Menopause and its causes

更年期及其原因

by Raymond Peat

When I was in graduate school at the University of Oregon, everyone in our lab was working on the problem of reproductive aging. Previously, people in the lab had established that the ovaries didn't “run out of eggs.” There was never really any basis for that ridiculous belief. Many people just said it, the way they said “old eggs” (but never old sperms) were responsible for birth defects, or that “estrogen is the female hormone,” a deficiency of which is the cause of menopausal infertility. (Old sperms have been implicated in some birth defects. People who are newly married, for example, were found to have children with fewer birth defects than people of the same age who had been married a long time, suggesting that more frequent intercourse involves fresher sperms.) When ovaries have been treated with x-rays to destroy their ability to ovulate, they have been found to produce more estrogen than before. Ovulation is one thing, and the production of hormones is another thing. You can't determine whether ovulation has occurred by measuring the hormones.

当我在俄勒冈大学读研究生时，我们实验室里的每个人都在研究生殖衰老的问题。此前，实验室的研究人员已经确定，卵巢并没有“耗尽卵子”。这种荒谬的信念从来就没有真正的根据。很多人就是这么说的，他们说“老的卵子”(但从未说过老的精子)是出生缺陷的原因，或者说“雌激素是女性荷尔蒙”，缺乏雌激素是绝经期不孕的原因。(一些先天缺陷与老精子有关。例如，研究发现，与已婚较长时间的同龄人相比，新婚夫妇的孩子出生缺陷更少，这表明更频繁的性交涉及更新鲜的精子。)当用x光照射卵巢以破坏其排卵能力时，发现它们比以前产生更多的雌激素。排卵是一回事，荷尔蒙的产生是另一回事。你不能通过测量激素来确定排卵是否发生。

Knowing the large amount of work that has gone into our understanding of the age-related decline in fertility, it is disturbing to see people on television and in popular health books saying that menopause occurs when the “ovaries run out of eggs.”

虽然我们在理解与年龄有关的生育能力下降方面做了大量的工作，但看到电视上和流行健康书籍上的人说“卵巢没有卵子时”就会绝经，这让人感到不安。

Around 1970, many people were saying that aging was caused by the loss of brain cells. There is a glimmer of truth in that silly idea, just as there would be in saying that “aging is caused by the death of skin cells,” making the skin thinner and drier and less elastic. Both the brain and the skin are sources of steroid hormones, and it is possible that the death of skin cells and neurons is one factor in the age-related decline in the “sex steroids.” An organism would be an easier thing to understand if cells just did their job for a certain period of time, and then died. A man named Hayflick has given people some publications to cite, when they want to simplify things by saying that aging occurs when cells have used up their quota of 50 divisions, but there are many more studies that clearly show that Hayflick's limit is nothing but a product of the cells' environment. The cell's environment, the signals and substances and energy it receives, is complex, but real progress is being made in understanding the things involved in the aging process. Luckily, the infinite complexity of the environment is channeled into an understandable array of processes by the cell's systematic ways of responding.

大约在1970年，很多人说衰老是由于脑细胞的损失。这个愚蠢的想法有一点道理，就像说“衰老是由皮肤细胞死亡引起的”，使皮肤更薄、更干燥、更没有弹性一样。大脑和皮肤都是类固醇激素的来源，皮肤细胞和神经元的死亡可能是与年龄相关的“性激素”下降的一个因素。如果细胞在一段时间内完成了它们的工作，然后死亡，那么有机体就更容易理解了。一个名叫海弗利克给了人们一些出版物引用,当他们想要简化事情说,发生在细胞老化使用配额50分歧,但也有更多的研究清楚地表明,海弗利克极限只是一个产品的细胞环境。细胞所处的环境，它所接收的信号、物质和能量，都是复杂的，但在理解衰老过程中涉及的事物方面，确实取得了进展。幸运的是，通过细胞系统的反应方式，环境的无限复杂性被引导到一系列可以理解的过程中。

I knew, from talking with L. C. Strong,1 that early reproductive maturity was associated with early death; in his strains of cancer-prone mice, he showed that high estrogen was the cause of early puberty, a high cancer incidence, and a relatively short life. D. A. Snowdon, et al., showed that the occurrence of menopause at an early age in women is associated with a greater risk of death from all causes, including strokes and coronary heart disease.2 (They saw ovarian aging as an indicator of general aging.) P. W. F. Wilson, et al., reported that postmenopausal estrogen use was associated with an increased incidence of heart disease and stroke.3 P. M. Wise showed that estrogen accelerates aging of the central nervous system, destroying the nerves which regulate the pituitary gonadotropins, and causing ovarian failure and infertility.4 Many other studies of particular tissues show that estrogen accelerates the rate of aging.

通过与L. C. Strong交谈，我知道，1生殖早熟与早死有关;在他的癌症易感小鼠品系中，他证明了高雌激素是导致青春期提前、高癌症发病率和相对较短的寿命的原因。D. a .斯诺登等人的研究表明，女性过早绝经与包括中风和冠心病在内的各种原因造成的死亡风险更高有关(他们认为卵巢老化是整体衰老的一个指标。)P. W. F. Wilson等报道绝经后雌激素的使用与心脏病和中风的发病率增加有关P. M. Wise发现雌激素加速了中枢神经系统的衰老，破坏了调节垂体促性腺激素的神经，导致卵巢衰竭和不孕许多其他关于特定组织的研究表明雌激素加速衰老。

In my work with hamsters, I found that the infertility that developed at middle age was caused by a high rate of oxygen consumption in the uterus, causing the oxygen needed by the developing embryo to be consumed by uterine tissues, and causing suffocation of the embryo. This is the central mechanism by which the estrogen-containing contraceptives work: at any stage of pregnancy, a sufficient dose of estrogen kills the embryo.

在我与仓鼠的工作中，我发现中年时发生的不孕症是由于子宫内的耗氧率高，使发育中的胚胎所需要的氧气被子宫组织消耗掉，导致胚胎窒息。这是含有雌激素的避孕药具发挥作用的核心机制:在怀孕的任何阶段，足够剂量的雌激素都会杀死胚胎。

Polvani and Nencioni,5 among others, found that in women, the onset of menopause (the first missed period, suddenly increased bone loss, nervous symptoms such as depression, insomnia, and flushing) corresponds to the failure to produce progesterone, while estrogen is produced at normal levels. This results in a great functional excess of estrogen, because it is no longer opposed by progesterone. Typically, it takes about four years for the monthly estrogen excess to disappear. They suggested that the bone loss sets in immediately when progesterone fails because cortisol then is able to dominate, causing bone catabolism; progesterone normally protects against cortisol. Other researchers have pointed out that estrogen dominance promotes mitosis of the prolactin-secreting cells of the pituitary, and that prolactin causes osteoporosis; by age 50, most people have some degree of tumefaction of the prolactin-secreting part of the pituitary. But estrogen dominance (or progesterone deficiency) also clearly obstructs thyroid secretion, and thyroid governs the rate of bone metabolism and repair. Correcting the thyroid and progesterone should take care of the cortisol/prolactin/osteo- porosis problem.

Polvani和Nencioni等人发现，在女性中，更年期的开始(第一次月经缺失，突然增加骨质流失，神经症状，如抑郁、失眠和脸红)与黄体酮的分泌失败有关，而雌激素的分泌处于正常水平。这导致了雌激素的大量功能过剩，因为它不再受到孕酮的反对。通常情况下，每月过量的雌性激素需要4年左右的时间才能消失。他们认为，当孕酮衰竭时，骨损失立即开始，因为皮质醇会占主导地位，导致骨分解代谢;黄体酮通常能抵抗皮质醇。其他研究人员指出，雌激素优势促进垂体泌乳素分泌细胞的有丝分裂，而泌乳素导致骨质疏松;到50岁时，大多数人的垂体泌乳素分泌部分都有一定程度的肿胀。但雌激素占优势(或孕酮缺乏)也明显阻碍甲状腺分泌，而甲状腺控制着骨骼代谢和修复的速度。纠正甲状腺和黄体酮应该解决皮质醇/催乳素/骨质疏松问题。

P. M. Wise4 has demonstrated that the “menopausal” pituitary hormones, high levels of LH and FSH, are produced because the regulatory nerves in the hypothalamus have lost their sensitivity to estrogen, not because estrogen is deficient. In fact, he showed that the nerves are desensitized precisely by their cumulative exposure to estrogen. If an animal's ovaries are removed when it is young, the regulatory nerves do not atrophy, and if ovaries are transplanted into these animals at the normally infertile age, they are fertile. But if animals are given larger doses of estrogen during youth, those nerves atrophy prematurely, and they become prematurely infertile.

P. M. Wise4已经证明，“更年期”垂体激素(高水平的LH和FSH)的产生是因为下丘脑的调节神经对雌激素失去了敏感性，而不是因为雌激素缺乏。事实上，他证明了神经的脱敏正是由于累积的雌激素暴露。如果动物的卵巢在它年轻的时候被切除，调节神经就不会萎缩，如果卵巢在正常的不孕年龄被移植到这些动物身上，它们就能生育。但如果动物在年轻时被给予更大剂量的雌激素，这些神经会过早萎缩，它们会过早地失去生育能力。

The mechanism by which estrogen desensitizes and kills brain cells is now recognized as the “excitotoxic” process, in which the excitatory transmitter glutamic acid is allowed to exhaust the nerve cells. (This explains the older observations that glutamic acid, or aspartic acid, or aspartame, can cause brain damage and reproductive failure.) Cortisol also activates the excitotoxic system, in other brain cells, causing stress-induced atrophy of those cells.6 Progesterone and pregnenolone are recognized as inhibitors of this excitotoxic process.

雌激素致敏和杀死脑细胞的机制现在被认为是“兴奋毒性”过程，在这个过程中，兴奋性递质谷氨酸被允许耗尽神经细胞。(这就解释了先前的观察，即谷氨酸，或天冬氨酸，或阿斯巴甜，会导致大脑损伤和生殖衰竭。)皮质醇也会激活其他脑细胞中的兴奋毒性系统，导致这些细胞因压力而萎缩孕酮和孕烯酮被认为是这一兴奋毒性过程的抑制剂。

Besides estrogen's promotion of excitotoxic cell death, leading to the failure of the gonadotropin regulatory system, estrogen's stress-mimicking action probably tends to increase the secretion of LH, in ways that can be corrected by supplementing progesterone and thyroid. Since Selye's work, it has been known that estrogen creates the same conditions as occur in the shock phase of the stress reaction. (And shock, in a potential vicious circle, can increase the level of estrogen.7) It has recently been demonstrated that estrogen stimulates the adrenal glands, independently of the pituitary's ACTH. This can increase the production of adrenal androgens, leading to hirsutism, and other male traits, including anabolic effects.8

除了雌激素促进兴奋毒性细胞死亡，导致促性腺激素调节系统的失效外，雌激素的模拟应激作用可能倾向于增加LH的分泌，这可以通过补充孕酮和甲状腺来纠正。自从Selye的工作以来，我们已经知道雌激素创造了与应激反应的休克阶段相同的条件。(休克，在一个潜在的恶性循环中，可以增加雌激素的水平。7)最近的研究表明，雌激素刺激肾上腺，不依赖于垂体的ACTH。这会增加肾上腺雄激素的分泌，导致多毛症和其他男性特征，包括合成代谢效应。

It was established in the 1950s that estrogen “erases” memories in well trained animals. I suppose that acute effect is related to the chronic toxicity that leads to cell death. (In the 1940s, DES was sold to prevent miscarriages, though it was already known that it caused them; then there was the argument that it slowed aging of the skin, despite the Revlon studies at the University of Pennsylvania showing that it accelerates all aspects of skin aging; lately there has been talk of promoting estrogen to improve memory.)

早在20世纪50年代，雌激素就已经在训练有素的动物身上“消除”了记忆。我认为急性效应与导致细胞死亡的慢性毒性有关。(20世纪40年代，DES被用来防止流产，尽管人们已经知道它会导致流产;尽管宾夕法尼亚大学露华浓的研究表明它加速了皮肤各个方面的老化，但还有人认为它延缓了皮肤的老化;最近，有人说要促进雌激素来改善记忆力。)

Estrogen's nerve-exciting action is known to lower seizure thresholds; premenstrual epilepsy is probably another acute sign of the neurotoxicity of estrogen.

众所周知，雌激素的神经刺激作用可以降低癫痫的阈值;经前癫痫可能是雌激素神经毒性的另一个急性症状。

When fatigue and lethargy are associated with aging, the brain stimulating action of estrogen can make a woman feel that she has more energy. (Large doses given to rats will make them run compulsively; running wheels with odometers have shown that they will run over 30 miles a day from the influence of estrogen.) Estrogen inhibits one of the enzymic routes for inactivating brain amines, and so it has more general effects on the brain than just the glutamate system. This generalized effect on brain amines is more like the effects of cocaine or amphetamine. If that is a woman's basis for wanting to use estrogen, a monoamine oxidase inhibitor would be safer.

当疲劳和昏睡与衰老相关联时，雌激素的大脑刺激作用会让女性感到精力充沛。(大剂量给老鼠会使它们强迫跑;带有里程表的跑步轮显示，在雌激素的影响下，她们每天可以跑30多英里。)雌激素会抑制一种酶的途径使大脑胺失活，所以它对大脑的影响比谷氨酸系统更广泛。这种对脑胺的普遍作用更像是可卡因或安非他命的作用。如果这是女性想要使用雌激素的基础，单胺氧化酶抑制剂会更安全。

The reason for the menopausal progesterone deficiency is a complex of stress-related causes. Free-radicals (for example, from iron in the corpus luteum) interfere with progesterone synthesis, as do prolactin, ACTH, estrogen, cortisol, carotene, and an imbalance of gonadotropins. A deficiency of thyroid, vitamin A, and LDL-cholesterol can also prevent the synthesis of progesterone. Several of the things which cause early puberty and high estrogen, also tend to work against progesterone synthesis. The effect of an intra-uterine irritant is to signal the ovary to suppress progesterone production, to prevent pregnancy while there is a problem in the uterus. The logic by which ACTH suppresses progesterone synthesis is similar, to prevent pregnancy during stress. Since progesterone and pregnenolone protect brain cells against the excitotoxins, anything that chronically lowers the body's progesterone level tends to accelerate the estrogen-induced excitotoxic death of brain cells.

绝经期孕酮缺乏的原因是一个复杂的压力相关的原因。自由基(例如，黄体中的铁)干扰孕酮的合成，还有催乳素、促肾上腺皮质激素、雌激素、皮质醇、胡萝卜素和促性腺激素失衡。甲状腺、维生素A和低密度脂蛋白胆固醇的缺乏也会阻止孕酮的合成。一些导致青春期提前和高雌激素水平的因素也会阻碍孕酮的合成。子宫内刺激物的作用是向卵巢发出信号，抑制孕酮的产生，防止子宫出现问题时怀孕。促肾上腺皮质激素抑制孕酮合成的逻辑是相似的，目的是在压力下防止怀孕。由于孕酮和孕烯酮保护脑细胞不受兴奋性毒素的影响，任何长期降低身体孕酮水平的东西往往会加速雌激素诱导的脑细胞兴奋性毒素死亡。

Since progesterone and pregnenolone protect brain cells against the excitotoxins, anything that chronically lowers the body's progesterone level tends to accelerate the estrogen-induced excitotoxic death of brain cells.

由于孕酮和孕烯酮保护脑细胞不受兴奋性毒素的影响，任何长期降低身体孕酮水平的东西往往会加速雌激素诱导的脑细胞兴奋性毒素死亡。

Chronic constipation, and anxiety which decreases blood circulation in the intestine, can increase the liver's exposure to endotoxin. Endotoxin (like intense physical activity) causes the estrogen concentration of the blood to rise. Diets that speed intestinal peristalsis might be expected to postpone menopause. Penicillin treatment, probably by lowering endotoxin production, is known to decrease estrogen and cortisone, while increasing progesterone. The same effect can be achieved by eating raw carrots (especially with coconut oil/olive oil dressing) every day, to reduce the amount of bacterial toxins absorbed, and to help in the excretion of estrogen. Finally, long hours of daylight are known to increase progesterone production, and long hours of darkness are stressful. Annually, our total hours of day and night are the same regardless of latitude, but different ways of living, levels of artificial illumination, etc., have a strong influence on our hormones. In some animal experiments, prolonged exposure to light has delayed some aspects of aging.

慢性便秘和焦虑会减少肠内血液循环，会增加肝脏暴露于内毒素。内毒素(就像剧烈的体育活动)会导致血液中的雌激素浓度升高。加速肠道蠕动的饮食可能会推迟更年期。青霉素治疗，可能通过降低内毒素的产生，已知减少雌激素和可的松，同时增加孕酮。每天吃生胡萝卜(特别是用椰子油/橄榄油调味)也能达到同样的效果，减少细菌毒素的吸收，并有助于雌激素的排泄。最后，众所周知，长时间的白天会增加孕酮的分泌，而长时间的黑暗则会带来压力。每年，无论纬度如何，我们白天和黑夜的总时间都是一样的，但不同的生活方式、人工照明水平等，对我们的荷尔蒙有很大的影响。在一些动物实验中，长时间暴露在光照下可以延缓衰老的某些方面。

General aging contributes to the specific changes that lead to menopause, but the animal experiments show that fertility can be prolonged to a much greater age by preventing excitotoxic exhaustion of the hypothalamic nerves. The question that still needs to be more clearly answered is, to what extent can general aging be prevented or delayed by protecting against the excitotoxins? Minimizing estrogen (and cortisone) with optimal thyroid activity, and maximizing pregnenolone and progesterone to prevent excitotoxic cell fatigue, can be done easily. A diet low in iron and unsaturated fats protects the respiratory apparatus from the damaging effects of excessive excitation, and–since pregnenolone is formed in the mitochondrion–also helps to prevent the loss of these hormones.

一般的衰老会导致导致更年期的特定变化，但动物实验表明，通过防止下丘脑神经兴奋毒性衰竭，生育能力可以延长到更大的年龄。仍然需要更清楚地回答的问题是，通过对兴奋毒素的保护，在多大程度上可以防止或推迟整体老化?尽量减少雌激素(和可的松)与最佳甲状腺活性，并最大限度地提高孕烯酮和孕酮，以防止兴奋毒性细胞疲劳，可以很容易做到。低铁和不饱和脂肪的饮食可以保护呼吸器官免受过度兴奋的损害，而且——因为孕烯醇是在线粒体中形成的——也有助于防止这些激素的流失。

REFERENCES

引用

1. L. C. Strong, Biological Aspects of Cancer and Aging, Pergamon Press, 1968.

2. D. A. Snowdon, et al., “Is early natural menopause a biologic marker of health and aging? Am. J. Public Health 79, 709-714, 1989.

3. P. W. F. Wilson, et al. [The Framingham Study], N. E. J. M. 313(17), 1038-1043, 1985

4. P. M. Wise, “Influence of estrogen on aging of the central nervous system: Its role in declining female reproductive function,” in Menopause: Evaluation, Treatment, and Health Concerns, pages 53-70, 1989.

5. Nencioni, T., and F. Polvani, Calcitonin, p. 297-305, A. Pecile, editor, Elsevier, N.Y., 1985.

6. T. I. Belova, “Structural damage to the mesencephalic reticular formation induced by immobilization stress,” Bull. Exp. Biol. & Med. 108(7), 126030, 1989.

7. F. Fourrier, et al., “Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock,” Circ. Shock 43(4), 171-178, 1994.

8. E. C. Ditkoff, et al., “The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome,” J. Clin. Endocrinol. Metab. 80(2), 603-607, 1995.

9. C. Bain, et al., “Use of postmenopausal hormones and risk of myocardial infarction,” Circulation 64, 42-46, 1981.

10. T. L. Bush, et al., “Estrogen use and all-cause mortality: Preliminary results from the Lipid Research Clinics Program follow-up study,” JAMA 249, 903-906, 1983.

11. M. S. Hunter and K. L. M. Liao, “Intentions to use hormone replacement therapy in a community sample of 45-year-old women,” Maturitas 20(1), 13-23, 1994. (Women who expressed an intention to use hormone replacement therapy at menopause reported significantly lower self-esteem, more depressed mood, anxiety, and negative attitudes toward menopause. The also expressed stronger beliefs in their doctors' ability–as opposed to their own–to control their menopause experience.)

12. L. Dennerstein, et al., “Psychological well-being, mid-life and the menopause,” Maturitas 20(1), 1-11, 1994.