Aging, estrogen, and progesterone

by Raymond Peat

“Estrogen” refers not just to a family of steroids but to a class of substances that can produce approximately the same effects as estradiol and its metabolites.

“雌激素”不仅指类固醇家族，还指一种能产生与雌二醇及其代谢物大致相同效果的物质。

Even before the pure substance was isolated in the 1930s, the effects of fluid from ovarian follicles were studied. It was soon discovered that many chemicals could produce similar effects.

By the middle of the century, many toxic effects of the estrogens were known, and more are being discovered.

早在20世纪30年代这种纯物质被分离出来之前，人们就开始研究来自卵泡的液体的作用。不久就发现许多化学物质也能产生类似的效果。

到本世纪中叶，雌激素的许多毒性作用已经为人所知，而且还在不断被发现。

Cancer, abnormal blood clotting, and infertility were known to be caused by estrogen before 1940, but at the same time the drug companies began calling estrogen “the female hormone,” and claiming that it would improve fertility.

在1940年之前，癌症、异常凝血和不孕症都是由雌激素引起的，但与此同时，制药公司开始称雌激素为“女性荷尔蒙”，并声称它能提高生育能力。

Since the 19th century, some people argued that aging was caused by hormonal deficiency; for example, the symptoms of thyroid deficiency resembled aging. The estrogen industry exploited this idea to create the “hormone replacement” business.

Some hormones do decrease with aging, but others increase.

自19世纪以来，一些人认为衰老是由激素缺乏引起的;例如，甲状腺机能丧失的症状与衰老相似。雌激素产业利用了这一理念，创造了“激素替代”业务。

有些激素确实会随着年龄的增长而减少，但有些则会增加。

All of the unpleasant consequences of estrogen excess happen to resemble some of the events of aging.

雌激素过量所造成的所有不愉快的后果都与衰老的某些事件类似。

If aging involves the same processes that are created by estrogen, then our knowledge of how to protect ourselves against estrogen can be used to protect ourselves against aging.

如果衰老和雌激素产生的过程是一样的，那么我们关于如何保护自己不受雌激素影响的知识可以用来保护我们自己不受衰老的影响。

Estrogen steals oxygen from mitochondria, shifting patterns of growth and adaptation.

雌激素从线粒体中窃取氧气，改变生长和适应的模式。

The balance between what a tissue needs and what it gets will govern the way that tissue functions, in both the short term and the long term. When a cell emits lactic acid and free radicals and the products of lipid peroxidation, it's reasonable to assume that it isn't getting everything that it needs, such as oxygen and glucose. With time, the cell will either die or adapt in some way to its deprived conditions.

从短期和长期来看，组织需要和获得之间的平衡将决定组织的功能。当细胞释放出乳酸、自由基和脂质过氧化产物时，我们有理由认为它没有得到所需的一切，比如氧气和葡萄糖。随着时间的推移，细胞要么死亡，要么以某种方式适应贫瘠的环境。

In aging, tissues generally atrophy, with loss of both substance and activity. Ordinarily, organisms react to stress with increased activity of the appropriate functional system, but when the stress is inescapable, organisms adopt the strategy of decreasing their demands, as in hibernation or the defensive inhibition that has been called parabiosis, the state of being “not fully alive.” In many situations, serotonin (which is closely associated with estrogen) seems to be an important inducer of this state. There are many indications that estrogen is a factor [e.g., Shvareva & Nevretdinova, 1989, Saltzman, et al., 1989] in functionally suppressed states such as hibernation, social subordination, learned helplessness and depression. Social subordination in animals often involves high estrogen and reduced fertility.

在衰老过程中，组织通常萎缩，物质和活性都丧失。通常情况下，生物体对压力的反应是适当的功能系统活动增加，但当压力不可避免时，生物体会采取减少需求的策略，如在冬眠或被称为异种共生的防御性抑制中，即“没有完全活着”的状态。在许多情况下，血清素(与雌激素密切相关)似乎是这种状态的重要诱因。有许多迹象表明雌激素是功能抑制状态(如冬眠、社会从属、习得性无助和抑郁)的一个因素[例如，Shvareva Nevretdinova, 1989, Saltzman等，1989]。动物的社会从属关系通常涉及高雌激素和低生育能力。

In good health, an animal's systems are designed so that certain tissues will be intensely but briefly stimulated by estrogen. This stimulation by estrogen doesn't produce the normal amount of carbon dioxide, so the tissue experiences oxygen deprivation, leading to swelling and cell division. (Along with the reduced carbon dioxide production, there is increased lipid peroxidation). Any similar stimulaton, whether it's produced by soot, or suffocation, or irradiation, will produce the broad range of estrogen's effects, beginning with inflammation but ending with atrophy or cancer if it is too prolonged.

在身体健康的情况下，动物的某些组织会受到雌激素强烈而短暂的刺激。雌激素的刺激不会产生正常量的二氧化碳，所以组织会缺氧，导致肿胀和细胞分裂。(随着二氧化碳产量的减少，脂质过氧化增加)。任何类似的刺激，无论是煤烟、窒息还是辐射，都会产生广泛的雌激素效应，开始时是炎症，但如果持续时间太长，最终会导致萎缩或癌症。

Although, as the 21st century begins, the US government hasn't decided whether to classify estrogen as a carcinogen, it was identified as a carcinogen in the first half of the 20th century–and a variety of carcinogens were found to be estrogenic.

虽然进入21世纪，美国政府还没有决定是否将雌激素归为致癌物，但它在20世纪上半叶就被确定为致癌物，并且发现多种致癌物都与雌激素有关。

Many people studying estrogen's biological effects observed that certain of its effects resembled the changes seen in aging, such as fibrotic changes of connective tissues, accelerated accumulation of age pigment, a tendency to miscarry, or the production of degenerative changes in various organs. But as far as I know, I was the first one to suggest that aging itself involves increased estrogen dominance. (Taking this perspective suggests many specific things to do for aging. And, if radiation injury, and stress, are “estrogenic,” it suggests that specific anti-estrogenic treatments could be appropriate.) I based my argument on the identity of the biochemical and tissue effects produced by aging and by estrogenic excess. At that time, techniques for the accurate measurement of very small amounts of estrogen hadn't been fully developed. I felt that the situation should have been clear, because of the previous decades of research, and I used that as the context for arguing that the reason for age-related infertility was the same as for estrogen-induced infertility or stress-related infertility, namely, the inability to deliver oxygen to the embryo. I thought of the developing embryo as a sensitive indicator of processes that occur throughout the body during aging and stress, and that the destruction of the embryo by the excessive estrogen of the birth control pill was closely analogous to the progressive loss of function that occus in so many tissues during normal aging.

许多研究雌激素生物学效应的人观察到，它的某些效应与衰老过程中看到的变化相似，如结缔组织的纤维化变化、衰老色素的加速积累、流产的倾向或各种器官的退行性变化的产生。但据我所知，我是第一个提出衰老本身与雌激素支配性增加有关的人。(从这个角度出发，我们可以为衰老做很多具体的事情。而且，如果辐射损伤和压力是“雌激素的”，这表明特定的抗雌激素治疗可能是合适的。)我的论点是基于衰老和雌激素过量所产生的生化和组织效应。当时，精确测量少量雌激素的技术还没有完全发展起来。我觉得这种情况应该是明确的,因为之前的几十年的研究,我使用的上下文认为老年性不孕的原因是一样的为雌不育或与压力有关的不孕症,即胚胎无法提供氧气。我认为发展中胚胎是一个敏感指标的过程,发生在整个身体在衰老和压力,过度的破坏胚胎的雌激素的避孕药密切类似于进步的损失函数,对在很多组织在正常老化。

After I wrote my dissertation, Terry Parkening, who had worked in the same lab, sent me data from rats, showing that his measurements confirmed the increase of estrogen with aging. Since then, many others have shown that either the absolute levels of estrogen, or the ratio of estrogen to the antiestrogens, increases with aging in a wide variety of organisms of both sexes, including humans.

In the 1970s, the claims about estrogen curing osteoporosis apparently had been debunked. At the time, that appeared to be the last of the major claims for the therapeutic properties of estrogen. Studies in dogs were starting to show that estrogen was an important cause of degenerative bone disease, as well as kidney disease, liver disease, thyroid disease, etc. Hormones used in contraceptives were producing cancer in dogs, as well as many other diseases, so dog research was widely abandoned by the drug industry/FDA, in favor of animals that were less sensitive, or differently sensitive, to the hormones. The claims that the industry was making were contradicted by the dog research, so they sought new animal “models” that wouldn't so clearly contradict their claims.

许多研究雌激素生物学效应的人观察到，它的某些效应与衰老过程中看到的变化相似，如结缔组织的纤维化变化、衰老色素的加速积累、流产的倾向或各种器官的退行性变化的产生。但据我所知，我是第一个提出衰老本身与雌激素支配性增加有关的人。(从这个角度出发，我们可以为衰老做很多具体的事情。而且，如果辐射损伤和压力是“雌激素的”，这表明特定的抗雌激素治疗可能是合适的。)我的论点是基于衰老和雌激素过量所产生的生化和组织效应。当时，精确测量少量雌激素的技术还没有完全发展起来。我觉得这种情况应该是明确的,因为之前的几十年的研究,我使用的上下文认为老年性不孕的原因是一样的为雌不育或与压力有关的不孕症,即胚胎无法提供氧气。我认为发展中胚胎是一个敏感指标的过程,发生在整个身体在衰老和压力,过度的破坏胚胎的雌激素的避孕药密切类似于进步的损失函数,对在很多组织在正常老化。

A great advantage, for the drug industry, of using rats instead of dogs is that expensive, and often embarrassing, long-term experiments aren't possible in such short-lived animals. Rats die when their tissues still appear to be relatively young. Although excess prolactin (resulting from excess estrogen) in humans is an important cause of osteoporosis, in rats at a certain age and on a certain diet, hyperprolactinemia can stimulate bone growth. [Piyabhan, et al., 2000, Yeh, et al., 1996] This trait of rats could be very advantageous to the estrogen industry.

对于制药业来说，用老鼠代替狗的一个巨大优势是昂贵，而且经常令人尴尬，长期的实验不可能在如此短命的动物身上进行。当老鼠的组织还相对年轻时，它们就会死亡。虽然人类体内过量的催乳素(由过量的雌激素引起)是骨质疏松症的重要原因，但在一定年龄和一定饮食的大鼠中，高催乳素血症可刺激骨骼生长。[Piyabhan, et al.，2000, Yeh, et al.， 1996]大鼠的这种特性可能对雌激素产业非常有利。

All of the maladies caused by estrogen excess appear to develop in the same way that it interferes with pregnancy, by driving the tissue to require more energy and oxygen than can be delivered to it. Necrosis, the death of sections of tissue, was produced acutely by extreme overdoses of estrogen, or gradually by less extreme overdoses, and if the estrogenic stimulation was milder but very prolonged, the result would usually be tumors, sometimes developing in the midst of atrophy or necrosis. An overdose of estrogen was used to shrink breasts and prevent lactation, and an even larger dose was used to kill breast tissue in treating cancer. A recent study (Toth, et al., 2000) shows that, at least in women, estrogen is closely associated with the general loss of fat-free tissue with aging. This shows a close association between the generalized atrophy of aging and the amount of estrogen in the tissues.

所有由雌激素过量引起的疾病似乎都以干扰怀孕的同样方式发展，通过驱动组织需要比输送更多的能量和氧气。坏死，即组织切片的死亡，是由过量雌激素引起的剧烈反应，或由不太过量雌激素引起的逐渐反应，如果雌激素刺激较轻但很长时间，结果通常是肿瘤，有时在萎缩或坏死的过程中发展。过量的雌激素被用来缩小乳房和防止哺乳，而更大剂量的雌激素被用来杀死乳腺癌组织。最近的一项研究(Toth, et al, 2000)表明，至少在女性中，雌激素与随着年龄增长而减少的无脂肪组织密切相关。这显示了衰老的广泛性萎缩和组织中雌激素的数量之间的密切联系。

In the case of the embryo that can't implant in the aged or estrogenized uterus, it is because oxygen is being consumed so fast by the uterus that very little is available for the embryo. The uterus is, effectively, in an inflamed state, and the embryo is in a state that requires abundant oxygen. The general loss of tissue that Toth associated with increased estrogen follows many of the same steps that occur in the failure of the embryo to implant in the uterus: Glycogen is depleted in futile oxidative cycles, protein synthesis is inhibited, lipid peroxides and free radicals accumulate, cellular defensive and repair processes replace normal functioning.

在胚胎不能植入衰老或雌激素化的子宫的情况下，这是因为子宫消耗的氧气非常快，胚胎能获得的氧气非常少。子宫实际上处于炎症状态，而胚胎则需要充足的氧气。托特认为，与雌激素增加相关的组织的一般损失遵循了胚胎在子宫内植入失败的许多相同步骤:糖原在无用的氧化循环中被耗尽，蛋白质合成被抑制，脂质过氧化物和自由基积聚，细胞防御和修复过程取代正常功能。

(With aging, the loss of glycogen in the brain has serious consequences, including insomnia. Estrogen's depletion of glycogen in other tissues is probably important for their functioning, and thyroid and progesterone are known to help maintain the glycogen stores.)

(随着年龄的增长，大脑中糖原的丢失会带来严重的后果，包括失眠。雌激素消耗其他组织中的糖原可能对它们的功能很重要，而甲状腺和黄体酮则有助于维持糖原的储存。)

In the last several years, according to the medical literature estrogen would seem to have outgrown nearly all of its bad traits. It protects the brain, the heart, the blood vessels, even the fetus, and it prevents many kinds of cancer, and improves memory, mood, and immunity. And it would still seem to be of great promise in treating breast cancer and prostate cancer, if we took some medical journals seriously. It achieves many of these nice things by functioning as an antioxidant and by increasing circulation, often acting through nitric oxide and serotonin or melatonin. Even though I have read thousands of the articles that said otherwise, the near unanimity of the current research literature can almost give me the feeling that things might not be exactly as they had seemed.

在过去的几年里，根据医学文献，雌激素似乎已经克服了它几乎所有的坏特性。它能保护大脑、心脏、血管，甚至胎儿，还能预防多种癌症，改善记忆力、情绪和免疫力。如果我们认真对待一些医学期刊的话，它在治疗乳腺癌和前列腺癌方面仍有很大的前景。它作为一种抗氧化剂，通过增加血液循环，通常通过一氧化氮和血清素或褪黑素发挥作用，从而实现这些好处。尽管我读过成千上万的文章，但当前的研究文献几乎一致，几乎让我觉得事情可能并不像它们看上去的那样。

In fact they aren't, but the change is in what passes for science, rather than in the way organisms respond to estrogen. Many little pictures are being presented, that seem to add up to a very different big picture. It is clear that this new picture is being painted by those who fund the research, and by some of those whose careers depend on that funding. The people who do the odd little studies of estrogen and cytokines, nitric oxide, regulatory genes, and so on, are usually getting the data they claim to get, and if they draw speculative conclusions about what their study means medically, that's their privilege. But hundreds of these little publications that would be harmless individually, add up to national policy endorsed by the FDA and other powerful agencies–they add up to the same sort of criminal conspiracy that the tobacco industry and its researchers perpretrated throughout the twentieth century.

事实并非如此，但这种变化是在科学层面上发生的，而不是在生物体对雌激素的反应方式上。许多小的画面被呈现出来，这些小的画面加起来似乎是一个非常不同的大画面。很明显，这一新的图景是由那些资助研究的人以及一些职业生涯依赖这些资助的人描绘的。那些对雌激素和细胞因子、一氧化氮、调控基因等进行少量研究的人，通常都得到了他们声称得到的数据，如果他们对自己的研究在医学上意味着什么得出推测性结论，那是他们的特权。但是成百上千的这样的小出版物本身是无害的，加起来就成了食品和药物管理局和其他权威机构支持的国家政策——它们加起来就成了烟草行业及其研究人员在整个20世纪犯下的同样的犯罪阴谋。

Journals that are considered to be the best in their field publish many papers that simply misrepresent some of the basic facts, while interpreting experimental results that would otherwise have unpleasant commercial implications.

被认为是该领域最好的期刊发表的许多论文只是歪曲了一些基本事实，而对实验结果的解释则会带来令人不快的商业影响。

For example, the follicular phase is a time of low steroid production by the ovary, until near the end of the phase, just before ovulation, when estrogen rises. The luteal phase is a time of high estrogen and high progesterone synthesis. Many publications describe the follicular phase as a time of high estrogen, and the luteal phase as a time of low estrogen, roughly the opposite of the actual situation. And an even larger number of studies get the results they want by using a short exposure to estrogen to study something which takes a long time to develop.

例如，卵泡期是卵巢产生低激素的时期，直到接近卵泡期的末期，即排卵前，雌激素上升。黄体期是高雌激素和高孕酮合成的时期。许多出版物将卵泡期描述为高雌激素期，而黄体期描述为低雌激素期，这与实际情况大致相反。还有更多的研究通过短暂接触雌激素来研究需要很长时间才能形成的东西，从而得到他们想要的结果。

In the last few years, one of the most common tricks of estrogen promotion is to argue that estrogen protects against heart disease and Alzheimer's disease because it relaxes blood vessels, by increasing the formation of nitric oxide. It does generally increase the formation of nitric oxide, but nitric oxide is a toxic free radical that plays a major role in degenerative diseases. And the inappropriate relaxation of blood vessels, coupled with increased clottability of the blood, is a major cause of pulmonary embolisms and venous disorders.

In studies of tendons, excess estrogen, aging, and cooking (the phenomenon of the curling pork chop) all caused hardening and contraction of the collagen. When people get to be 90 or 100 years old, the opening between their eyelids is sometimes contracted, presumably because of this process of collagen shrinkage. If this shrinkage of connective tissue affects the large blood vessels, they become narrower and stiffer, so that the blood has to travel faster if the same amount is to be delivered in the same time.

在过去的几年里，一种最常见的促进雌激素的把戏是争辩说雌激素可以预防心脏病和阿尔茨海默病，因为它通过增加一氧化氮的形成来松弛血管。它通常会增加一氧化氮的形成，但一氧化氮是一种有毒的自由基，在退行性疾病中起主要作用。而血管不适当的松弛，加上血液的凝结性增加，是肺栓塞和静脉疾病的主要原因。

在对肌腱的研究中，过量的雌激素、衰老和烹饪(猪排的卷曲现象)都导致了胶原蛋白的硬化和收缩。当人们90岁或100岁时，眼睑之间的开口有时会收缩，可能是因为胶原蛋白收缩的过程。如果结缔组织的收缩影响到大血管，它们就会变窄、变硬，因此，如果要在同样的时间内输送同样数量的血液，就必须更快地移动。

Ultrasound can be used to measure the velocity of the blood flow, and increased velocity will correspond to constriction of the channel, if the same amount of blood is being delivered. But many people praise estrogen's vascular benefits on the basis of tests showing increasedblood velocity in large arteries such as the aorta, without evidence that more blood is being circulated. With aging, as arteries become constricted, increased blood velocity is taken as evidence of the pathology. Velocity measurements have to be interpreted in the contexts of tissue perfusion, cardiac output, etc. When the diameter of the artery is considered along with the velocity of the blood, the volume of flow can be determined, and then it appears that progesterone increases blood flow, while estrogen can decrease it. [Dickey and Hower, 1996.] This would be consistent with the known ability of an estrogen excess to cause retarded growth of the fetus, as well as specific birth defects.

Estrogen does increase the blood flow to particular organs, but apparently less than it increases their oxygen demand, as can be seen from the color change of estrogenized tissues, toward purple, rather than pink. Measurements of oxygen tension in the tissue show that estrogen decreases the relative availability of oxygen. And when the level of estrogen is very high, metabolically demanding tissues, such as the kidney and adrenal cortex, simply die, especially under conditions that restrict blood flow. [E.g., Kocsis, et al., 1988, McCaig, et al., 1998, Yang, et al., 1999.] When estrogen's effects overlap with the stimulating effects of other hormones, such as pituitary hormones, particular organs undergo something similar to “excitotoxicity.” When estrogen overlaps with endotoxin (as it tends to do), multiple organ failure is the result.

超声可以用来测量血流速度，如果等量的血液被输送，血流速度的增加将与通道的收缩相对应。但许多人称赞雌激素对血管的益处，因为他们的试验显示，大动脉(如主动脉)的血流速度加快，但没有证据表明有更多的血液在循环。随着年龄的增长，动脉变得狭窄，血流速度的增加被认为是病理的证据。速度测量必须在组织灌注、心输出量等情况下进行解释。当考虑动脉直径随血流速度变化时，就可以确定血流量，这时就会出现孕激素增加血流量，而雌激素减少血流量的情况。[迪基和豪尔，1996年。这与已知的雌激素过量会导致胎儿发育迟缓以及特定的出生缺陷的能力是一致的。

雌激素确实增加了流向特定器官的血流量，但显然比它增加器官的氧气需求要少，这从被雌激素化的组织的颜色变化中可以看出，它们变成了紫色，而不是粉红色。组织中氧张力的测量显示雌激素降低了氧的相对可用性。当雌激素水平非常高时，需要代谢的组织，如肾脏和肾上腺皮质，就会死亡，尤其是在限制血液流动的情况下。例如，Kocsis等人，1988,McCaig等人，1998,Yang等人，1999。当雌激素的作用与其他激素(如垂体激素)的刺激作用重叠时，某些器官就会发生类似于“兴奋性毒性”的反应。当雌激素与内毒素重叠时(通常如此)，就会导致多器官衰竭。

The simple need for more oxygen is a stimulus to increase the growth of blood vessels, and estrogen's stimulation of non-mitochondrial oxygen consumption with the production of lactic acid stimulates blood vessel formation. Progesterone, by increasing oxidative efficiency, opposes this “angiogenic” (neovascularization) effect of estrogen.

单纯的需要更多的氧气是一种促进血管生长的刺激，而雌激素刺激非线粒体氧的消耗与乳酸的产生刺激血管的形成。孕酮通过增加氧化效率，对抗雌激素的“血管生成”(新生血管)作用。

Szent-Gyorgyi spent most of his career studying muscles–from the anal sphincter to pigeon breast to tense goats. One of his most interesting experiments investigated the effects of estrogen and progesterone on the heart muscle. He showed that estrogen excess prevents the increase of stroke volume as the speed increases, but that progesterone increases the stroke volume as the heart accelerates, making pumping more effective without unnecessary acceleration of the heart rate. These effects are parallel to Selye's observation that estrogen imitates the shock reaction.

圣捷尔吉职业生涯的大部分时间都在研究肌肉——从肛门括约肌到鸽胸肌再到紧张的山羊。他最有趣的实验之一是研究雌激素和黄体酮对心肌的影响。他指出，过量的雌激素会阻止每搏流量随着心跳速度的增加而增加，而孕酮则会随着心跳加速而增加每搏流量，这使得泵血更有效，而不会造成不必要的心率加速。这些效果与Selye观察到的雌激素模仿休克反应是一致的。

In shock, the blood pressure decreases, mainly because the blood volume decreases. Water is taken up by the tissues, out of the blood. Much of the remaining blood volume is accumulated in the relaxed veins, and little is returned to the heart, yet the increased need for circulation accelerates the heart, causing each stroke to pump only a small amount. The reduced blood pressure caused many people to think that adrenaline would help to improve the circulation, but actually the “resistance arteries,” small arteries that provide blood to the arterioles and capillaries, are constricted in shock, (Lin, et al., 1998,) and adrenaline usually makes the situation worse. When tissue is poorly oxygenated (or is exposed to estrogen) it takes up water, swelling and becoming more rigid, turgid. (It also takes up calcium, especially under the influence of estrogen, causing muscles to contract.) This swelling effect will be much more noticeable in small arteries than in major arteries with very large channels, but when the effect is prolonged, it will affect even the heart, causing it to “stiffen,” weakening its ability to pump. There is some evidence that estrogen can make large arteries stiffen, over a span of a few months. (Giltay, et al., 1999)

Estrogen, by creating an oxygen deficiency, stimulates first swelling, and then collagen synthesis. Collagen tends to accumulate with aging.

休克时，血压下降，主要是因为血容量减少。水从血液中被组织吸收。剩余的血量大部分在放松的静脉中积累，只有很少的血量返回心脏，然而血液循环需求的增加加速了心脏，导致每次跳动只泵出少量的血。血压降低使许多人认为肾上腺素有助于改善血液循环，但实际上，“阻力动脉”，即向细动脉和毛细血管提供血液的小动脉，在休克时收缩(Lin, et al.， 1998)，而肾上腺素通常会使情况更糟。当组织缺氧(或暴露在雌激素下)时，它会吸水，肿胀，变得更硬，肿胀。(它也会吸收钙，尤其是在雌激素的作用下，会导致肌肉收缩。)这种肿胀效应在小动脉中比在通道非常大的大动脉中更为明显，但当这种效应延长时，它甚至会影响心脏，导致其“僵硬”，削弱其泵血能力。有证据表明，在几个月的时间内，雌激素可以使大动脉硬化。(Giltay等，1999)

雌激素，通过造成缺氧，首先刺激肿胀，然后刺激胶原蛋白的合成。胶原蛋白会随着年龄的增长而积累。

In shock, the cells are in a very low energy state, and infusions of ATP have been found to be therapeutic, but simple hypertonic solutions of glucose and salt are probably safer, and are very effective. The low energy of cells causes them to take up water, but it also causes the veins (which always receive blood after most of its oxygen and nutrients have been extracted) to lose their tone, allowing blood to pool in them, instead of returning to the heart. (Abel and Longnecker, 1978) This contributes to varicose veins (Ciardullo, et al., 2000), and to orthostatic hypotension, which is seen in women who are exposed to too much estrogen, and very frequently in old people.

The energy failure resulting from estrogen excess has been remarkably well characterized (but the meaning of this for the cell hasn't been explored). The electron transfer process of the mitochondria is interrupted by the futile redox cycling catalyzed by estrogens.

在休克时，细胞处于非常低的能量状态，注射ATP已被发现有治疗作用，但简单的高渗葡萄糖和盐溶液可能更安全，而且非常有效。细胞的低能量导致它们吸收水分，但也会导致静脉(在大部分氧气和营养物质被提取后，静脉总是接受血液)失去张力，使血液聚集在血管中，而不是返回心脏。(Abel and Longnecker, 1978)这导致静脉曲张(Ciardullo, et al.， 2000)和直立性低血压，这在接触过多雌激素的女性和老年人中很常见。

雌激素过量导致的能量衰竭已经被很好地描述了(但这对细胞的意义还没有被探索)。在雌激素的催化下，线粒体的电子传递过程被无用的氧化还原循环所打断。

Good sleep requires fairly vigorous metabolism and a normal body temperature. In old age, the metabolic rate is decreased, and sleep becomes defective. Protein synthesis declines with aging, as the metabolic rate slows. At least in the brain, protein synthesis occurs most rapidly in deep sleep. [Nakanishi, et al., 1997; Ramm and Smith, 1990]

良好的睡眠需要相当旺盛的新陈代谢和正常的体温。在老年，新陈代谢率下降，睡眠变得有缺陷。蛋白质合成随着年龄的增长而下降，因为新陈代谢速度减慢。至少在大脑中，蛋白质合成在深度睡眠时发生得最快。

In old age, the catabolic hormones such as cortisol are relatively dominant [Deuschle, et al., 1998], and even in youth, cortisol rises during darkness, reaching its peak around dawn. Even in young women, bone loss occurs almost entirely during the night, when cortisol is high. The hormones that are commonly said to prevent bone loss, estrogen and growth hormone, are high at night, rising along with cortisol. Estrogen causes growth hormone to increase, and in the morning, young women's growth hormone has been found to be 28 times higher than men's.[Engstrom, et al., 1999] The growth hormone response to estrogen is probably the result of the changed use of glucose under estrogen's influence, making it necessary to mobilize free fatty acids from tissues. While estrogen is usually highest at night, progesterone is lowest during the night. These observations should suggest that progesterone, not estrogen, is the bone protective substance.

在老年，像皮质醇这样的分解代谢激素相对占主导地位[Deuschle, et al.， 1998]，甚至在青年时期，皮质醇在黑暗中上升，在黎明前后达到顶峰。即使是年轻女性，骨质流失也几乎完全发生在皮质醇水平较高的夜间。通常被认为是防止骨质流失的激素，雌激素和生长激素，在晚上会很高，和皮质醇一起上升。雌激素会导致生长激素增加，在早上，年轻女性的生长激素比男性高28倍。[Engstrom等，1999]生长激素对雌激素的反应可能是在雌激素的影响下改变了葡萄糖的使用，使其有必要从组织中动员游离脂肪酸。雌激素通常在夜间最高，而孕酮则在夜间最低。这些观察表明，黄体酮，而不是雌激素，是骨骼保护物质。

The disappearance of water from the blood, as it moves into the tissues during the night, makes sleep resemble a state of shock or inflammation. Since rats, that are active at night, experience the same blood thickening, it's actually the darkness, rather than sleep, that creates this “inflammatory” state. Estrogen increases, and acts through, the inflammatory mediators, serotonin and histamine, to increase vascular leakiness, at the same time that it causes cells to take up water and calcium. The formation of lactic acid, in place of carbon dioxide, tends to coordinate these effects.

当水分在夜间进入组织时，从血液中消失，使睡眠类似于休克或炎症状态。因为老鼠在晚上活动，也经历了同样的血液增厚，实际上是黑暗，而不是睡眠，造成了这种“炎症”状态。雌激素增加并通过炎症介质，血清素和组胺，增加血管渗漏，与此同时，它导致细胞吸收水和钙。乳酸的形成代替了二氧化碳，趋向于协调这些影响。

In sleep, as in shock, hyperventilation is common, and it sometimes produces extreme vasoconstriction, because of the loss of carbon dioxide.

在睡眠中，和休克时一样，过度换气是很常见的，由于二氧化碳的流失，它有时会导致极端的血管收缩。

Since glucose and salt are used to treat shock (intravenous 7.5% salt solutions are effective), it seems appropriate to use carbohydrate (preferably sugar, rather than starch) and salty foods during the night, to minimize the stress reaction. They lower adrenalin and cortisol, and help to maintain the volume and fluidity of blood. Thyroid, to maintain adequate carbon dioxide, is often all it takes to improve the blood levels of salt, glucose, and adrenalin.

由于葡萄糖和盐被用来治疗休克(静脉注射7.5%的盐溶液是有效的)，似乎在夜间使用碳水化合物(最好是糖，而不是淀粉)和咸的食物，以减少应激反应。它们能降低肾上腺素和皮质醇，帮助维持血液的容量和流动性。甲状腺，维持足够的二氧化碳，通常是提高血液中的盐，葡萄糖和肾上腺素水平所需要的。

Temperature falls during sleep. Recent experiments show that hypothermia during surgery exacerbates the edema produced by stress, and that hypertonic (hyperosmotic or hyperoncotic) solutions alleviate the swelling. It is possible that light's action directly on the cells helps them to prevent swelling, and that the body's infrared emissions have a similar function. Whatever the mechanism is, adequate temperature improves sleep, and an excessive nocturnal temperature drop probably increases edema, with all of its harmful consequences.

睡眠时温度会下降。最近的实验表明，手术中降低体温会加剧压力引起的水肿，而高渗(高渗或高渗)溶液可以缓解肿胀。光线直接作用在细胞上可能有助于它们防止肿胀，身体的红外发射也有类似的功能。无论其机制是什么，充足的温度可以改善睡眠，而夜间温度的过度下降可能会增加水肿，并带来所有有害的后果。

At least some of the redox cycles involving NAD/NADH and NADP/NADPH keep electrons from moving beyond ubiquinone (coQ10) and energizing the mitochondria. The cycle that makes nitric oxide is one of these, but some forms of estrogen participate directly as catalysts in this energy-stealing process. One of the effects of blocking electron transfer in the mitochondria is to lower the energy charge of the cells, mimicking the function of the age-damaged mitochondria. Glutathione and protein sulfhydryls are oxidized, because the normal energy pathways that maintain them have been disrupted.

至少有一些涉及NAD/NADH和NADP/NADPH的氧化还原循环会阻止电子越过泛素(coQ10)并激活线粒体。制造一氧化氮的循环就是其中之一，但某些形式的雌激素作为催化剂直接参与这个能量窃取过程。在线粒体中阻断电子传递的作用之一是降低细胞的能量电荷，模仿衰老损伤的线粒体的功能。谷胱甘肽和蛋白质巯基被氧化，因为维持它们的正常能量途径被破坏了。

Estrogen directly lowers the temperature, while progesterone raises the temperature. Estrogen sets the brain's temperature regulator lower, but, acting through serotonin and other mediators, it can actually lower the metabolic rate, too.

雌性激素直接降低体温，而孕酮则升高体温。雌性激素降低了大脑的温度调节器，但是，它通过血清素和其他介质发挥作用，实际上也可以降低代谢率。

Far from being just the “hormone of estrus,” estrogen, in the form of estradiol and the related steroids, plays a role in organisms as diverse as yeasts, worms and mollusks, and in modifying the function of practically every type of animal cell–skin, nerve, muscle, bone, hair, gland, etc. But, as more and more of its functions come to be understood, it turns out that many toxic chemicals and stressful physical processes can activate the same functions, and that estrogen's association with the functions of stress makes it a kind of window into some universal biological functions.

雌激素远非仅仅是“发情激素”，它以雌二醇和相关类固醇的形式存在于各种各样的有机体中，如酵母、蠕虫和软体动物中，并在几乎所有类型的动物细胞——皮肤、神经、肌肉、骨骼、毛发、腺体等——的功能中发挥作用。但是，随着人们对它的功能越来越多的了解，事实证明，许多有毒的化学物质和有压力的物理过程可以激活同样的功能，而雌激素与压力功能的关联使它成为一种了解某些普遍生物功能的窗口。

When Hans Selye brought it to our attention that “stress” was a general life process, he began a process of generalization that led people to be able to see that the changes of aging were also the result of complex interactions between organisms and their environment, rather than some genetic program that operates like a clock running down.

当汉斯Selye把我们的注意力,“压力”是一个一般的生活过程中,他开始一个泛化的过程,让人们能够看到衰老的变化也复杂有机体与环境之间的相互作用的结果,而不是一些遗传程序,就像时钟运行。

When W. Donner Denckla demonstrated that the removal of an animal's pituitary (or, in the case of an octopus, its equivalent optic gland) radically extended the animal's life span, he proposed the existence of a death hormone in the pituitary gland. But the case of the octopus makes it clear that the catabolic, death-inducing hormone is produced by the ovary, under the influence of the optic gland's gonadotropins. This sacrifice of “the old” (the individual) for “the new” (the progeny) is analogous to the tissue wasting we see under the influence of estrogen, as it stimulates cell division.

当w·唐纳·登克拉(W. Donner Denckla)证明切除动物的脑垂体(或者章鱼的等效视神经腺)从根本上延长了动物的寿命时，他提出脑垂体中存在一种死亡激素。但章鱼的例子清楚地表明，这种分解代谢、导致死亡的激素是由卵巢在视腺促性腺激素的影响下产生的。这种牺牲“老的”(个人)为“新的”(后代)，类似于我们在雌激素影响下看到的组织损耗，因为它刺激细胞分裂。

In Selye's classical stress, the destruction of tissues by the catabolic hormones makes sense in terms of the “functional system” described by Anokhin, in which the hormones of adaptation dissolve one tissue for use by the system which is adaptively functioning, with the production of carbon dioxide by the functional tissue, stabilizing it and regulating the adequate delivery of blood.

Progesterone is both an anticatabolic hormone and an antiestrogenic hormone, and in both cases, it protects the functional systems from atrophy.

The extreme generality of the phenomenon of “estrogenicity” that was built up during the twentieth century has taken the concept beyond the specific functions of estrus, and reproduction, and the activation of genetic programs of the female animal, to make it necessary to see it as a way that living substance responds to certain kinds of stimulus. And these ways of responding turn out to be involved in the complex but coherent ways that organisms respond to aging.

Selye gave various names to the biology of stress, but the “general adaptation syndrome”expressed the idea accurately. But the biology of estrogenicity, like the biology of aging, is so central that any name is likely to be misleading. The historical accident of naming a hormone for estrus shouldn't keep us from thinking about the way estrogen affects our energetics and structure, and how those processes relate to aging, atrophy, cancerization, etc.

在Selye经典压力的描述中：破坏组织的分解代谢的激素有意义的“功能系统”被Anokhin,荷尔蒙的适应解散一个组织使用的系统自适应功能,生产二氧化碳的功能组织,稳定它并调节足够的血液输送。

黄体酮既是一种抗代谢激素，也是一种抗雌激素激素，在这两种情况下，它都能保护功能系统免受萎缩。

“求偶性”的极端现象的普遍性,在二十世纪已经发情的特定功能之外的概念,和繁殖,雌性动物的遗传程序的激活,使有必要把它看作一种生活物质响应某些刺激。这些反应方式被证明与生物对衰老的复杂而连贯的反应方式有关。

Selye给压力的生物学起了不同的名字，但是“一般适应综合症”准确地表达了这个观点。但雌激素的生物学，就像衰老的生物学一样，是如此重要，以至于任何名称都可能会误导人。为发情期命名一种激素的历史偶然事件不应阻止我们思考雌激素如何影响我们的能量和结构，以及这些过程与衰老、萎缩、癌变等的关系。

While progesterone is probably the most perfect antiestrogenic hormone, and therefore an anti-stress and anti-aging hormone, the recognition of a wide variety of estrogen's effects has made it possible to adjust many things in our diet and environment to more perfectly oppose the estrogenic and age-accelerating influences.

虽然黄体酮可能是最完美的抗雌激素激素，因此是一种抗压力和抗衰老的激素，但对多种雌激素效应的认识，使我们有可能调整饮食和环境中的许多东西，以更完美地对抗雌激素和加速衰老的影响。

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Medicina (B Aires) 1998;58(2):171-8. [Myeloperoxidase as a factor of oxidative damage of the myocardium: inactivation of dihydrolipoamide dehydrogenase]. Gutierrez Correa J, Stoppani AO. “Myocardial dihydrolipoamide dehydrogenase (LADH) is inactivated after incubation at 30 degree C, with myeloperoxidase (MPO)-dependent systems.”

J Natl Cancer Inst 1981 Aug;67(2):455-9. Synergism of estrogens and X-rays in mammary carcinogenesis in female ACI rats. Holtzman S, Stone JP, Shellabarger CJ.

Br J Exp Pathol 1988 Apr;69(2):157-67. Effect of the anti-oestrogen tamoxifen on the development of renal cortical necrosis induced by oestrone + vasopressin administration in rats. Kocsis J, Karacsony G, Karcsu S, Laszlo FA. Bilateral renal cortical necrosis was observed after vasopressin administration in rats pretreated with oestrone acetate. Histochemical (succinic dehydrogenase, trichrome, periodic acid Schiff) and electronmicroscopic methods were used to examine how the anti-oestrogen, Tamoxifen, influences the development of this renal cortical necrosis. The experiments revealed that in most rats vasopressin did not induce renal tubular necrosis if the anti-oestrogen was administered simultaneously, even during oestrogen pretreatment. The results suggest that oestrogen receptors in the kidney are involved in the induction of renal cortical necrosis by vasopressin.

Br J Exp Pathol 1987 Feb;68(1):35-43. Histochemical and ultrastructural study of renal cortical necrosis in rats treated with oestrone + vasopressin, and its prevention with a vasopressin antagonist. Kocsis J, Karacsony G, Karcsu S, Laszlo FA. Renal cortical necrosis was induced by the administration of vasopressin to oestrogen-pretreated rats. Histochemical (succinic dehydrogenase, trichrome, perjod acid Schiff) and electronmicroscopic methods were applied to examine how the vasopressin antagonist d(CH2)5Tyr(Met)AVP influences the development of this renal cortical necrosis. The experiments revealed that vasopressin did not induce hypoxia or necrosis in the renal tubules if the antagonist was administered simultaneously, even after oestrogen pretreatment. The conclusion is drawn that this pressor antagonist may be of value for the prevention of renal cortical necrosis in rats or in human beings.

Invest Radiol 1979 Jul-Aug;14(4):295-9. Serioangiographic study of renal cortical necrosis induced by administration of estrin and vasopressin in rats. Kocsis J, Szabo E, Laszlo FA. We report a serioangiographic method in rats which permits assessment of the course and dimensions of the renal arteries, the durations of the arterial and venous phases, and the intensity and uniformity of the renal parenchymal filling. The procedure was employed to study the mechanism by which administration of vasopressin to rats pretreated with estrin leads to renal cortical necrosis. The pathogenetic significance of the spasm localized on the larger renal arteries was proved directly; the possible role of the arteriovenous shunt in the development of the renal ischemia was excluded.

Contrib Nephrol 1981;28:1-216. Renal cortical necrosis. Experimental induction by hormones. Laszlo FA.

Morphol Igazsagugyi Orv Sz 1974 Jan;14(1):8-12 [The effect os estrogen, ACTH and cortisone administration, as well as hypophysectomy on histological changes in unilateral renal hilus ligation]. [Article in Hungarian] Laszlo F, Monus Z.

Eur J Neurosci 1997 Feb;9(2):271-9. Positive correlations between cerebral protein synthesis rates and deep sleep in Macaca mulatta. Nakanishi H, Sun Y, Nakamura RK, Mori K, Ito M, Suda S, Namba H, Storch FI, Dang TP, Mendelson W, Mishkin M, Kennedy C, Gillin JC, Smith CB, Sokoloff L.

Can J Physiol Pharmacol 2000 Oct;78(10):757-65. Changes in the regulation of calcium metabolism and bone calcium content during growth in the absence of endogenous prolactin and during hyperprolactinemia: a longitudinal study in male and female Wistar rats. Piyabhan P, Krishnamra N, Limlomwongse L “Since endogenous prolactin has been shown to enhance food consumption, calcium absorption, and bone calcium turnover in the pregnant rat, the role of endogenous prolactin in the regulation of calcium metabolism was investigated in 3-day balance studies of female Wistar rats from the age of 3 to 11 weeks.” “Results showed that rapid growth occurred between 3 and 6 weeks with maximum fractional calcium absorption and calcium retention at 5 weeks of age in both sexes. The data also showed a physiological significance of endogenous prolactin in enhancing calcium absorption and retention in 5 week old rats. In an absence of prolactin, peak calcium absorption was delayed in 7-week old animals, and vertebral calcium content of 11-week old animals was reduced by 18%. Hyperprolactinemia in the AP group was found to enhance fractional calcium absorption and calcium retention at 7, 9, and 11 weeks and increased the femoral calcium content by 16%. It could be concluded that a physiological role of prolactin is the stimulation of calcium absorption and maintainance of bone calcium content during growth and development.”

Physiol Behav 1990 Nov;48(5):749-53. Rates of cerebral protein synthesis are linked to slow wave sleep in the rat. Ramm P, Smith CT. Using L-[1-14C]leucine autoradiography, rates of cerebral and local cerebral protein synthesis were studied during wakefulness, slow wave sleep (SWS) and REM sleep in the rat. In the cerebrum as a whole, the rate at which labelled leucine was incorporated into tissues was positively correlated with the occurrence of slow wave sleep. We failed to observe a significant correlation of protein synthesis rate with either wakefulness or REM sleep. As in the cerebrum as a whole, most discrete brain regions showed moderate positive correlations between the occurrence of SWS and rates of protein synthesis. There were no brain regions in which rates of protein synthesis showed striking correlations with sleep-wake states. Thus, the occurrence of SWS is associated with higher rates of protein synthesis throughout the brain. These data suggest that SWS sleep favors the restoration of cerebral proteins.

Surgery 1991 Oct;110(4):685-8; discussion 688-90. The effect of hypertonic saline resuscitation on bacterial translocation after hemorrhagic shock in rats. Reed LL, Manglano R, Martin M, Hochman M, Kocka F, Barrett J. “Recent work suggests that moderate hypovolemia causes gut arteriolar constriction, which is ameliorated by hypertonic saline resuscitation. Bacterial translocation should, therefore, be reduced when hypertonic saline (HS) is used as the resuscitative fluid.” “Compared to autotransfusion, hemodilutional resuscitation from hemorrhagic shock with hypertonic saline resulted in a significant reduction in bacterial translocation (p values were 0.03 and 0.04 for 3% and 7.5% hypertonic saline, respectively). The reduction in translocation after hypertonic saline resuscitation may be the consequence of microcirculatory alterations preventing gut hypoperfusion.”

Am J Physiol 1999 Feb;276(2 Pt 2):H563-71. Changes in resistance vessels during hemorrhagic shock and resuscitation in conscious hamster model. Sakai H, Hara H, Tsai AG, Tsuchida E, Johnson PC, Intaglietta M. “The unanesthetized hamster dorsal skinfold preparation was used to monitor diameters and blood flow rates in resistance arteries (small arteries, A0: diameter, 156 +/- 23 micrometers) and capacitance vessels (small veins, V0: 365 +/- 64 micrometers), during 45 min of hemorrhagic shock at 40 mmHg mean arterial pressure (MAP) and resuscitation. A0 and V0 vessels constricted significantly to 52 and 70% of the basal values, respectively, whereas precapillary arterioles (A1-A4, 8-60 micrometers) and collecting venules (VC-VL, 26-80 micrometers) did not change or tended to dilate. Blood flow rates in the microvessels declined to <20% of the basal values.”

Horm Behav 1998 Feb;33(1):58-74. Suppression of cortisol levels in subordinate female marmosets: reproductive and social contributions. Saltzman W, Schultz-Darken NJ, Wegner FH, Wittwer DJ, Abbott DH “Cortisol levels of cycling females were significantly higher than those of subordinates at all parts of the cycle, but were significantly higher than those of ovariectomized females only during the midcycle elevation. Unexpectedly, subordinates had significantly lower cortisol levels than ovariectomized females, as well as higher estradiol and estrone levels and lower progesterone and luteinizing hormone (LH) levels.”

Zh Evol Biokhim Fiziol 1989 Jan-Feb;25(1):52-9. [Seasonal characteristics of the functioning of the hypophysis-gonad system in the suslik Citellus parryi]. Shvareva NV, Nevretdinova ZG “In experiments on the arctic ground squirrel C. parryi, studies have been made on seasonal changes in the weight of testes, follicular diameter in the ovaries and the content of sex and gonadotropic hormones in the peripheral blood. Testicular involution and arrest of follicular development were observed in prehibernation period. During hibernation, follicular growth and the increase in the weight of testes take place.” “Estradiol secretion was noted in hibernating females, whereas progesterone was found in the blood only in May.”

Maturitas 1984 Nov;6(3):269-78. Spontaneous skin flushing episodes in the aging female rat. Simpkins JW. It is well known that with the loss of gonadal function most women experience hot flushes, characterized by a rapid regional increase in cutaneous blood flow. Animal models for this vasomotor syndrome have been elusive, thus hampering efforts to evaluate the endocrine and neuronal substrates of the hot flush. In this report, evidence is reported for the occurrence in aging female rats of spontaneous tail skin temperature (TST) fluctuations which are similar in amplitude, duration and frequency to hot flushes reported for peri-menopausal women. Paradoxically, these TST pulses occur in animals with senescent reproductive states in which serum estrogen levels are moderately elevated and ovariectomy eliminates these rat flushing episodes. This demonstration of steroid-dependent, spontaneous flushing episodes indicates that the aging female rat can be used to evaluate the neuronal and hormonal basis of vasomotor instability.

Carcinogenesis 1994 Nov;15(11):2637-43. The metabolism of 17 beta-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. Sipe HJ Jr, Jordan SJ, Hanna PM, Mason RP. Electron spin resonance (ESR) spectroscopy and oxygen consumption measurements using a Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by lactoperoxidase. Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO,molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine dinucleotide (NADH) to generate the NAD. radical. The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide radical, which is then spin-trapped by DMPO. The superoxide generated may either spontaneously dismutate to form hydrogen peroxide or react with another NADH to form NAD., thus propagating a chain reaction leading to oxygen consumption and hydrogen peroxide accumulation. Ascorbate inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate radical. These results demonstrate that the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence. The accumulation of intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently reported for female breast cancer tissue.

Endocrinol Metab Clin North Am 1995 Sep;24(3):531-47. Idiopathic edema. Pathogenesis, clinical features, and treatment. Streeten DH. “Idiopathic edema is usually orthostatic.” “It occurs almost exclusively in post-pubertal women. . . .”

Carcinogenesis 1995 Apr;16(4):891-5. Mitochondrial enzyme-catalyzed oxidation and reduction reactions of stilbene estrogen. Thomas RD, Roy D. “We have demonstrated for the first time that mitoplasts (i.e. mitochondria without outer membrane) were able to convert stilbene estrogen (diethylstilbestrol, DES) to reactive metabolites, which covalently bind to mitochondrial (mt)DNA. Depending on the cofactor used, mitochondrial enzymes catalyzed the oxidation and/or reduction of DES. DES was oxidized to DES quinone by peroxide-supported mitochondrial enzyme.” “DES quinone was reduced to DES by mitoplasts in the presence of NADH.” “DES quinone was also reduced to DES by pure diaphorase, a mitochondrial reducing enzyme, in the presence of NADH.” “These data provide direct evidence of mitochondrial enzyme-catalyzed oxidation and reduction reactions of DES. In the cell, activation of DES in the mitochondria (the organelle in which mtDNA synthesis, mtDNA repair and transcription systems are localized) is of utmost importance, because an analogous in vivo mitochondrial metabolism of DES through covalent modifications in mitochondrial genome may produce instability in the mitochondrial genome of the cells. These modifications may in turn play a role in the development of DES-induced hepatocarcinogenicity.”

J Clin Endocrinol Metab 2000 Apr;85(4):1382-7. Regulation of protein metabolism in middle-aged, premenopausal women: roles of adiposity and estradiol. Toth MJ, Tchernof A, Rosen CJ, Matthews DE, Poehlman ET. The age-related loss of fat-free mass (FFM) is accelerated in women during the middle-age years and continues at an increased rate throughout the postmenopausal period. Because protein is the primary structural component of fat-free tissue, changes in FFM are largely due to alterations in protein metabolism. Knowledge of the hormonal and physiological correlates of proteinmetabolism in middle-aged women, therefore, has important implications for understanding the mechanisms underlying changes in FFM. We measured leucine kinetics (expressed relative to FFM: micromol/kg FFM/h) in 46 middle-aged, premenopausal women (mean +/- SD, 47 +/- 3 yr) after an overnight fast (i.e. basal) and during euglycemic hyperinsulinemia (40 mU/m2/min) using a 5.5-h nfusion of [1-13C]leucine. Additionally, we measured insulin-stimulated glucose disposal by euglycemic hyperinsulinemic clamp, body composition by dual energy -ray absorptiometry, abdominal fat distribution by computed tomography, and hormone levels by RIA as possible correlates of protein metabolism. Under basal onditions, stepwise regression analysis showed that leucine appearance (i.e. protein breakdown) was related to percent body fat and serum estradiol (r2 = 40%; P < 0.01), and leucine oxidation was related to serum estradiol and percent ody fat (r2 = 26%; P < 0.05). Under euglycemic hyperinsulinemic conditions, no variables correlated with the percent change in leucine appearance. The percent change in leucine oxidation was related to intraabdominal adipose tissue area and glucose disposal rate (r2 = 48%; P < 0.01). Correlates and r2 values for nonoxidative leucine disposal (i.e. protein synthesis) under basal and euglycemic hyperinsulinemic conditions were similar to those observed for leucine appearance. From these results, we conclude that adiposity and/or serum estradiol may contribute to the regulation of protein metabolism and FFM in middle-aged, premenopausal women.

J Korean Med Sci 1999 Jun;14(3):277-85. The metabolic effects of estriol in female rat liver. Yang JM, Kim SS, Kim JI, Ahn BM, Choi SW, Kim JK, Lee CD, Chung KW, Sun HS, Park DH, Thurman RG. “Basal oxygen consumption of perfused liver increased significantly in estriol or ethanol-treated rats.” “These findings suggest that the metabolic effects of estriol (two mg per 100 mg body wt) can be summarized to be highly toxic in rat liver, and these findings suggest that oral administration of estrogens may induce hepatic dysfunctions and play a role in the development of liver disease.”

Bone 1996 May;18(5):443-50. Ovariectomy-induced high turnover in cortical bone is dependent on pituitary hormone in rats. Yeh JK, Chen MM, Aloia JF.. “Our results confirmed that OV increased and HX suppressed systemic and periosteal bone formation parameters in both bone sites, OV increased and HX suppressed the gain in bone size and bone mass. When OV rats were HX, the serum levels of osteocalcin and periosteal bone formation parameters of the tibial shaft and the fifth lumbar vertebrae were, however, depressed and did not differ from that of the HX alone. DXA results show that the effect of OV on bone size and bone mass is also abolished by HX. In conclusion, we have demonstrated that OV increases tibial and lumbar vertebral bone formation and bone growth and this effect is pituitary hormone dependent.”

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