Progesterone, not estrogen, is the coronary protection factor of women. by Raymond Peat
黄体酮才是女性的冠状动脉保护因子而非雌激素
In the 1940s, around the time that Hans Selye was reporting that estrogen causes shock, and that progesterone protects against many stress-related problems, the anthropologist Ashley Montague published The Natural Superiority of Women. Later, as I looked at the history of endocrine research, it seemed apparent that progesterone was responsible for many of the biological advantages of females, such as a longer average life-span, while testosterone was responsible for men’s advantage in muscular strength.
20世纪40年代，大约在汉斯·塞利(Hans Selye)报告雌激素会导致休克、黄体酮能预防许多与压力有关的问题的时候，人类学家阿什利·蒙塔古(Ashley Montague)发表了《女性的天然优势》(the Natural Superiority of Women)一书。后来，当我回顾内分泌研究的历史时，我发现孕激素对女性的许多生理优势都有明显的作用，比如延长平均寿命，而睾酮则对男性的肌肉力量有优势。
Although evidence of estrogen’s toxicity had been accumulating for decades, pharmaceutical promotion was finding hundreds of things to treat with estrogen, which they called “the female hormone.” By the 1940s, it was known to produce excessive blood clotting, miscarriage, cancer, age-like changes in connective tissue, premenstrual syndrome, varicose veins, orthostatic hypotension, etc., but, as Mark Twain said, a lie can run around the world before the truth gets its boots on.
尽管雌激素毒性的证据已经积累了几十年，但药物推广发现了数百种用雌激素治疗的药物，他们称之为“女性荷尔蒙”。到20世纪40年代，众所周知，它会导致过度凝血、流产、癌症、结缔组织的年龄样变化、经前综合症、静脉曲张、直立性低血压等等。但是，就像马克·吐温说的，谎言可以在真相大白之前传遍世界。
After the DES fiasco, in which “the female hormone” which had been sold to prevent miscarriages was proven to cause them, the estrogen industry decided to offer men the protection against heart attacks that women supposedly got from their estrogen. The men who received estrogen in the study had an increased incidence of heart attacks, so that campaign was postponed for about 30 years.
DES惨败后，雌激素行业决定为男性提供预防心脏病的保护，而女性本应从雌激素中获得这种保护。在研究中接受雌激素治疗的男性心脏病发病率增加，因此这项运动推迟了大约30年。
The Shutes used vitamin E to treat the excessive blood clotting caused by estrogen, and vitamin E was considered to be an estrogen antagonist. Estrogen affected the liver’s production of clot-regulating proteins, and it also relaxed large veins, allowing blood pooling that slowed the blood sufficiently to give it time to form clots before returning to the lungs. Early in the century, unsaturated fats were found to inactivate the proteolytic enzymes that dissolve clots, and vitamin E was known, by the 1940s, to provide protection against the toxicity of the unsaturated fats. The toxic synergy of estrogen and unsaturated fats had already been recognized.
舒特使用维生素E治疗雌激素引起的过多血凝，维生素E被认为是雌激素拮抗剂。雌激素会影响肝脏中凝块调节蛋白的生成，同时也会放松大静脉，使血液淤积在一起，从而使血液在返回肺部之前有足够的时间形成凝块。在本世纪初，人们发现不饱和脂肪可以使溶解凝块的蛋白水解酶失活，而到了20世纪40年代，人们发现维生素E可以防止不饱和脂肪的毒性。雌激素和不饱和脂肪的毒性协同作用已经被认识到。
But in the 1950s, the seed oil industry, ignoring the toxic, carcinogenic effects of the unsaturated oils, began intensified promotion of their products as beneficial foods. (Decades earlier, Mark Twain had reported on the plans of the cottonseed industry to make people eat their by-product instead of butter.)
但在20世纪50年代，籽油行业忽视了不饱和油的有毒和致癌作用，开始大力宣传其产品为有益食品。(几十年前，马克·吐温(Mark Twain)曾报道过棉籽工业计划让人们食用其副产品而不是黄油。)
While estrogen was being offered as the hormone that protects against heart attacks, the liquid vegetable oils were being advertised as the food that would prevent heart attacks. Just a few years after the estrogen industry suffered the setbacks of the DES and heart attack publicity, the oil industry cancelled some tests of the “heart protective diet,” because it was causing both more heart attacks and more cancer deaths.
当雌激素作为防止心脏病发作的激素被提供时，液体植物油被宣传为可以预防心脏病发作的食物。就在雌激素行业遭受DES和心脏病宣传的挫折后的几年，石油行业取消了一些“心脏保护饮食”的测试，因为它会导致更多的心脏病发作和更多的癌症死亡。
Somehow, these two fetid streams converged: Estrogen, like the unsaturated oils, lowered the amount of cholesterol in the blood, and an excess of blood cholesterol was said to cause heart attacks. (And, more recently, the estrogenic effects of the seed oils are claimed to offer protection against cancer.)
不知怎的，这两股恶臭的血液交汇在一起:雌激素，就像不饱和的油一样，降低了血液中的胆固醇含量，而血液中胆固醇过高据说会导致心脏病发作。(最近，人们还声称，这种籽油的雌激素作用可以预防癌症。)
The ability to lower the cholesterol “risk factor” for heart attacks became a cultural icon, so that the contribution of estrogen and unsaturated oils to the pathologies of clotting could be ignored. Likewise, the contribution of unsaturated fats’ lipid peroxidation to the development of atherosclerotic plaques was simply ignored. But one of estrogen’s long established toxic effects, the reduction of tone in veins, was turned into something like a “negative risk factor”: The relaxation of blood vessels would prevent high blood pressure and its consequences, in this new upside down paradigm. This vein-dilating effect of estrogen has been seen to play a role in the development of varicose veins, in orthostatic hypotension, and in the formation of blood clots in the slow-moving blood in the large leg veins.
降低心脏病“危险因素”胆固醇的能力成为了一种文化标志，因此雌激素和不饱和油对凝血病理的贡献可以被忽略。同样，不饱和脂肪的脂质过氧化对动脉粥样硬化斑块的发展的贡献也被简单地忽略了。但雌激素长期存在的毒性作用之一，即静脉张力的降低，却变成了一种类似于“负面风险因素”的东西:在这种新的倒置范式中，血管的松弛可以防止高血压及其后果。雌激素的这种静脉扩张作用已经被发现在静脉曲张的发展、直立性低血压和大腿部静脉中缓慢移动的血液凝块的形成中发挥作用。
When it was discovered that the endothelial relaxing factor was nitric oxide, a new drug business came into being. Nitroglycerine had been in use for decades to open blood vessels, and, ignoring the role of nitrite vasodilators in the acquired immunodeficiency syndrome, new drugs were developed to increase the production of nitric oxide. The estrogen industry began directing research toward the idea that estrogen works through nitric oxide to “improve” the function of blood vessels and the heart.
当发现内皮松弛因子是一氧化氮时，一种新的药物企业应运而生。几十年来，硝化甘油一直被用于打开血管，并且，忽略了亚硝酸盐血管扩张剂在获得性免疫缺陷综合征中的作用，开发了新的药物来增加一氧化氮的产生。雌激素产业开始将研究方向转向雌激素通过一氧化氮“改善”血管和心脏功能的想法。
(Besides the argument based on “risk factors,” many people cite the published observations that “women who take estrogen are healthier” than women who don’t use it. But studies show that their “control groups” consisted of women who weren’t as healthy to begin with.)
(除了基于“风险因素”的论点之外，许多人引用了已发表的观察结果，即“服用雌激素的女性比不服用雌激素的女性更健康”。但研究表明，他们的“对照组”由健康状况不佳的女性组成。)
In the 1970s, after reading Szent-Gyorgyi’s description of the antagonistic effect of progesterone and estrogen on the heart, I reviewed the studies that showed that progesterone protects against estrogen’s clotting effect. I experimented with progesterone, showing that it increases the muscle tone in the walls of veins, which is very closely related to the effects Szent-Gyorgyi described in the heart. And progesterone opposes estrogen’s ability to increase the amount of free fatty acids circulating in the blood.
20世纪70年代，在阅读了圣-乔吉关于孕酮和雌激素对心脏的拮抗作用的描述后，我回顾了一些研究，这些研究表明孕酮可以抵御雌激素的凝血作用。我用黄体酮做了个实验，发现它能增强血管壁的肌肉张力，这和圣乔吉所描述的心脏作用密切相关。黄体酮会抑制雌激素增加血液中游离脂肪酸含量的能力。
More recently, it has been discovered that progesterone inhibits the expression of the enzyme nitric oxide synthase, while estrogen stimulates its expression. At the time of ovulation, when estrogen is high, a woman breathes out 50% more nitric oxide (“NO”) than men do, but at other times, under the influence of increased progesterone and thyroid, and reduced estrogen, women exhale much less NO than men do. (Nitric oxide is a free radical, and it decomposes into other toxic compounds, including the free radical peroxynitrile, which damages cells, including the blood vessels. brain, and heart. Carbon dioxide tends to inhibit the production of peroxynitrile.)
最近，人们发现孕酮抑制一氧化氮合酶的表达，而雌激素则刺激其表达。在排卵期，当雌激素较高时，女性呼出的一氧化氮(NO)比男性多50%，但在其他时候，在孕激素和甲状腺增加以及雌激素减少的影响下，女性呼出的NO比男性少得多。(一氧化氮是一种自由基，它分解成其他有毒化合物，包括自由基过氧腈，它会损害细胞，包括血管。大脑和心脏。二氧化碳倾向于抑制过氧腈的产生。)
If nitric oxide produced under the influence of estrogen were important in preventing cardiovascular disease, then men’s larger production of nitric oxide would give them greater protection than women have.
如果在雌激素影响下产生的一氧化氮对预防心血管疾病很重要，那么男性产生的一氧化氮量会比女性提供更大的保护。
From more realistic perspectives, nitric oxide is being considered as a cause of aging, especially brain aging. Nitric oxide interacts with unsaturated fats to reduce oxygen use, damage mitochondria, and cause edema.
从更现实的角度来看，一氧化氮被认为是衰老的原因，尤其是大脑衰老。一氧化氮与不饱和脂肪相互作用，减少氧气消耗，破坏线粒体，并引起水肿。
I think we can begin to see that the various “heart protective” ideas that have been promoted to the public for fifty years are coming to a dead end, and that a new look at the fundamental problems involved in heart disease would be appropriate. Basic principles that make heart disease more understandable will also be useful for understanding shock, edema, panic attacks, high altitude sickness, high blood pressure, kidney disease, some lung diseases, MS, multiple organ failure, and excitotoxicity or “programmed” cell death of the sort that causes degenerative nerve diseases and deterioration of other tissues.
我想我们可以开始看到，50年来一直向公众推广的各种“保护心脏”的想法正在走向死胡同，而对与心脏病有关的基本问题进行新的审视将是合适的。使心脏病更容易理解的基本原理也有助于理解休克，水肿，惊恐发作，高原反应，高血压，肾病，一些肺部疾病，多发性硬化症，多器官衰竭，以及引起神经退行性疾病和其他组织恶化的兴奋性毒性或“程序性”细胞死亡。
The research supporting this view is remarkably clear, but it isn’t generally known because of the powerful propaganda coming from the drug and oil industries and their public servants.
支持这一观点的研究非常清楚，但由于来自毒品和石油行业及其公务员的强大宣传，这一观点并不为人所知。
Broda Barnes was right when he said that the “riddle of heart attacks” was solved when he demonstrated that hypothyroidism caused heart attacks, and that they were prevented by correcting hypothyroidism. He also observed that correcting hypothyroidism prevented the degenerative conditions (including heart disease) that so often occur in diabetics. Since hypothyroidism and diabetes are far more frequent in women, who have fewer heart attacks than men, it is appropriate to wonder why women tolerate hypothyroidism better than men.
布罗达·巴恩斯(Broda Barnes)说，当他证明甲状腺功能减退导致心脏病发作，而通过纠正甲状腺功能减退可以预防心脏病发作时，“心脏病之谜”就解开了。他还观察到，纠正甲状腺功能减退症可以预防糖尿病患者经常发生的退行性疾病(包括心脏病)。由于甲状腺机能减退和糖尿病在女性中更为常见，而女性的心脏病发作次数却比男性少，因此我们有理由怀疑，为什么女性能比男性更好地忍受甲状腺机能减退。
In hypothyroidism and diabetes, respiration is impaired, and lactic acid is formed even at rest, and relatively little carbon dioxide is produced. To compensate for the metabolic inefficiency of hypothyroidism, adrenalin and noradrenalin are secreted in very large amounts. Adrenalin causes free fatty acids to circulate at much higher levels, and the lactic acid, adrenalin, and free fatty acids all stimulate hyperventilation. The already deficient carbon dioxide is reduced even more, producing respiratory alkalosis. Free fatty acids, especially unsaturated fats, increase permeability of blood vessels, allowing proteins and fats to enter the endothelium and smooth muscle cells of the blood vessels. Lactic acid itself promotes an inflammatory state, and in combination with reduced CO2 and respiratory alkalosis, contributes to the hyponatremia (sodium deficiency) that is characteristic of hypothyroidism. This sodium deficiency and osmotic dilution causes cells to take up water, increasing their volume.
甲状腺功能减退症和糖尿病患者的呼吸功能受损，即使在休息时也会形成乳酸，产生的二氧化碳相对较少。为了弥补甲状腺机能减退的代谢效率低下，肾上腺素和去甲肾上腺素的分泌量非常大。肾上腺素使游离脂肪酸以更高的水平循环，乳酸、肾上腺素和游离脂肪酸都刺激过度通气。本就不足的二氧化碳更减少，产生呼吸性碱中毒。游离脂肪酸，特别是不饱和脂肪，增加血管的渗透性，使蛋白质和脂肪进入血管的内皮细胞和平滑肌细胞。乳酸本身促进炎症状态，并与减少的二氧化碳和呼吸性碱中毒结合，导致低钠血症(钠缺乏)，这是甲状腺功能减退的特征。钠的缺乏和渗透稀释会导致细胞吸水，增加细胞体积。
In hyperventilation, the heart’s ability to work is decreased, and the work it has to do is increased, because peripheral resistance is increased, raising blood pressure. One component of peripheral resistance is the narrowing of the channels in blood vessels caused by endothelial swelling. In the heart, a similarly waterlogged state makes complete contraction and complete relaxation impossible.
在过度通气时，心脏的工作能力下降，而它必须做的工作增加，因为外周阻力增加，血压升高。外周阻力的一个组成部分是由内皮细胞肿胀引起的血管通道狭窄。在心脏，类似的浸水状态使得完全收缩和完全放松是不可能的。
Estrogen itself intensifies all of these changes of hypothyroidism, increasing perrmeability and edema, and decreasing the force of the heart-beat, impairing the diastolic relaxation. Besides its direct actions, and synergism with hypothyroidism, estrogen also chronically increases growth hormone, which causes chronic exposure of the blood vessels to higher levels of free fatty acids (with a bias toward unsaturated fatty acids), and promotes edema and vascular leakage. Hyperestrogenism, like hypothyroidism, tends to produce dilution of the body fluids, and is associated with increased bowel permeability, leading to endotoxemia; both dilution of the plasma and endotoxemia impair heart function.
雌激素本身加剧了所有这些甲状腺功能减退的变化，增加了渗透性和水肿，降低了心跳的力度，损害了舒张舒张。除了直接作用和与甲状腺功能减退症的协同作用外，雌激素还长期增加生长激素，这导致血管长期暴露于较高水平的游离脂肪酸(偏向不饱和脂肪酸)，并促进水肿和血管渗漏。与甲状腺机能减退一样，雌激素过多会稀释体液，并增加肠道通透性，导致内毒素血症;血浆稀释和内毒素血症均损害心脏功能。
Progesterone’s effects are antagonistic to estrogen’s:. Progesterone decreases the formation of nitric oxide, decreasing edema; it strengthens the heart beat, by improving venous return and increasing stroke volume, but at the same time it reduces peripheral resistance by relaxing arteries (by inhibiting calcium entry but also by other effects, and independently of the endothelium) and decreasing edematous swelling.
黄体酮的作用与雌激素的作用是对立的。孕酮减少一氧化氮的形成，减轻水肿;它通过改善静脉回流和增加卒中量来加强心脏跳动，但同时它通过松弛动脉(通过抑制钙的进入，也通过其他作用，独立于内皮)和减少水肿肿胀来减少外周阻力。
The effects of progesterone on the heart and blood vessels are paralleled by those of carbon dioxide: Increased carbon dioxide increases perfusion of the heart muscle, increases its stroke volume, and reduces peripheral resistance. The physical and chemical properties of carbon dioxide that I have written about previously include protective anti-excitatory and energy-sustaining functions that explain these effects. Since these effects have been known for many years, I think it is obvious that the obsessive interest in explaining these functions in terms of other molecules, such as nitric oxide, is motivated by the desire for new drugs, not by a desire to understand the physiology with which the researchers are pretending to deal.
孕酮对心脏和血管的影响与二氧化碳的影响是平行的:二氧化碳的增加增加心肌的灌注，增加其卒中量，并减少外周阻力。我之前写过的二氧化碳的物理和化学特性，包括保护、抗兴奋和维持能量的功能，解释了这些效应。因为这些影响已经知道多年来,我认为这是明显的兴趣解释这些函数的其他分子,如一氧化氮、是出于对新药的渴望,而不是由一个渴望了解的生理研究人员正在假装交易。
Although women, because of estrogen’s antithyroid actions, are much more likely to suffer from hypothyroidism than men are, until menopause they have much higher levels of progesterone than men do. The effects of hyperestrogenism and hypothyroidism, with lower carbon dioxide production, are offset by high levels of progesterone. After menopause, women begin to have heart attacks at a rapidly increasing rate.
尽管由于雌激素的抗甲状腺作用，女性比男性更容易患甲状腺功能减退症，但在更年期之前，她们的孕酮水平要比男性高得多。高雌激素和甲状腺功能减退的影响，低二氧化碳的产生，抵消了高水平的孕酮。绝经后，女性心脏病发病率开始迅速上升。
During the years that men are beginning to have a considerable risk of heart attacks, with declining thyroid function indicated by lower T3, their testosterone and progesterone are declining, while their estrogen is rising. Men who have heart attacks have much higher levels of estrogen than men at the same age who haven’t had a heart attack.
在这些年里，男性开始有相当大的心脏病发作风险，甲状腺功能下降，T3降低，他们的睾丸激素和黄体酮下降，而雌激素上升。心脏病患者的雌激素水平比同龄未患心脏病的男性高得多。
Whether the issue is free radical damage, vascular permeability with fat deposition, vascular spasm, edema, decreased heart efficiency, or blood clotting, the effects of chronic estrogen exposure are counter-adaptive. Progesterone, by opposing estrogen, is universally protective against vascular and heart disease.
无论问题是自由基损伤，血管通透性与脂肪沉积，血管痉挛，水肿，心脏效率降低，或血凝，慢性雌激素暴露的影响是反适应的。孕酮与雌激素相反，能普遍预防血管和心脏疾病。
So far, the rule in most estrogen/progesterone research has been to devise experiments so that claims of benefit can be made for estrogen, with the expectation that they will meet an uncritical audience. In some studies, it’s hard to tell whether idiocy or subterfuge is responsible for the way the experiment was designed and described, for example when synthetic chemicals with anti-progesterone activity are described as “progesterone.” Since one estrogen-funded researcher who supposedly found progesterone to be ineffective as treatment for premenstrual syndrome practically admitted to me in conversation an intent to mislead, I think it is reasonable to discount idiocy as the explanation for the tremendous bias in published research. With the vastly increased resources in the estrogen industry, resulting from the product promotion “for the prevention of heart disease,” I think we should expect the research fraud to become increasingly blatant.
到目前为止，大多数雌激素/孕激素研究的规则都是设计实验，这样就可以宣称雌激素的益处，并期望他们会遇到不挑剔的听众。在一些研究中，很难判断是白痴还是假话导致了实验的设计和描述方式，例如，当具有抗孕酮活性的合成化学品被描述为“孕酮”时。由于一位由雌激素资助的研究人员发现孕激素对经前综合症的治疗无效，实际上他在谈话中向我承认，他有意误导我，所以我认为，对已发表的研究中存在巨大偏见的原因，我们有理由不把“白痴”作为解释。由于“预防心脏病”的产品推广，雌激素行业的资源大幅增加，我认为我们应该期待研究欺诈变得越来越猖狂。
Rather than being “heart protective,” estrogen is highly heart-toxic, and it is this that makes its most important antagonist, progesterone, so important in protecting the heart and circulatory system.
雌激素不是“保护心脏”的，而是高度心脏毒性的，这使得它最重要的拮抗剂，孕酮，在保护心脏和循环系统中如此重要。
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引用
JAMA 1998 Aug 19;280(7):605-13. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E University of California, San Francisco 94143, USA. CONTEXT: Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. OBJECTIVE: To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. DESIGN: Randomized, blinded, placebo-controlled secondary prevention trial. SETTING: Outpatient and community settings at 20 US clinical centers. PARTICIPANTS: A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. INTERVENTION: Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years. MAIN OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death.Secondary cardiovascular outcomesincluded coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. RESULTS: Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). CONCLUSIONS: During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD
医学杂志1998年8月19日;280(7):605-13。雌激素联合黄体酮用于绝经后妇女冠心病二级预防的随机试验心脏与雌激素/黄体酮替代研究(HERS)研究组。huley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E University of California, San Francisco 94143, USA。背景:观察性研究发现，绝经后服用雌激素的妇女患冠心病(CHD)的比例低于未服用雌激素的妇女，但这一潜在益处尚未在临床试验中得到证实。目的:确定雌激素加黄体酮治疗是否改变已确诊冠心病绝经后妇女冠心病事件的风险。设计:随机、盲法、安慰剂对照二级预防试验。环境:20个美国临床中心的门诊和社区环境。研究对象:2763名患有冠心病的女性，年龄小于80岁，绝经后子宫完整。平均年龄为66.7岁。干预:0.625 mg结合马雌激素加2.5 mg醋酸甲羟孕酮，每日一片(n = 1380)或相同外观的安慰剂(n = 1383)。平均随访4.1年;接受激素治疗的患者中有82%在1年底服用，75%在3年底服用。主要观察指标:主要观察指标为发生非致死性心肌梗死(MI)或冠心病死亡。次要心血管结果包括冠状动脉重建、不稳定心绞痛、充血性心力衰竭、心脏骤停复苏、中风或短暂性缺血发作和外周动脉疾病。全因死亡率也被考虑在内。结果:总体而言，在主要结局或任何次要心血管结局方面，两组之间没有显著差异:激素组172名女性和安慰剂组176名女性有心肌梗死或冠心病死亡(相对危险[RH]， 0.99;95%置信区间[CI]， 0.80-1.22)。尽管与安慰剂组相比，激素组的低密度脂蛋白胆固醇水平净降低11%，高密度脂蛋白胆固醇水平净提高10%(各P<.001)，但总体效果仍不明显。在总的无效效应中，有一个统计上显著的时间趋势，在第1年激素组比安慰剂组有更多的冠心病事件，在第4年和第5年更少。激素组比安慰剂组有更多的女性发生静脉血栓栓塞事件(34 vs 12;RH, 2.89;95% CI, 1.50-5.58)和胆囊疾病(84 vs 62;RH, 1.38;95%可信区间,1.00 - -1.92)。在能量受限的其他几个终点，包括骨折、癌症和总死亡率(131例vs 123例;RH, 1.08;95%可信区间,0.84 - -1.38)。结论:在平均4.1年的随访期间，口服马雌激素联合醋酸甲羟孕酮并没有降低已确诊冠心病的绝经后妇女冠心病事件的总发生率。治疗确实增加了血栓栓塞事件和胆囊疾病的发生率。基于没有整体心血管益处的发现和早期冠心病事件风险增加的模式，我们不建议以冠心病二级预防为目的开始这种治疗。然而，考虑到冠心病的有利模式
Am J Med 1982 Dec;73(6):872-81. Serum estrogen levels in men with acute myocardial infarction. Klaiber EL, Broverman DM, Haffajee CI, Hochman JS, Sacks GM, Dalen JE Serum estradiol and serum estrone levels were assessed in 29 men in 14 men in whom myocardial infarction was ruled out; in 12 men without apparent coronary heart disease but hospitalized in an intensive care unit; and in 28 men who were not hospitalized and who acted as control subjects. (The 12 men who were hospitalized but who did not have coronary heart disease were included to control for physical and emotional stress of a severe medical illness.) Ages ranged from 21 to 56 years. Age, height, and weight did not differ significantly among groups. Blood samples were obtained in the patient groups on each of the first three days of hospitalization. The serum estrone level was significantly elevated in all four patient groups when compared with that in the control group. Estrone level, then, did not differentiate patients with and without coronary heart disease. Serum estradiol levels were significantly elevated in the groups with myocardial infarction, unstable angina, and in the group in whom myocardial infarction was ruled out. However, estradiol levels were not significantly elevated in the group in the intensive care unit without coronary heart disease when compared to the level in the normal control group. Serum estradiol levels, then, were elevated in men with confirmed or suspected coronary heart disease but were not elevated in men without coronary heart disease even under the stressful conditions found in an intensive care unit. Serum estradiol levels were significantly and positively correlated (p less than 0.03) with serum total creatine phosphokinase levels in the patients with myocardial infarction. The five patients with myocardial infarction who died within 10 days of admission had markedly elevated serum estradiol levels. The potential significance of these serum estradiol elevations is discussed in terms of estradiol's ability to enhance adrenergic neural activity and the resultant increase in myocardial oxygen demand.
美国医学杂志1982年12月;73(6):872-81。急性心肌梗死男性血清雌激素水平。在排除心肌梗死的14名男性中，评估29名男性的血清雌二醇和血清雌二醇水平;12名没有明显冠心病但在重症监护病房住院的男性;28名没有住院的男性作为对照组(12名没有冠心病的住院男性被纳入研究，以控制严重疾病带来的身体和情绪压力。)年龄从21岁到56岁不等。年龄、身高和体重在各组之间没有显著差异。在患者组中，在住院的前三天里，每一天都采集血液样本。四组患者血清雌激素水平均明显高于对照组。因此，雌激素水平并不能区分是否患有冠心病。心肌梗死组、不稳定心绞痛组及排除心肌梗死组血清雌二醇水平显著升高。然而，与正常对照组相比，无冠心病的重症监护室组雌二醇水平没有明显升高。因此，在确诊或疑似冠心病的男性中，血清雌二醇水平升高，而在没有冠心病的男性中，即使在重症监护病房中发现的压力条件下，雌二醇水平也没有升高。心肌梗死患者血清雌二醇水平与血清总肌酸磷酸激酶水平显著正相关(p < 0.03)。5例在入院10天内死亡的心肌梗死患者血清雌二醇水平显著升高。这些血清雌二醇水平升高的潜在意义是根据雌二醇增强肾上腺素能神经活动的能力和由此引起的心肌氧需求的增加来讨论的。
JAMA 1978 Apr 3;239(14):1407-9. Noncontraceptive estrogens and nonfatal myocardial infarction. Jick H, Dinan B, Rothman KJ We obtained information on 107 women younger than 46 years discharged from a hospital with a diagnosis of acute myocardial infarction. In the series there were 17 women aged 39 to 45 years who were otherwise apparently healthy and had had a natural menopause, hysterectomy, or tubal ligation or whose spouse had had a vasectomy. Among them, nine (53%) were taking noncontraceptive estrogens just prior to admission. Among 34 control women, four (12%) were taking estrogens. The relative risk estimate, comparing estrogen users with nonusers, is 7.5,with 90% confidence limits of 2.4 and 24. All but one of the 17 ml subjects were cigarette smokers. While this illness is rare in most healthy young women, the risk in women older than about 38 years who both smoke and take estrogens appears to be substantial.
医学杂志1978年4月3日;239(14):1407-9。非避孕雌激素和非致死性心肌梗死。我们获得了107名年龄小于46岁的女性出院时诊断为急性心肌梗死的信息。在这个系列中，有17名年龄在39到45岁之间的女性，她们在其他方面都很健康，有自然绝经、子宫切除或输卵管结扎，或者她们的配偶有输精管结扎。其中9例(53%)在入院前服用了非避孕雌激素。在34名对照组女性中，4人(12%)服用雌激素。相对风险估计，比较雌激素使用者和非使用者，是7.5,90%置信限为2.4和24。在17毫升的受试者中，除了一人之外，其余都是吸烟者。虽然这种疾病在大多数健康的年轻女性中很少见，但在38岁以上同时吸烟和服用雌激素的女性中，这种风险似乎相当大。
JAMA 1978 Apr 3;239(14):1403-6. Oral contraceptives and nonfatal myocardial infarction. Jick H, Dinan B, Rothman KJ We obtained information on 107 women younger than 46 years who were discharged from a hospital with a diagnosis of acute myocardial infarction. In the series 26 women were otherwise apparently healthy and potentially childbearing. Among these 26 women, 20 (77%) were taking oral contraceptives just prior to admission, and one was taking conjugated estrogens. Among 59 control women, 14 (24%) were taking oral contraceptives and one was taking conjugated estrogens. The relative risk estimate, comparing oral contraceptive users with nonusers, is 14 with 90% confidence limits of 5.5 and 37. All but two of the 26 women were cigarette smokers. While this illness is rare in most healthy young women, the risk in women older than about 37 years who both smoke and take oral contraceptive appears to be high.
医学杂志1978年4月3日;239(14):1403-6。口服避孕药和非致死性心肌梗死。我们获得了107名年龄小于46岁的女性的信息，她们被诊断为急性心肌梗死出院。在这个系列中，26名女性都很健康，有生育的潜力。在这26名女性中，20名(77%)在入院前服用口服避孕药，1名服用共轭雌激素。在59名对照组女性中，14名(24%)服用口服避孕药，1名服用共轭雌激素。相对风险估计，比较口服避孕药使用者和非使用者，是14,90%置信限为5.5和37。在26名女性中，除两名外，其余都是吸烟者。虽然这种疾病在大多数健康的年轻女性中很少见，但在年龄超过37岁、同时吸烟和服用口服避孕药的女性中，这种风险似乎很高。
M. Karmazyn, et al., “Changes in coronary vascular resistance associated with prolonged hypoxia in isolated rat hearts: A possible role of prostaglandins,”Life Sciences 25, 1991-1999, 1979. “if…hypoxic perfusion is prolonged, the initial dilatation passes off and an intense vasoconstriction results.” “The constriction could be prevented by progesterone but not by estradiol or testosterone.” “There is increasing evidence that angina pectoris and myocardiaol infarction may often be due to active caronary constriction.” “Inhibitors of PG synthesis at high concentrations prevented or reversed the constriction.” (Besides aspirin) “Chloroquine, procaine and propranolol can all behave as PG antagonists….” “The failure of estradiol or testosterone to have any effect and the complete prevention of the constriction by physiological levels of progesterone suggest that more attention should be paid to this last steroid.” “…hypoxia can cause coronary constriction and…the effect does not occur in young or progesterone-treated hearts….”
M. Karmazyn等，“与长期缺氧相关的冠状动脉血管阻力的变化:前列腺素的可能作用”，《生命科学》25,1991-1999,1979。“如果……低氧灌注延长，最初的扩张消失，导致强烈的血管收缩。”黄体酮可以防止这种收缩，但雌二醇或睾酮不能。”“越来越多的证据表明，心绞痛和心肌梗死往往是由于活跃的冠状动脉收缩。”高浓度的PG合成抑制剂阻止或逆转了这种收缩。(除了阿司匹林)氯喹，普鲁卡因和普萘洛尔都可以作为PG拮抗剂….“雌二醇或睾酮不起任何作用，而生理水平的孕酮完全阻止了收缩，这表明我们应该更多地关注这最后一种类固醇。”＂…缺氧会导致冠状动脉收缩这种影响不会发生在年轻或接受黄体酮治疗的心脏….“
Am J Epidemiol 1996 May 15;143(10):971-8. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Observational studies have demonstrated that women who have used postmenopausal estrogen replacement therapy (ERT) are at reduced risk of coronary heart disease. The authors examined whether premenopausal women who subsequently elected to use ERT during menopause had a better cardiovascular risk factor profile prior to use than did nonusers. A total of 541 premenopausal women had their cardiovascular risk factors and psychosocial characteristics evaluated at study entry. After approximately 8 years, 355 women had become postmenopausal, and 157 women reported ERT use during the follow-up period (mean = 93.4 months). The authors compared the premenopausal characteristics of users with those of nonusers. Relative to nonusers, ERT users were better educated (63 vs. 81% with at least some college), and prior to the use of ERT had higher levels of high density lipoprotein (HDL) cholesterol (1.49 vs. 1.59 mmol/liter), HDL2 (0.50 vs. 0.57 mmol/liter), HDL3 (0.98 vs. 1.02 mmol/liter), leisure physical activity (5, 122 vs. 7,158 Kjoules), and alcohol intake (7.5 vs. 9.7 g/day), and lower levels of apolipoprotein B (0.97 vs. 0.90g/liter), systolic blood pressure (112.1 vs. 107.1 mmHg) and diastolic blood pressure (73.8 vs. 71.4 mmHg), weight (68.5 vs. 64.2 kg), and fasting insulin (9.10 vs. 7.66 microU/liter). Prior to use of ERT, in comparison with nonusers, subsequent users reported on standardized questionnaires that they often exhibited Type A behavior, more aware of their feelings, motives, and symptoms, and had more symptoms of stress. Women who elect to use ERT have a better cardiovascular risk factor profile prior to the use of ERT than do women who subsequently do not use this treatment during the menopause, which supports the hypothesis that part of the apparent benefit associated with the use of ERT is due to preexisting characteristics of women who use ERT. This study underscores the widely recognized importance of randomized clinical trials to estimate the direct benefit of postmenopausal ERT for protecting women from cardiovascular disease.
美国流行病学杂志1996年5月15日;143(10):971-8。在使用雌激素替代疗法之前，使用者是否比不使用者更健康?Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P.观察研究表明，使用绝经后雌激素替代疗法(ERT)的妇女患冠心病的风险降低。作者研究了绝经前妇女在绝经期间选择使用ERT是否比未使用时有更好的心血管危险因素。共有541名绝经前女性在研究开始时评估了她们的心血管危险因素和社会心理特征。大约8年后，355名妇女绝经后，157名妇女报告在随访期间使用了ERT(平均= 93.4个月)。作者比较了服用者和不服用者绝经前的特征。相对于使用者,ERT用户更好的教育(63 vs 81%至少有一些大学),和之前使用的ERT有较高水平的高密度脂蛋白(HDL)胆固醇(1.49 vs 1.59更易/升),HDL2 (0.50 vs 0.57更易/升),HDL3 (0.98 vs 1.02更易/升),休闲体育活动(122比7158 Kjoules),以及较低水平的载脂蛋白B (0.97 vs. 0.90g/升)、收缩压(112.1 vs. 107.1 mmHg)和舒张压(73.8 vs. 71.4 mmHg)、体重(68.5 vs. 64.2 kg)和空腹胰岛素(9.10 vs. 7.66 microU/升)。在使用ERT之前，与未使用者相比，后续使用者在标准化问卷中报告称，他们经常表现出A型行为，更清楚自己的感受、动机和症状，有更多的压力症状。女性选择使用ERT有更好的心血管风险因素概要文件之前使用的ERT比后来的女性不使用这种治疗更年期期间,支持相关的假设明显受益的一部分使用的ERT是由于先前存在的特点,利用ERT的女人。这项研究强调了被广泛认可的随机临床试验的重要性，以评估绝经后ERT对保护妇女免受心血管疾病的直接益处。
“Effects of androgens on haemostasis,” Winkler UH, Maturitas, 1996 Jul, 24:3, 147-55. “Androgen deficiency is associated with an increased incidence of cardiovascular disease. There is evidence that thromboembolic disease as well as myocardial infarction in hypogonadic males are mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor PAI 1.”
“雄激素对止血的影响”，Winkler UH, Maturitas, 1996年7月24:3,147-55。“雄激素缺乏与心血管疾病的发病率增加有关。有证据表明性腺功能减退的男性的血栓栓塞性疾病和心肌梗死是由低基线纤溶活性介导的。男性性腺功能减退通过增加纤溶酶原激活物抑制剂PAI 1的合成而增强纤溶抑制。”
M. Mabry White, et al., “Estrogen, progesterone, and vascular reactivity: Potential cellular mechanisms,”Endocrine Reviews 16(6), 739, 1995. “Female hormones are broadly recognized as affecting susceptibility to vascular disease….” Migraines, Raynaud's phenomena, primary pulmonary hypertension are mentioned as vascular disorders with a female predominance.
M. Mabry White等，“雌激素、孕酮和血管反应性:潜在的细胞机制”，《内分泌评论》16(6)，739,1995。“女性荷尔蒙被广泛认为会影响血管疾病的易感性….”偏头痛，雷诺氏现象，原发性肺动脉高压被认为是女性占优势的血管疾病。
J. Boczkowski, et al., “Induction of diaphragmatic nitric oxide synthase after endotoxin administration in rats; role on diaphragmatic contractile dysfunction,” J. Clin. Invest. 98, 1550-1559, 1996. “We conclude that iNOS [inducible nitric oxide synthase] was induced…” by endotoxin.
“内毒素对大鼠膈一氧化氮合酶的诱导作用;对膈肌收缩功能障碍的作用”。投资。98,1550-1559,1996。“我们得出结论，iNOS[诱导型一氧化氮合酶]是由内毒素诱导的。”
Arch Int Pharmacodyn Ther 1986 May;281(1):57-65. Effects of 17 beta-estradiol on the isolated rabbit heart.Raddino R, Manca C, Poli E, Bolognesi R, Visioli O. We have studied the effects of 17 beta-estradiol on the left ventricular pressure and on the coronary perfusion pressure in isolated rabbit heart, in order to evaluate the action of this hormone on the myocardial contractility and on the coronary resistances. 17 beta-Estradiol has induced a negative inotropic effect starting from a concentration of 10(-6) M and a vasodilation starting from 10(-7) M when administered on a vasopressin-induced coronary spasm. These effects are not related to sex or to alpha-, beta-adrenergic, histaminergic, anaesthetic-like mechanisms, but seem to interfere with calcium transport.
Arch Int Pharmacodyn Ther 1986 May;281(1):57-65。17 -雌二醇对离体兔心脏的影响。Raddino R, Manca C, E波里,Bolognesi R, Visioli o .我们学习了17个beta雌二醇的影响左心室压力和孤立的兔心脏冠状动脉灌注压,以评估这种激素的作用对心肌收缩性和冠状电阻。当使用垂体后叶素引起的冠状动脉痉挛时，-雌二醇从浓度为10(-6)M开始诱导负性肌力作用和从10(-7)M开始的血管舒张作用。这些作用与性或肾上腺素能、组胺能、麻醉机制无关，但似乎干扰了钙的运输。
Med Hypotheses 1997 Aug;49(2):183-5.Coronary artery spasm: a hypothesis on prevention by progesterone. Kanda I, Endo M. Department of Surgery, Heart Institute of Japan, Tokyo Women's Medical College, Japan. The mechanism of coronary artery spasm has been hypothesized as follows: the dormant gene of the smooth muscle of the human coronary artery is identical or similar to the active gene of the smooth muscle of ductus arteriosus, but can be activated by estrogen. The activation could be preventable by progesterone. The prevention is due to the reduction of the number of estrogen receptors of the smooth muscle of the coronary artery.
医学假设1997 8月;49(2):183-5。冠状动脉痉挛:孕激素预防的假说。神田I，远藤m，日本东京女子医学院心脏研究所外科。冠状动脉痉挛的发生机制有如下假设:人冠状动脉平滑肌的休眠基因与动脉导管平滑肌的活跃基因相同或相似，但可被雌激素激活。这种激活可以用孕激素来预防。这种预防是由于减少了冠状动脉平滑肌的雌激素受体数量。
J. Bolanos, et al., “Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes,” J. Neurochem. 63, 910-916, 1994.
“一氧化氮对培养星形胶质细胞线粒体呼吸链的抑制作用”，《神经化学杂志》，63,910-916,1994。
M. Cleeter, et al., “Reversible inhibition of cytochrome C oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide,” FEBS Lett. 345, 50-54, 1994.
“一氧化氮对线粒体呼吸链末端酶——细胞色素C氧化酶的可逆抑制作用”，《中华内分泌杂志》34,50 -54,1994。
Ann Thorac Surg 1999 Sep;68(3):925-30. Coronary perfusate composition influences diastolic properties, myocardial water content, and histologic characteristics of the rat left ventricle. Starr JP, Jia CX, Amirhamzeh MM, Rabkin DG, Hart JP, Hsu DT, Fisher PE, Szabolcs M, Spotnitz HM. “Recent studies found that edema, histology, and left ventricular diastolic complianceexhibit quantitative relationships in rats. Edema due to low osmolarity coronary perfusates increases myocardial water content and histologic edema score and decreases left ventricular filling. The present study examined effects of perfusate osmolarity and chemical composition on rat hearts.” “Myocardial water content reflected perfusate osmolarity, being lowest in Stanford and University of Wisconsin solutions (p<0.05 versus other groups) and highest in dilute Plegisol (p<0.05). Left ventricular filling volumes were smallest in dilute Plegisol and Plegisol (p<0.05).” “Perfusate osmolarity determined myocardial water content and left ventricular filling volume. However, perfusate chemical composition influenced the histologic appearance of edema. Pathologic grading of edema can be influenced by factors other than osmolarity alone.”
Ann Thorac Surg 1999九月;68(3):925-30。冠状动脉灌注成分影响大鼠左心室舒张特性、心肌含水量和组织学特征。Starr JP, Jia CX, Amirhamzeh MM, Rabkin DG, Hart JP, Hsu DT, Fisher PE, Szabolcs M, Spotnitz HM。最近的研究发现，在大鼠中，水肿、组织学和左心室舒张顺应性表现出定量关系。低渗透压引起的水肿冠状动脉灌注增加心肌含水量和组织学水肿评分，减少左心室充盈。本研究探讨了灌流渗透压和化学成分对大鼠心脏的影响。心肌含水量反映了灌注渗透压，斯坦福和威斯康辛大学溶液中最低(与其他组相比p<0.05)，稀释Plegisol中最高(p<0.05)。稀凝素和凝血素组左室充盈量最小(p<0.05)。”灌流渗透压测定心肌含水量和左心室充盈量。然而，灌注化学成分影响水肿的组织学表现。除渗透压外，水肿的病理分级还受其他因素的影响。
Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages. Miller L; et al J Leukoc Biol, 59(3):442-50 1996 Mar. The purpose of this study was to determine whether the female hormones estradiol-l7 beta (E2) and progesterone (P4) influence inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) by interferon gamma (IFN-gamma) and lipopolysaccharide (LPS)-activated mouse macrophages. Treatment with P4 alone caused a time- and dose-dependent inhibition of NO production by macrophage cell lines (RAW 264.7, J774) and mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW 264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within females and males that relates to macrophage-mediated host defense.
孕酮抑制小鼠巨噬细胞诱导型一氧化氮合酶基因表达和一氧化氮生成。米勒L;et al J Leukoc, 59(3): 442 - 50 1996年3月本研究的目的是确定雌性激素estradiol-l7β(E2)和孕酮(P4)影响诱导一氧化氮合酶(间接宾语)和一氧化氮(NO)的生产干扰素γ(IFN-gamma)和脂多糖(LPS)激活小鼠巨噬细胞。单独使用P4可以抑制巨噬细胞(RAW 264.7, J774)和小鼠骨髓培养来源的巨噬细胞(通过亚硝酸盐积累来评估)产生的NO。瞬时转染iNOS基因启动子/荧光素酶报告基因构建的RAW 264.7细胞，在P4存在的情况下，用IFN-gamma/LPS刺激，显示出荧光素酶活性和NO生成降低。通过Northern blot杂交分析RAW 264.7细胞，发现p4介导的iNOS mRNA同时降低。这些观察表明，p4介导的NO抑制可能是雌性和雄性之间重要的性别差异，与巨噬细胞介导的宿主防御有关。
Testosterone relaxes rabbit coronary arteries and aorta. Yue P; Chatterjee K; Beale C; Poole-Wilson PA; Collins P Department of Cardiac Medicine, National Heart and Lung Institute, London, UK. Circulation, 1995 Feb 15, 91:4, 1154-60 “Testosterone induces endothelium-independent relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin I2 or cyclic GMP. Potassium conductance and potassium channels but not ATP-sensitive potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The in vitro relaxation is independent of sex and of a classic receptor. The coronary artery is significantly more sensitive to relaxation by testosterone than the aorta. Testosterone is a more potent relaxing agent of rabbit coronary artery than other testosterone analogues.”
睾丸激素可松弛兔冠状动脉和主动脉。悦P;Chatterjee K;比尔C;Poole-Wilson PA;英国伦敦国家心肺研究所心脏医学科Collins P。睾酮可诱导离体兔冠状动脉和主动脉内皮依赖性舒张，这既不是前列腺素I2介导的，也不是环GMP介导的。钾离子电导和钾离子通道可能部分参与睾酮诱导的舒张机制，但不包括atp敏感的钾离子通道。体外松弛与性别和典型受体无关。冠状动脉对睾酮舒张的敏感性明显高于主动脉。睾酮是一种比其他睾酮类似物更有效的兔冠状动脉舒张剂。
J. Nakamura, et al., “Estrogen regulates vascular endothelial growth permeability factor expression in 7,12-dimethyl- benz(a)anthracene-induced rat mammary tumors,” Endocrinology 137(12_, 5589-5596, 1996. (“…one mechanism by which estrogen acts as a mammary tumor promotor is by stimulating VEG/PF, leading to increased tumor angiogenesis and/or permeability of the microvessels to allow tumor cell migration.”)
J. Nakamura等，“雌激素调节7,12-二甲基- benz(a)蒽诱导的大鼠乳腺肿瘤中血管内皮生长通透性因子的表达”，《内分泌学》137(12_，5589-5596,1996)。(“…雌激素作为乳腺肿瘤启动子的一种机制是通过刺激VEG/PF，导致肿瘤血管生成和/或微血管通透性增加，从而允许肿瘤细胞迁移。”)
D. A. Barber, et al., “Endothelin receptors are modulated in association with endogenous fluctuations in estrogen,” Amer. J. of Physiology–Heart and Circulatory Physiology 40(5), H1999-H2006, 1996. (“…contractions to endothelin-1 but not endothelin-3 or sarafotoxin S6c were significantly greater in coronary arterial rings from female comparred with male pigs….” “In addition, independent of endogenous estrogen status, coronary arteries from female pigs generate significantly greater contractions to endothelin-1 compared with male pigs. This phenomenon occurs at the level of smooth muscle and is not dependent on the endothelium or synthesis of nitric oide or prostaglandins.”
et al.，“内皮素受体被调节与雌激素的内源性波动，”Amer。acta physologica sinica(物理学报)，40(5)，H1999-H2006, 1996。(“…与公猪相比，母猪冠状动脉环对内皮素-1的收缩显著增加，而不是内皮素-3或萨拉霉素S6c。….”“此外，与公猪相比，母猪冠状动脉内皮素-1的收缩明显更大，这与内源性雌激素状态无关。这种现象发生在平滑肌水平，不依赖于内皮细胞或一氧化氮或前列腺素的合成。”
T. M. Chou, et al, “Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo,” Circulation 94(10), 2614-2619, 1996.
“睾酮诱导犬冠状动脉传导和阻力动脉的扩张”，心血管病杂志94(10)，2614-2619,1996。
K. Sudhir, et al., “Estrogen enhances basal nitric oxide release in the forearm vasculature in perimenopausal women,” Hypertension 28(3), 330-334, 1996.
“雌激素增强围绝经期妇女前臂血管中基础一氧化氮的释放”《高血压》28(3)，330-334,1996。
G. Sitzler, et al., “Investigation of the negative inotropic effects of 17-beta-oestradiol in human isolated myocardial tissues,” British J. of Pharmacology 119(1), 43-48, 1996.
G. Sitzler等，“17- β -雌二醇在人离体心肌组织中的负性肌力作用的研究”，英国药理学杂志119(1)，43-48,1996。
S. M. Hyder, et al., “Uterine expression of vascular endothelial growth factor is increased by estradiol and tamoxifen,”Cancer Research 56(17), 3954-3960, 1996. (“These findings raise the possibility that estrogen and antiestrogen effects on uterine edema, proliferation, and tumor incidence may involve local increases in tissue VEGF production.”)
“雌激素和它莫西芬可增加子宫血管内皮生长因子的表达”，《癌症研究》56(17)，3954- 3960,1996。(“这些发现提高了雌激素和反雌激素对子宫水肿、增殖和肿瘤发生率的影响可能涉及组织中VEGF产生的局部增加。”)
N. Ferrara and T. Davis-Smyth, “The biology of vascular endothelial growth factor,” Endocrine Reviews 18(1), 4-19,? 1997. “…induces vasodilatation in vitro in a dose-dependent fashion and produces transient tachycardia, hypotension, and a decrease in cardiac output when injected intravenously in conscious…rats. Such effects appear to be caused by a decrease in venous return, mediated primarily by endothelial cell-derived nitric oxide….” “Recently, elevation of VEGF in the peritoneal fluid of patients with endometriosis has been reported.”“…it has been suggested that VEGF up-regulation plays a pathogenic role in the capillary hyperpermeabilitythat characterizes ovarian hyperstimulation syndrome as well as in the dysfunctional endothelium of preeclampsia.”
N.费拉拉和T. Davis-Smyth，“血管内皮生长因子的生物学”，内分泌评论18(1)，4-19，?1997. ＂…在体外以剂量依赖的方式诱导血管扩张，并产生短暂的心动过速、低血压和心输出量的减少，当静脉注射在有意识的大鼠。这些影响似乎是由静脉回流减少引起的，主要是由内皮细胞来源的一氧化氮介导的….”。最近，子宫内膜异位症患者腹膜液中VEGF的升高已被报道。有人认为，VEGF上调在毛细血管通透性(卵巢过度刺激综合征的特征)以及子痫前期功能失调的内皮细胞中发挥致病作用。”
B. Jilma, et al, “Sex differences in concentrtions of exhaled nitric oxide and plasma nitrate,” Life Sciences 58*6), 469-476, 1996. (“Nitric oxide is generally considered as an endogenous vasoprotective agent.” “…men exhaled 50% more NO and had 99% higher (nitrate) NO3 levels than women.”
B. Jilma等，“呼出一氧化氮和血浆硝酸盐浓度的性别差异”，《生命科学》58*6,469-476,1996。(“一氧化氮通常被认为是一种内源性血管保护剂。”＂…男性呼出的NO比女性多50%，(硝酸盐)NO3含量比女性高99%。”
Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages. Miller L; et al J Leukoc Biol, 59(3):442-50 1996 Mar. “Treatment with P4 alone caused a time- and dose-dependent inhibition of NO productionby macrophage cell lines (RAW 264.7, J774) and mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW 264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within females and males that relates to macrophage-mediated host defense.”
孕酮抑制小鼠巨噬细胞诱导型一氧化氮合酶基因表达和一氧化氮生成。米勒L;“单独使用P4可以抑制巨噬细胞(RAW 264.7, J774)和小鼠骨髓培养来源的巨噬细胞产生的一氧化氮(NO)，通过亚硝酸盐积累进行评估。瞬时转染iNOS基因启动子/荧光素酶报告基因构建的RAW 264.7细胞，在P4存在的情况下，用IFN-gamma/LPS刺激，显示出荧光素酶活性和NO生成降低。通过Northern blot杂交分析RAW 264.7细胞，发现p4介导的iNOS mRNA同时降低。这些观察表明，p4介导的NO抑制可能是雌性和雄性之间重要的性别差异，与巨噬细胞介导的宿主防御有关。”
Int J Epidemiol 1990 Jun;19(2):297-302. Relationship of menopausal status and sex hormones to serum lipids and blood pressure. Wu ZY, Wu XK, Zhang YW. “Conditional logistic regression analysis found that progesterone is a protective factor only and testosterone is one of the risk factors for hypertension.”
国际流行病学1990年6月;19(2):297-302。绝经状态、性激素与血脂、血压的关系。吴征镒，吴新科，张永文。“条件logistic回归分析发现，孕酮只是一个保护因素，而睾酮是高血压的危险因素之一。”
Pharmacol Biochem Behav 1990 Oct;37(2):325-7. Steroid sex hormones and cardiovascular function in healthy males and females: a correlational study. Lundberg U, Wallin L, Lindstedt G, Frankenhaeuser M Department of Psychiatry and Psychology, Karolinska Institutet, Sweden. “The relationship of serum estradiol and testosterone levels to systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) was examined in healthy nonsmoking males (n = 30) and females (n = 22), 30-50 years of age (mean age for men = 41.2, women = 39.9). Postmenopausal women and women taking oral contraceptives had been excluded. Testosterone levels in women were positively correlated with SBP, DBP and HR, after removing the effects of age and body mass. Positive correlations were also found between estradiol and SBP and HR in women.”
中国生物化学学报1990,10月;37(2):325-7。类固醇性激素与健康男性和女性心血管功能的相关性研究Lundberg U, Wallin L, Lindstedt G, Frankenhaeuser M瑞典卡罗林斯卡学院精神病学和心理学系。“我们检测了30-50岁健康不吸烟男性(n = 30)和女性(n = 22)的血清雌二醇和睾酮水平与收缩压(SBP)、舒张压(DBP)和心率(HR)的关系(男性平均年龄为41.2，女性为39.9)。绝经后妇女和服用口服避孕药的妇女被排除在外。排除年龄和体重的影响后，女性睾酮水平与收缩压、舒张压和心率呈正相关。雌二醇与女性收缩压和心率呈正相关。”
Scand J Clin Lab Invest 1993 Jul;53(4):353-8. Effects of ovarian stimulation on blood pressure and plasma catecholamine levels. Tollan A, Oian P, Kjeldsen SE, Holst N, Eide I. “After stimulation a positive correlation was observed between systolic blood pressure and arterial adrenaline (r = 0.73, p = 0.027), and between systolic blood pressure and the arterial-venous difference for adrenaline (r = 0.81, p = 0.007). The increased venous noradrenaline levels may be a reflex-mediated activation of the sympathetic nervous tone due to a decrease in blood pressure, or may indicate reduced neuronal re-uptake of released noradrenaline. The mechanisms behind the strong correlation between adrenaline and blood pressure are unclear, but may be induced by the supraphysiological oestradiol levels.”
Scand J临床实验室投资1993年7月;53(4):353-8。卵巢刺激对血压和血浆儿茶酚胺水平的影响。刺激后，收缩压与动脉肾上腺素(r = 0.73, P = 0.027)、收缩压与肾上腺素动静脉差(r = 0.81, P = 0.007)呈正相关。静脉去甲肾上腺素水平升高可能是由于血压下降引起的交感神经张力的反射性激活，或者可能表明释放去甲肾上腺素的神经元再摄取减少。肾上腺素和血压之间的强烈相关性背后的机制尚不清楚，但可能是由超生理学的雌二醇水平诱导的。”
J Mol Cell Cardiol 1986 Dec;18(12):1207-18. Post-ischemic cardiac chamber stiffness and coronary vasomotion: the role of edema and effects of dextran.Vogel WM, Cerel AW, Apstein CS. “Contributions of edema to left ventricular (LV) chamber stiffness and coronary resistance after ischemia were studied in isolated buffer-perfused rabbit hearts, with constant LV chamber volume, subjected to 30 min global ischemia and 60 min reperfusion. During reperfusion hearts were perfused with standard buffer or with 3% dextran to increase oncotic pressure and decrease water content.” “Coronary resistance in untreated ischemic hearts increased by 26% from 2.0 +/- 0.06 to 2.6 +/- 0.06 mmHg/ml/min after 60 min reperfusion. In treated hearts coronary resistance increased by 16% from 1.9 +/- 0.09 to 2.2 +/- 0.09 mm/Hg/ml/min (P less than 0.01 v. untreated ischemic). To determine whether the decrease in coronaryresistance with dextran could be ascribed to active vasodilation, dilator responses to 2 min hypoxia or 10(-4)M adenosine were tested in nonischemic and reperfused ischemic hearts. Dilator responses were stable in nonischemic hearts or hearts reperfused after 15 min ischemia but after 30 min ischemia the dilator response to hypoxia was reduced by 72% (P less than 0.025) and the dilator response to adenosine was eliminated (P less than 0.02). Thus the response to dextran was unlike that of a direct vasodilator. These data suggest that myocardial edema plays a significant role in maintaining increased ventricular chamber stiffness and coronary resistance during reperfusion after ischemia.”
J Mol Cell Cardiol 1986 12月;18(12):1207-18。缺血后心室僵硬和冠状动脉血管舒缩:水肿的作用和右旋糖酐的作用。Vogel WM, Cerel AW, Apstein CS。“我们研究了肺水肿对缺血后左室硬度和冠状动脉阻力的贡献。再灌注时，用标准缓冲液或3%右旋糖酐灌注心脏，以增加瘤压并降低水含量。“再灌注60分钟后，未经治疗的缺血心脏的冠状动脉阻力从2.0 +/- 0.06增加到2.6 +/- 0.06 mmHg/ml/min，增加了26%。在接受治疗的心脏中，冠状动脉阻力增加了16%，从1.9 +/- 0.09 mm/Hg/ml/min增加到2.2 +/- 0.09 mm/Hg/ml/min (P < 0.01 v.未经治疗的缺血性)。为了确定右旋糖酐降低冠状动脉阻力是否可归因于主动血管扩张，我们在非缺血和再灌注缺血心脏中检测了扩张剂对2分钟缺氧或10(-4)M腺苷的反应。无缺血心脏或缺血15 min后再灌注心脏扩张器反应稳定，缺血30 min后缺氧扩张器反应降低72% (P < 0.025)，腺苷扩张器反应消除(P < 0.02)。因此，右旋糖酐的反应不同于直接的血管扩张剂。这些数据表明，心肌水肿在维持缺血后再灌注时心室硬度和冠状动脉阻力的增加方面起着重要作用。”
Experientia 1980 Dec 15;36(12):1402-3.Bilinear correlation between tissue water content and diastolic stiffness of the ventricular myocardium. Pogatsa G. In oedematous and dehydrated canine hearts a close bilinear correlation was demonstrated between myocardial water content and diastolic stiffness (characterized by the passive elastic modulus) with an optimal minimum of stiffness at normal myocardial water content.
经验1980十二月15;36(12):1402-3。组织含水量与心室心肌舒张刚度的双线性关系。在水肿和脱水的犬心脏中，心肌含水量与舒张期刚度(以被动弹性模量为特征)之间显示出密切的双线性相关，在正常心肌含水量下，其刚度最小值为最佳。
S Afr Med J 1975 Dec 27;49(55):2251-4. Effect of natural oestrogens on blood pressure and weight in postmenopausal women. Notelovitz M. “An investigation of the effect of conjugated oestorgens (USP) on the blood pressure and weight gain of postmenopausal women was undertaken. Fifty-one unselected women were treated for one year with cyclically administered conjugated oestrogen. Both the mean systolic and diastolic blood pressures ofthose in the group increased, but only the diastolic was significantly elevated.” “The significance of the change in blood pressure is commented upon, and the recommendation that postmenopausal women on oestrogen replacement therapy should have their blood pressure measured every 6 months is made.”
S Afr Med J 1975 Dec 27;49(55):2251-4。天然雌激素对绝经后妇女血压和体重的影响。“一项关于结合雌激素(USP)对绝经后妇女血压和体重增加的影响的调查进行了。51名未被选中的女性接受了为期一年的周期性结合雌激素治疗。该组患者的平均收缩压和舒张压均升高，但仅舒张压显著升高。“对血压变化的重要性进行了评论，并建议接受雌激素替代疗法的绝经后妇女每6个月测量一次血压。”
Am J Hypertens 1995 Mar;8(3):249-53. Ambulatory blood pressure in mild hypertensive women taking oral contraceptives. A case-control study.Narkiewicz K, Graniero GR, D'Este D, Mattarei M, Zonzin P, Palatini P. “Both daytime and nighttime systolic blood pressure values were significantly higher in oral contraceptive users. There was an average 8.3 mm Hg difference (95% confidence interval, 3.0 to 13.7 mm Hg; P = .003) for the daytime and 6.1 mm Hg difference (95% confidence interval, 0.4 to 11.8 mm Hg; P = .04) for the nighttime.” “Our results support the opinion that alternative methods of contraception should be considered for hypertensive women in place of oral contraceptives.”
科学(d辑:地球科学)1995年3月;服用口服避孕药的轻度高血压妇女的动态血压。病例对照研究。Narkiewicz K, Graniero GR, D'Este D, Mattarei M, Zonzin P, Palatini P.“口服避孕药使用者白天和夜间收缩压值均显著较高。平均差异为8.3 mm Hg(95%可信区间3.0至13.7 mm Hg;P = 0.003)和6.1 mm Hg差值(95%置信区间，0.4到11.8 mm Hg;P = 0.04)。“我们的研究结果支持了高血压女性应该考虑替代口服避孕药的替代避孕方法的观点。”
Am J Surg Pathol 1995 Apr;19(4):454-62.Reversible ischemic colitis in young women. Association with oral contraceptive use. Deana DG, Dean PJ. .”Ischemic colitis, a condition of middle-aged to elderly patients, occurs uncommonly in younger persons.” “Ten women (59%) were using low-dose estrogenic oral contraceptive agents, compared with the 1988 national average of 18.5% oral contraceptive users among females aged 15 to 44 years. The calculated odds ratio yielded a greater than sixfold relative risk for the occurrence of ischemic colitis among oral contraceptive users. In addition, four women not currently on hormonal contraceptive therapy had a past history of oral contraceptive use; the three remaining women were taking estrogen as replacement therapy after oophorectomy. In one patient, documented reversible ischemic colitis recurred on resumption of oral contraceptive use….” “…spontaneous ischemic colitis is a disorder found almost exclusively in women and is associated with the clinical use of exogenous estrogenic agents.”
病理外科杂志1995年4月19(4):454-62。年轻女性可逆性缺血性结肠炎。与口服避孕药有关。缺血性结肠炎是一种中老年患者的疾病，在年轻人中不常见。“有10名妇女(59%)使用低剂量口服雌激素避孕药，而1988年全国15至44岁女性口服避孕药使用者的平均比例为18.5%。”计算的优势比显示口服避孕药使用者发生缺血性结肠炎的相对风险大于6倍。此外，4名目前未接受激素避孕治疗的女性过去有口服避孕药的使用史;其余三名女性在卵巢切除术后服用雌激素作为替代疗法。在1例患者中，记录的可逆性缺血性结肠炎在恢复口服避孕药使用….后复发”“……自发性缺血性结肠炎是一种几乎只在女性中发现的疾病，与临床使用外源性雌激素有关。”
J Clin Endocrinol Metab 1993 Jun;76(6):1542-7. Differential changes in serum concentrations of androgens and estrogens (in relation with cortisol) in postmenopausal women with acute illness. Spratt DI, Longcope C, Cox PM, Bigos ST, Wilbur-Welling C. “We evaluated relationships between changes in serum levels of cortisol (F), androgens, estrogens, and gonadotropins in 20 postmenopausal women with acute critical illness to determine if changes in adrenal androgens and estrogens paralleled gonadal axis suppression or adrenal stimulation. Two patterns of changes in sex steroids were observed. Admission serum levels of androstenedione (delta 4-A), estradiol, and estrone, like F, were increased compared to healthy controls (P < 0.0001). delta 4-A and estrone then decreased toward normal by day 5 in parallel with cortisol (r = 0.56 and 0.60).” “The decreased serum T levels suggest inhibition of 17 beta-OH-dehydrogenase and/or increased aromatization to estradiol.The marked increase in serum estrogen levels also suggests increased aromatization. The absence of increases in DHEA and DHEA-S suggest enhanced activity of 3 beta-hydroxysteroid dehydrogenase and/or inhibition of C17,20-lyase activity of P-450c17.”.
《临床内分泌杂志》1993年6月;76(6):1542-7。绝经后急性疾病妇女血清雄激素和雌激素浓度的差异变化(与皮质醇相关)索兰托迪,Longcope C,考克斯点,Bigos圣,Wilbur-Welling C。”我们评估血清皮质醇水平的变化之间的关系(F)、雄激素、雌激素,促性腺激素在急性病危的20绝经后妇女肾上腺雄激素和雌激素的变化是否平行抑制或肾上腺刺激性腺的轴。观察到性激素的两种变化模式。与健康对照组相比，入院时血清中雄烯二酮(delta 4-A)、雌二醇和雌二醇水平均增加(P < 0.0001)。在第5天，delta 4-A和雌酮与皮质醇平行向正常水平下降(r = 0.56和0.60)。“血清T水平下降表明17 - oh -脱氢酶受到抑制和/或雌二醇芳构化增加。”血清雌激素水平的显著升高也提示芳构化增加。脱氢表雄酮(DHEA)和脱氢表雄酮- s (DHEA- s)含量没有增加，表明3 -羟类固醇脱氢酶活性增强，P-450c17的C17 - 20-裂解酶活性受到抑制。”
http://raypeat.com/articles/aging/coronaryprogesterone.shtml
@“徐泾东八号出口”#p576 钠的缺乏和渗透稀释会导致细胞吸水，增加细胞体积。
这个和凌宁的观点如何统一起来思考？
凌宁：On cell volume control: In normal cells equipped with its full complement of ATP, the c-value of intracellular β- and γ-carboxyl groups are low. And accordingly they strongly prefer K+ over Na+. In consequence, isotonic KCl causes extensive cell swelling by dissociating volume-maintaining salt linkages, but isotonic NaCl—present in the normal blood plasma-cannot. During cell injury, however, ATP level falls. With loss of this major EWC, the c-value of the β- and γ-carboxyl groups rises; and with it the preference for Na + also rises. Now the normally harmless isotonic NaCl in the plasma becomes as effective as isotonic KCl in bringing about (pathological) cell swelling. 关于细胞体积控制。在配备了全部ATP的正常细胞中，细胞内的β-和γ-羧基的c值很低。因此，它们非常喜欢K+而不是Na+。因此，等渗氯化物通过解离维持体积的盐联系而引起广泛的细胞肿胀，但等渗氯化物–存在于正常血浆中–不能。然而，在细胞损伤期间，ATP水平下降。随着这一主要EWC的丧失，β-和γ-羧基的c值上升；而且对Na+的偏好也随之上升。现在，血浆中通常无害的等渗NaCl变得和等渗KCl一样有效，可以带来（病理性的）细胞肿胀。