RU486, Cancer, Estrogen, and Progesterone.
RU486，癌症，雌激素和孕激素
by Raymond Peat
Recently many people have been disturbed by reading claims that progesterone can cause cancer, or diabetes, or autoimmune diseases, or heart disease, or Alzheimer's disease. A flurry of press conferences, and a few groups of “molecular biologists” working on “progesterone receptors,” and the results of studies in which Prempro (containing a synthetic “progestin”) increased breast cancer, have created great confusion and concern, at least in the English speaking countries.
Wyeth, the manufacturer of Prempro, has been highly motivated to recover their sales and profits that declined about 70% in the first two years after the Women's Health Initiative announced its results. When billions of dollars in profits are involved, clever public relations can achieve marvelous things.
Women and other mammals that are deficient in progesterone, and/or that have an excess of estrogen, have a higher than average incidence of cancer. Animal experiments have shown that administering progesterone could prevent cancer. Cells in the most cancer-susceptible tissues proliferate in proportion to the ratio of estrogen to progesterone. When the estrogen dominance persists for a long time without interruption, there are progressive distortions in the structure of the responsive organs–the uterus, breast, pituitary, lung, liver, kidney, brain, and other organs–and those structural distortions tend to progress gradually from fibroses to cancer.
最近，很多人都被孕激素会导致癌症、糖尿病、自身免疫性疾病、心脏病或阿尔茨海默病的说法所困扰。一连串的新闻发布会，几个“分子生物学家”小组对“孕激素受体”的研究，以及Prempro(含有一种合成的“孕激素”)增加乳腺癌发病率的研究结果，至少在英语国家引起了极大的困惑和担忧。
Prempro的制造商惠氏(Wyeth)在妇女健康倡议(Women’s Health Initiative)公布结果后，一直积极恢复其销售额和利润，在最初两年下降了约70%。当涉及到数十亿美元的利润时，巧妙的公共关系可以取得不可思议的成就。
缺乏黄体酮和/或雌激素过多的妇女和其他哺乳动物患癌症的几率高于平均水平。动物实验表明，服用黄体酮可以预防癌症。最易患癌组织中的细胞增殖与雌激素和孕酮的比例成正比。当雌激素的主导地位持续很长一段时间而不受干扰时，反应器官——子宫、乳腺、脑下垂体、肺、肝、肾、脑和其他器官——的结构就会发生渐进式的扭曲，这些结构扭曲倾向于从纤维化逐渐发展为癌症。
As a result of the early studies in both humans and animals, progesterone was used by many physicians to treat the types of cancer that were clearly caused by estrogen, especially uterine, breast, and kidney cancers. But by the 1950s, the drug industry had created the myth that their patented synthetic analogs of progesterone were medically more effective than progesterone itself, and the result has been that medroxyprogesterone acetate and other synthetics have been widely used to treat women's cancers, including breast cancer.
Unfortunately, those synthetic compounds have a variety of functions unlike progesterone, including some estrogenic and/or androgenic and/or glucocorticoid and/or antiprogesterone functions, besides other special, idiosyncratic side effects. The rationale for their use was that they were “like progesterone, only better.” The unpleasant and unwanted truth is that, as a group, they are seriously carcinogenic, besides being toxic in a variety of other ways. Thousands of researchers have drawn conclusions about the effects of progesterone on the basis of their experiments with a synthetic progestin.
通过对人类和动物的早期研究，黄体酮被许多医生用于治疗明显由雌激素引起的各种癌症，尤其是子宫癌、乳腺癌和肾癌。但到了20世纪50年代，制药业创造了一个神话，认为他们的孕酮专利合成类似物在医学上比孕酮本身更有效，结果是醋酸甲羟孕酮和其他合成物被广泛用于治疗女性癌症，包括乳腺癌。
不幸的是，这些合成化合物具有不同于孕酮的多种功能，包括一些雌激素和/或雄激素和/或糖皮质激素和/或抗孕酮功能，此外还有其他特殊的、特殊的副作用。使用它们的理由是，它们“就像黄体酮，只是更好”。令人不快和不想要的事实是，作为一个群体，它们除了在许多其他方面具有毒性外，还具有严重的致癌性。成千上万的研究人员在合成黄体酮实验的基础上，对黄体酮的效果得出了结论。
The earliest studies of estrogen and progesterone in the 1930s had the great advantage of a scientific culture that was relatively unpolluted by the pharmaceutical industry. As described by Carla Rothenberg, the massive manipulation of the medical, regulatory, and scientific culture by the estrogen industry began in 1941. After that, the role of metaphysics, word magic, and epicycle-like models increasingly replaced empirical science in endocrinology and cell physiology.
As the estrogen industry began losing billions of dollars a year following the 2002 report from the Women's Health Initiative regarding estrogen's toxicity, and as it was noticed that progesterone sales had increased more than 100-fold, it was clear what had to be done–the toxic effects of estrogen had to be transferred to progesterone. For more than 50 years, progesterone was recognized to be antimitotic and anti-inflammatory and anticarcinogenic, but suddenly it has become a mitogenic pro-inflammatory carcinogen.
20世纪30年代对雌激素和黄体酮的最早研究有一个很大的优势，那就是科学文化相对没有受到制药工业的污染。正如卡拉·罗森伯格(Carla Rothenberg)所描述的，雌激素产业对医疗、监管和科学文化的大规模操纵始于1941年。在那之后，在内分泌学和细胞生理学中，形而上学、文字魔法和类本轮模型的作用逐渐取代了经验科学。
雌激素产业开始每年损失数十亿美元在2002年妇女健康倡议的报告关于雌激素的毒性,当它发现孕酮销售增加了100倍以上,很清楚要做什么——雌激素的毒性作用必须转移到孕激素。50多年来，黄体酮被认为是抗有丝分裂、抗炎和抗癌的，但突然间它变成了一种促有丝分裂的致癌物。
Science used to involve confirmation or refutation of published results and conclusions. A different experimenter, using the technique described in a publication, would often get a different result, and a dialog or disputation would develop, sometimes continuing for years, before consensus was achieved, though many times there would be no clear conclusion or consensus.
In that traditional scientific environment, it was customary to recognize that a certain position remained hypothetical and controversial until some new technique or insight settled the question with some degree of clarity and decisiveness. People who cherry-picked studies to support their position, while ignoring contradictory evidence, were violating the basic scientific principles of tentativeness and reasonableness. Contradictory, as well as confirmatory, data have to be considered.
But when a single experiment involves several people working for a year or more, at a cost of a million or more dollars, who is going to finance an experiment that “would merely confirm” those results? The newly developed techniques for identifying specific molecules are often very elaborate and expensive, and as a result only a few kinds of molecule are usually investigated in each experiment. The results are open to various interpretations, and most of those interpretations depend on results from other studies, whose techniques, results, and conclusions have never been challenged, either. There is no significant source of funding to challenge the programs of the pharmaceutical industry.
科学过去涉及对已发表的结果和结论的确认或反驳。不同的实验者，使用出版物中描述的技术，通常会得到不同的结果，然后会产生对话或争论，有时持续多年，直到达成共识，尽管很多时候没有明确的结论或共识。
在传统的科学环境中，人们习惯承认，在某种新技术或见解以某种程度的清晰和果断解决问题之前，某一立场仍然是假设的和有争议的。那些挑选一些研究来支持自己的观点，而忽视相互矛盾的证据的人，违反了试探性和合理性的基本科学原则。既要考虑矛盾的数据，也要考虑证实的数据。
但是，当一个单独的实验需要几个人工作一年或更长时间，花费100万或更多美元时，谁会资助一个“只是证实”那些结果的实验呢?新开发的识别特定分子的技术通常是非常复杂和昂贵的，因此在每次实验中通常只研究几种分子。研究结果可以有各种各样的解释，而这些解释大多依赖于其他研究的结果，这些研究的技术、结果和结论也从未受到质疑。没有重要的资金来源来挑战制药行业的计划。
The result is that the pronouncements of the principal investigator, and the repetitions of those conclusions in the mass media, create a culture of opinion, without the foundation of multiple confirmations that used to be part of the scientific process. The process has taken on many of the features of a cult, in which received opinions are repeatedly reinforced by the investment of money and authority. Newspaper reporters know that the team of investigators spent two years on their project, and the lead investigator wears a white lab coat during the interview, so the reporters don't notice that the investigators' conclusion is a non sequitur, supported by chains of non sequiturs.
The public gets most of its information about science from the mass media, and the increasingly concentrated ownership of the media contributes to the use of scientific news as an adjunct to their main business, advertising and product promotion. The pharmaceutical industry spends billions of dollars annually on direct-to-consumer advertising, so the big scientific news, for the media, is likely to be anything that will increase their advertising revenue.
其结果是，主要研究者的声明，以及这些结论在大众媒体上的重复，创造了一种意见文化，而没有了曾经是科学过程一部分的多重确认的基础。这一过程具有许多邪教的特征，在这个过程中，接受的意见通过金钱和权威的投资不断得到加强。新闻记者知道，调查小组在他们的项目上花了两年时间，而首席调查人员在采访时穿着白大褂，所以记者没有注意到调查人员的结论是一个不合理的结论，由一系列不合理的结论支持。
公众从大众媒体获得大部分关于科学的信息，而媒体所有权的日益集中使得人们把科学新闻作为他们主要业务、广告和产品推广的辅助手段。制药行业每年在直接面向消费者的广告上花费数十亿美元，所以对媒体来说，重大的科学新闻可能是任何能增加广告收入的东西。
Social-economic cults often simplify the thought processes required by the participants, by inventing a scapegoat. The estrogen cult has decided that progesterone will be its scapegoat.
Hans Selye argued that steroid hormones should be named by their origin, or by their chemical structural names, rather than their effects, because each hormone has innumerable effects. To name a substance according to its effects is to predict and to foreordain the discoveries that will be made regarding its effects.
The common system of hormonal names according to their putative effects has allowed ideology and metaphysical ideas to dominate endocrinology. The worst example of metaphysical medicine was the use, for more than 50 years, of “estrogen, the female hormone” to treat prostate cancer, in the belief that “male hormones” cause the cancer, and that the female hormone would negate it. This word magic led to a vast psychotic medical endeavor, that has only recently been reconsidered.
Within the scheme of hormones understood according to their names, “hormone receptors” were proposed to be the mechanism by which hormones produced their effects. Each hormone had a receptor. If another substance bound more strongly than the hormone to its receptor, without producing the effects of the hormone, it was called an antihormone.
社会经济崇拜往往通过发明替罪羊来简化参与者所需的思维过程。雌激素狂热分子决定将黄体酮作为他们的替罪羊。
Hans Selye认为类固醇激素应该根据它们的来源或化学结构来命名，而不是根据它们的作用来命名，因为每种激素都有无数的作用。根据一种物质的作用来命名它，就是预测并预先决定关于它的作用将会有哪些发现。
荷尔蒙名称的共同体系根据它们假定的作用，使得意识形态和形而上学的观念支配了内分泌学。形而上学医学最糟糕的例子是，在超过50年的时间里，使用“雌激素，女性荷尔蒙”来治疗前列腺癌，因为他们相信“男性荷尔蒙”会导致癌症，而女性荷尔蒙会抵消它。“魔法”这个词引发了一场大规模的精神病医学尝试，直到最近才被重新考虑。
在根据其名称理解的激素体系中，“激素受体”被提出是激素产生其作用的机制。每种激素都有一个受体。如果另一种物质比激素与受体结合更强，而不产生激素的效果，它就被称为抗激素。
The industry of synthetic hormones used the ideology of unitary hormonal action to identify new substances as pharmaceutical hormones, that were always in some way said to be better than the natural hormones–for example by being “orally active,” unlike natural hormones, supposedly. Physicians docilely went along with whatever the drug salesmen told them. If a drug was classified as a “progestin” by a single reaction in one animal tissue, then it had a metaphysical identity with the natural hormone, except that it was better, and patentable.
The natural hormones eventually were assigned any of the toxic properties that were observed for the pharmaceutical products “in their class.” If synthetic progestins caused heart disease, birth defects, and cancer, then the “natural progestin” was assumed to do that, too. It's important to realize the impact of logical fallacies on the medical culture.
Like the hormones themselves, which metaphysically supposedly acted upon one receptor, to activate one gene (or set of genes), the antihormones came to be stereotyped. If a particular hormonal action was blocked by a chemical, then that substance became an antagonistic antihormone, and when its administration produced an effect, that effect was taken to be the result of blocking the hormone for which it was “the antagonist.”
The “antiprogesterone” molecule, RU486, besides having some progesterone-like and antiestrogenic properties, also has (according to Hackenberg, et al., 1996). some androgenic, antiandrogenic, and antiglucocorticoid properties. Experiments in which it is used might have pharmaceutical meaning, but they so far have very little clear biological meaning.
合成激素工业利用单一激素作用的意识形态，将新物质识别为药物激素，这些药物激素总被认为在某种程度上比天然激素更好，例如被认为“具有口服活性”，而不像天然激素。医生顺从地接受药品销售人员告诉他们的任何事情。如果一种药物因为在一个动物组织中的单一反应而被归类为“黄体酮”，那么它就有了与天然激素的形象化的身份，除了它更好，而且可以申请专利。
这些天然激素最终被赋予了“同类”药品的任何毒性。如果合成黄体酮会导致心脏病、出生缺陷和癌症，那么“天然黄体酮”也会导致这些。认识到逻辑谬误对医学文化的影响是很重要的。
就像激素本身一样，从形而上学的角度来看，它们作用于一个受体，激活一个基因(或一组基因)，抗激素也被定型了。如果一种化学物质阻断了某种特定的激素作用，那么这种物质就变成了一种拮抗性的抗激素，当它的作用产生了效果时，这种效果就被认为是阻断了它作为“拮抗剂”的激素的结果。
“抗孕酮”分子RU486除了具有类似孕酮和抗雌激素的特性外，还具有(据Hackenberg等人，1996年)。一些雄激素，抗雄激素和抗糖皮质激素的特性。使用它的实验可能具有药物意义，但到目前为止，它们几乎没有明确的生物学意义。
Adding to the conceptual sloppiness of the “molecular biology” wing of endocrinology, the culture in which pharmaceutical products had come to dominate medical ideas about hormones allowed the conventional pharmaceutical vehicles to be disregarded in most experiments, both in vitro and in vivo. If progesterone was injected into patients mixed with sesame oil and benzyl alcohol, then it often didn't occur to animal experimenters to give control injections of the solvent. For in vitro studies, in a watery medium, oil wouldn't do, so they would use an alcohol solvent, and again often forgot to do a solvent control experiment.
The importance of the solvent was seen by an experimenter studying the effect of vitamin E on age pigment in nerves. It occurred to that experimenter to test the ethyl alcohol alone, and he found that it produced almost the same effect as that produced by the solution of alcohol and vitamin E. Workers with hormones often just assume that a little alcohol wouldn't affect their system. But when the effects of alcohol by itself have been studied, many of the effects produced by very low concentrations happen to be the same effects that have been ascribed to hormones, such as progesterone.
再加上内分泌学“分子生物学”这一分支概念上的混乱，制药产品主导了有关激素的医学观念，使得传统的制药载体在大多数体外和体内实验中都被忽视了。如果将黄体酮与芝麻油和苄醇混合注射到患者体内，动物实验人员通常不会进行对照注射。在体外实验中，在水介质中，油不适合，所以他们会使用酒精溶剂，而且经常忘记做溶剂对照实验。
研究维生素E对神经色素的影响的实验者看到了溶剂的重要性。实验人员突然想到单独测试酒精，他发现它产生的效果几乎与酒精和维生素e溶液产生的效果相同。有荷尔蒙的工作人员通常认为少量酒精不会影响他们的系统。但当我们研究酒精本身的作用时，发现极低浓度的酒精产生的许多作用恰好与孕酮等激素产生的作用相同。
In some cases, the solvent allows the hormone to crystallize, especially if the solvent is water-miscible, and fails to distribute it evenly through the medium and cells as the experimenter assumed would happen, and so the experimenter reports that the hormone is not effective in that kind of cell, even though the hormone didn't reach the cells in the amount intended.
These are four of the common sources of error about progesterone: (1) Saying that progesterone has produced an effect which was produced by a different substance. (2) Saying that progesterone is the cause of a certain effect, if an “anti-progesterone” chemical prevents that effect. (3) Saying that progesterone caused something, when in fact the solvent caused it. And (4) saying that progesterone fails to do something, when progesterone hasn't been delivered to the system being studied.
在某些情况下,允许激素结晶溶剂,特别是水溶性液体溶剂,并未能分配均匀介质和细胞实验者认为会发生,所以实验者报道激素不是有效的细胞,即使激素没有达到预期的数量。
以下是关于孕酮的四个常见错误来源:(1)说孕酮产生了一种由不同物质产生的效果。(2)如果一种“抗孕酮”的化学物质阻止了某种效果，就说孕酮是某种效果的原因。(3)说孕酮引起了什么，实际上是溶剂引起的。(4)当孕酮还没有进入被研究的系统时，说孕酮不起作用。
Many years ago, experimenters who wanted to minimize the problems involved in administering progesterone in toxic solvents found that, with careful effort, progesterone could be transferred to a protein, such as albumin, and that the albumin-progesterone complex could be washed to remove the solvent. In this form, the progesterone can be delivered to cells in a form that isn't radically different from the form in which it naturally circulates in the body. Apparently, the labor involved discourages the widespread use of this technique.
Although the industry's early generalizations about estrogen and progesterone, defining them as “the female hormone” and “the pregnancy hormone,” were radically mistaken, some useful generalizations about their effects were gradually being built up during the first few decades in which their chemical and physiological properties were studied.
Estrogen's name, derived from the gadfly, accurately suggests its role as an excitant, getting things started. Progesterone's name, relating to pregnancy, is compatible with thinking of it as an agent of calming and fulfillment. But these properties show up in every aspect of physiology, and the special cases of female estrus and pregnancy can be properly understood only in the larger context, in which, for example, progesterone is a brain hormone in both sexes and at all ages, and estrogen is an essential male hormone involved in the sperm cell's function and male libido.
Progesterone can, without estrogen, create the uterine conditions for implantation of an embryo (Piccini, 2005, progesterone induces LIF; Sherwin, et al., 2004, LIF can substitute for estrogen), and it has many other features that can be considered apart from estrogen, such as its regulation of salts, energy metabolism, protein metabolism, immunity, stress, and inflammation, but without understanding its opposition to estrogen, there will be no coherent understanding of progesterone's biological meaning.
Both estrogen and progesterone are hydrophobic molecules (progesterone much more so than estrogen) which bind with some affinity to many components of cells. Certain proteins that strongly bind the hormones are called their receptors.
许多年前，那些想要尽量减少在有毒溶剂中使用黄体酮所涉及的问题的实验者发现，经过仔细的努力，黄体酮可以转移到一种蛋白质上，比如白蛋白，而且白蛋白-黄体酮复合物可以被清洗以去除溶剂。在这种形式下，孕酮可以以一种与它在体内自然循环的形式没有根本不同的形式被输送到细胞中。显然，涉及的劳动力不鼓励这种技术的广泛使用。
虽然该行业的早期概括关于雌激素和孕激素,将他们定义为“女性荷尔蒙”和“妊娠激素”是完全错误的,一些有用的总结对他们的影响是逐步建立在前几十年里,它们的化学和生理特性进行了研究。
雌激素的名字，来源于牛虻，准确地暗示了它作为刺激物的作用，使事情开始。黄体酮的名字与怀孕有关，它被认为是一种平静和满足的媒介。但这些属性出现在生理学的方方面面,和女性发情和怀孕的特殊情况只能在更大的背景下,正确理解,例如,孕酮是一种大脑荷尔蒙性别和年龄,是一个重要的雄性激素和雌激素参与精子细胞的功能和男性的性欲。
在没有雌激素的情况下，孕激素可以为胚胎着床创造子宫条件(Piccini, 2005，孕激素诱导LIF;Sherwin, et al.， 2004, LIF可以替代雌激素)，它还有许多可以被认为是雌激素之外的其他特征，例如它对盐的调节、能量代谢、蛋白质代谢、免疫、压力和炎症的调节，但不了解它与雌激素的对立，对黄体酮的生物学意义将没有连贯的理解。
雌激素和黄体酮都是疏水分子(黄体酮比雌激素更疏水)，它们以某种亲和力结合细胞的许多成分。某些与激素紧密结合的蛋白质称为激素受体。
Cells respond to stimulation by estrogen by producing a variety of molecules, including the “progesterone receptor” protein. When progesterone enters the cell, binding to these proteins, the estrogenic stimulation is halted, by a series of reactions in which the estrogen receptors disintegrate, and in which estrogen is made water soluble by the activation of enzymes that attach sulfate or a sugar acid, causing it leave the cell and move into the bloodstream, and by reactions that prevent its reentry into the cell by inactivating another type of enzyme, and that suppress its de novo formation in the cell, and that oxidize it into a less active form. Progesterone terminates estrogen's cellular functions with extreme thoroughness.
A recent publication in Science (“Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist,” Poole, et al., Dec. 1, 2006), with associated press conferences, reported an experiment in which a special kind of mouse was prepared, which lacked two tumor-suppressing genes called BRCA and p53.
细胞对雌激素刺激的反应是产生多种分子，包括“孕酮受体”蛋白。当孕激素进入细胞,这些蛋白质绑定,停止了雌激素的刺激,通过一系列反应中雌激素受体瓦解,而雌性激素是由水溶性酶的激活附加硫酸或糖酸,使其离开细胞进入血液,通过一些反应，通过灭活另一种酶来阻止它重新进入细胞，抑制它在细胞中的重新形成，并将其氧化成一种活性较低的形式。孕酮极其彻底地终止了雌激素的细胞功能。
Poole等人，2006年12月1日发表在《科学》杂志上的一篇文章(“通过孕酮拮抗剂预防小鼠中brca1介导的乳腺肿瘤发生”)和相关新闻发布会报道了一项实验，该实验准备了一种特殊类型的小鼠，这种小鼠缺乏两种肿瘤抑制基因，即BRCA和p53。
One of the functions of the BRCA gene product is to repair genetic damage, and another function is to (like progesterone) suppress the estrogen receptor and its functions. Estrogen, and some environmental carcinogens, can suppress the BRCA gene product. Estrogen can also turn off the tumor suppressor protein, p53. So it is interesting that a group of experimenters chose to produce a mouse that lacked both the normal BRCA and p53 genes. They had a mouse that was designed to unleash estrogen's effects, and that modeled some of the features of estrogen toxicity and progesterone deficiency.
This mouse, lacking an essential gene that would allow progesterone to function normally, probably affecting progesterone's ability to eliminate the estrogen receptor, also lacked the tumor suppressor gene p53, which is required for luteinization (Cherian-Shaw 2004); in its absence, progesterone synthesis is decreased, estrogen synthesis is increased.
(Chen, Y, et al., 1999: BRCA represses the actions of estrogen and its receptor, and, like progesterone, activates the p21 promoter, which inhibits cell proliferation. Aspirin and vitamin D also act through p21.)
BRCA基因产物的功能之一是修复遗传损伤，另一个功能是(如孕酮)抑制雌激素受体及其功能。雌激素和一些环境致癌物可以抑制BRCA基因产物。雌激素还可以关闭肿瘤抑制蛋白p53。所以有趣的是，一组实验人员选择制造了一只同时缺乏正常BRCA和p53基因的老鼠。他们设计了一只释放雌激素作用的老鼠，并模拟了雌激素毒性和孕酮缺乏的一些特征。
这只小鼠缺乏使黄体酮正常工作的必要基因，可能影响黄体酮消除雌激素受体的能力，同时也缺乏黄体化所需的肿瘤抑制基因p53 (Cherian-Shaw 2004);如果没有它，孕激素的合成就会减少，雌激素的合成就会增加。
(Chen, Y, et al.， 1999: BRCA抑制雌激素及其受体的作用，并且像孕酮一样激活p21启动子，抑制细胞增殖。阿司匹林和维生素D也通过p21起作用。)
The mutant BRCA gene prevents the cell, even in the presence of progesterone, from turning off estrogen's effects the way it should. The antiestrogenic RU486 (some articles below), which has some of progesterone's effects (including therapeutic actions against endometrial and breast cancer), appears to overcome some of the effects of that mutation.
It might have been proper to describe the engineered mouse that lacked both the BRCA and the p53 genes as a mouse in which the effects of estrogen excess and progesterone deficiency would be especially pronounced and deadly. To speak of progesterone as contributing to the development of cancer in that specially designed mouse goes far beyond bad science. However, that study makes sense if it is seen as preparation for the promotion of a new drug similar in effect to RU486, to prevent breast cancer.
The study's lead author, Eva Lee, quoted by a university publicist, said “We found that progesterone plays a role in the development of breast cancer by encouraging the proliferation of mammary cells that carry a breast cancer gene.” But they didn't measure the amount of progesterone present in the animals. They didn't “find” anything at all about progesterone. The “anti-progesterone” drug they used has been used for many years to treat uterine, ovarian, and breast cancers, in some cases with progesterone, to intensify its effects, and its protective effects are very likely the result of its antiestrogenic and anti-cortisol effects, both of which are well established, and relevant. In some cases, it acts like progesterone, only more strongly.
突变的BRCA基因阻止了细胞，即使在孕酮存在的情况下，也无法以应有的方式关闭雌激素的作用。抗雌激素RU486(下面有一些文章)具有孕激素的一些作用(包括对子宫内膜癌和乳腺癌的治疗作用)，它似乎克服了这种突变的一些影响。
将既缺乏BRCA基因又缺乏p53基因的转基因小鼠描述为雌性激素过多和孕激素缺乏的影响尤其明显和致命的小鼠也许是恰当的。说黄体酮对那只特别设计的老鼠的癌症发展有贡献，远远超出了糟糕的科学。然而，如果这项研究被认为是为推广一种与RU486效果相似的预防乳腺癌的新药做准备，那么这项研究是有意义的。
该研究的主要作者伊娃·李(Eva Lee)被一所大学的宣传人员引用说:“我们发现，孕激素通过鼓励携带乳腺癌基因的乳腺细胞增殖，在乳腺癌的发展中发挥了作用。”但他们没有测量动物体内孕酮的含量。他们没有“发现”任何与孕激素有关的东西。“anti-progesterone反黄体酮”药物他们使用多年来一直用于治疗子宫、卵巢,乳腺癌,与孕激素在某些情况下,加强其效果,及其保护作用很可能其抗雌激素的和anti-cortisol反皮质醇效应的结果,这两个已经很成熟,并且相关。在某些情况下，它的作用类似孕酮，只是更强烈。
“Other more specific progesterone blockers are under development,” Lee notes. And the article in Science magazine looks like nothing more than the first advertisement for one that her husband, Wen-Hwa Lee, has designed.
According to publicists at the University of California, Irvine, “Lee plans to focus his research on developing new compounds that will disrupt end-stage cancer cells. The goal is a small molecule that, when injected into the blood stream, will act as something of a biological cruise missile to target, shock and awe the cancerous cells.” “In this research, he will make valuable use of a breast cancer model developed by his wife.” “She developed the model, and I will develop the molecule,” Lee says. “We can use this model to test a new drug and how it works in combination with old drugs.”
“Previously we blamed everything,” Lee says of his eye cancer discovery. “We blamed electricity, we blamed too much sausage - but in this case it's clear: It's the gene's fault.”
“其他更具体的孕激素阻滞剂正在研发中，”Lee指出。《科学》(Science)杂志上的这篇文章看起来不过是她丈夫李文华(Wen-Hwa Lee)设计的那篇文章的第一个广告。
据加州大学欧文分校的宣传人员说，“李计划将他的研究重点放在开发新的化合物，将破坏末期癌细胞。”我们的目标是制造一种小分子，当这种小分子被注射到血液中时，它就会像某种生物巡航导弹一样，瞄准并震慑癌细胞。”“在这项研究中，他将充分利用妻子开发的乳腺癌模型。”“她开发了模型，我将开发分子，”李说。“我们可以用这个模型来测试一种新药，以及它是如何与老药结合的。”
“以前我们指责一切，”李谈到他的眼癌发现时说。“我们怪罪电力，怪罪太多香肠——但在这件事上很清楚:这是基因的错。”
The things that these people know, demonstrated by previous publications, but that they don't say in the Science article, are very revealing. The retinoblastoma gene (and its protein product), a specialty of Wen-Hwa Lee, is widely known to be a factor in breast cancer, and to be responsive to progesterone, RU486, and p21. Its links to ubiquitin, the hormone receptors, proteasomes, and the BRCA gene are well known, but previously they were seen as linking estrogen to cell proliferation, and progesterone to the inhibition of cellular proliferation.
By organizing their claims around the idea that RU486 is acting as an antiprogesterone, rather than as a progesterone synergist in opposing estrogen, Eva Lee's team has misused words to argue that it is progesterone, rather than estrogen, that causes breast cancer. Of the many relevant issues that their publication ignores, the absence of measurements of the actual estrogen and progesterone in the animals' serum most strongly suggests that the project was not designed for proper scientific purposes.
这些人知道的事情，在以前的出版物中展示过，但他们没有在《科学》的文章中说，是非常具有启发性的。视网膜母细胞瘤基因(及其蛋白产物)是李文华(Wen-Hwa Lee)的专长，众所周知是乳腺癌的一个因素，并且对孕酮、RU486和p21有反应。它与泛素、激素受体、蛋白酶体和BRCA基因的联系是众所周知的，但以前它们被认为与雌激素与细胞增殖有关，而孕酮与抑制细胞增殖有关。
通过围绕RU486作为一种抗孕酮，而不是作为一种孕酮协同剂来对抗雌激素这一观点来组织他们的观点，伊娃·李的团队误用了词语来争论是孕酮而不是雌激素导致了乳腺癌。在他们的论文中忽略了许多相关问题，其中，缺乏对动物血清中实际雌激素和黄体酮的测量最强烈地表明，该项目不是为适当的科学目的而设计的。
They chose to use techniques that are perfectly inappropriate for showing what they claim to show.
In the second paragraph of their article, Poole, et al., say “Hormone replacement therapy with progesterone and estrogen, but not estrogen alone, has been associated with an elevation risk in postmenopausal women.” Aside from the gross inaccuracy of saying “progesterone,” rather than synthetic progestin, they phrase their comment about “estrogen alone” in a way that suggests an identity of purpose with the estrogen industry apologists, who have been manipulating the data from the WHI estrogen-only study, clearly to lay the blame on progesterone. (Women who took estrogen had many more surgeries to remove mammographically abnormal breast tissue. This would easily account for fewer minor cancer diagnoses; despite this, there were more advanced cancers in the estrogen group.)
While the Poole, et al., group are operating within a context of new views regarding estrogen, progesterone, and cancer, they are ignoring the greater part of contemporary thinking about cancer, a consensus that has been growing for over 70 years: All of the factors that produce cancer, including breast cancer, produce inflammation and cellular excitation.
他们选择使用完全不合适的技术来展示他们声称要展示的东西。
在他们文章的第二段，Poole等人说，“黄体酮和雌激素的激素替代疗法，但不是单独的雌激素，与绝经后妇女的风险升高有关。”除了总误差说“黄体酮”,而不是人工合成的黄体酮,他们一句话评论“雌激素”的方式表明身份的目的与雌激素行业辩护者,被操纵的数据单独使用雌激素WHI研究中,明确将归咎于孕激素。(服用雌激素的女性接受了更多的手术来移除乳房x光检查中异常的乳房组织。这将很容易解释较少的轻微癌症诊断;尽管如此，雌激素组的晚期癌症患者更多。)
当Poole等人在一个关于雌激素、黄体酮和癌症的新观点的背景下工作时，他们忽视了大部分关于癌症的当代思考，一个已经增长了70多年的共识:所有导致癌症的因素，包括乳腺癌，都会产生炎症和细胞兴奋。
Progesterone is antiinflammatory, and reduces cellular excitation.
Even within their small world of molecular endocrinology, thinking in ways that have been fostered by computer technology, about gene networks, interacting nodes, and crosstalk between pathways, their model and their arguments don't work. They have left out the complexity that could give their argument some weight.
The medical mainstream has recognized for 30 years that progesterone protects the uterus against cancer; that was the reason for adding Provera to the standard menopausal hormonal treatment. The new claim that natural progesterone causes breast cancer should oblige them to explain why the hormone would have opposite effects in different organs, but the mechanisms of action of estrogen and progesterone are remarkably similar in both organs, even when examined at the molecular level. If “molecular endocrinologists” are going to have interpretations diametrically opposed to classical endocrinology (if black is to be white, if apples are to fall up), they will have to produce some very interesting evidence.
孕酮是抗炎的，并减少细胞兴奋。
即使在他们的分子内分泌学这个由计算机技术培养起来的小世界里，关于基因网络、相互作用的节点和路径之间的串音，他们的模型和论点都不成立。他们忽略了可能给他们的论点增加一些分量的复杂性。
30年来，医学主流已经认识到孕激素可以保护子宫免受癌症的侵害;这就是在标准的更年期激素治疗中加入Provera的原因。天然黄体酮导致乳腺癌的新说法迫使他们解释为什么激素会在不同的器官中产生相反的作用，但雌激素和黄体酮在两个器官中的作用机制非常相似，即使在分子水平上检查也是如此。如果“分子内分泌学家”的解释与经典内分泌学完全相反(如果黑是白，如果苹果会掉下来)，他们就必须提供一些非常有趣的证据。
Cancer is a malignant (destructive, invasive) tumor that kills the organism. The main dogma regarding its nature and origin is that it differs genetically from the host, as a result of mutations. Estrogen causes mutations and other forms of genetic instability, as well as cancer itself. Progesterone doesn't harm genes or cause genetic instability.
The speculative anti-progesterone school has put great emphasis on the issue of cellular proliferation, with the reasoning that proliferating cells are more likely to undergo genetic changes. And synthetic progestins often do imitate estrogen and increase cellular proliferation. People like the Lees are asserting as an established fact that progesterone increases cellular proliferation.
A paper by Soderqvist has been cited as proof that progesterone increases the proliferation of breast cells. He saw more mitoses in the breasts during the luteal phase of the menstrual cycle, and said the slightly increased mitotic rate was “associated with” progesterone. Of course, estrogen increased at the same time, and estrogen causes sustained proliferation of breast cells, while progesterone stimulation causes only two cell divisions, ending with the differentiation of the cell. (Groshong, et al., 1997, Owen, et al., 1998)
癌症是一种杀死机体的恶性(破坏性、侵袭性)肿瘤。关于它的性质和起源的主要教条是，由于突变，它在基因上与宿主不同。雌激素会导致突变和其他形式的基因不稳定，以及癌症本身。孕激素不会伤害基因或导致基因不稳定。
推测性的抗孕酮学派非常重视细胞增殖问题，其理由是增殖的细胞更有可能发生基因变化。合成黄体酮经常模仿雌激素，增加细胞增殖。像李氏夫妇这样的人认为孕酮会增加细胞增殖是一个既定事实。
Soderqvist的一篇论文被引用作为黄体酮促进乳腺细胞增殖的证据。他发现，在月经周期的黄体期，乳房中有丝分裂更多，并表示，有丝分裂率的轻微增加与黄体酮“有关”。当然，雌激素同时增加，雌激素导致乳腺细胞持续增殖，而孕酮刺激只导致两次细胞分裂，以细胞分化结束。(Groshong等，1997年;Owen等，1998年)
One of the ways that progesterone stops proliferation and promotes differentiation is by keeping the retinoblastoma protein in its unphosphorylated, active protective state (Gizard, et al., 2006) The effects of estrogen and progesterone on that protein are reciprocal (Chen, et al., 2005). It's hard for me to imagine that the Lees don't know about these hormonal effects on Wen-Hwa's retinoblastoma gene product.
The inactivation of that protein by hyperphosphorylation is part of a general biological process, in which activation of a cell (by injury or nervous or hormonal or other stimulation, including radiation) leads to the activation of a large group of about 500 enzymes, phosphorylases, which amplify the stimulation, and cause the cell to respond by becoming active in many ways, for example, by stopping the synthesis of glycogen, and beginning its conversion to glucose to provide energy for the adaptive responses, that include the activation of genes and the synthesis or destruction of proteins. Another set of enzymes, the phosphatases, remove the activating phosphate groups, and allow the cell to return to its resting state.
The “molecular” endocrinologists and geneticists are committed to a reductionist view of life, the view that DNA is the essence, the secret, of life, and that it controls cells through its interactions with smaller molecules, such as the hormone receptors.
黄体酮阻止增殖和促进分化的方法之一是保持视网膜母细胞瘤蛋白处于未磷酸化的活性保护状态(Gizard等，2006)雌激素和黄体酮对该蛋白的影响是相互的(Chen等，2005)。我很难想象李氏夫妇不知道这些激素对文华的视网膜母细胞瘤基因产物的影响。
蛋白质的失活hyperphosphorylation是一个通用的生物过程的一部分,激活的细胞(由伤害或紧张或激素或其他刺激,包括辐射)导致一大群约500的激活酶、磷酸化酶,放大的刺激,通过多种方式使细胞变得活跃，例如停止糖原的合成，并开始将其转化为葡萄糖，为适应性反应提供能量，包括基因的激活和蛋白质的合成或破坏。另一组酶，即磷酸酶，去除激活的磷酸基，使细胞恢复到静止状态。
“分子”内分泌学家和遗传学家对生命持一种还原论的观点，认为DNA是生命的本质和秘密，它通过与更小的分子(如激素受体)的相互作用来控制细胞。
The idea of hormone receptors can be traced directly to the work of Elwood Jensen, who started his career working in chemical warfare, at the University of Chicago. Jensen claims that an experiment he did in the 1950s “caused the demise” of the enzymic-redox theory of estrogen's action, by showing that uterine tissue can't oxidize estradiol, and that its only action is on the genes, by way of “the estrogen receptor.” But the uterus and other tissues do oxidize estradiol, and its cyclic oxidation and reduction is clearly involved in some of estrogen's toxic and excitatory effects.
For some reason, the military is still interested in hormone receptors. Lawrence National Weapons Laboratory (with its giant “predictive science” computer) is now the site of some of the anti-progesterone research.
Molecular biologists have outlined a chain of reactions, starting at the cell surface, and cascading through a series of phosphorylations, until the genes are activated. The cell surface is important, because cells are always in contact with something, and their functions and structure must be appropriate for their location. But the reductionist view of a network of phosphorylating enzymes ignores some facts.
Glycogen phosphorylase was the first enzyme whose activity was shown to be regulated by structural changes, allosterism. The active form is stabilized by phosphorylation, but this process takes seconds or minutes to develop, and the enzyme becomes active immediately when the cell is stimulated, for example in muscle contraction, within milliseconds. This kind of allosteric activation (or inactivation) can be seen in a variety of other enzymes, the cold-labile enzymes. A coherent change of the cell causes coordinated changes in its parts. These processes of enzymic regulation are fast, and can occur throughout a cell, practically simultaneously. Strict reductionists don't like to talk about them. “Network analysis” becomes irrelevant.
激素受体的概念可以直接追溯到Elwood Jensen的研究，他的职业生涯始于芝加哥大学的化学战争研究。詹森声称，他在20世纪50年代做的一项实验“导致了”雌激素作用的酶-氧化还原理论的“消亡”，实验表明子宫组织不能氧化雌二醇，它唯一的作用是通过“雌激素受体”作用于基因。但子宫和其他组织确实会氧化雌二醇，它的循环氧化和还原显然与雌激素的一些毒性和兴奋作用有关。
出于某种原因，军方仍然对激素受体感兴趣。劳伦斯国家武器实验室(拥有巨大的“预测科学”计算机)现在是一些抗孕酮研究的场所。
分子生物学家概述了一系列反应，从细胞表面开始，通过一系列磷酸化，直到基因被激活。细胞表面很重要，因为细胞总是与某些东西接触，它们的功能和结构必须与它们的位置相适应。但是磷酸化酶网络的还原论者的观点忽略了一些事实。
糖原磷酸化酶是第一个被证明受结构变化、变构作用调节的酶。活性形式通过磷酸化来稳定，但这一过程需要几秒钟或几分钟的发展，当细胞受到刺激时，例如在肌肉收缩时，酶立即变得活跃，在毫秒内。这种变构活化(或失活)可以在其他各种酶中看到，即冷不稳定酶。细胞的连续变化导致其各部分的协调变化。这些酶的调节过程是快速的，并且可以在整个细胞中几乎同时发生。严格的简化论者不喜欢谈论它们。“网络分析”变得无关紧要。
While a cell in general is activated by a wave of phosphorylation, certain processes (including glycogen synthesis) are blocked. When BRCA1 or retinoblastoma protein is hyperphosphorylated, its anti-estrogenic, anti-proliferative functions are stopped. The communication between cells is another function that's stopped by injury-induced phosphorylation.
Estrogen generally activates phosphorylases, and inactivates phosphatases. Progesterone generally opposes those effects.
Phosphorylation is just one of the regulatory systems that are relevant to the development of cancer, and that are acted on oppositely by estrogen and progesterone. To reduce the explanation for cancer to a gene or two or three may be an attractive idea for molecular endocrinologists, but the idea's simplicity is delusive.
Each component of the cell contributes complexly to the cell's regulatory stability. Likewise, a drug such as RU486 complexly modifies the cell's stability, changing thresholds in many ways, some of which synergize with progesterone (e.g., supporting the GABA system), others of which antagonize progesterone's effects (e.g., increasing exposure to prostaglandins).
There are other proteins in cells, besides the “hormone receptors,” that bind progesterone, and that regulate cell functions globally. The sigma receptor, for example, that interacts with cocaine to excite the cell, interacts with progesterone to quiet the cell. The sigma receptor is closely related functionally to the histones, that regulate the activity of chromosomes and DNA, and progesterone regulates many processes that control the histones.
当细胞通常被磷酸化波激活时，某些过程(包括糖原合成)被阻断。当BRCA1或视网膜母细胞瘤蛋白过度磷酸化时，其抗雌激素、抗增殖功能停止。细胞间的通讯是另一种因损伤引起的磷酸化而停止的功能。
雌激素通常能激活磷酸化酶，也能使磷酸酶失活。黄体酮通常会对抗这些影响。
磷酸化只是与癌症发展相关的调节系统之一，雌激素和黄体酮对其起相反的作用。对于分子内分泌学家来说，将癌症的解释简化为一个或两个或三个基因可能是一个有吸引力的想法，但这种想法的简单性是令人迷惑的。
细胞的每个组成部分都对细胞的调节稳定性起着复杂的作用。类似地，RU486这样的药物可以复杂地改变细胞的稳定性，在许多方面改变阈值，其中一些与孕酮协同(例如，支持GABA系统)，其他的拮抗孕酮的作用(例如，增加前列腺素的暴露)。
除了“激素受体”，细胞中还有其他蛋白质结合孕酮，并全面调节细胞功能。例如sigma受体，它与可卡因相互作用使细胞兴奋，与孕酮相互作用使细胞安静。西格玛受体在功能上与组蛋白密切相关，组蛋白调节染色体和DNA的活性，而孕酮调节许多控制组蛋白的过程。
The GABA receptor system, and the systems that respond to glutamic acid (e.g., the “NMDA receptors”) are involved in the inhibitory and excitatory processes that restrain or accelerate the growth of cancer cells, and progesterone acts through those systems to quiet cells, and restrain growth.
The inhibitor of differentiation, Id-1, is inhibited by progesterone, activated by estrogen (Lin, et al., 2000). Proteins acting in the opposite direction, PTEN and p21, for example, are activated by progesterone, and inhibited by estrogen.
The inflammatory cytokines, acting through the NFkappaB protein to activate genes, are generally oppositely regulated by estrogen and progesterone.
Prostaglandins, platelet activating factor, nitric oxide, peroxidase, lipases, histamine, serotonin, lactate, insulin, intracellular calcium, carbon dioxide, osmolarity, pH, and the redox environment are all relevant to cancer, and are affected systemically and locally by estrogen and progesterone in generally opposing ways.
About ten years ago, Geron corporation announced that it was developing products to control aging and cancer, by regulating telomerase, the enzyme that lengthens a piece of DNA at the end of the chromosomes. Their argument was that telomeres get shorter each time a cell divides, and that after about 50 divisions, cells reach the limit identified by Leonard Hayflick, and die, and that this accounts for the aging of the organism. Cancer cells are immortal, they said, because they maintain active telomerase, so the company proposed to cure cancer, by selling molecules to inhibit the enzyme, and to cure aging, by providing new enzymes for old people. However, Hayflick's limit was mainly the effect of bad culture methods, and the theory that the shortening of telomeres causes aging was contradicted by the finding of longer telomeres in some old people than in some young people, and different telomere lengths in different organs of the same person.
GABA受体系统和对谷氨酸作出反应的系统(例如，“NMDA受体”)参与抑制和兴奋过程，抑制或加速癌细胞的生长，而孕酮通过这些系统使细胞安静，抑制生长。
分化抑制剂Id-1被孕酮抑制，被雌激素激活(Lin, et al.， 2000)。相反方向的蛋白质，例如PTEN和p21，被孕酮激活，而被雌激素抑制。
炎症细胞因子通过NFkappaB蛋白激活基因，通常受到雌激素和孕酮的相反调节。
前列腺素、血小板激活因子、一氧化氮、过氧化物酶、脂肪酶、组胺、血清素、乳酸、胰岛素、细胞内钙、二氧化碳、渗透压、pH值和氧化还原环境都与癌症有关，并且受到全身和局部的雌激素和黄体酮的影响，但通常是相反的。
大约十年前，Geron公司宣布，他们正在开发通过调节端粒酶来控制衰老和癌症的产品，端粒酶是一种延长染色体末端DNA片段的酶。他们的论点是，每次细胞分裂，端粒都会变短，大约50次分裂后，细胞会达到伦纳德·海弗利克(Leonard Hayflick)所确定的极限，然后死亡，这就是有机体衰老的原因。他们说，癌细胞是不朽的，因为它们保持着端粒酶的活性，所以该公司提议通过出售抑制这种酶的分子来治疗癌症，通过为老年人提供新的酶来治疗衰老。然而，Hayflick的局限性主要在于不良培养方法的影响，端粒的缩短导致衰老的理论与一些老年人的端粒比一些年轻人的端粒长，以及同一个人不同器官的端粒长度不同的发现相矛盾。
But it's true that cancer cells have active telomerase, and that most healthy cells don't. It happens that telomerase is activated by cellular injury, such as radiation, that activates phosphorylases, and that it is inactivated by phosphatases. Estrogen activates telomerase, and progesterone inhibits it.
Molecular endocrinology is very important to the pharmaceutical industry, because it lends itself so well to television commercials and corporate stock offerings. Monsanto and the Pentagon believe they can use reductionist molecular biology to predict, manipulate, and control life processes, but so far it is only their ability to damage organisms that has been demonstrated.
Besides the early animal studies that showed experimentally that progesterone can prevent or cure a wide variety of tumors, the newer evidence showing that progesterone is a major protective factor against even breast cancer, would suggest that dishonest efforts to protect estrogen sales by preventing women from using natural progesterone will be causing more women to develop cancer.
但癌细胞确实有活性的端粒酶，而大多数健康细胞没有。端粒酶会被细胞损伤激活，比如辐射激活磷酸化酶，而它又会被磷酸酶灭活。雌激素激活端粒酶，而孕酮则抑制它。
分子内分泌学对制药行业非常重要，因为它非常适合电视广告和公司股票发行。孟山都和五角大楼相信他们可以利用还原分子生物学来预测、操纵和控制生命过程，但到目前为止，只有他们破坏生物体的能力得到了证实。
除了早期的动物实验表明孕酮可以预防或治愈多种肿瘤外，最新的证据表明，孕酮甚至是对抗乳腺癌的主要保护因素，这表明，通过阻止女性使用天然黄体酮来保护雌激素销售的不诚实努力将导致更多女性患癌症。
The recent report that the incidence of breast cancer in the United States fell drastically between 2002 and 2004, following the great decline in estrogen sales, shows the magnitude of the injury and death caused by the falsifications of the estrogen industry–a matter of millions of unnecessary deaths, just in the years that I have been working on the estrogen issue. The current campaign against progesterone can be expected to cause many unnecessary cancer deaths (e.g., Plu-Bureau, et al., Mauvais-Jarvis, et al.), while distracting the public from the culpability of the estrogen industry.
最近的一份报告显示，在2002年至2004年间，随着雌激素销量的大幅下降，美国的乳腺癌发病率急剧下降。报告显示，雌激素行业造假造成的伤害和死亡的严重程度——数百万人不必要地死亡，这几年我一直在研究雌激素问题。目前反对黄体酮的运动可能会导致许多不必要的癌症死亡(例如，plus - bureau等人，mauvaisjarvis等人)，同时分散公众对雌激素行业的罪责。
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