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<head><title>Progesterone, not estrogen, is the coronary protection factor of women.</title></head>
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<h1>
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Progesterone, not estrogen, is the coronary protection factor of women.
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</h1>
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<article class="posted">
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<p>
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In the 1940s, around the time that Hans Selye was reporting that estrogen causes shock, and that
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progesterone protects against many stress-related problems, the anthropologist Ashley Montague published
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<em>The Natural Superiority of Women.</em> Later, as I looked at the history of endocrine research, it
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seemed apparent that progesterone was responsible for many of the biological advantages of females, such
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as a longer average life-span, while testosterone was responsible for men’s advantage in muscular
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strength.
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</p>
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<p>
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Although evidence of estrogen’s toxicity had been accumulating for decades, pharmaceutical promotion was
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finding hundreds of things to treat with estrogen, which they called “the female hormone.” By the 1940s,
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it was known to produce excessive blood clotting, miscarriage, cancer, age-like changes in connective
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tissue, premenstrual syndrome, varicose veins, orthostatic hypotension, etc., but, as Mark Twain said, a
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lie can run around the world before the truth gets its boots on.
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</p>
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<p>
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After the DES fiasco, in which “the female hormone” which had been sold to prevent miscarriages was
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proven to cause them, the estrogen industry decided to offer men the protection against heart attacks
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that women supposedly got from their estrogen. The men who received estrogen in the study had an
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increased incidence of heart attacks, so that campaign was postponed for about 30 years.
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</p>
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<p>
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The Shutes used vitamin E to treat the excessive blood clotting caused by estrogen, and vitamin E was
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considered to be an estrogen antagonist. Estrogen affected the liver’s production of clot-regulating
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proteins, and it also relaxed large veins, allowing blood pooling that slowed the blood sufficiently to
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give it time to form clots before returning to the lungs. Early in the century, unsaturated fats were
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found to inactivate the proteolytic enzymes that dissolve clots, and vitamin E was known, by the 1940s,
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to provide protection against the toxicity of the unsaturated fats. The toxic synergy of estrogen and
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unsaturated fats had already been recognized.
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</p>
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<p>
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But in the 1950s, the seed oil industry, ignoring the toxic, carcinogenic effects of the unsaturated
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oils, began intensified promotion of their products as beneficial foods. (Decades earlier, Mark Twain
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had reported on the plans of the cottonseed industry to make people eat their by-product instead of
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butter.)
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</p>
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<p>
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While estrogen was being offered as the hormone that protects against heart attacks, the liquid
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vegetable oils were being advertised as the food that would prevent heart attacks. Just a few years
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after the estrogen industry suffered the setbacks of the DES and heart attack publicity, the oil
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industry cancelled some tests of the “heart protective diet,” because it was causing both more heart
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attacks and more cancer deaths.
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</p>
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<p>
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Somehow, these two fetid streams converged<strong>: Estrogen, like the unsaturated oils, lowered the
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amount of cholesterol in the blood,</strong> and an excess of blood cholesterol was said to cause
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heart attacks. (And, more recently, the estrogenic effects of the seed oils are claimed to offer
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protection against cancer.)
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</p>
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<p>
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The ability to lower the cholesterol “risk factor” for heart attacks became a cultural icon, so that the
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contribution of estrogen and unsaturated oils to the pathologies of clotting could be ignored. Likewise,
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the contribution of unsaturated fats’ lipid peroxidation to the development of atherosclerotic plaques
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was simply ignored. But one of estrogen’s long established toxic effects, the reduction of tone in
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veins, was turned into something like a “negative risk factor”<strong>:</strong> The relaxation of blood
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vessels would prevent high blood pressure and its consequences, in this new upside down paradigm.
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<strong>This vein-dilating effect of estrogen has been seen to play a role in the development of
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varicose veins, in orthostatic hypotension, and in the formation of blood clots in the slow-moving
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blood in the large leg veins.</strong>
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</p>
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<p>
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When it was discovered that the endothelial relaxing factor was nitric oxide, a new drug business came
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into being. Nitroglycerine had been in use for decades to open blood vessels, and, ignoring the role of
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nitrite vasodilators in the acquired immunodeficiency syndrome, new drugs were developed to increase the
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production of nitric oxide. The estrogen industry began directing research toward the idea that estrogen
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works through nitric oxide to “improve” the function of blood vessels and the heart.
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</p>
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<p>
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(Besides the argument based on “risk factors,” many people cite the published observations that “women
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who take estrogen are healthier” than women who don’t use it. But studies show that their “control
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groups” consisted of women who weren’t as healthy to begin with.)
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</p>
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<p>
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In the 1970s, after reading Szent-Gyorgyi’s description of the antagonistic effect of progesterone and
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estrogen on the heart, I reviewed the studies that showed that progesterone protects against estrogen’s
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clotting effect. I experimented with progesterone, showing that it increases the muscle tone in the
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walls of veins, which is very closely related to the effects Szent-Gyorgyi described in the heart. And
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progesterone opposes estrogen’s ability to increase the amount of free fatty acids circulating in the
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blood.
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</p>
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<p>
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More recently, it has been discovered that progesterone inhibits the expression of the enzyme nitric
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oxide synthase, while estrogen stimulates its expression. At the time of ovulation, when estrogen is
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high, a woman breathes out 50% more <strong><em>nitric oxide (“NO”)</em></strong> than men do, but at
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other times, under the influence of increased progesterone and thyroid, and reduced estrogen, women
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exhale much less NO than men do. (Nitric oxide is a free radical, and it decomposes into other toxic
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compounds, including the free radical peroxynitrile, which damages cells, including the blood vessels.
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brain, and heart. Carbon dioxide tends to inhibit the production of peroxynitrile.)
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</p>
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<p>
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If nitric oxide produced under the influence of estrogen were important in preventing cardiovascular
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disease, then men’s larger production of nitric oxide would give them greater protection than women
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have.
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</p>
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<p>
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From more realistic perspectives, nitric oxide is being considered as a cause of aging, especially brain
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aging. <strong>Nitric oxide interacts with unsaturated fats to reduce oxygen use, damage mitochondria,
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and cause edema.
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</strong>
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</p>
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<p> </p>
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<p>
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I think we can begin to see that the various “heart protective” ideas that have been promoted to the
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public for fifty years are coming to a dead end, and that a new look at the fundamental problems
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involved in heart disease would be appropriate. Basic principles that make heart disease more
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understandable will also be useful for understanding <strong>shock, edema, panic attacks, high altitude
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sickness, high blood pressure, kidney disease, some lung diseases, MS, multiple organ failure, and
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excitotoxicity or “programmed” cell death of the sort that causes degenerative nerve diseases and
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deterioration of other tissues.</strong>
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</p>
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<p>
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The research supporting this view is remarkably clear, but it isn’t generally known because of the
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powerful propaganda coming from the drug and oil industries and their public servants.
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</p>
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<p>
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Broda Barnes was right when he said that the “riddle of heart attacks” was solved when he demonstrated
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that hypothyroidism caused heart attacks, and that they were prevented by correcting hypothyroidism. He
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also observed that correcting hypothyroidism prevented the degenerative conditions (including heart
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disease) that so often occur in diabetics. Since hypothyroidism and diabetes are far more frequent in
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women, who have fewer heart attacks than men, it is appropriate to wonder why women tolerate
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hypothyroidism better than men.
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</p>
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<p>
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In hypothyroidism and diabetes, respiration is impaired, and lactic acid is formed even at rest, and
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relatively little carbon dioxide is produced. To compensate for the metabolic inefficiency of
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hypothyroidism, adrenalin and noradrenalin are secreted in very large amounts. Adrenalin causes free
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fatty acids to circulate at much higher levels, and the <strong>lactic acid, adrenalin, and free fatty
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acids all stimulate hyperventilation.</strong> The already deficient carbon dioxide is reduced even
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more, producing respiratory alkalosis. Free fatty acids, especially unsaturated fats, increase
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permeability of blood vessels, allowing proteins and fats to enter the endothelium and smooth muscle
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cells of the blood vessels. Lactic acid itself promotes an inflammatory state, and in combination with
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reduced CO2 and respiratory alkalosis, contributes to the hyponatremia (sodium deficiency) that is
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characteristic of hypothyroidism. This sodium deficiency and osmotic dilution causes cells to take up
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water, increasing their volume.
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</p>
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<p>
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In hyperventilation, the heart’s ability to work is decreased, and the work it has to do is increased,
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because peripheral resistance is increased, raising blood pressure. One component of peripheral
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resistance is the narrowing of the channels in blood vessels caused by endothelial swelling. In the
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heart, a similarly waterlogged state makes complete contraction and complete relaxation impossible.
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</p>
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<p>
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Estrogen itself intensifies all of these changes of hypothyroidism, increasing perrmeability and edema,
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and decreasing the force of the heart-beat, impairing the diastolic relaxation. Besides its direct
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actions, and synergism with hypothyroidism, estrogen also chronically increases growth hormone, which
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causes <strong>chronic exposure of the blood vessels to higher levels of free fatty acids (with a bias
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toward unsaturated fatty acids)</strong>, and promotes edema and vascular leakage. Hyperestrogenism,
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like hypothyroidism, tends to produce dilution of the body fluids, and is associated with increased
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bowel permeability, leading to endotoxemia<strong>;</strong> both dilution of the plasma and endotoxemia
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impair heart function.
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</p>
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<p>
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Progesterone’s effects are antagonistic to estrogen’s<strong>:</strong>. Progesterone decreases the
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formation of nitric oxide, decreasing edema<strong>;</strong> it strengthens the heart beat, by
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improving venous return and increasing stroke volume, but at the same time it reduces peripheral
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resistance by relaxing arteries (by inhibiting calcium entry but also by other effects, and
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independently of the endothelium) and decreasing edematous swelling.
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</p>
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<p>
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The effects of progesterone on the heart and blood vessels are paralleled by those of carbon
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dioxide<strong>: Increased carbon dioxide increases perfusion of the heart muscle, increases its stroke
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volume, and reduces peripheral resistance.
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</strong> The physical and chemical properties of carbon dioxide that I have written about previously
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include protective anti-excitatory and energy-sustaining functions that explain these effects. Since
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these effects have been known for many years, I think it is obvious that the obsessive interest in
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explaining these functions in terms of other molecules, such as nitric oxide, is motivated by the desire
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for new drugs, not by a desire to understand the physiology with which the researchers are pretending to
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deal.<strong></strong>
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</p>
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<p>
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Although women, because of estrogen’s antithyroid actions, are much more likely to suffer from
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hypothyroidism than men are, until menopause they have much higher levels of progesterone than men do.
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The effects of hyperestrogenism and hypothyroidism, with lower carbon dioxide production, are offset by
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high levels of progesterone. After menopause, women begin to have heart attacks at a rapidly increasing
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rate.
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</p>
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<p>
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During the years that men are beginning to have a considerable risk of heart attacks, with declining
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thyroid function indicated by lower T3, their testosterone and progesterone are declining, while their
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estrogen is rising. Men who have heart attacks have much higher levels of estrogen than men at the same
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age who haven’t had a heart attack.
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</p>
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<p>
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Whether the issue is free radical damage, vascular permeability with fat deposition, vascular spasm,
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edema, decreased heart efficiency, or blood clotting, the effects of chronic estrogen exposure are
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counter-adaptive. <strong>Progesterone, by opposing estrogen, is universally protective against vascular
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and heart disease.</strong>
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</p>
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<p>
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So far, the rule in most estrogen/progesterone research has been to devise experiments so that claims of
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benefit can be made for estrogen, with the expectation that they will meet an uncritical audience. In
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some studies, it’s hard to tell whether idiocy or subterfuge is responsible for the way the experiment
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was designed and described, for example when synthetic chemicals with anti-progesterone activity are
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described as “progesterone.” Since one estrogen-funded researcher who supposedly found progesterone to
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be ineffective as treatment for premenstrual syndrome practically admitted to me in conversation an
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intent to mislead, I think it is reasonable to discount idiocy as the explanation for the tremendous
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bias in published research. With the vastly increased resources in the estrogen industry, resulting from
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the product promotion “for the prevention of heart disease,” I think we should expect the research fraud
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to become increasingly blatant.
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</p>
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<p>
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Rather than being “heart protective,” estrogen is highly heart-toxic, and it is this that makes its most
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important antagonist, progesterone, so important in protecting the heart and circulatory system.
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</p>
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<p> </p>
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<p><h3>REFERENCES</h3></p>
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<p>
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JAMA 1998 Aug 19;280(7):605-13. <strong>
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Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in
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postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.</strong>
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Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E University of California, San
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Francisco 94143, USA. CONTEXT: Observational studies have found lower rates of coronary heart disease
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(CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has
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not been confirmed in clinical trials. OBJECTIVE: To determine if estrogen plus progestin therapy alters
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the risk for CHD events in postmenopausal women with established coronary disease. DESIGN: Randomized,
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blinded, placebo-controlled secondary prevention trial. SETTING: Outpatient and community settings at 20
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US clinical centers. PARTICIPANTS: A total of 2763 women with coronary disease, younger than 80 years,
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and postmenopausal with an intact uterus. <strong>Mean age was 66.7 years.</strong> INTERVENTION: Either
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0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily
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(<strong><hr /></strong>. Follow-up averaged 4.1 years;<strong>
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82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end
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of 3 years.</strong> MAIN OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal
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myocardial infarction (MI) or CHD death.<strong> Secondary cardiovascular outcomes</strong> included
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coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest,
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stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also
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considered. RESULTS: Overall, there were no significant differences between groups in the primary
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outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women
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in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI],
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0.80-1.22). The lack of an overall effect<strong>
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occurred despite a net 11% lower low-density lipoprotein cholesterol level</strong> and 10% higher
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high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each
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P<.001). Within the overall null effect, there was a statistically significant time trend, with more
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<strong>CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5.
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</strong>More women in the hormone group than in the placebo group experienced venous thromboembolic
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events (34 vs 12; RH, <strong>2.89</strong>; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH,
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1.38; 95% CI, 1.00-1.92). <strong>There were no significant differences in several other end points for
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which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH,
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1.08;</strong> 95% CI, 0.84-1.38). CONCLUSIONS: <strong>During an average follow-up of 4.1 years,
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treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the
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overall rate of CHD events in postmenopausal women with established coronary disease. The treatment
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did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no
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overall cardiovascular benefit and a pattern of early increase in risk of CHD events,</strong> we do
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not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the
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favorable pattern of CHD
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</p>
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<p>
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Am J Med 1982 Dec;73(6):872-81. <strong>Serum estrogen levels in men with acute myocardial
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infarction.</strong> Klaiber EL, Broverman DM, Haffajee CI, Hochman JS, Sacks GM, Dalen JE Serum
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estradiol and serum estrone levels were assessed in 29 men in 14 men in whom myocardial infarction was
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ruled out; in 12 men without apparent coronary heart disease but hospitalized in an intensive care unit;
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and in 28 men who were not hospitalized and who acted as control subjects. (The 12 men who were
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hospitalized but who did not have coronary heart disease were included to control for physical and
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emotional stress of a severe medical illness.) Ages ranged from 21 to 56 years. Age, height, and weight
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did not differ significantly among groups. Blood samples were obtained in the patient groups on each of
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the first three days of hospitalization. The serum estrone level was significantly elevated in all four
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patient groups when compared with that in the control group. Estrone level, then, did not differentiate
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patients with and without coronary heart disease. <strong>Serum estradiol levels were significantly
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elevated in the groups with myocardial infarction, unstable angina,</strong> and in the group in
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whom myocardial infarction was ruled out. However, estradiol levels were not significantly elevated in
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the group in the intensive care unit without coronary heart disease when compared to the level in the
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normal control group. <strong>Serum estradiol levels, then, were elevated in men with confirmed or
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suspected coronary heart disease</strong> but were not elevated in men without coronary heart
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disease even under the stressful conditions found in an intensive care unit. Serum estradiol <strong
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>levels were significantly and positively correlated (p less than 0.03) with serum total creatine
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phosphokinase</strong> levels in the patients with myocardial infarction. The five patients with
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myocardial infarction who died within 10 days of admission had markedly elevated serum estradiol levels.
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The potential significance of these serum estradiol elevations is discussed in terms of estradiol's
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ability to enhance adrenergic neural activity and the resultant increase in myocardial oxygen demand.
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</p>
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<p>
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JAMA 1978 Apr 3;239(14):1407-9. <strong>
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Noncontraceptive estrogens and nonfatal myocardial infarction.</strong> Jick H, Dinan B, Rothman KJ
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We obtained information on 107 women younger than 46 years discharged from a hospital with a diagnosis
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of acute myocardial infarction. In the series there were 17 women aged 39 to 45 years who were otherwise
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apparently healthy and had had a natural menopause, hysterectomy, or tubal ligation or whose spouse had
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had a vasectomy. Among them, nine (53%) were taking noncontraceptive estrogens just prior to admission.
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Among 34 control women, four (12%) were taking estrogens. The relative risk estimate, <strong>comparing
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estrogen users with nonusers, is 7.5,</strong> with 90% confidence limits of 2.4 and 24. All but one
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of the 17 ml subjects were cigarette smokers. While this illness is rare in most healthy young women,
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the risk in women older than about 38 years who both smoke and take estrogens appears to be substantial.
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</p>
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<p>
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JAMA 1978 Apr 3;239(14):1403-6. <strong>
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Oral contraceptives and nonfatal myocardial infarction.</strong> Jick H, Dinan B, Rothman KJ We
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obtained information on 107 women younger than 46 years who were discharged from a hospital with a
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diagnosis of acute myocardial infarction. In the series 26 women were otherwise apparently healthy and
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potentially childbearing. Among these 26 women, 20 <strong>(77%) were taking oral contraceptives just
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prior to admission, and one was taking conjugated estrogens. Among 59 control women, 14 (24%) were
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taking oral contraceptives and one was taking conjugated estrogens.</strong> The relative risk
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estimate, comparing oral contraceptive users with nonusers, is <strong>14 with</strong> 90% confidence
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limits of 5.5 and 37. All but two of the 26 women were cigarette smokers. While this illness is rare in
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most healthy young women, the risk in women older than about 37 years who both smoke and take oral
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contraceptive appears to be high.
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</p>
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<p>
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M. Karmazyn, et al., <strong>"Changes in coronary vascular resistance associated with prolonged hypoxia
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in isolated rat hearts: A possible role of prostaglandins,"</strong>
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<em>Life Sciences 25,</em> 1991-1999, 1979. "if...hypoxic perfusion is prolonged, the initial dilatation
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passes off and an intense vasoconstriction results." <strong>"The constriction could be prevented by
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progesterone but not by estradiol or testosterone."</strong> "There is increasing evidence that
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angina pectoris and myocardiaol infarction may often be due to active caronary constriction."
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"Inhibitors of PG synthesis at high concentrations prevented or reversed the constriction." (Besides
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aspirin) "Chloroquine, procaine and propranolol can all behave as PG antagonists...." "The failure of
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estradiol or testosterone to have any effect and the complete prevention of the constriction by
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physiological levels of progesterone suggest that more attention should be paid to this last steroid."
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<strong>"...hypoxia can cause coronary constriction and...the effect does not occur in young or
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progesterone-treated hearts...."</strong>
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</p>
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<p>
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Am J Epidemiol 1996 May 15;143(10):971-8.<strong>
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Prior to use of estrogen replacement therapy, are users healthier than nonusers?</strong> Matthews
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KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Observational studies have demonstrated that women who
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have used postmenopausal estrogen replacement therapy (ERT) are at reduced risk of coronary heart
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disease. The authors examined whether<strong>
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premenopausal women who subsequently elected to use ERT during menopause had a better cardiovascular
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risk factor profile prior to use than did nonusers. A total of 541 premenopausal women had</strong>
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<hr />
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<strong>
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Prior to use of ERT, in comparison with nonusers, subsequent users reported on standardized
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questionnaires that they often exhibited Type A behavior, more aware of their feelings, motives, and
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symptoms, and had more symptoms of stress. Women who elect to use ERT have a better cardiovascular
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risk factor profile prior to the use of ERT than do women who subsequently do not use this treatment
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during the menopause, which supports the hypothesis that part of the apparent benefit associated
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with the use of ERT is due to preexisting characteristics of women who use ERT. This study
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underscores the widely recognized importance of randomized</strong> clinical trials to estimate the
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direct benefit of postmenopausal ERT for protecting women from cardiovascular disease.
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</p>
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<p>
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<strong>"Effects of androgens on haemostasis,"</strong> Winkler UH, Maturitas, 1996 Jul, 24:3, 147-55.
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<strong>"Androgen deficiency is associated with an increased incidence of cardiovascular disease. There
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is evidence that thromboembolic disease as well as myocardial infarction in hypogonadic males are
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mediated by low baseline fibrinolytic activity.</strong> Hypogonadism in males is associated with an
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enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor
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PAI 1.<strong>” </strong>
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</p>
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<p>
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M. Mabry White, et al., <strong>“Estrogen, progesterone, and vascular reactivity: Potential cellular
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mechanisms,"</strong> Endocrine Reviews 16(6), 739, 1995. "Female hormones are broadly recognized as
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affecting susceptibility to vascular disease...." Migraines, Raynaud's phenomena, primary pulmonary
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hypertension are mentioned as vascular disorders with a female predominance.
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</p>
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||
<p>
|
||
J. Boczkowski, et al., <strong>"Induction of diaphragmatic nitric oxide synthase after endotoxin
|
||
administration in rats; role on diaphragmatic contractile dysfunction,"</strong> J. Clin. Invest.
|
||
98, 1550-1559, 1996. "We conclude that iNOS [inducible nitric oxide synthase] was induced..." by
|
||
endotoxin.
|
||
</p>
|
||
<p>
|
||
Arch Int Pharmacodyn Ther 1986 May;281(1):57-65. <strong>Effects of 17 beta-estradiol on the isolated
|
||
rabbit heart.</strong> 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 <strong>induced a negative inotropic effect
|
||
starting from a concentration of 10(-6) M and a vasodilation</strong> 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.
|
||
</p>
|
||
<p>
|
||
Med Hypotheses 1997 Aug;49(2):183-5.<strong>
|
||
Coronary artery spasm: a hypothesis on prevention by progesterone.</strong> Kanda I, Endo M.
|
||
Department of Surgery, Heart Institute of Japan, Tokyo Women's Medical College, Japan. <strong>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.
|
||
</strong>
|
||
</p>
|
||
<p>
|
||
J. Bolanos, et al., <strong>"Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in
|
||
cultured astrocytes,"</strong> J. Neurochem. 63, 910-916, 1994.
|
||
</p>
|
||
<p>
|
||
M. Cleeter, et al., <strong>"Reversible inhibition of cytochrome C oxidase, the terminal enzyme of the
|
||
mitochondrial respiratory chain, by nitric oxide,"</strong> FEBS Lett. 345, 50-54, 1994.
|
||
</p>
|
||
<p>
|
||
Ann Thorac Surg 1999 Sep;68(3):925-30. <strong>Coronary perfusate composition influences diastolic
|
||
properties, myocardial water content, and histologic characteristics of the rat left
|
||
ventricle.</strong> 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 <strong>ventricular diastolic
|
||
compliance</strong> exhibit quantitative relationships in rats. Edema due to low osmolarity coronary
|
||
perfusates increases myocardial water content and histologic edema score and <strong>decreases left
|
||
ventricular filling.</strong> 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.”
|
||
</p>
|
||
<p>
|
||
<strong>Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide
|
||
production in murine macrophages.</strong> 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.
|
||
</p>
|
||
<p>
|
||
<strong>Testosterone relaxes rabbit coronary arteries and aorta.</strong> 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 “<strong>Testosterone induces endothelium-independent
|
||
relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin
|
||
I2 or cyclic GMP.</strong> Potassium conductance and potassium channels but not ATP-sensitive
|
||
potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The
|
||
<strong>in vitro relaxation is independent of sex and of a classic receptor.</strong> 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.”
|
||
</p>
|
||
<p>
|
||
J. Nakamura, et al., <strong>"Estrogen regulates vascular endothelial growth permeability factor
|
||
expression in 7,12-dimethyl- benz(a)anthracene-induced rat mammary tumors,"
|
||
</strong>Endocrinology 137(12_, 5589-5596, 1996.<strong></strong> ("...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.")
|
||
</p>
|
||
<p>
|
||
D. A. Barber, et al., <strong>"Endothelin receptors are modulated in association with endogenous
|
||
fluctuations in estrogen,"</strong> 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 <strong>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."
|
||
</strong>
|
||
</p>
|
||
<p>
|
||
T. M. Chou, et al, <strong>"Testosterone induces dilation of canine coronary conductance and resistance
|
||
arteries in vivo,"</strong> Circulation 94(10), 2614-2619, 1996.
|
||
</p>
|
||
<p>
|
||
K. Sudhir, et al., <strong>"Estrogen enhances basal nitric oxide release in the forearm vasculature in
|
||
perimenopausal women,"</strong> Hypertension 28(3), 330-334, 1996.
|
||
</p>
|
||
<p>
|
||
G. Sitzler, et al., <strong>"Investigation of the negative inotropic effects of 17-beta-oestradiol in
|
||
human isolated myocardial tissues,"</strong> British J. of Pharmacology 119(1), 43-48, 1996.
|
||
</p>
|
||
<p>
|
||
S. M. Hyder, et al., <strong>"Uterine expression of vascular endothelial growth factor is increased by
|
||
estradiol and tamoxifen,"</strong> 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.")
|
||
</p>
|
||
<p>
|
||
N. Ferrara and T. Davis-Smyth, <strong>"The biology of vascular endothelial growth factor,"</strong>
|
||
Endocrine Reviews 18(1), 4-<strong>19</strong>,? 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 <strong>decrease
|
||
in venous return, mediated primarily by endothelial cell-derived nitric oxide...."</strong>
|
||
"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 <strong
|
||
>capillary hyperpermeability</strong> that characterizes ovarian hyperstimulation syndrome as well as in
|
||
the dysfunctional endothelium of preeclampsia."
|
||
</p>
|
||
<p>
|
||
B. Jilma, et al, <strong>"Sex differences in concentrtions of exhaled nitric oxide and plasma
|
||
nitrate,"</strong> 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."
|
||
</p>
|
||
<p>
|
||
<strong>
|
||
Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in
|
||
murine macrophages.</strong> Miller L; et al J Leukoc Biol, 59(3):442-50 1996 Mar. “Treatment with
|
||
P4 alone caused a time- and dose-dependent <strong>inhibition of NO production</strong> 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.”
|
||
</p>
|
||
<p>
|
||
Int J Epidemiol 1990 Jun;19(2):297-302. <strong>Relationship of menopausal status and sex hormones to
|
||
serum lipids and blood pressure.</strong> Wu ZY, Wu XK, Zhang YW. <strong>“Conditional logistic
|
||
regression analysis found that progesterone is a protective factor only and testosterone is one of
|
||
the risk factors for hypertension.”
|
||
</strong>
|
||
</p>
|
||
<p>
|
||
Pharmacol Biochem Behav 1990 Oct;37(2):325-7. <strong>Steroid sex hormones and cardiovascular function
|
||
in healthy males and females: a correlational study.</strong>
|
||
<hr />
|
||
<strong>Positive correlations were also found between estradiol and SBP and HR in women.”</strong>
|
||
</p>
|
||
<p>
|
||
Scand J Clin Lab Invest 1993 Jul;53(4):353-8. <strong>Effects of ovarian stimulation on blood pressure
|
||
and plasma catecholamine levels.</strong> Tollan A, Oian P, Kjeldsen SE, Holst N, Eide I. <strong
|
||
><hr /></strong>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>strong
|
||
correlation between adrenaline and blood pressure are unclear, but may be induced by the
|
||
supraphysiological oestradiol levels.”</strong>
|
||
</p>
|
||
<p>
|
||
J Mol Cell Cardiol 1986 Dec;18(12):1207-18. <strong>Post-ischemic cardiac chamber stiffness and coronary
|
||
vasomotion: the role of edema and effects of dextran.</strong> 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
|
||
coronary<strong>
|
||
resistance 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.”
|
||
</strong>
|
||
</p>
|
||
<p>
|
||
Experientia 1980 Dec 15;36(12):1402-3.<strong>
|
||
Bilinear correlation between tissue water content and diastolic stiffness of the ventricular
|
||
myocardium.</strong> Pogatsa G<strong>. 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.
|
||
</strong>
|
||
</p>
|
||
<p>
|
||
S Afr Med J 1975 Dec 27;49(55):2251-4. <strong>Effect of natural oestrogens on blood pressure and weight
|
||
in postmenopausal women.</strong> 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 of<strong>
|
||
those in the group increased, but only the diastolic was significantly elevated.”
|
||
</strong>“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.”
|
||
</p>
|
||
<p>
|
||
Am J Hypertens 1995 Mar;8(3):249-53. <strong>
|
||
Ambulatory blood pressure in mild hypertensive women taking oral contraceptives. A case-control
|
||
study.</strong> Narkiewicz K, Graniero GR, D'Este D, Mattarei M, Zonzin P, Palatini P. “Both daytime
|
||
and nighttime systolic<strong>
|
||
blood pressure values were significantly higher in oral contraceptive users. There was an average
|
||
8.3 mm</strong>
|
||
<hr />
|
||
</p>
|
||
<p>
|
||
Am J Surg Pathol 1995 Apr;19(4):454-62.<strong>
|
||
Reversible ischemic colitis in young women. Association with oral contraceptive use.</strong> 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.<strong>
|
||
The calculated odds ratio yielded a greater than sixfold relative risk for the occurrence of
|
||
ischemic colitis among oral contraceptive users.</strong> 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.” <strong></strong>
|
||
</p>
|
||
<p>
|
||
J Clin Endocrinol Metab 1993 Jun;76(6):1542-7.<strong>
|
||
Differential changes in serum concentrations of androgens and estrogens (in relation with cortisol)
|
||
in postmenopausal women with acute illness.
|
||
</strong>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. <strong><hr /></strong> “The decreased serum T levels
|
||
suggest inhibition of 17 beta-OH-dehydrogenase <strong>and/or increased aromatization to
|
||
estradiol.</strong>
|
||
<strong>The marked increase in serum estrogen levels also suggests increased aromatization.</strong> 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.”.<strong></strong>
|
||
</p>
|
||
<p> </p>
|
||
</article>
|
||
</body>
|
||
</html>
|