Estrogen, at least when it is not opposed by a very large concentration of progesterone, creates all of the conditions known to be involved in the aging process. These effects of estrogen include interference with oxidative metabolism, formation of lipofuscin (the age-pigment), retention of iron, production of free radicals and lipid peroxides, promotion of excitotoxicity and death of nerve cells, impaired learning ability, increased tendency to form blood clots and to have vascular spasms, increased autoimmunity and atrophy of the thymus, elevated prolactin, atrophy of skin, increased susceptibility to a great variety of cancers, lowered body temperature, lower serum albumin, increased tendency toward edema, and many of the features of shock. In recent years, it has been found to be responsible even for neonatal masculinization and the masculinization of the polycystic ovary syndrome. Although the pharmaceutical industry has often referred to it as "the female hormone," I don't know of any competent scientist who has ever called it that.
Since the 1930s, estrogen's toxic potential has become very clear. However, the estrogen industry doesn't want people to understand what estrogen is, because it is the source of billions of dollars per year for them. Estrogen is a shock hormone with pro-aging effects. In the 1930s and 1940s Loeb, Lipschutz, the Shutes, Selye, L.C. Strong, and others showed that it causes cancer, excessive clotting of the blood, shock, miscarriage, and tissue degeneration, but at the same time, the shills of the drug companies were promoting its use for preventing miscarriages and even for preventing the complications of pregnancy and toxemia it was known to cause.
The diuretic industry complemented the estrogen industry in its assault on pregnancy, creating a myth of pregnancy as a sodium-retention syndrome, when in fact an increased intake of salt is highly protective against the effects of excess estrogen and toxemia of pregnancy. (In hypovolemic shock, even a hypertonic salt solution is known to be therapeutic, and hypovolemia with hypoalbuminemia was clearly recognized as a feature of eclampsia). Thousands of well-meaning teachers and physicians helped to spread and perpetuate the fraudulent ideas originating with the corrupt pharmaceutical industry. (The U.S. Dept. of Justice and FBI found fraud in connection with research on diuretics, but it didn't affect the FDA's approval.) After Tom Brewer's work (which built on R. Ross' and M. B. Strauss's 1935 work, and many other studies in the 1940s and 1950s), the FDA's continued approval of those drugs could only be characterized as malfeasance. (In 1834, J. Lever recognized that malnutrition and restricted salt intake could cause eclampsia. "Cases of puerperal convulsions," Guy's Hospital Reports vol. 1, series 2, 495-517, 1843.) By 1950, there was sufficient knowledge available for controlling this disease of estrogen-excess, but the mere concept of too much estrogen was anathema to the industry-agency conspirators. This is a disturbing issue, because even in 1996, prestigious professors of medicine (NPR's "Science Friday") are pretending that toxemia and eclampsia are mysterious.
Histamine mimics estrogen's effects on the uterus, and antihistamines block estrogen's effects (Szego, 1965, Szego and Davis, 1967). Estrogen mimics the shock reaction. Stress, exercise, and toxins cause a rapid increase in estrogen. Males often have as much estrogen as females, especially when they are tired or sick. Estrogen increases the brain's susceptibility to epileptic seizures, and recent research shows that it (and cortisol) promote the effects of the "excitotoxins," which are increasingly implicated in degenerative brain diseases.
Just after Szego's work was published, I suggested that antihistamines might be used to resist some of estrogen's toxic effects, including cancer. A few people tried the idea, with some benefit, but the basic idea of a physiological counterforce is opposed by the ideology of "specific chemotherapy," in cancer, epilepsy, arthritis, infertility, osteoporosis, immunodeficiency, Alzheimer's disease, etc.
The pooling of blood in veins, a basic feature of shock, has recently become another of estrogen's "protective" features for the circulatory system--the reasoning seems to be that reduced circulation of blood makes life easier for the circulatory system. The relevant contexts, though, are the contribution this makes to the formation of blood clots, and the quality of oxygenation of all tissues.
Besides causing stress, estrogen levels are increased by stress. For example, a male runner's estrogen is often doubled after a race. Men and women who are hospitalized for serious sickness typically have greatly increased estrogen levels. Estrogen's role in terminal illness, a vicious circle in which stress decreases the person's ability to tolerate stress, is seldom appreciated. Circulatory collapse, multi-organ failure, intravascular coagulation (and the consequent depletion of fibrinogen, leading to internal bleeding) are so commonly seen in the people who die in hospitals that it would seem scandalous to suspect that estrogen could be a major contributing factor. The willingness to cover up estrogen's involvement in strokes was evident in a recent newspaper report in which a woman won a large financial settlement after her husband died from a series of strokes, caused by a pharmacy's mistakenly giving him "a female sex hormone." The mass media seem to have a "speak no evil about estrogen" policy.
Currently, estrogen marketing emphasizes appearance and the danger of osteoporosis. Evidence occasionally turns up implicating estrogen in thinning of the skin10 and bones (see the discussions of osteoporosis and prolactin, and of prolactin and estrogen, in the Yearbook of Endocrinology, in the 1980s). Studies of the tendons in rats' tails showed that estrogen causes loss of elasticity in the connective tissue, imitating aging, and that progesterone reverses or retards those changes. (Everitt, The Pituitary and Aging.) Recent studies (Liehr and Roy, Sipe) show that estrogen can promote a cycle of free radical production. In 1972 (dissertation, Univ. of Oregon) I reviewed the evidence for a contribution of estrogen to the formation of age pigment, including its association with lipid peroxidation.
Estrogen's brain-toxic effects have been known since the 1950s, or earlier. Text-books in the 1960s discussed experiments in which either estrogen or insulin stopped growth of the fetus's brain, and also in the 1960s experiments were showing that progesterone fosters brain growth and intelligence. Zamenhoff's work showed that the prenatal abundance of glucose is a central factor in brain growth. Since estrogen and insulin lower blood sugar, and progesterone and thyroid sustain it, Zamenhoff's work showed that the level of glucose was a common factor in many of the previous experiments, though other factors, including blood volume and body temperature, are also important. The epidemiological evidence is clear that women with toxemia of pregnancy, which involves inadequate delivery of glucose to the fetus, have babies with subnormal intelligence. Among obstetricians, it used to be common knowledge (before insulin treatment became common) that diabetic women were likely to have intellectually precocious children. As the work of Shanklin, Hodin, and the Brewers shows, there is a large group of Americans with neurological damage resulting from their mothers' treatment during pregnancy.
While I was studying the effects of light on health, many of the women with the pre- or peri-menstrual syndrome told me that they had few symptoms during the summer months, so I began in the 1960s to examine the role of progesterone in health, because its synthesis is promoted by long days. I saw that many of the sicknesses that mainly affect women had often been described as the consequence of an excess of estrogen. When animal experiments support the clinical reports and epidemiological evidence, as they do in the case of the "estrogen sicknesses," the goal of research becomes understanding the mechanisms involved, and discovering the safest way to avoid or to correct the problem. In the period between 1940 and 1960, thyroid, progesterone, and vitamins E and A had often been described as antiestrogenic substances, and some of this information persists in classical textbooks, in spite of the efforts of the drug industry to suppress the facts by giving their financial support to journals and symposia which exclude research which uses the concept of excess estrogen. For example, Goodman and Gilman's text on pharmacology discusses the ability of estrogen to make animals susceptible to seizures, and progesterone's opposing effect. One might suppose that the fact that all of the "official" approved drugs for treating epilepsy are teratogens should have been mentioned at that point, so that it would be brought to the attention of physicians that they had the option of using natural hormones to prevent seizures during pregancy, instead of making women choose between having a baby with birth defects, or having seizures during pregnancy. But that is not how the subject of epilepsy is presented to medical students.
It turns out that the meaning of "excess estrogen" has to be interpreted in relation to the balance of estrogen (and the multitude of factors which mimic estrogen's effects) with all of the antiestrogen factors. I have concentrated on thyroid, progesterone, and red light as the most important factors that protect against estrogen, and these all turn out to be protective against stress, shock, ionizing radiation, free radicals, lipid peroxidation, thymic atrophy, osteoporosis, arthritis, scleroderma, apoptotic cell death, and other problems that are involved in tissue degeneration or aging..
Although the so-called regulatory agencies have served the giant drug corporations well, by suppressing their competition and approving the most profitable drugs, in exchange for lucrative drug industry jobs offered to the officials* who do their jobs satisfactorily, the current trend in the US is to remove all constraints from the powerful corporations. Vice President Quail, with major family interests in the drug business, was put in charge of a commission to make it even easier for businesses to avoid the regulations, and similar favors are being done for the timber industry, the mass media, the banks, and the insurance industry.
New channels must be found to inform the public about the threats to their health. Even the "health food" industry is dominated by the giant corporations, so their publications don't present the alternative that used to exist, thirty years ago, in a few magazines like Prevention.
*Note: The revolving-door between the agency and the industry--the delayed bribe--applies only for the well qualified officials. The basic function of allowing industry to do what it wants is also served by staffing the agency at lower levels with ridiculously unqualified people. The technical "training" given to people who lack any formal background in the field apparently consists mainly of teaching them to scoff at evidence because it was published in a British or French or German or Japanese or Russian or Italian scientific journal, or because it hasn't been discussed recently in an American journal. And at all levels, the institutional principle is that if a drug doesn't cause cancer or Azheimer's disease within five years, then it is proven to be safe. At the highest level, when the agency is presented with clear evidence of fraud or malfeasance, the final response is that the agency doesn't handle complaints by individuals. I have been forced to believe that something more than incompetency is involved when officials refuse to say in writing things they have told me orally, and when they make misstatements in writing, or make deletions from documents provided under the Freedom of Information Act.. And these are the guys that "work for us."
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2. S. Shanklin and J.Hodin, Maternal Nutrition and Child Health, 1976, and Gail and Tom Brewer, What Every Pregnant Woman Should Know, Random House, 1977.
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4. G. H. Zeilmaker, "Effects of prolonged feeding of an ovulation inhibitor (Lyndiol) on ageing of the hypothalamic-ovarian axis and pituitary gland tumorigenesis in rats," J. Endocrin. 43, xxi, 1969).
5. Wise, P. M., "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.
6. Wise, P.M., et al., "Neuroendocrine influences on aging of the female reproductive system," Frontiers in Neuroendocrinology 12, 323-356, 1991.
7. M. H. Li and W. U. Gardner, "Experimental Studies on the pathogenesis and histogenesis of ovarian tumors in mice," Cancer Research 7, 549-566, 1947.
8. W. U. Gardner, "Hormonal imbalance in tumorigenesis," Cancer Research 8, 397-411, 1948.
9. M. H. Li and W. U. Gardner, "Further studies on the pathogenesis of ovarian tumors in mice," Cancer Research 9, 532-536, 1949.
10. H. S. Kaplan, "Influence of ovarian function on incidence fo radiation-induced ovarian tumors in mice," J. Natl. Cancer Inst., 11, 125-132, 1950.
11. Lee, N. C., et al., "Estrogen therapy and the risk of breast, ovary and endometrial cancer," in Aging, Reproduction, and the Climacteric," L. Mastroianni, Jr., and C. A. Paulsen, editors, Plenum, N.Y. & London, 1986. To the extent that oral contraceptives suppress the pituitary gonadotropic hormones, the ovary is protected from the stimulation that can produce cancer. However, the estrogen used to treat menopause doubles the risk of ovarian cancer after ten years. If the estrogen was used for more than 6 years, the risk is tripled.
12. Bauer, D. C., et al., "Skin thickness, estrogen use and bone mass in older women," Menopause 1(3), 131-136, 1991. "We found no evidence that estrogen preserves skin thickness; indeed, estrogen use is associated with thinner skin." "Our findings further support an association between skin thickness and bone mass." "Skin thickness and bone mass are related, but skin thickness cannot be used to predict bone mass."
13. L. C. Strong, Biological Aspects of Cancer and Aging, Pergamon Press, 1968. [Also see D. T. Janerich, et al., "Maternal pattern of reproduction and risk of breast cancer in daughters: Results from the Utah population data base," J. Nat. Cancer Inst. 86(21), 1634-1639, 1994. "Several studies have found that daughters born to older mothers have an elevated risk of breast cancer, and an endocrine hypothesis, among others, has been developed to explain these findings."]
14. D. A. Snowdon, et al., "Is early natural menopause a biologic marker of health and aging? Am. J. Public Health 79, 709-714, 1989.
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17. T. I. Belova, "Structural damage to the mesencephalic reticular formation induced by immobilization stress," Bull. Exp. Biol. & Med. 108(7), 126030, 1989.
18. F. Fourrier, et al., "Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock," Circ. Shock 43(4), 171-178, 1994.
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20. C. Bain, et al., "Use of postmenopausal hormones and risk of myocardial infarction," Circulation 64, 42-46, 1981.
21. 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.
22. 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.)
23. L. Dennerstein, et al., "Psychological well-being, mid-life and the menopause," Maturitas 20(1), 1-11, 1994.
24. H. Kaunitz and C. A. Slanetz, and W. B. Atkinson, "Estrogen response and pigmentation of the uterus in vitamin E-deficient rat," Proc. Soc. Exp. Biol. Med. 70, 302-304, 1948.
25. S. W. Brown, et al., "Effect of continuous radiation on reproductive capacity," page 103 in Effects of Ionizing Radiation on the Reproductive System, Carlson and Gassner, editors, MacMillan, N.Y., 1964.
26. D. L. Ingram and A. M. Mandl, "The hypophysial control of the x-ray sterilized ovary," J. Endocrin. 17, 1-12, 1958. [Also see Mandl and Zuckerman, 1956, who found that radiation produces vaginal cornification, the classical test for estrogenic activity.]
27. Winfried G. Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology 30(3/4) 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a pituitary site, have been determined as concomitants of aging in women." "...aging may impair the negative feedback sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of functional aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure facilitates the loss of hypothalamic neurons...."
28. J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107, 274-279, 1980.
29. J. Herbert and S. Zuckerman, "Ovarian stimulation from cerebral lesion in ferrets," J. Endocrinology 17(4), 433-443, 1958.
30. G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals." "...this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results "in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic effects of estradiol cause a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." Treatment with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian cycles" in estrogen-treated rats.
31. G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women using naloxone," Neuroendocrinology 39, 60-63, 1984.
32. H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. ...the estradiol phenoxyl radical abstracts hydrogen from...NADH to generate the NAD radical." "...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."
33. S. Santagati, et al., "Estrogen receptor is expressed in different types of glial cells in culture," J. Neurochem. 63(6), 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..."
34. D. X. Liu and L. P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo," Free Radical Biol. Med. 18(3), 571-576, 1995. "Free radicals and some free fatty acids, such as arachidonic acid metabolites...may form a feedback loop in which generation of one type leads to formation of the other." "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...."
35. J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2 alpha," Brain Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its metabolites may bias neurons towards excitation." [Estrogen appears to support this excitatory system at every level, while prostaglandin F2 alpha alters steroid balance, by suppressing progesterone synthesis.]
36. E. A. Quail and G. C. T. Yeoh, "The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase expression in rat liver," FEBS Lett. 359(2-3), 126-128, 1995. "...the overexpression of GAPDH mRNA in iron deficiency is probably due to increased message stability." [This is one of the points discussed by Henics. Estrogen, which increases iron retention, also modifies mRNA stability.]
37. J. G. Liehr, et al., "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes: Implications for the mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995. "... elicits biological activities distinct from estradiol, most notably an oxidant stress response induced by free radicals generated by metabolic redox cycling reactions."
38. J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8, 415-423, 1990.
39. P. Aschheim, "Resultats fournis par la greffe heterochrone des ovaires dan l'etude de la regulation hypothalamo-hypophyso-ovarienne de la ratte senile," Gerontologia 10, 65-75, 1964/65. "Our last experiment, grafting ovaries...into senile rats which had been castrated (ovariectomized) when young, and its result, the appearance of estrous cycles, seems explicable by this hypothesis. Everything happens as if the long absence of ovarian hormones... had kept the cells of the hypothalamus in the state of youth. It's as if the messages of the circulating steroids fatigued the hypothalamic memory." "What are the factors that cause this diminution of the hypothalamic sensitivity...? Kennedy incriminates a decrease in the cellular metabolism in general...."
40. P. Ascheim, "Aging in the hypothalamic-hypophyseal-ovarian axis in the rat," pp. 376-418 in: A. V. Everitt and J. A. Burgess, editors, Hypothalamus, Pituitary and Aging, C. C. Thomas, Springfield, 1976.
41. C. A. Frye and J. D. Sturgis, "Neurosteroids affect spatial reference, working, and long-term memory of female rats," Neurobiol. Learn. Memory 64(1), 83-96, 1995. [Female rats take longer to acquire a spatial task during behavioral estrus.] (CA Frye, boston univ., dept biol, behavioral neurosci lab, boston 02215) "Estrus-associated decrements in a water maze task are limited to acquisition," Physiol. Behav. 57(1), 5-14, 1995.