理局，原则都是一样的:监管机构被监管行业俘获。
另一个降低成本的地方是生育酚。生育酚醋酸酯确实具有维生素E活性，但由于它的吸收效率只有普通生育酚的一半左右，因此每盎司节省几美元就会失去一半的治疗效果，这是一个错误。将天然生育酚中的天然孕酮与其他成分进行比较的人坚持认为其他成分不能含有孕酮。
天然维生素E的味道比合成维生素E的味道强，但由于这种混合物会被它接触的任何组织吸收，包括肠道的各个部分，所以可以用胶囊服用。如果使用少量橄榄油，皮肤吸收非常迅速。许多妇女在阴道使用它，把它铺在隔膜上，使它与隔膜接触。所有途径的吸收效率是如此之高，以至于病人应该被警告对其麻醉效果，直到他们的剂量需要大致知道。一些医生更喜欢浓度高于10%，但浓度越高，意外醉酒或麻醉的风险越大。
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.
像罗伊·赫兹这样的医学研究人员认为他们通过结合注射和栓剂来给病人注射最大剂量的生育酚溶液，却从来没有提到过过量使用会产生麻醉效果的问题，这表明生育酚溶液的高可用性。同样，这也证明了微量黄体酮的可获得性极差，研究人员每天给药数百毫克，没有提到过量服用的症状。因为困难参与科学研究不同配方的临床疗效,我认为最实用的方式评估不同的孕激素制剂的有效性是衡量从红细胞可抽出的,几小时后血清水平已经达到峰值。这将合理地反映到达脑细胞、肾上腺和其他各种细胞的数量，而黄体酮在这些细胞上具有治疗作用。
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